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Influence of nitric oxide synthase and cyclooxygenase blockade on expression of cyclooxygenase and hemodynamics in rats with portal hypertension. The importance of nitric oxide (NO) in the pathogenesis of portal hypertension (PHT) has been extensively studied, but whether or not prostacyclin (PGI(2)) plays a role in formation and development of hyperdynamic circutatory state in PHT has not been verified. The present study was undertaken to investigate the possible interaction between prostacyclin (PGI(2)) and nitric oxide (NO) in the hyperdynamic circulatory state of rats with chronic portal hypertension (PHT), by measuring the hemodynamic changes and expression of cyclooxygenase (COX) mRNA in vessels and small intestine after administration of N(omega)-nitro-L-arginine (L-NNA) or indomethacin (INDO) either in the short-term (7 days) or long-term (15 days). Ninety-seven male Sprague-Dawley rats were divided into three groups: intrahepatic portal hypertension (IHPH) induced by injection of CCl(4), prehepatic portal hypertension (PHPH) induced by partial stenosis of the portal vein, and sham-operated controls (SO). Animals of each group received L-NNA or INDO either for 7 or 15 days, with saline as control. Splanchnic hemodynamics was measured by the radioactive microsphere technique. The concentration of NO in serum was determined as the nitrate; nitrite ratio (NO(2)(-)/NO(3)(-), micromol/L) by a colorometric method, and that of PGI(2) was measured by specific radioimmunoassay for its stable hydrolysis product 6-keto-PGF(1alpha) (pg/ml). The reverse transcription-polymerase chain reaction measured the levels of COX-1 mRNA in the superior mesenteric artery, thoracic aorta, and small intestine of these rats. Compared with SO rats, COX-1 mRNA expression and the concentrations of plasma 6-keto-PGF(1alpha) and serum NO(2)(-)/NO(3)(-) were enhanced in both IHPH and PHPH rats; splanchnic vascular resistance (SVR) decreased, but portal venous inflow (PVI) markedly increased (P<0.05). Seven or 15 days of L-NNA treatment reduced COX-1 mRNA expression in these vessels and the small intestine, concomitant with a significant decrease in the concentration of plasma PGI(2) and serum NO in IHPH and PHPH rats (P<0.05). At the same time, PVI decreased but SVR increased significantly (P<0.05). In both IHPH and PHPH rats, the COX-1 mRNA expression and the concentration of plasma PGI(2) after No synthase (NOS) blockade for 15 days were higher than those for 7 days, whereas the hyperdynamic circulatory state was improved after NOS blockade for 15 days compared with 7 days. The concentration of PGI(2) treated by INDO for 15 days was not significantly different from that after 7-day COX blockade, and hemodynamics restored hyperdynamic circulatory state. The hyperdynamic circulatory state in rats with PHT is correlated with the concentration of serum NO. There is a possible interaction between PGI(2) and NO in the hyperhemodynamics of PHT. PGI(2) is probably not the mediator in the formation and development of the hyperdynamic circulatory state in rats with chronic PHT.

Comparison of gamma-glutamyl hydrolase (conjugase; EC 3.4.22.12) and amylase treatment procedures in the microbiological assay for food folates. 1. It has been suggested that deconjugation of food folates with pig kidney, compared with chicken pancreas, may increase measureable folate by approximately 50% (Phillips & Wright, 1983). Therefore deconjugation with conjugases from these two enzyme sources was optimized and compared. Folate was measured microbiologically with Lactobacillus casei (ATCC 7469) as the test organism at pH 5.6. 2. Treatment for 6 h with 200 mg pig kidney/200 mg sample was compared with the conventional assay employing overnight incubation with 20 mg chicken pancreas/5 g sample. Comparison of the deconjugation systems showed chicken pancreas to be superior for peas (Pisum sativum) and beans (Phaseolus vulgaris), while there was no difference for potatoes. 3. gamma-Glutamyl hydrolase (conjugase; EC 3.4.22.12) treatment for 2 and 20 h with pig kidney and chicken pancreas was optimized for raw potatoes and green frozen peas. Treatments with pig kidney were conducted at pH 4.6, which is optimal, and at pH 5.2. There was no significant difference between 2 and 20 h treatments at pH 5.2. Treatments with chicken pancreas were conducted at pH 6.1. Treatment for 2 h was preferred as it resulted in significantly higher measureable folate activity in peas and potatoes, and because overnight treatment can be influenced by microbial production of folate. 4. With optimal treatment conditions the source of enzymes did not significantly influence measureable folate activity. Chicken pancreas is the traditional source of conjugase in Scandinavia and was preferred for deconjugation. 5. Chicken pancreas, 20 and 60 mg, was used for deconjugation of sixteen different food samples, each containing approximately 200 ng folate. Chicken pancreas at 60 mg/sample gave significantly higher results. Further addition of enzyme did not increase the folate values. 6. A combined amylase treatment using heat-resistant alpha-amylase (EC 3.2.1.1) during extraction to ensure the gelatinization of the sample, and glucan 1,4-alpha-glucosidase (amyloglucosidase; EC 3.2.1.3), along with the incubation with chicken pancreas to complete the digestion, was shown to give a small but significant increase in folate values of starch-containing samples. 7. Folate results using the recommended procedure are given for raw potatoes, wheat bran, rolled oats, wheat flour and dark rye bread. 8. Chicken pancreas was shown to contain equally high amounts of amylases as did the alpha-amylase and amyloglucosidase sources. This finding may explain the relatively small benefit of a specific amylase addition.

Current trials and new aspects in soft tissue sarcoma of adults. For high-risk soft tissue sarcoma (HR-STS) of adults new treatment strategies are needed to improve outcome with regard to local control and overall survival. Therefore, systemic chemotherapy has been integrated either after (adjuvant) or before (neoadjuvant) optimal local treatment by surgery and radiotherapy in HR-STS. The Soft Tissue and Bone Sarcoma Group (STBSG) of the European Organization for Research and Treatment of Cancer (EORTC) is conducting an open randomized trial of adjuvant chemotherapy in high-grade primary or recurrent STS at any site (EORTC 62931). In all cases primary surgery should be curative in intent. All eligible patients are randomized after completion of definitive surgery to receive either radiotherapy alone with no further treatment (observation arm) or five cycles of doxorubicin (70 mg/m(2)) plus ifosfamide (5 g/m(2)) using G-CSF to support dose intensity followed by radiotherapy (chemotherapy arm). This more aggressive chemotherapy regimen within an adjuvant setting might retain sufficient antitumor activity to convert response rates into survival benefit. At present more than 220 patients have been recruited for this trial. To explain the rationale for the EORTC 62931 protocol, reported results of other clinical adjuvant protocols including a meta-analysis are given. In close collaboration with the European Society of Hyperthermic Oncology (ESHO) the STBSG has also initiated a randomized trial of neoadjuvant chemotherapy in primary or recurrent HR-STS as an EORTC Intergroup study. According to the inclusion criteria as defined (tumor size >or=5 cm + grade II or III + deep location + extracompartmental extension) for the EORTC 62961/ESHO RHT-95 Intergroup study, the majority of patients with HR-STS recruited for this pre- and postoperative multimodality treatment protocol cannot be cured by standard procedures. All eligible patients are randomized to receive either four cycles of EIA (etoposide 250 mg/m(2) + ifosfamide 6 g/m(2) + doxorubicin 50 mg/m(2)) within 12 weeks (chemotherapy arm) or the same EIA regimen combined with regional hyperthermia (RHT + chemotherapy arm). The patients then receive optimal local treatment using adequate surgery immediately followed by radiotherapy. Thereafter an additional four cycles of EIA chemotherapy are given with or without RHT according to the initial randomization. At present more than 150 patients have been recruited for this trial. The integration of RHT as a new potent treatment modality if combined with EIA chemotherapy as first-line treatment for well-defined risk groups is based upon encouraging long-term results of phase II studies both in pretreated patients with HR-STS and in those with locally advanced disease. In summary, significant prognostic variables recognized for patients with STS have been addressed in the design of two open phase III clinical trials on adjuvant and neoadjuvant chemotherapy. The best chance for offering such treatment strategies following evidence-based medicine criteria to eligible patients with HR-STS depends upon early contact with the coordinator of the individual protocol prior to any treatment.

How to measure hazards/risks following exposures to nanoscale or pigment-grade titanium dioxide particles. Due to its multifunctional applications, titanium dioxide particles have widespread use in commerce. The particle-types function as sources of pigment color, in food products, anti-bacterial components, ultraviolet radiation scavengers, catalysts, as well as in cosmetics. Because of its inherent properties in a diverse number of products, exposures may occur via any of the major point-of-entry routes, i.e., inhalation, oral or dermal. Although the majority of TiO2 applications are known to exist in the pigment-grade form, nanoscale forms of TiO2 are also common components in several products. This brief review is designed to identify relevant toxicology and risk-related issues which inform health effects assessments on the various forms of titanium dioxide particles. While there has been an abundance of hazard data generated on titanium dioxide particulates, many of the published reports have limited informational value for assessing health effects due, in large part, to shortcomings in experimental design issues, such as: (1) inadequate material characterization of test samples; (2) questionable relevance of experimental systems employed to simulate human exposures; (3) applications of generally high doses, exclusive focus on acute toxicity endpoints, and a lack of reference benchmark control materials, to afford interpretation of measured results; and/or (4) failure to recognize fundamental differences between hazard and risk concepts. Accordingly, a number of important toxicology issues are identified and integrated herein to provide a more comprehensive assessment of the health risks of different forms of pigment-grade and nanoscale titanium dioxide particles. It is important to note that particle-types of different TiO2 compositions may have variable toxicity potencies, depending upon crystal structure, particle size, particle surface characteristics and surface coatings. In order to develop a more robust health risk evaluation of TiO2 particle exposures, this review focuses on the following issues: (1) Introduction to TiO2 particle chemistry/functionality and importance of robust material characterization of test samples; (2) Implementation of meaningful hazard studies for gauging EHS safety issues – pulmonary bioassay data and development of the Nano Risk Framework for developmental nano TiO2 compounds; (3) Epidemiological study findings on titanium dioxide workers – the most heavily-exposed populations; (4) Methodologies for setting occupational exposure limits including benchmarking or bridging comparisons; and (5) The importance of particle overload data in the lungs of rats as it relates to gauging the relevance of health effects for humans. A comprehensive evaluation of the existing animal and human health data is a necessary prerequisite for facilitating accurate assessments of human health risks to TiO2 exposures.

Pretreatment with growth hormone-releasing peptide-2 directly protects against the diastolic dysfunction of myocardial stunning in an isolated, blood-perfused rabbit heart model. Brief coronary occlusion followed by reperfusion leads to reversible myocardial dysfunction (stunning) which can induce irreversible damage of other organ systems. We studied the effects of pretreatment with recombinant human GH (rhGH) and the GH-secretagogue GHRP-2 on myocardial stunning in a blood-perfused isolated rabbit heart model. In a first set of experiments, effects of bolus rhGH administration (3.5 mg/kg) (n = 5) into the aortic root of unpretreated animals were compared with those of saline (n = 6). In a second set, animals were pretreated for 14 days with SC rhGH 3.5 mg/kg x day (n = 9) or 160 microg/kg x day GHRP-2 (n = 8) in two divided doses. Body weight and plasma concentrations of rhGH, rabbit GH (rGH) and IGF-I were determined before and at the end of 14 days pretreatment. Hearts were excised and submitted to 15 min ischemia followed by 80 min reperfusion, after which postischemic recovery was compared with nonischemic hearts mounted into the same system. At study end, all hearts were snap-frozen to examine markers of apoptosis. Circulating levels of rabbit GH (rGH) remained identical in all animals. Pretreatment with rhGH for 14 days induced a 142 +/- 116% rise of serum IGF-I vs. 8 +/- 15% with GHRP-2 (P < 0.001) and increased body weight with 6.8 +/- 2.5% vs. 3.4 +/- 3.3% with GHRP-2 (P = 0.01). A bolus injection of rhGH did not alter myocardial function compared with saline allowing data from these experiments to be pooled into one ischemic control group for further analysis of the effect of pretreatment. No difference in postischemic recovery of left ventricular systolic function among the unpretreated, rhGH pretreated and GHRP-2 pretreated hearts was apparent. At the end of reperfusion, a 3-fold higher end-diastolic pressure (EDP) persisted in the unpretreated and rhGH pretreated hearts compared with the nonischemic hearts. In the GHRP-2 pretreated hearts, EDP decreased to half the pressure observed in unpretreated and rhGH pretreated hearts (all P < or = 0.02), a level which was indistinguishable from that in the non-ischemic hearts, suggesting full postischemic recovery of diastolic function. There were no signs of increased apoptosis in the experimental groups. In conclusion, 14 days pretreatment with GHRP-2, but not rhGH, protected selectively against the diastolic dysfunction of myocardial stunning in this model. This observation may open perspectives for GH-secretagogues as cardioprotective agents.

Effects of microbial phytase, low calcium and phosphorus, and removing the dietary trace mineral premix on carcass traits, pork quality, plasma metabolites, and tissue mineral content in growing-finishing pigs. An experiment was conducted to determine the effects of phytase addition, reduced Ca and available P (aP), and removing the trace mineral premix (TMP) on growth performance, plasma metabolites, carcass traits, pork quality, and tissue mineral content in growing-finishing swine. One hundred twenty cross-bred pigs (initial and final BW of 22 and 109 kg, respectively) were allotted to five dietary treatments on the basis of weight within gender in a randomized complete block design. There were three replications of barrows and three replications of gilts, with four pigs per replicate pen. The dietary treatments were as follows: 1) corn-soybean meal (C-SBM), 2) C-SBM with reduced Ca and aP, 3) C-SBM with reduced Ca and aP plus 500 phytase units/kg of diet, 4) Diet 1 without the TMP, and 5) Diet 3 without the TMP. The Ca and aP were reduced by 0.10% in the low Ca and aP diets and the diets with added phytase. Daily gain, hot carcass weight, dressing percent, kilograms of carcass lean, bone ash percent, and bone strength were decreased (P = 0.10), but liver and kidney weight were increased (P = 0.10) in pigs fed diets with reduced Ca and aP; adding phytase reversed these responses (P = 0.10). The Commission Internationale de I'Eclairage L* was decreased (P = 0.09) in pigs fed the low Ca and aP diet plus phytase relative to those fed the control diet. Removing the TMP had no effect on overall growth performance, but it increased (P = 0.03) 10th-rib backfat thickness and fasting glucose and decreased (P = 0.03) carcass length and ham weight. Liver weight and liver weight as a percentage of final BW were not affected when phytase was added to the control diet, but removing the TMP increased liver weight and liver weight as a percentage of final BW; adding phytase reversed these responses (phytase x TMP, P = 0.06). Removing the TMP decreased (P = 0.08) Zn concentrations in the bone, muscle, and liver, and Cu and Fe concentrations in the bile but increased (P = 0.08) Mn concentrations in the bile and liver of pigs. The addition of phytase reversed the negative effects of the reduced Ca and aP diets. These data indicate that removing the TMP in diets for growing-finishing pigs has no negative effects on growth performance or pork quality, but it had negative effects on carcass traits and had variable effects on tissue mineral content.

Anticancer drug-induced kidney disorders. Nephrotoxicity is an inherent adverse effect of certain anticancer drugs. Renal dysfunction can be categorised as prerenal uraemia, intrinsic damage or postrenal uraemia according to the underlying pathophysiological process. Renal hypoperfusion promulgates prerenal uraemia. Intrinsic renal damage results from prolonged hypoperfusion, exposure to exogenous or endogenous nephrotoxins, renotubular precipitation of xenobiotics or endogenous compounds, renovascular obstruction, glomerular disease, renal microvascular damage or disease, and tubulointerstitial damage or disease. Postrenal uraemia is a consequence of clinically significant urinary tract obstruction. Clinical signs of nephrotoxicity and methods used to assess renal function are discussed. Mechanisms of chemotherapy-induced renal dysfunction generally include damage to vasculature or structures of the kidneys, haemolytic uraemic syndrome and prerenal perfusion deficits. Patients with cancer are frequently at risk of renal impairment secondary to disease-related and iatrogenic causes. This article reviews the incidence, presentation, prevention and management of anticancer drug-induced renal dysfunction. Dose-related nephrotoxicity subsequent to administration of certain chloroethylnitrosourea compounds (carmustine, semustine and streptozocin) is commonly heralded by increased serum creatinine levels, uraemia and proteinuria. Additional signs of streptozocin-induced nephrotoxicity include hypophosphataemia, hypokalaemia, hypouricaemia, renal tubular acidosis, glucosuria, aceturia and aminoaciduria. Cisplatin and carboplatin cause dose-related renal dysfunction. In addition to increased serum creatinine levels and uraemia, electrolyte abnormalities, such as hypomagnesaemia and hypokalaemia, are commonly reported adverse effects. Rarely, cisplatin has been implicated as the underlying cause of haemolytic uraemic syndrome. Pharmaceutical antidotes to cisplatin-induced nephrotoxicity include amifostine, sodium thiosulfate and diethyldithiocarbamate. Dose- and age-related proximal tubular damage is an adverse effect of ifosfamide. In addition to renal wasting of electrolytes, glucose and amino acids, Fanconi syndrome, rickets and osteomalacia have occurred with ifosfamide treatment. High dose azacitidine causes renal dysfunction manifested by tubular acidosis, polyuria and increased urinary excretion of electrolytes, glucose and amino acids. Haemolytic uraemia is a rare adverse effect of gemcitabine. Methotrexate can cause increased serum creatinine levels, uraemia and haematuria. Acute renal failure is reported following administration of high dose methotrexate. Urinary alkalisation and hydration confer protection against methotrexate-induced renal dysfunction. Dose-related nephrotoxicity, including acute renal failure, are reported subsequent to treatment with pentostatin and diaziquone. Acute renal failure is a rare adverse effect of treatment with interferon-alpha. Haemolytic uraemic syndrome occurs with mitomycin administration. A mortality rate of 50 to 100% is reported in patients developing mitomycin-induced haemolytic uraemic syndrome. Capillary leak syndrome occurring with aldesleukin therapy can cause renal dysfunction. Infusion-related hypotension during infusion of high dose carmustine can precipitate renal dysfunction.

[A study on the relationship between endoplasmic reticulum aminopeptidase2 genetic polymorphisms and non-small cell lung cancer in Yunnan Han population]. To evaluate the association between the genetic polymorphisms of endoplasmic reticulum aminopeptidase 2 (ERAP2) and the susceptibility of non-small cell lung cancer (NSCLC) in Yunnan Han population. A total of 223 patients with NSCLC and 205 healthy controls in Yunnan Han population were included in the present study. The SNP of rs2248374 and rs2549782 in ERAP2 gene were genotyped using TaqMan fluorescence probe technique, and their haplotypes were constructed. Then, the association between the two SNPs with NSCLC was assessed. The allele A and allele G frequencies for rs2248374 in NSCLC patients and the control groups were 45.5% (203/446), 54.5% (243/446) and 37.8% (155/410), 62.2% (255/410), respectively (χ² = 5.220, P < 0.05). The genotypic GG, GT, TT for rs2549782 in NSCLC patients and the control groups were 21.5% (48/223), 48.9% (109/223), 29.6% (66/223) and 11.7% (24/205), 49.8% (102/205), 38.5% (79/205), respectively(χ² = 8.656, P < 0.05). And the allele G and allele T frequencies for rs2549782 in NSCLC patients and the control groups were 46.0% (205/446), 54.0% (241/446) and 36.6% (150/410), 63.4% (260/410), respectively (χ² = 7.741, P < 0.05). The frequencies of haplotype rs2248374/rs2549782-AG were 44.6% (199/446), 36.1% (148/410) and rs2248374/rs2549782-GT were 53.1% (237/446), 61.7% (253/410), which also showed difference between NSCLC patients and the control groups (χ² = 6.567, P < 0.01;χ² = 6.567, P < 0.01). The allele A and allele G frequencies for rs2248374 were 52.9% (72/136), 47.1% (64/136) and 42.3% (131/310), 57.7% (179/310) in the Cigarette-smoking group and the Non-smoking group, respectively (χ² = 4.498, P < 0.05), while the allele G and allele T frequencies for rs2549782 were 54.4% (74/136), 45.6% (62/136) and 42.3% (131/310), 57.7% (179/310) in the Cigarette-smoking group and the Non-smoking group, respectively(χ² = 5.831, P < 0.05). The genotypic AA,AG,GG for rs2248374 were 17.3% (24/139), 56.1% (78/139), 26.6% (37/139) and 27.8% (22/79), 38.0% (30/79), 34.2% (27/79) in lung squamous cell carcinoma and lung adenocarcinoma, respectively (χ² = 6.999, P < 0.05), while the genotypic GG, GT, TT for rs2549782 were 18.7% (26/139), 55.4% (77/139), 25.9% (36/139) and 27.8% (22/79), 36.7% (29/79), 35.4% (28/79) in lung squamous cell carcinoma and lung adenocarcinoma, respectively (χ² = 7.093, P < 0.05). ERAP2 rs2248374 and rs2549782 had a strong association with NSCLC and the pathological pattern. The rs2248374/rs2549782-AG haplotype was associated with increased NSCLC risk (OR = 1.435, 95%CI: 1.088-1.893), whereas the rs2248374/rs2549782-GT haplotype individuals may have a reduced NSCLC risk (OR = 0.697, 95%CI: 0.528-0.919).

A prospective evaluation assessing the effectiveness of the 'Dynamax' mandibular appliance in the management of obstructive sleep apnoea. Obstructive sleep apnoea syndrome (OSAS) affects 4-6% of the middle-aged UK population and is responsible for significant partnership disharmony. Nasal CPAP therapy is effective but has poor compliance in less severe cases- bulky with poor portability and frequently deemed socially unacceptable. The 'Dynamax mandibular appliance (DMA) is a current treatment for Skeletal 11 malocclusion characterised by mandibular retrusion. It has the advantage of both maxillary expansion and mandibular advancement and is developed and tailored on an individual basis by orthodontic sculpture. These facilities are widely available in hospital-based orthodontic departments. For these reasons we have explored its use in the treatment of mild to moderate cases of OSAS. 35 symptomatic patients (29 males) with mild to moderate OSAS, determined from sleep study analysis, had dental impressions taken and the 'Dynamax' appliance constructed. Following fitting and instructions for use, all patients were entered into the study. After two months, repeat overnight oximetry was undertaken for 16 patients and both an Epworth sleep score (ESS) and quality of life questionnaire completed. The mean age was 51 (range 29-71) years. The mean ESS pre-treatment was 12 (range 7-19) with a significant fall post-treatment by 7 (range 3-14) (p < 0.0001). Pre-treatment oximetry data confirmed typical tracings and patterns of OSAS with a mean low oxygen saturation (SaO2) of 83% (range 71-90%). Post-treatment oximetry was available in 16 patients and showed significant improvement in the number of hourly SaO2 desaturation dips and a mean increase of 4.7% in the lowest SaO2 recorded (p < 0.0001). Thirty (86%) patients found the appliance of 'great to moderate' benefit and 18 (60%) were able to tolerate it and be fully compliant within days. Of 10 patients who had previously experienced CPAP, 80% of them felt it was easier to tolerate the DA. Sixty-seven percent of these patients stated the appliance was more portable and acceptable to their bed partner. Twenty-one (70%) of bed partners reported softer and less frequent snoring. Ninety percent of the patients in this study wished to wear the DMA long-term. The DMA provides a satisfactory alternative therapy in the treatment of OSAS of'mild-moderate' severity. This oral device is conveniently small, readily portable and well tolerated by both patients and bed partners alike. It can be fashioned in orthodontic departments available in all district general hospitals and will enhance the provision and development of any local sleep service.

Food intake and satiety following a serving of pulses in young men: effect of processing, recipe, and pulse variety. Diets containing beans have been associated with a lower risk of obesity and overweight in several dietary surveys. These results suggest a benefit might be derived from beans and other pulses, possibly due to improved satiety or satiation and therefore lowering energy intake. Such a hypothesis has not been tested. To investigate the effect of processing, recipe, and pulse variety on short-term food intake (FI), subjective appetite, and glycemic response after pulse consumption in healthy young men. Three experiments were conducted. In a randomized repeated-measures design, young men aged 18-35 years with a body mass index of 20-25 kg/m(2) were fed the test treatments. In experiment 1 (n = 14), navy beans canned in Canada or in the United Kingdom were compared with homemade navy beans and 300 ml of glucose drink, each containing 50 g of available carbohydrate. In experiment 2 (n = 14), canned navy beans in tomato sauce, maple style, with pork and molasses, and homemade navy beans with pork and molasses were compared with white bread, each containing 50 g of available carbohydrate. In experiment 3 (n = 15), 4 equicaloric (300-kcal) treatments of pulses were compared with both a white bread and water control. Blood glucose and subjective appetite were measured from immediately before consumption of the treatment to 120 minutes later when FI from a pizza meal was measured. All caloric treatments decreased subjective appetite. In no experiment did any pulse treatment lower FI at 120 minutes compared with white bread or result in lower cumulative FI (sum of calories from treatment and pizza meal) compared with either 50 g of available carbohydrate as a glucose drink (experiment 1) or from white bread (experiment 2) or compared with equal food energy from white bread (experiment 3). Glycemic response to navy beans was affected by recipe, but not processing, and as with the other pulses, it was lower than with white bread. An inverse relationship was observed between glycemic response and both subjective appetite and FI at 120 minutes in experiment 3 (r = -0.4, p = 0.001) but not in experiments 1 (r = 0.1, p = 0.62) and 2 (r = 0.2, p = 0.10). The short-term effect of pulse consumption on subjective appetite and FI at a meal 120 minutes later and in cumulative food intake was determined primarily by energy content and was little influenced by composition, processing, recipe, or variety. Thus, the epidemiological associations between frequent pulse consumption and lower risk of obesity and overweight are not explained by short-term effect of pulses on satiety and FI.

Metabolism and udder health at dry-off in cows of different breeds and production levels. The effects of milk yield at dry-off (DO), different calving intervals (CI; 12 and 15 mo) and breed on metabolism and udder health were studied in 56 primiparous and multiparous cows of the Swedish Red and White (SRB) and Swedish Holstein (SH) breeds. The cows were dried off 55 +/- 5 d prior to expected parturition. They were fed 4 kg of DM as silage and wheat straw ad libitum for 5 d, and were milked in the morning of d 2 and 5. Depending on their daily milk yield, the cows were divided into 3 numerically equal groups on 2 d during the week prior to DO: low (LY; 5.0 to 11.4 kg of milk/d, n = 19), medium (MY; 11.5 to 17.7 kg of milk/d, n = 19), and high (HY; 17.8 to 29.5 kg of milk/d, n = 18). The plasma cortisol concentration increased during DO only in MY and HY cows. Plasma nonesterified fatty acids increased during DO in all groups, but the maximum nonesterified fatty acid concentration was related to the milk yield prior to DO. The plasma glucose level during the DO period was not significantly affected by yield, but the insulin concentration decreased after DO, with a more pronounced drop in the HY group. The CI 15-mo group had a higher glucose level and tended to have a higher insulin level in plasma than the CI 12-mo group before DO. They also had a higher body condition than the CI 12-mo group. The results indicate that the CI 15-mo cows had a more positive nutrient balance. There were no effects of CI on milk production or composition during DO. The SRB and SH breeds did not differ in any of the measured plasma parameters or milk production. However, the lower somatic cell counts in SRB than in SH observed before and during DO, as well as after parturition, were attributed to being an effect of breed. The proportion of cows with intramammary infections (IMI) was significantly lower just after calving in the LY group than in the other yield groups. At 2 and 3 wk after DO, significantly fewer cows in the LY group had open teat canals compared with the HY and MY groups, respectively, but teat-end condition did not differ between yield groups. The yield before DO did not significantly influence the somatic cell counts during the first 4 wk after parturition or the presence of IMI 4 wk after parturition. We concluded that in the present study, higher milk yield prior to DO gave rise to a more pronounced metabolic response and a higher risk of contracting IMI during the dry period, at calving, or both, but yield at DO did not have any long-term effects on udder health. A prolonged CI did not facilitate a rapid decrease in milk production. The SRB and SH breeds responded equally in decreasing the milk production during DO, but the SRB breed had lower somatic cell counts.

Results of treatment of subtrochanteric femoral fractures with the AO/ASIF Long Trochanteric Fixation Nail (LTFN). This retrospective study reports on the clinical results of a group of 23 patients with subtrochanteric femoral fractures using the Long Trochanteric Fixation Nail (LTFN). Between January 2005 and January 2008, 23 patients (20 women, 3 men; average age: 64.8 years old) with subtrochanteric femoral fractures were treated surgically. According to the AO/ASIF Classification, the most frequent fracture type was an 32-A1. They were also classified regarding the Seinsheimer Classification, in which the commonest type was the IIB. Of the 23 fractures, 14 of them had been the result of an unexpected fall, 2 were the result of a high-energy trauma and 7 consisted of pathologic fractures. All the patients were treated using the LTFN device and they all received clinical and radiological follow-ups at least until their fractures were consolidated. The average surgery time, average decrease in haemoglobin in the first 24 hours post- surgery, average need for red blood cell transfusion, postoperative mortality at a 6th month follow-up, time to autonomous deambulation, most frequent destination at the time of discharge, average time for consolidation of the fracture and average follow-up time were reported. Intraoperative and postoperative complications were also recorded. The average surgery time from cut to stitch was 97.45 minutes with the decrease in haemoglobin averaging 26.45 g/L and, on average, the need for red blood cell transfusion was 1.12 concentrates. In the first postoperative week, 57.1% of the total number patients were capable of deambulation. The time to hospital discharge was 12.9 days. After an average follow-up of 13.9 months, total weightbearing was achieved in the 64.7% of the patients. The average consolidation time was 21.6 weeks and none of the patients developed pseudoarthrosis. Technical failures were seen in 4.3% of the cases: 1 patient suffered a migration of the distal locking screw. There were no cases of deep infection, cut-out, bending/breaking of the implant, malrotation or fracture of the femoral shaft at the tip of the implant. From a mechanical point of view the use of a long intramedullary nail in combination with a blade or a screw seems to be the most appropriate treatment for subtrochanteric fractures of the femur. Despite the improvement of implants and surgical techniques, failures due to complications are still considerable. The low distal shaft diameter of the LTFN, in combination with an extremely precise positioning of the blade in the middle of the femoral head, can prevent mechanical complications. Open reduction and cerclage cabling may be required so as to obtain a correct alignment of the fracture. We conclude that the LTFN is a safe and reliable intramedullary device for the treatment of subtrochanteric fractures of the femur. Deambulation within the first postoperative surgery is possible when positioned properly. Its implantation requires more surgical time than the standard nails.

Crystalline structure analysis of cellulose treated with sodium hydroxide and carbon dioxide by means of X-ray diffraction and FTIR spectroscopy. Crystalline structures of cellulose (named as Cell 1), NaOH-treated cellulose (Cell 2), and subsequent CO2-treated cellulose (Cell 2-C) were analyzed by wide-angle X-ray diffraction and FTIR spectroscopy. Transformation from cellulose I to cellulose II was observed by X-ray diffraction for Cell 2 treated with 15-20 wt% NaOH. Subsequent treatment with CO2 also transformed the Cell 2-C treated with 5-10 wt% NaOH. Many of the FTIR bands including 2901, 1431, 1282, 1236, 1202, 1165, 1032, and 897 cm(-1) were shifted to higher wave number (by 2-13 cm(-1)). However, the bands at 3352, 1373, and 983 cm(-1) were shifted to lower wave number (by 3-95 cm(-1)). In contrast to the bands at 1337, 1114, and 1058 cm(-1), the absorbances measured at 1263, 993, 897, and 668 cm(-1) were increased. The FTIR spectra of hydrogen-bonded OH stretching vibrations at around 3352 cm(-1) were resolved into three bands for cellulose I and four bands for cellulose II, assuming that all the vibration modes follow Gaussian distribution. The bands of 1 (3518 cm(-1)), 2 (3349 cm(-1)), and 3 (3195 cm(-1)) were related to the sum of valence vibration of an H-bonded OH group and an intramolecular hydrogen bond of 2-OH ...O-6, intramolecular hydrogen bond of 3-OH...O-5 and the intermolecular hydrogen bond of 6-O...HO-3', respectively. Compared with the bands of cellulose I, a new band of 4 (3115 cm(-1)) related to intermolecular hydrogen bond of 2-OH...O-2' and/or intermolecular hydrogen bond of 6-OH...O-2' in cellulose II appeared. The crystallinity index (CI) was obtained by X-ray diffraction [CI(XD)] and FTIR spectroscopy [CI(IR)]. Including absorbance ratios such as A1431,1419/A897,894 and A1263/A1202,1200, the CI(IR) was evaluated by the absorbance ratios using all the characteristic absorbances of cellulose. The CI(XD) was calculated by the method of Jayme and Knolle. In addition, X-ray diffraction curves, with and without amorphous halo correction, were resolved into portions of cellulose I and cellulose II lattice. From the ratio of the peak area, that is, peak area of cellulose I (or cellulose II)/total peak area, CI(XD) were divided into CI(XD-CI) for cellulose I and CI(XD-CII) for cellulose II. The correlation between CI(XD-CI) (or CI(XD-CII)) and CI(IR) was evaluated, and the bands at 2901 (2802), 1373 (1376), 897 (894), 1263, 668 cm(-1) were good for the internal standard (or denominator) of CI(IR), which increased the correlation coefficient. Both fraction of the absorbances showing peak shift were assigned as the alternate components of CI(IR). The crystallite size was decreased to constant value for Cell 2 treated at >or= 15 wt% NaOH. The crystallite size of Cell 2-C (cellulose II) was smaller than that of Cell 2 (cellulose I) treated at 5-10 wt% NaOH. But the crystallite size of Cell 2-C (cellulose II) was larger than that of Cell 2 (cellulose II) treated at 15-20 wt% NaOH.

VLA-4-mediated interactions between normal human hematopoietic progenitors and stromal cells. The alpha 4 beta 1 integrin very late activation antigen-4 (VLA-4) has been implicated to play a role in the adhesive interactions between hematopoietic progenitor cells (HPC) and bone marrow stromal cells which express the vascular cell adhesion molecule-1 (VCAM-1) or produce fibronectin (FN). Here, we summarize some of the recent advances made in the elucidation of the role of these particular adhesive interactions for the regulation of normal hematopoiesis. HPC bind to stroma mainly through VLA-4/VCAM-1 interactions. There is evidence which suggests that more primitive HPC constitutively express VLA-4 in a high-affinity state. In vitro studies in the mouse have shown that monoclonal antibodies (mAb) against VLA-4 partly block the development of lymphocytes, myelopoietic cells, and erythropoiesis, whereas in the human system outgrowth of TdT+ B cells is severely retarded by such mAb. In vivo studies revealed that VLA-4 is involved in erythropoietic development, and is particularly important for homing and lodgement of HPC in the bone marrow. Hematopoiesis in mice with deficient expression of alpha 4 integrin or VLA-4's ligand VCAM-1 appears to develop normally. However, chimeras developed from wild-type blastocysts and beta 1 -/- embryonic stem cells do not contain beta 1 -/- hematopoietic cells, although these are present as blood islands in the yolk sac. These beta 1 -/- hematopoietic cells are capable of forming colonies, indicating that beta 1-integrin is not involved in hematopoietic differentiation, but is primarily important for migration of hematopoietic cells into the fetal hematopoietic organs. In addition to the role of VLA-4 in migration, it may also have other regulatory functions. It has been demonstrated that ligation of VLA-4 induces phosphorylation of the protein tyrosine kinase (PTK) pp125FAK as well as other proteins which may be involved in the regulation of ligand affinity. Indeed, it has been shown that tyrosine kinase-dependent stimulation of CD34+ hematopoietic cell lines with c-kit ligand (KL), IL-3 or GM-CSF transiently activates the ability of VLA-4 to bind to VCAM-1 or FN. These events are most probably involved in the induction of quiescence in HPC which adhere to stromal cells. This claim was recently substantiated: when HPC were treated with Fab fragments of an anti-VLA-4 mAb, entry into S-phase of the cell cycle was prevented. Taken together, the present data point to a role for VLA-4 in HPC migration, cell cycle regulation, erythropoiesis and B-lymphopoiesis. Moreover, these insights may explain how defects in adhesive behavior of leukemic HPC through VLA-4 contribute to their dysregulated growth and provide a rationale for therapeutically correcting those defects.

Trans people's experiences with assisted reproduction services: a qualitative study. What are the experiences of trans persons (i.e. those whose gender identity does not match the gender assigned to them at birth) who sought or accessed assisted reproduction (AR) services in Ontario, Canada, between 2007 and 2010? The majority of trans persons report negative experiences with AR service providers. Apart from research examining desire to have children among trans people, most of the literature on this topic has debated the ethics of assisting trans persons to become parents. To-date, all of the published research concerning trans persons' experiences with AR services is solely from the perspective of service providers; no studies have examined the experiences of trans people themselves. Secondary qualitative research study of data from nine trans-identified people and their partners (total n = 11) collected as part of a community-based study of access to AR services for sexual and gender minority people between 2010 and 2012. Trans-identified volunteers (and their partners, when applicable) who had used or attempted to access AR services since 2007 from across Ontario, Canada, participated in a 60-90 minute, semi-structured qualitative interview. Qualitative analysis was performed using a descriptive phenomenological approach. Emerging themes were continually checked against the data as part of an iterative process. The data highlight barriers to accessing AR services for trans people. Participant recommendations for improving AR service provision to better meet the needs of this population are presented. These recommendations address the following areas: (i) AR service provider education and training; (ii) service provider and clinic practices and (iii) clinic environment. The majority of study participants were trans people who identified as men and who resided in major urban areas; those living in smaller communities may have different experiences that were not adequately captured in this analysis. While existing literature debates the ethics of assisting trans people to become parents through the use of AR, our study demonstrates that they are already accessing or attempting to access these services. This reality necessitates a shift toward exploring the ways in which AR services can be improved to better meet the needs of this population, from the perspectives of both service users and service providers. This project was supported by the Canadian Institutes of Health Research-Institute of Gender and Health, in partnership with the Assisted Human Reproduction Canada: Catalyst Grant: Psychosocial Issues Associated with Assisted Human Reproduction (FRN-103595). S.M. was supported by a Canada Graduate Scholarship from the Social Science and Humanities Research Council, as well as research funding from Osgoode Hall Law School, York University. S.J.-A. was supported by an Ontario Graduate Scholarship funded by the Province of Ontario and the University of Toronto. N/A.

Doxazosin for treating lower urinary tract symptoms compatible with benign prostatic obstruction: a systematic review of efficacy and adverse effects. To evaluate the efficacy and adverse effects of doxazosin for treating lower urinary tract symptoms (LUTS) compatible with benign prostatic obstruction (BPO). Randomized controlled trials were included in the meta-analysis if: the study duration was > or = 1 month; the study involved men with symptomatic BPO; and doxazosin was compared with placebo or active controls. Study and patient characteristics and outcome data were extracted in duplicate onto standardized forms using a prospectively developed protocol. Thirteen studies involving 6033 men with (mean age 64 years) met the inclusion criteria; 10 were placebo-controlled, including two with combined doxazosin/finasteride therapy and finasteride monotherapy arms. Three trials were a comparison with other alpha-blockers. The study duration was 1-54 months. The mean baseline symptom scores and peak urinary flow (PUF) rates were indicative of moderate BPO. Doxazosin gave significant improvements in LUTS, assessed by symptom scores, vs placebo and finasteride in the short- to long-term. Two long-term studies (1 and 4 years) reported mean changes from baseline for the International Prostate Symptom Score of - 8.3 and - 6.6 points (-49% and - 39%) for doxazosin and - 5.7 and - 4.9 points (-33% and - 29%) for placebo, respectively. Doxazosin significantly increased PUF rates vs placebo. In pooled results from three studies, the weighted mean difference in the mean change from baseline vs placebo was 1.6 mL/s (95% confidence interval 1.2-2.1). Efficacy was comparable with other alpha1-blockers. In the long-term (>4 years) doxazosin was no better then finasteride in improving PUF. Combined doxazosin and finasteride significantly reduced the risk of overall clinical progression of BPO vs each drug separately in men followed for >4 years. Absolute risk reductions vs placebo were 11.3%, 6.9% and 6.4% for combined therapy, doxazosin and finasteride, respectively (P < 0.001). Improvements in symptom scores and PUF were also significantly greater with combined than monotherapy, and the former reduced the need for invasive treatment for BPO and the risk of long-term urinary retention, although the absolute reductions in risk vs placebo were small (<4%). Dizziness and fatigue were significantly more common with doxazosin than placebo (11% vs 7%, and 6% vs 3%, respectively). Adverse events reported for combined therapy were similar to those with each monotherapy. The evidence indicates that doxazosin is effective and generally well tolerated for improving LUTS and PUF in men with symptomatic BPO. Combined therapy was better than doxazosin alone in reducing the risk of clinical progression of BPO and other long-term complications related to BPO.

[Influence of high-voltage electric burn on the microcirculation of heart in rabbit]. To study the influence of high-voltage electric burn on the microcirculation of heart in rabbit. One-hundred and twenty New Zealand rabbits of clean grade were divided into control group (C) and electric burn group (EB) according to the random number table, with 60 rabbits in each group. Rabbits in EB group were subjected to high-voltage electric burn (the electrical current flow into the left foreleg at the lateral side of proximal end and out from the corresponding site of the right hind leg) with voltage regulator and experimental transformer. Rabbits in C group were sham injured with the same devices without electrification. At 15 minutes before injury, and 5 minutes, 1, 2, 4, 8 hour (s) post injury (PIM or PIH), ten rabbits in each group were chosen to examine the cardiac apex microcirculation hemoperfusion (CAMH) with laser Doppler hemoperfusion image instrument. The morphologic changes of microvessels of left ventricular wall tissues of 2 rabbits from each of the 10 rabbits collected at above-mentioned time points were observed with light microscope and transmission electron microscope. Auricular vein blood of rabbit was harvested at above-mentioned time points for the determination of aspartate amino transferase (AST), lactate dehydrogenase (LDH), hydroxybutyrate dehydrogenase (HBDH), creatine kinase (CK), and creatine kinase isozyme MB (CK-MB) by full-automatic biochemical analyzer. Data were processed with two-factor analysis of variance and LSD test. (1) The differences between C group and EB group in detection results were statistically significant, with F values from 425.991 to 3046.834, P values all below 0.01. Only the data within EB group were comparable. (2) At PIM 5, the CAMH value of rabbits in EB group was (1.96 ± 0.09) V, which was lower than that at 15 minutes before injury [(4.34 ± 0.35) V, P < 0.01]. The CAMH value of rabbits in EB group was increased at PIH 1 [(3.43 ± 0.30) V], and then it showed a tendency of decrease. (3) Bleeding and microthrombus formation were observed in venule and capillary vessel of rabbits in EB group at PIH 8. Breakage of basement membrane of capillary endothelial cells, mitochondrial swelling, and severe degranulation from damaged endoplasmic reticulum were observed in rabbits of EB group at PIH 8. (4) Levels of AST, LDH, HBDH, CK, and CK-MB in rabbits of EB group were significantly higher at PIH 1, 2, 4, 8 than at 15 minutes before injury (with P values all below 0.01). The AST level peaked at PIH 2 [(164 ± 39) U/L]. Levels of LDH and HBDH peaked at PIH 4, which were respectively (1016 ± 246) U/L and (487 ± 54) U/L. The CK level peaked at PIH 8 [(7799 ± 738) U/L]. The CK-MB level peaked at PIH 2 [(1848 ± 65) U/L]. High-voltage electric burn can bring damage to the microvessels of heart in rabbits and change blood flow of microcirculation, which should be given adequate attention during the treatment.

Drug metabolism by cultured human hepatocytes: how far are we from the in vivo reality? The investigation of metabolism is an important milestone in the course of drug development. Drug metabolism is a determinant of drug pharmacokinetics variability in human beings. Fundamental to this are phenotypic differences, as well as genotypic differences, in the expression of the enzymes involved in drug metabolism. Genotypic variability is easy to identify by means of polymerase chain reaction-based or DNA chip-based methods, whereas phenotypic variability requires direct measurement of enzyme activities in liver, or, indirectly, measurement of the rate of metabolism of a given compound in vivo. There is a great deal of phenotypic variability in human beings, only a minor part being attributable to gene polymorphisms. Thus, enzyme activity measurements in a series of human livers, as well as in vivo studies with human volunteers, show that phenotypic variability is, by far, much greater than genotypic variability. In vitro models are currently used to investigate the hepatic metabolism of new compounds. Cultured human hepatocytes are considered to be the closest model to the human liver. However, the fact that hepatocytes are placed in a microenvironment that differs from that of the cells in the liver raises the question of to what extent drug metabolism variability observed in vitro actually reflects that in the liver in vivo. This issue has been examined by investigating the metabolism of the model compound, aceclofenac (an approved analgesic/anti-inflammatory drug), both in vitro and in vivo. Hepatocytes isolated from programmed liver biopsies were incubated with aceclofenac, and the metabolites formed were investigated by HPLC. The patients were given the drug during the course of clinical recovery, and the metabolites, largely present in urine, were analysed. In vitro and in vivo data from the same individual were compared. There was a good correlation between the in vitro and in vivo relative abundance of oxidised metabolites (4'-OH-aceclofenac + 4'-OH-diclofenac; Spearman's rho = 0.855), and the hydrolysis of aceclofenac (diclofenac + 4'-OH-aceclofenac + 4'-OH-diclofenac; rho = 0.691), while the conjugation of the drug in vitro was somewhat lower than in vivo. Globally, the metabolism of aceclofenac in vitro correlated with the amount of metabolites excreted in urine after 16 hours (rho = 0.95). Overall, although differing among assays, the in vitro/in vivo metabolism data for each patient were surprisingly similar. Thus, the variability observed in vitro appears to reflect genuine phenotypic variability among the donors.

Expression in mouse embryos and in adult mouse brain of three members of the amyloid precursor protein family, of the alpha-2-macroglobulin receptor/low density lipoprotein receptor-related protein and of its ligands apolipoprotein E, lipoprotein lipase, alpha-2-macroglobulin and the 40,000 molecular weight receptor-associated protein. We have analysed by northern blotting and by in situ hybridization the expression patterns of eight different genes during the second half of mouse embryonic development and in adult mouse brain: we compared the messenger RNA levels of amyloid precursor protein and of the two amyloid precursor protein-like proteins 1 and 2 and we have analysed expression of apolipoprotein E and of its main receptor in brain, the alpha-2-macroglobulin/low density lipoprotein receptor-related protein and three other ligands: the proteinase inhibitor alpha-2-macroglobulin, the modifying enzyme lipoprotein lipase and the 44,000 molecular weight heparin binding protein, a ligand of unknown function. During embryogenesis the temporal expression pattern differs considerably for the three members of the amyloid precursor proteins. Total embryo messenger RNA levels of amyloid precursor protein and amyloid precursor protein-like protein 2 increased progressively, while amyloid precursor protein-like protein 1 messenger RNA showed a burst of synthesis between days 10 and 13 post-coitum. Significantly, expression of the alpha-2-macroglobulin/low density lipoprotein receptor-related protein and of its associated protein, the 44,000 molecular weight heparin binding protein, exhibited their most important increase very similar to that of amyloid precursor protein-like protein 1, between days 10 and 13 post-coitum. Apolipoprotein E, lipoprotein lipase and alpha-2-macroglobulin messenger RNA levels in total embryos increased progressively, beginning most pronounced at days 13, 15 and 17, respectively. In mouse embryos, in situ hybridization established amyloid precursor protein, amyloid precursor protein-like protein 2 and alpha-2-macroglobulin/low density lipoprotein receptor-related protein messenger RNA to be expressed in most organs, with the notable exception of the liver, while expression of the other studied proteins was much more restricted. Among adult mouse tissues, the genes investigated were expressed very prominently in brain, except for lipoprotein lipase and for the complete absence of alpha-2-macroglobulin messenger RNA. In adult mouse brain, the cortex and hippocampus exhibited strong signals for most genes analysed. Exceptions are lipoprotein lipase and apolipoprotein E messenger RNAs, and the absent alpha-2-macroglobulin messenger RNA. Several interesting features, similarities as well as differences, between brain tissue sections hybridized with probes for amyloid precursor protein, amyloid precursor protein-like proteins 1 and 2 and between alpha-2-macroglobulin/low density lipoprotein receptor-related protein and heparin binding protein-44 were observed and are described. The results are further discussed in view of the known or anticipated physiological functions of the proteins examined and of their possible role in the etiology of Alzheimer's disease.

Effects of circulating tumor necrosis factor on the neuronal activity and expression of the genes encoding the tumor necrosis factor receptors (p55 and p75) in the rat brain: a view from the blood-brain barrier. Tumor necrosis factor is a potent activator of myeloid cells, which acts via two cell-surface receptors, the p55 and p75 tumor necrosis factor receptors. The present study describes the cellular distribution of both receptor messenger RNAs across the rat brain under basal conditions and in response to systemic injection with the bacterial endotoxin lipopolysaccharide and recombinant rat tumor necrosis factor-alpha. Time-related induction of the messenger RNA encoding c-fos, cyclo-oxygenase-2 enzyme and the inhibitory factor kappa B alpha was assayed as an index of activated neurons and cells of the microvasculature by intravenous tumor necrosis factor-alpha challenge. The effect of the proinflammatory cytokine on the hypothalamic-pituitary-adrenal axis was determined by measuring the transcriptional activity of corticotropin-releasing factor and plasma corticosterone levels. Constitutive expression of p55 messenger RNA was detected in the circumventricular organs, choroid plexus, leptomeninges, the ependymal lining cells of the ventricular walls and along the blood vessels, whereas p75 transcript was barely detectable in the brain under basal conditions. Immunogenic insults caused up-regulation of both tumor necrosis factor receptors in barrier-associated structures, as well as over the blood vessels, an event that was associated with a robust activation of the microvasculature. Indeed, intravenous tumor necrosis factor-alpha provoked a rapid and transient transcription of inhibitory factor kappa B alpha and cyclo-oxygenase-2 within cells of the blood-brain barrier, and a dual-labeling technique provided the anatomical evidence that the endothelium of the brain capillaries expressed inhibitory factor kappa B alpha. Circulating tumor necrosis factor-alpha also rapidly stimulated c-fos expression in nuclei involved in the autonomic control, including the bed nucleus of the stria terminalis, the paraventricular nucleus of the hypothalamus, the central nucleus of the amygdala, the nucleus of the solitary tract and the ventrolateral medulla. A delayed c-fos mRNA induction was detected in the circumventricular organs, organum vascularis of the lamina terminalis, the subfornical organ, the median eminence and the area postrema. The paraventricular nucleus of the hypothalamus exhibited expression of corticotropin-releasing factor primary transcript that was associated with a sharp increase in the plasma corticosterone levels 1h after intravenous tumor necrosis factor-alpha administration. Taken together, these data provide the evidence that p55 is the most abundant tumor necrosis factor receptor in the central nervous system and is expressed in barrier-associated structures. Circulating tumor necrosis factor has the ability to directly activate the endothelium of the brain's large blood vessels and small capillaries, which may produce soluble molecules (such as prostaglandins) to vehicle the signal through parenchymal elements. The pattern of c-fos-inducible nuclei suggests complex neuronal circuits solicited by the cytokine to activate neuroendocrine corticotropin-releasing factor and the corticotroph axis, a key physiological response for the appropriate control of the systemic inflammatory response.

[Effect of multidrug resistant associated protein 4 overexpression on lipopolysaccharide-induced vascular endothelial hyperpermeability and its mechanism]. To investigate the effect of multidrug resistance protein 4 (MRP4) overexpression on lipopolysaccharide (LPS)-induced vascular endothelial hyperpermeability of rat pulmonary micro-vascular endothelial cells (PMVECs) and its molecule mechanism. Three to six passages of PMVECs were cultured in vitro, and they were divided into three groups: the cells in LPS group were only challenged by LPS 10 μg/mL after being cultured in serum-free medium for 24 hours; the cells in Ad-shRNA and Ad-MRP4 groups were infected with the empty virus control or recombinant adenovirus expressing MRP4 for 2 hours, and then were cultured in serum-free medium for 24 hours followed by stimulation of LPS 10 μg/mL. Endothelial permeability was assayed by the Transwell chamber models at 2, 6, 12, and 24 hours after LPS stimulation. Intracellular cyclic adenosine monophosphate (cAMP) levels were detected by enzyme-linked immunosorbent assay (ELISA). The morphological characteristics and distribution of F-actin was determined by laser confocal fluorescence microscope. The protein expressions of MRP4, β-catenin, vascular endothelium-cadherin (VE-cad) and ZO-1 were measured by Western Blot. (1) After LPS stimulation, endothelium permeability and intracellular cAMP levels in PMVECs were significantly increased, peaked at 12 hours, and then decreased after 24 hours. Compared with LPS group and Ad-shRNA group, PMVECs of Ad-MRP4 group were exhibited a significant increase in endothelial permeability [12-hour permeability (A value): 1.88±0.06 vs. 1.12±0.17, 1.10±0.18] and a significant decrease in intracellular cAMP level [12-hour cAMP (μg/L): 2.39±0.02 vs. 2.97±0.01, 3.00±0.02, all P < 0.05]. There was no significant difference in endothelium permeability and intracellular cAMP levels at all time points between the LPS group and the Ad-shRNA group (all P > 0.05). (2) Under laser confocal fluorescence microscope, after LPS stimulation, the stress fiber formation was induced in three groups. But there were pronounced irregular aggregation of fiber in PMVECs of Ad-MRP4 group. (3) Furthermore, compared with LPS group and Ad-shRNA group, protein expression of MRP4 in Ad-MRP4 group was dramatically increased (gray value: 0.76±0.03 vs. 0.44±0.02, 0.43±0.02, both P < 0.05), and the protein expressions of β-catenin, VE-cad, and ZO-1 were significantly decreased [β-catenin (gray value): 0.14±0.03 vs. 0.23±0.04, 0.23±0.03); VE-cad (gray value): 0.21±0.01 vs. 0.34±0.02, 0.35±0.04; ZO-1 (gray value): 0.14±0.02 vs. 0.37±0.06, 0.33±0.07, all P < 0.05]. There was no significant difference in all protein expressions between the LPS group and Ad-shRNA group (all P > 0.05). MRP4 overexpression can decrease intracellular cAMP levels, reduce intercellular junction protein expression, and then exaggerate LPS-induced vascular endothelial hyperpermeability.

[Electron microscopy of the lesions produced in the human dura mater by Quincke beveled and Whitacre needles]. Comparisons of Quincke needles and non traumatic "pencil point" needles in recent years have reported lower rates of post dural puncture headache using the later type. Our new understanding of the morphology of the human dura mater motivated us to study dural lesions caused by the Whitacre 25 G and Quincke 26 G needles, using scanning electron microscopy with the aim of determining whether there is an anatomic basis for the different outcomes. The dura mater from three fresh cadavers of individuals aged 65, 70 and 72 years were punctured 40 times at an angle of 90 degrees each time. The Whitacre 25 G needle was used for 20 punctures and the Quincke 26 G needle was used for the other 20. Half the punctures were performed with the bevel in the parallel alignment and the other half with the bevel perpendicular to the spinal column. Fifteen min after causing the punctures, specimens were fixed in solutions of glutaraldehyde phosphate buffer and dehydrated in acetone. After critical point removal of the acetone, after the specimens were treated with carbon and metallized with gold. The lesions were examined externally and internally and expressed as the ratio of area of lesion to diameter of the needle that had caused them. Whitacre needle: each lesion consisted in the superimposition of multiple damaged layers that started to close individually. After 15 min the outermost layers were 90% closed and the innermost ones had closed entirely. Layers in the arachnoid surface of the dura mater had closed from 86 to 88%, while deeper layers in the thick part had closed 97 to 98%. Quincke needle: lesions were V-shaped or half-moon shaped, much like the opening formed by a can opener, on both the external and internal surfaces. Alignment of the bevel of the needle parallel to the spinal column did not lead to a different shape of puncture. After 15 min the lesions had closed 94 to 95% on the epidural surface and 95 to 96% on the arachnoid side, a difference attributable to the retraction of the arachnoid layers over the spinal column. Non traumatic beveled dural needles, termed "pencil point needles", only partially separate dural fibers, and lesions caused by these needles develop in a more complex way. The Quincke 26G needle produced a puncture that is morphologically different from that caused by the Whitacre 25G needle, although lesions produced by both types close more than 94% after 15 min. We believe the size of the lesion caused by these needles does not explain the difference in post dural puncture headache due to loss of spinal fluid.

"It's All About How You Carry Yourself About": How Medical Students Conceptualize Professionalism in Trinidad & Tobago. Phenomenon: This paper concerns itself with the value system that informs and motivates medical students of the twenty-first century as distinct from earlier cohorts. It notes a shift from an era of altruism within which the medical professional was a 'pillar of society' always 'on duty' and always concerned foremost for the patient to an era in which he/she is just another member of the work force, subject to public scrutiny and criticism, to patient autonomy and to a self-serving ethos which characterizes the present age. Whilst concerns have been raised for a continuing and separate morality of medicine, young professionals in other studies have cited a range of characteristics including honesty, trustworthiness and respect alongside competence and medical skill. However, the notion of 'performance' has made a strong thrust into the literature, with students citing the putting on and taking off of dual personae as part of their complex identity in this present time. They are entitled to their own lives, to drop the act and just be themselves when off duty, picking it back up again with the duty call. The present study then investigated the views on this subject of two groups of medical students in Trinidad & Tobago in the Caribbean, one made up entirely of nationals and one including students from other parts of the Caribbean and the USA. They discussed the topic in focus groups of eight; their responses were then analysed thematically and subject to discourse analysis. The study revealed diverse attitudes with some embracing the ethical standards of a high calling that whilst others were concerned that too much was expected, that they had a right to break free and be themselves as long as they did not transgress too far from their expected roles. There were two distinct groups both concerned with 'how' they 'carried themselves about' but this meant different things to each dependent on which of the two perspectives they embraced. As a whole, the study revealed an ongoing conflict of value systems with concern for patient welfare just remaining uppermost. Insights: As The University of the West Indies has now stepped into the field of medical professionalism actively it would hope to support students in resolving their conflicts more consciously in response to the range of philosophical stances which currently present themselves.

Assessment of two measurement techniques of cervical spine and C1-C2 rotation in the outcome research of axis fractures: a morphometrical analysis using dynamic computed tomography scanning. In vivo study on cervical spine motion. To estimate the accuracy of clinical measurements, using a handheld goniometer for the assessment of total cervical neck rotation in outcome research of patients with C2 fractures and particularly odontoid fractures. Investigation on whether functional computed tomography (CT)-scanning is decisive in the investigation of functional outcome after C2 fractures. Pertinent literature exists concerning indications, techniques, complications of treatment, and risk factors for nonunion in C2 fractures; however, there are scarce data regarding the functional outcome in C2 fractures. Only a few studies assess functional outcome in terms of clinical outcome vehicles and clinical investigation of axial neck rotation, using a handheld goniometer. Measurements of axial neck rotation using a handheld goniometer are assumed not sufficient to compare the results of treatment strategies for C2-fractures or elucidate the ability for posttreatment rotation of C1-C2. The authors selected a homogenous group of 35 patients treated for C2 fractures using nonsurgical and surgical techniques. 69% of patients had odontoid fractures. Mean age of patients was 52 years. Patients were subjected to clinical assessment of axial cervical range of motion for rotation, using a handheld goniometer. Patients were also subjected to functional CT-scanning and measurements of total neck and atlantoaxial rotation were performed according to an established protocol. With clinical measurements mean range of motion for left and right axial neck rotation was both 56 degrees. According to the functional CT scans, the mean left-sided and right-sided axial neck rotation was 48.6 degrees and 52.0 degrees. The mean for left- and right-sided atlantoaxial rotation was 20.2 degrees and 20.6 degrees. Total axial atlantoaxial rotation on CT scans was 40.3 degrees and total axial neck rotation was 103.3 degrees. In comparison to age and gender matched normal individuals total cervical neck rotation was reduced to a mean of 69.5%. The differences between total axial neck rotation assessed using a handheld goniometer and with functional CT-scanning were strongly significant (P < 0.0001). In addition, there was no statistically significant correlation between the clinically assessed total neck rotation to either the left or the right side and the ipsilateral percentage atlantoaxial rotation of total head neck rotation. The current study demonstrated that for the comparison of functional outcome after different therapies of C2 fractures clinical measurements do not serve for reliable data on total neck rotation and particularly atlantoaxial rotation and the percentage of C1-C2 rotation of total neck rotation. The use of dynamic CT-scans in the analysis of functional outcome after C2 fractures is strongly recommended.

[Expression and significance of heat shock protein 70 in maternal serum, umbilical cord blood and placenta of patients with hypertensive disorders complicating pregnancy]. To investigate the expression of heat shock protein 70 (HSP70) in maternal serum, umbilical cord blood and placenta of patients with hypertensive disorders complicating pregnancy (HDCP) and to discuss its role in the pathogenesis of HDCP. Totally 90 patients with HDCP were recruited as HDCP group, and were devided into three subgroups, including gestational hypertension group (30 cases), mild preeclampsia group (30 cases) and severe preeclampsia group (30 cases). A totally of 30 cases of healthy pregnant women were defined as the control group. All of them were admitted to Xuzhou Maternity and Child Health Care Hospital from August 2011 to December 2012. ELISA was used to detect the expression of HSP70 in maternal serum and umbilical cord blood. Immunohistochemistry streptavidin peroxidase (SP) was used to detect the protein in placenta, and semi-quantitative reverse transcription (RT)- PCR was used to detect the expression of HSP70 mRNA. (1) The levels of HSP70 in maternal serum and cord blood of mild preeclampsia group were (2.61 ± 0.98) and (0.78 ± 0.27) µg/L, respectively; and were (3.10 ± 1.18) and (0.96 ± 0.28) µg/L in severe preeclampsia group. The levels of HSP70 in mild and severe preeclampsia groups were significantly higher than those in the control group [(1.88 ± 0.79) and (0.61 ± 0.15) µg/L, respectively] and gestational hypertension group [(2.13 ± 0.71) and (0.64 ± 0.18) µg/L, respectively; P < 0.05]. The level of HSP70 in severe preeclampsia group was significantly higher than that in mild preeclampsia group (P < 0.05). And the level of HSP70 in gestational hypertension group was higher than that in the control group, but there was no statistical difference (P > 0.05). (2) The positive rate of placental HSP70 in gestational hypertension group, mild and severe preeclampsia group [83% (25/30), 90% (27/30) and 100% (30/30)], respectively were significantly higher than those in the control group (43%, 13/30; P < 0.05). The positive rate of placental HSP70 in severe preeclampsia group was significantly higher than that in gestational hypertension group and mild preeclampsia group (P < 0.05). (3) The expression of placental HSP70 mRNA in gestational hypertension group, mild and severe preeclampsia group (0.82 ± 0.27, 0.92 ± 0.26 and 1.36 ± 0.29, respectively) were significantly higher than that in the control group (0.45 ± 0.18), with statistically significant differences (P < 0.05). The expression of placental HSP70 mRNA in severe preeclampsia group was significantly higher than that in gestational hypertension group and mild preeclampsia group (P < 0.05). The expression of HSP70 increased significantly in maternal serum, umbilical cord blood and placenta of patients with HDCP, and it had positive correlation with the severity of the disease, indicating that HSP70 may play a role in the pathogenesis of HDCP.

The Society of Thoracic Surgeons Intermacs Database Annual Report: Evolving Indications, Outcomes, and Scientific Partnerships. The Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs), a joint effort among the National Heart, Lung, and Blood Institute, the Food and Drug Administration, the Centers for Medicare and Medicaid Services, and others, was established in 2005 at the University of Alabama at Birmingham. The registry examined clinical outcomes and quality-of-life metrics of patients who received an Food and Drug Administration-approved durable mechanical circulatory support (MCS) device to treat advanced heart failure. On January 1, 2018, the Intermacs Database became part of The Society of Thoracic Surgeons National Database, providing additional resources for quality assessment and improvement and scientific advancement. The Intermacs Database Annual Report summarizes outcomes in patients (≥19 years of age) who underwent durable MCS implant between June 23, 2006, and December 31, 2017. Outcomes are presented for patients who underwent isolated continuous flow left ventricular assist device (CF LVAD) support, CF LVAD support with concomitant right ventricular assist device (RVAD) implant, or total artificial heart implant. Analyses of patients with CF LVADs are stratified by axial flow and centrifugal flow configurations. Because of the association of era with outcomes, the survival analyses are restricted to isolated CF LVADs implanted in the 2012 to 2016 era. There were 25,145 adult patients with MCS reported to Intermacs, of whom 18,539 (74%) received CF LVADs, 667 (2.6%) had an RVAD with CF LVAD, 339 received a total artificial heart (1.3%), and 20 (0.07%) received an isolated RVAD. Of the CF LVADs, mean age was 57 ± 1 years, 26% were listed for transplantation, and 51% were in cardiogenic shock (profile 1 to 2) preoperatively. CF LVADs included 14,527 axial flow (78%) and 4,012 centrifugal flow (22%) devices. Intermacs patient phenotype has evolved over time to include more patients with profile 3 (26% in 2006 to 2011 versus 35% in 2012 to 2016) and fewer patients with profile 2 (40% versus 35%), patients with better markers of preoperative renal and hepatic function, and more patients who received implants for destination therapy (29% versus 48%) indication. In 2017, centrifugal flow implants (51%) approximated that of axial flow devices (49%). Mean CF LVAD support duration was 20 months (31,563 patient-years). One-year survival for isolated CF LVADs was 83% and 5-year survival was 46%. One-year survivals for centrifugal versus axial flow devices were 85% and 84%, respectively. Patients who required concomitant RVAD support had 1- and 5-year survivals of 58% and 28%, respectively. Freedom from all-cause readmission was 70% at 1 month and 20% at 1 year. At 1 year, stroke occurred in 20% of patients on centrifugal flow and 13% of patients on axial flow support (p < 0.001), gastrointestinal bleeding affected 20% of patients with centrifugal flow devices and 25% of patients with axial flow devices (p < 0.001), and pump-related infection occurred in 28% of patients with centrifugal flow devices versus 25% of patients with axial flow devices (p = 0.01). Neurologic dysfunction (19% of deaths) and multisystem organ dysfunction (15%) were the most common causes of death. With the evolution of MCS, patient phenotype and outcomes are also changing over time. CF LVAD support is increasingly being used in the less ill patient phenotype and more patients are supported for destination therapy. Mean survival is now approaching 5 years, but adverse events, especially neurologic events, continue to have a detrimental impact on the success of CF LVAD support.

Prooxidant and antioxidant hepatic factors in rats chronically fed an ethanol regimen and treated with an acute dose of lindane. While acute lindane treatment and chronic ethanol feeding to rats have been associated with hepatic oxidative stress, the possible roles of these stresses in the pathogenesis of hepatic lesions reported in acute lindane intoxication and in those observed in some models of chronic alcoholism have not been established. Our previous studies in rats chronically fed ethanol regimens and then treated with a single intraperitoneal (i.p.) dose of lindane (20 mg/kg) showed that while lindane per se was invariably associated with hepatic oxidative stress, chronic ethanol feeding only produced this stress when the dietary level of vitamin E was relatively low. Chronic ethanol pretreatment did not significantly affect the lindane-associated oxidative stress, and neither chronic ethanol feeding nor acute lindane, single or in combination, produced any histologic and biochemical evidence of liver damage. In the present experiment, the acute dose of lindane was increased to 40 mg/kg, and we have studied a larger number of prooxidant and antioxidant hepatic factors. Male Wistar rats (115.5 +/- 5.4 g) were fed ad lib for 11 weeks a calorically well-balanced and nutritionally adequate basal diet, or the same basal diet plus a 32% ethanol/25% sucrose solution, also ad lib, and were then injected i.p. with a single dose of lindane or with equivalent amounts of corn oil. The results indicated that acute lindane treatment to naive rats increased practically all the prooxidant hepatic factors examined (cytochromes P450 and b5, NADPH cytochrome c reductase, NADPH oxidase), as well as the generation of microsomal superoxide radical and thiobarbituric acid reactive substances of liver homogenates, but did not modify any of the antioxidant hepatic factors studied. Conversely, the chronic administration of ethanol alone did not significantly affect the prooxidant hepatic factors but reduced some of the antioxidants (i.e., the activities of GSH-Px and the contents of alpha-tocopherol and ubiquinols 9 and 10). Although chronic ethanol pretreatment further increased the superoxide generation induced by lindane per se, it did not increase but generally reduced the effects of lindane per se on the other prooxidant factors studied. Furthermore, although acute lindane administration to ethanol-pretreated rats was associated with decreases in GSH and catalase (not affected by ethanol or lindane treatment alone), it did not substantially modify the reducing effects of ethanol feeding per se on GSH-Px, alpha-tocopherol, and ubiquinols. Once again, neither chronic ethanol feeding nor lindane treatment, single or in combination, was associated with any evidence of liver damage.

The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness. Poor adherence to medication treatment can have devastating consequences for patients with mental illness. The goal of this project was to develop recommendations for addressing adherence problems to improve patient outcomes. The editors identified important topics and questions concerning medication adherence problems in serious mental illness that are not fully addressed in the literature. A survey was developed containing 39 questions (521 options) asking about defining nonadherence, extent of adherence problems in schizophrenia and bipolar disorder, risk factors for nonadherence, assessment methods, and interventions for specific types of adherence problems. The survey was completed by 41 (85%) of the 48 experts to whom it was sent. Results of the literature review and survey were used to develop recommendations for assessing and improving adherence in patients with serious mental illness. ASSESSING ADHERENCE: The experts endorsed percentage of medication not taken as the preferred method of defining adherence, with 80% or more of medication taken endorsed as an appropriate cut-off for adherence in bipolar disorder and schizophrenia. Although self- and physician report are the most common methods used to assess adherence in clinical settings, they are often inaccurate and may underestimate nonadherence. The experts recommend that, if possible, clinicians also use more objective measures (e.g., pill counts, pharmacy records, and, when appropriate, serum levels such as are used for lithium). Use of a validated self-report scale may help improve accuracy. The majority of the experts believed the average patient with schizophrenia or bipolar disorder in their practices takes only 51%-70% of prescribed medication. FACTORS ASSOCIATED WITH NONADHERENCE: The experts endorsed poor insight and lack of illness awareness, distress associated with specific side effects or a general fear of side effects, inadequate efficacy with persistent symptoms, and believing medications are no longer needed as the most important factors leading to adherence problems in schizophrenia and bipolar disorder. The experts considered weight gain a side effect that is very likely to lead to adherence problems in patients with schizophrenia and bipolar disorder; sedation was considered a more important contributor to adherence problems in bipolar disorder than schizophrenia. The experts rated persistent positive or negative symptoms in schizophrenia and persistent grandiosity and manic symptoms in bipolar disorder as the most important symptomatic contributors to adherence problems in these illnesses. It is important to identify the specific factors that may be contributing to a patient's adherence problems in order to customize interventions to target those problems. Multiple problems may be involved, requiring a combination of interventions. Adherence problems are complex and multidetermined. The experts recommended customized interventions focused on the underlying causes.

Facing the challenge: decreasing case fatality rates in severe sepsis despite increasing hospitalizations. To determine recent trends in severe sepsis-related rates of hospitalization, mortality, and hospital case fatality in a large geographic area and to determine the impact of age, race, and gender on these outcomes. Trend analysis for the period of 1995 to 2002. Acute care hospitals in New Jersey. Subjects > or = 18 yrs of age with severe sepsis who were hospitalized in New Jersey during the period of 1995 to 2002. None. We analyzed data from the 1995-2002 New Jersey State Inpatient Databases (SID) developed as part of the Healthcare Cost and Utilization Project (HCUP), covering all acute care hospitals in the state. On the basis of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for septicemia and organ dysfunction, we identified 87,675 patients with severe sepsis. The percentage of patients with severe sepsis among all hospitalized patients with sepsis grew steadily, from 32.7% to 44.7% (p < .0001), during these years. The crude rate of hospitalization with severe sepsis increased 54.2%, from 135.0/100,000 population in 1995 to 208.2/100,000 population in 2002 (p < .0001). Over time, the crude mortality rate rose by 35.8% (p < .0001), whereas the crude case fatality rate (number of deaths/number of cases) fell from 51.0% to 45.0% (p < .0001). For any given year, the rates of hospitalization and mortality were greater among older patients. After adjustment by age, the rates among blacks were greater than among whites, and they were greater among males than females. At the same time, there was no significant difference in the age-adjusted hospital case fatality rates with regard to gender and race. There was a significant increase in age-adjusted gender- and race-specific rates for hospitalization and mortality from 1995 to 2002. Blacks were more likely than whites to be admitted to the intensive care unit: for males, odds ratio = 1.19 (95% confidence interval, 1.13-1.26), and for females, odds ratio = 1.35 (95% confidence interval, 1.29-1.42). However, although case fatality rate was increased among patients admitted to the intensive care unit, this was not reflected in an increased case fatality among blacks. In addition, age-adjusted gender- and race-specific case fatality rates declined during 1995-2002. In spite of increasing rates of hospitalization and mortality, there is a decreasing case fatality rate for severe sepsis. These data suggest that advances in critical care practice before and during the study period have resulted in improved outcomes for this population.

[Effects of estrogen on ACE-Ang II-AT1 axis in ovariectomy and hypoxic pulmonary hypertension rats]. To explore the effects of estrogen (E2) on angiotensin converting enzyme-angiotensin II-angiotensin type 1 receptor (ACE-Ang II-AT1) axis in hypoxic pulmonary hypertension rats. A total of 60 healthy female Sprague-Dawdley (SD) rats were divided randomly into 6 groups (n = 10 each) of sham operation, pure ovariectomy (OVX), pure hypoxia,OVX+hypoxia,OVX+E2 and OVX+hypoxia+E2. Abdominal cavity was opened for sham operation group and bilateral ovaries were left intact without any other procedure. The pure OVX group underwent oophorectomy. The pure hypoxia group were placed into a low-oxygen environment (24 hour, 8 weeks). The OVX+hypoxia group were placed into a low-oxygen environment after bilateral oophorectomy. The OVX+E2 group received a subcutaneous injection of E2 (20 µg×kg(-1)×d(-1)) after bilateral oophorectomy. The OVX+hypoxia+E2 group had an injection of E2 and was placed into a low-oxygen environment after bilateral oophorectomy. The rats were feed continuously for 8 weeks to establish hypoxic pulmonary hypertension model. The mean pulmonary artery pressure (mPAP) was measured after bloodletting. Then right ventricle hypertrophy index (RVHI) and hematoxylin-eosin pulmonary artery remodeling (HPSR) were observed. And electron microscope was employed to observe pulmonary arteriolar ultrastructure. The methods of radio-immunity assay, ultraviolet spectroscopy, Western blot and reverse transcription PCR were used to measure the levels of CE,Ang II and AT1 in sera, lung and pulmonary artery. The vascular walls of pure hypoxia and OVX+hypoxia groups became thickened and lumen narrowed.mPAP and RVHI were (32.4 ± 2.2) mmHg (1 mmHg = 0.133 kPa),0.331 ± 0.032 and (37.9 ± 1.6) mmHg,0.433 ± 0.033. Both were significantly higher than those of Sham operation group ((12.6 ± 1.8) mmHg,0.233 ± 0.029) (both P < 0.05); the above parameters of OVX+Hypoxia+E2 group changed little. And mPAP ((26.1 ± 1.4) mmHg) was significantly higher than that in sham operation group (P < 0.05) while the difference in RVHI between OVX+ Hypoxia+ E2 (0.267 ± 0.040) and sham operation groups had no statistical significance (P > 0.05). Compared with Sham operation group, the expression levels of ACE,Ang II and AT1 in pure OVX, pure hypoxia and OVX+ hypoxia groups rose markedly (all P < 0.05).However, the OVX+E2 and OVX+ hypoxia+E2 groups had no obvious change (all P > 0.05). The intervention effect of E2 for hypoxic pulmonary hypertension may be partly mediated by the down-regulated expressions of ACE and AT1 in lung tissue resulting in the reduced activity of ACE-AngII-AT1 axis.

Evaluating use of the Siebens Domain Management Model during inpatient rehabilitation to increase functional independence and discharge rate to home in stroke patients. To evaluate use of the Siebens Domain Management Model (SDMM) during stroke inpatient rehabilitation (IR) to increase functional independence and rate of discharge to home. Before and after study. IR facility. Before the intervention: 154 patients with ischemic/hemorrhagic strokes who were admitted to an IR facility in 2010; on average, they were admitted 9.1 days after receiving acute care. After the intervention: 151 patients with ischemic/hemorrhagic strokes who were admitted to an IR facility in 2012; on average they were admitted 7.3 days after receiving acute care. The comorbidity tier severity and prestroke living setting and living support appeared to be similar in both the preintervention and postintervention groups. Use of the SDMM involving weekly adjustments of IR care focused on potential barriers to discharge home including medical/surgical issues, cognitive/emotional coping issues, physical function, and living environment/community re-entry needs. Use of Functional Independence Measure (FIM) score change during IR length of stay (LOS; FIM-LOS efficiency) and rates of discharge to community/home, acute care, and long-term care (LTC) to compare 2010/preintervention data with postintervention data from 2012, along with comparison of facility data to national aggregate data from the Uniform Data System for Medical Rehabilitation (UDSMR) for both years. Preintervention 2010 FIM-LOS efficiency was 1.44 compared with a 2012 postintervention FIM-LOS efficiency of 2.24, which was significant (t = 4.3; P < .0001). Comparison of the UDSMR 2012 national FIM-LOS efficiency score (1.72) to the 2012 postintervention score of 2.24 reached significance (t = 2.6; P < .01). In addition, a significant difference was found between groups for discharge location: In the preintervention group, 57.8% were discharged to home/community, 14.9% to LTC, and 27.3% back to acute care compared with the postintervention group, in which 81.2% were discharged to home/community, 9.4% to LTC, and 9.4% back to acute care (χ(2) = 8.98; P < .001). Also significant was comparison between the 2012 postintervention group and the 2012 national UDSMR data for the same 3 discharge locations (χ(2) = 3.94; P < .05). Comparison of 2010 to 2012 facility data then shows a 23.4% increase in discharge to the community compared with an increase of 5.8% for the UDSMR 2010 to 2012 data, representing a community discharge rate that is 4 times greater for the 2012 facility postintervention group (χ(2) = 83.596; P < .0001). Use of the SDMM during stroke IR may convey improvement in functional independence and is associated with an increased discharge rate to home/community and a reduction in institutionalization and acute-care transfers.

Selection criteria for internal rectal prolapse repair by Delorme's transrectal excision. The aim of this study was to review our results of Delorme's transrectal excision for internal rectal prolapse, with a view to determining preoperative selection criteria associated with a satisfactory outcome. Between 1992 and 1998, 20 patients with internal rectal prolapse underwent Delorme's transrectal excision. The last patient was excluded from the study because of a follow-up period shorter than six months. The remaining 19 patients were prospectively followed up and classified into two groups according to their preoperative selection criteria. Group I consisted of eight patients operated on between January 1992 and October 1993 who were selected for surgery after medical treatment during a three-month period failed to improve symptoms. Initial results were reviewed, with a follow-up of at least six months, to assess predictive criteria correlating with poorer surgical outcome. These adverse criteria were used to exclude patients from selection into Group II, which included 11 patients operated on between June 1994 and June 1997. In each group the degree of improvement of symptoms was graded: Grade 1 = complete improvement with resolution of all symptoms; Grade 2 = significant improvement with resolution of dyschezia but not of other symptoms; Grade 3 = no improvement; and Grade 4 = worsened condition or reoperation. The two groups were compared according to ultimate outcomes. Of the Group I patients, three had preoperative chronic diarrhea, one had proximal internal rectal prolapse with rectosacral separation at defecography, and the other two were incontinent to liquid stool. An additional patient had incontinence to liquid stool but no diarrhea. Three other patients had major perineal descent (>9 cm). Results were Grade 1 for one patient, Grade 2 for one patient, Grade 3 for five patients, and Grade 4 for one patient (subsequent abdominal rectopexy). Data review showed that proximal internal prolapse with rectosacral separation at defecography, preoperative chronic diarrhea, fecal incontinence, and descending perineum (>9 cm on straining) were associated with a poorer outcome (Grades 3 and 4). These adverse criteria were used to exclude patients from selection into Group II. In this group results were Grade 1 for seven patients and Grade 2 for four patients. During the course of follow-up (mean, 43; standard deviation, 19; range, 8-73 months), outcome was better in Group II (P = 0.007). CONCLUSION. These data suggest that a favorable outcome can be achieved after Delorme's transrectal excision for internal rectal prolapse by applying stringent patient-selection criteria.

Renal epithelioid angiomyolipoma with atypia: a series of 40 cases with emphasis on clinicopathologic prognostic indicators of malignancy. As epithelioid cellular morphology can be seen in clinically benign usual angiomyolipomas (AMLs), we divide epithelioid AMLs into those without and with atypia, the latter category associated in the literature with malignant potential. We herein report the histologic spectrum and biologic behavior of 40 consecutive cases of epithelioid AML with atypia and assess whether cases can be stratified prognostically based on clinical and pathologic features. Atypical epithelioid cells were defined as atypical polygonal cells with abundant cytoplasm, vesicular nuclei, prominent nucleoli, and nuclear size that exceeds x2 the size of adjacent nuclei. The degree of atypia was divided to moderate and severe. Cases with bland epithelioid cells with minimal variation in nuclear size were not included. Mean age was 50.5 years (range 17 to 81), and the female to male ratio was 1.6:1. Average tumor size was 7.2 cm (range 1.0 to 17.7). The percentage of epithelioid component ranged from 5%-100% (mean 68%). Of the epithelioid component, the percentage of cells exhibiting nuclear atypia ranged in individual cases from 5% to 100% (mean of 58.4% atypical cells); 26/40 (65%) cases showed severe nuclear atypia. Cells displaying severe nuclear atypia were typically of large size with abundant cytoplasm, compared with those with moderate atypia being of small to intermediate in size with scant to moderate amount of cytoplasm. Neoplastic multinucleated giant cells and necrosis was present in 22 cases (55%) and 15 cases (37.5%), respectively. Mitoses were identified in 72.5% (29/40) of cases and ranged from 1 to 6 per 10 hpf with 7 cases showing atypical mitotic figures. Lymphovascular invasion or renal vein invasion was present in 3 cases each. Hilar and perinephric fat involvement was present in 5 and 6 cases, respectively. Clinical follow-up was available in 34 out of the 40 cases. Of the 34 cases, 9 (26%) were malignant and showed local recurrence or distant metastases. Of the 9 patients with malignant tumors, 4 died of the disease at 6, 12, 15, and 34 months after the original diagnosis was rendered, and 4 were alive with disease (mean follow-up period of 52 mo, range 24 to 72 mo). Twenty-four patients showed no evidence of recurrence and/or metastases with a mean follow-up period of 34 months (range 1 to 156 mo). We compared the 21 cases of atypical epithelioid AMLs that exhibited a benign clinical course with a minimum follow-up period of 6 months postsurgery to the 9 cases with malignant behavior. All of these were more frequently observed in clinically malignant cases: older age, larger tumor size, higher percentage of epithelioid component, severe atypia, higher percentage of atypical cells, higher mitotic count, atypical mitotic figures, necrosis, lymphovascular invasion, and renal vein invasion. Using these features, we developed a predictive model of 4 atypical features that included: (1) > or =70% atypical epithelioid cells, (2) > or =2 mitotic figures per 10 hpf, (3) atypical mitotic figures, and (4) necrosis; the presence of 3 or all of the features was highly predictive of malignant behavior. This model accurately categorized 78% of clinically malignant and 100% of the clinically benign epithelioid AMLs with atypia.

The assessment of body sway and the choice of the stability parameter(s). This methodological study aims at comparison of the practical usefulness of several parameters of body sway derived from recordings of the center of pressure (CoP) with the aid of a static force platform as proposed in the literature. These included: mean displacement velocity, maximal range of movement along x- and y-co-ordinates, movement area, planar deviation, phase plane parameter of Riley and the parameters of the diffusion stabilogram according to Collins. They were compared in over 850 experiments in a group of young healthy subjects (n = 10, age 21-45 years), a group of elderly healthy (n = 38, age 61-78 years) and two groups of elderly subjects (n = 10 and n = 21, age 65-89 years) with stability problems under different conditions known to interfere with stability as compared to standing with open eyes fixing a visual anchoring point: closing the eyes, standing on plastic foam in stead of a firm surface and performing a cognitive task: the modified stroop test. A force platform (Kistler) was used and co-ordinates of the body's center of pressure were recorded during 60 s of quiet barefoot standing with a sampling frequency of 10 Hz. In general, the results show important overlapping among groups and test conditions. Mean displacement velocity shows the most consistent differences between test situations, health conditions and age ranges, but is not affected by an extra cognitive task in healthy old people. Mean maximal sideways sway range is different among groups and test conditions except for the cognitive task in young and elderly subjects. Standardised displacement parameters such as standard deviations of displacements and planar deviation discriminate less well than the actual range of motion or the velocity. The critical time interval derived from the diffusion stabilogram according to Collins et al. seems to add a specific type of information since it shows significant influence from addition of a cognitive task in old subjects standing on a firm surface but not when standing on plastic foam. The critical time interval shows no consistent relation to any other parameter. The influence of cognitive activity on balance merits further exploration. A new parameter, sum of maximal deviation time (SDT) was proposed showing complete discrimination between frail elderly and other old subjects when obtained while visual input was suppressed. It was concluded that mean displacement velocity seems to be the most informative parameter in most situations.

The Role of Metformin in Metformin-Associated Lactic Acidosis (MALA): Case Series and Formulation of a Model of Pathogenesis. Lactic acidosis is an adverse event associated with metformin usage. Patients with metformin-associated lactic acidosis (MALA), however, often have other conditions contributing to the event. The relative contribution of metformin is often unclear. MALA is usually diagnosed without measuring the plasma concentrations of metformin. The objectives of this study were, first, to examine the plasma concentrations of metformin, lactate and creatinine and the arterial pH of patients with suspected MALA and, second, to review critically the mechanisms of MALA. Patients who were suspected of having MALA were identified during the period October 2008-September 2011. Repeated blood samples were collected to determine the plasma concentrations of lactate, metformin and creatinine. The pH of arterial blood was also measured on several occasions in each patient. Patients (n = 15; 9 female, 6 male) were 70 ± 12 years of age. There was one acute metformin overdose (estimated dose 5 g). Metformin was undetectable in one patient and one patient had therapeutic concentrations of metformin on admission (<5 mg/L). There were ten patients with chronic kidney disease, whereby the estimated glomerular filtration rate (eGFR) was less than 60 mL/min/1.73 m(2) before the acidotic event. Metformin doses ranged from 1 to 3 g daily (excluding the deliberate overdose). On admission, the mean plasma concentration of metformin on admission was 29.8 ± 19.1 mg/L (mean ± SD), the mean lactate concentration was 12.9 ± 6.1 mmol/L and the mean pH was 7 ± 0.2. The mean creatinine concentration on admission was 481 ± 225 μmol/L. The main pre-admission symptoms were vomiting and diarrhoea (n = 12). There were linear relationships between venous lactate, venous creatinine and arterial pH, with the venous plasma concentrations of metformin in most patients. Three patients died but metformin was unlikely to have been a significant factor. Most patients with MALA presented to the hospital with high metformin concentrations. The following factors appear to have been involved in the development of MALA in these patients: vomiting and diarrhoea, acute kidney injury, high doses or excessive accumulation of metformin, and acute disease states leading to tissue hypoxia. The extent of metformin accumulation in patients with MALA can be determined by investigating the concentrations of metformin. We suggest that the development of MALA is due to a positive feedback system involving one or more of these factors. While nausea is a common adverse effect of metformin, vomiting and diarrhoea out of the ordinary is a clear first sign of MALA. In this condition, dosage with metformin should be stopped and patients should receive urgent medical attention.

ECG-correlated image reconstruction from subsecond multi-slice spiral CT scans of the heart. Subsecond spiral computed tomography (CT) offers great potential for improving heart imaging. The new multi-row detector technology adds significantly to this potential. We therefore developed and validated dedicated cardiac reconstruction algorithms for imaging the heart with subsecond multi-slice spiral CT utilizing electrocardiogram (ECG) information. The single-slice cardiac z-interpolation algorithms 180 degrees CI and 180 degrees CD [Med. Phys. 25, 2417-2431 (1998)] were generalized to allow imaging of the heart for M-slice scanners. Two classes of algorithms were investigated: 180 degrees MCD (multi-slice cardio delta), a partial scan reconstruction of 180 degrees + delta data with a < phi (fan angle) resulting in effective scan times of 250 ms (central ray) when a 0.5 s rotation mode is available, and 180 degrees MCI (multi-slice cardio interpolation), a piecewise weighted interpolation between successive spiral data segments belonging to the same heart phase, potentially providing a relative temporal resolution of 12.5% of the heart cycle when a four-slice scanner is used and the table increment is chosen to be greater than or equal to the collimated slice thickness. Data segments are selected by correlation with the simultaneously recorded ECG signal. Theoretical studies, computer simulations, as well as patient measurements were carried out for a multi-slice scanner providing M = 4 slices to evaluate these new approaches and determine the optimal scan protocol. Both algorithms, 180 degrees MCD and 180 degrees MCI, provide significant improvements in image quality, including extremely arythmic cases. Artifacts in the reconstructed images as well as in 3D displays such as multiplanar reformations were largely reduced as compared to the standard z-interpolation algorithm 180 degrees MLI (multi-slice linear interpolation). Image quality appears adequate for precise calcium scoring and CT angiography of the coronary arteries with conventional subsecond multislice spiral CT. It turned out that for heart rates fH > or = 70 min(-1) the partial scan approach 180 degrees MCD yields unsatisfactory results as compared to 180 degrees MCI. Our theoretical considerations show that a freely selectable scanner rotation time chosen as a function of the patient's heart rate, would further improve the relative temporal resolution and thus further reduce motion artifacts. In our case an additional 0.6 s mode besides the available 0.5 s mode would be very helpful. Moreover, if technically feasible, lower rotation times such as 0.3 s or even less would result in improved image quality. The use of multi-slice techniques for cardiac CT together with the new z-interpolation methods improves the quality of heart imaging significantly. The high temporal resolution of 180 degrees MCI is adequate for spatial and temporal tracking of anatomic structures of the heart (4D reconstruction).

Relative growth of the limbs and trunk in sifakas: heterochronic, ecological, and functional considerations. Limb, trunk, and body weight measurements were obtained for growth series of Milne-Edwards's diademed sifaka, Propithecus diadema edwardsi, and the golden-crowned sifaka, Propithecus tattersalli. Similar measures were obtained also for primarily adults of two subspecies of the western sifaka: Propithecus verreauxi coquereli, Coquerel's sifaka, and Propithecus verreauxi verreauxi, Verreaux's sifaka. Ontogenetic series for the larger-bodied P. d. edwardsi and the smaller-bodied P. tattersalli were compared to evaluate whether species-level differences in body proportions result from the differential extension of common patterns of relative growth. In bivariate plots, both subspecies of P. verreauxi were included to examine whether these taxa also lie along a growth trajectory common to all sifakas. Analyses of the data indicate that postcranial proportions for sifakas are ontogenetically scaled, much as demonstrated previously with cranial dimensions for all three species (Ravosa, 1992). As such, P. d. edwardsi apparently develops larger overall size primarily by growing at a faster rate, but not for a longer duration of time, than P. tattersalli and P. verreauxi; this is similar to results based on cranial data. A consideration of Malagasy lemur ecology suggests that regional differences in forage quality and resource availability have strongly influenced the evolutionary development of body-size variation in sifakas. On one hand, the rainforest environment of P. d. edwardsi imposes greater selective pressures for larger body size than the dry-forest environment of P. tattersalli and P. v. coquereli, or the semi-arid climate of P. v. verreauxi. On the other hand, as progressively smaller-bodied adult sifakas are located in the east, west, and northwest, this apparently supports suggestions that adult body size is set by dry-season constraints on food quality and distribution (i.e., smaller taxa are located in more seasonal habitats such as the west and northeast). Moreover, the fact that body-size differentiation occurs primarily via differences in growth rate is also due apparently to differences in resource seasonality (and juvenile mortality risk in turn) between the eastern rainforest and the more temperate northeast and west. Most scaling coefficients for both arm and leg growth range from slight negative allometry to slight positive allometry. Given the low intermembral index for sifakas, which is also an adaptation for propulsive hindlimb-dominated jumping, this suggests that differences in adult limb proportions are largely set prenatally rather than being achieved via higher rates of postnatal hindlimb growth.(ABSTRACT TRUNCATED AT 400 WORDS)

[Influence of surgery and radiotherapy on growth and pubertal development in children treated for brain tumour]. The increasing number of childhood cancer survivors has resulted in a growing interest in the late effects, which depend on type of treatment. Frequently, a brain tumour and its therapy in children are endocrinologically devastating. The aim of study was to compare growth and pubertal development in children after brain tumour therapy treated or not treated with recombinant growth hormone (rGH). 18 children were included in this study. Group I - (12/18) not treated with rGH, after total resection of brain tumour: craniopharyngeoma (8/12), astrocytoma (2/12) ependymoma (1/12), germinoma (1/12). Mean time of remission was 5,0yrs (+/- 0,9). Group II - (6/12) treated with rGH, after subtotal resection of craniopharyngeoma (4/6), ependymoma (1/6), medulloblastoma (1/6) and cranial irradiation with mean total doses 46,5 Gy (+/- 5,65). Children were qualified for rGH replacement according to deceleration of growth and lower growth hormone secretion (< 10 ng/ml) in stimulating tests. Mean time of remission was 6,5 yrs (+/- 2,41). Growth, height in centimeters converted to standard deviation score--SDS, body mass index (BMI), pubertal status and hormonal tests, were also evaluated. All patients were treated with surgery with no cranial irradiation in prepubertal age. 100% children of group I needed substitution because of secondary hypothyreosis, 83% due to secondary adrenal insufficiency and 53% of diabetes insipidus. Mean height after brain tumour surgical treatment in group I was - 1,24 SDS (+/- 0,85) and did not significantly change in the time of observation. Two girls needed hormonal substitution for hypogonadotropic hypogonadism. Mean BMI after total resection of brain tumour was 18,09 (+/- 4,20) and significantly increased to 23,73 (+/- 2,82). In group II - all children presented multihormonal pituitary insufficiency. Mean deviation score of height before rGH treatment was - 3,84 SDS (+/- 2,87) and after mean time of rGH therapy of 1,5 yrs (+/- 1,2) decreased to 2,6 (+/- 1,06). Mean BMI before treatment with rGH 18, 06 (+/- 4,4) increased to 22,41 (+ 0,74) in the time of observation and decreased to 18,5 (+/- 2,87) after 1,5 years (+/- 1,2) of rGH treatment. 1. Children treated with surgery for brain tumour need substitution for secondary hypothyroidism, part of then need treatment for secondary adrenal and gonadal insufficiency and diabetes incipidus. 2. Children who were treated with surgery and/or cranial irradiation developed multihormonal pituitary insufficiency, growth failure and replacement rGh therapy was needed. 3. Total resection of brain tumour without chemo- and radiotherapy did not impair growth in first years after surgery.

Early weight bearing versus delayed weight bearing in medial opening wedge high tibial osteotomy: a randomized controlled trial. The need for a period of non-weight bearing after medial opening wedge high tibial osteotomy remains controversial. It is hypothesized that immediate weight bearing after medial opening wedge high tibial osteotomy would have no difference in functional scores at one year compared to delayed weight bearing. Fifty patients, median age 54 years (range 40-65), with medial compartment osteoarthritis, underwent a medial opening wedge high tibial osteotomy utilizing a locking plate without bone grafting. Patients were randomized into an Immediate or a Delayed (2 months) weight bearing group. All patients were assessed at one-year follow-up and the two groups compared. The primary outcome measure was the IKS score. Secondary outcome measures included the IKDC score, the VAS pain score and rate of complications. The functional scores significantly improved in both groups. The IKS score increased from 142 ± 31 to 171 ± 26 in the Immediate group (p < 0.001) and from 148 ± 22 to 178 ± 23 in the Delayed group (p < 0.001). The IKDC score increased from 49 ± 17 pre-operatively to 68 ± 14 one-year post-operatively in the Immediate group (p < 0.0001) and from 44 ± 16 to 69 ± 19 in the Delayed group (p < 0.001). The average VAS for pain 2 months after surgery was 3 ± 3 in the Immediate group and 3 ± 2 in the Delayed (n.s.). There was no significant difference between the two groups in any of the outcome measures. The mean mechanical femorotibial angle changed from 6° of varus (0°-15° of varus, SD = 3°) to 4° of valgus (5°-11° of valgus, SD = 3°) in the Immediate group and from 5° of varus (0°-10° of varus, SD = 3°) to 3° of valgus (2° of varus to 8° of valgus, SD = 3°) in the Delayed group. No difference was seen between groups, and no loss of correction was observed in any patient. Two cases of non-union occurred, one in each group. One infection and one deep vein thrombosis occurred in the Immediate group. Immediate weight bearing after medial opening wedge high tibial osteotomy had no effect on functional scores at 1 year follow-up and did not significantly increase the complication rate. Immediate weight bearing after medial opening wedge high tibial osteotomy appears to be safe and can allow some patients a quicker return to activities of daily living and a decreased convalescence period. II.

Personalized dosimetry with intensification using 90Y-loaded glass microsphere radioembolization induces prolonged overall survival in hepatocellular carcinoma patients with portal vein thrombosis. The objective of this study was to evaluate the response rate and survival of hepatocellular carcinoma portal vein thrombosis (PVT) patients treated with (90)Y-loaded glass microspheres using a personalized dosimetry and intensification concept. The microspheres were administered to 41 hepatocellular carcinoma PVT patients (main = 12; lobar/segmental = 29). (99m)Tc-macroaggregated albumin SPECT/CT quantitative analysis was used to calculate the tumor dose (TD), healthy injected liver dose (HILD), and injected liver dose (ILD). Response was evaluated at 3 mo using the criteria of the European Association for the Study of the Liver, with CT follow-up lasting until disease progression or death. Survival was assessed using the Kaplan-Meier method. The mean injected activity was 3.1 ± 1.5 GBq, and mean ILD was 143 ± 49 Gy. When a TD threshold of 205 Gy was applied, (99m)Tc-macroaggregated albumin SPECT/CT achieved a 100% sensitivity and 90% overall accuracy (0 false-negatives; 4 false-positives) in response prediction. On the basis of TD and HILD values, 37% of patients received an intensification of the treatment (increased injected activity with the aim of achieving a TD ≥ 205 Gy and HILD < 120 Gy, applying an ILD > 150 Gy). This intensification resulted in a high response rate (85%) without increased liver toxicity of grade 3 or higher (6% vs. 12% in the patients who did not receive treatment intensification; not statistically significant). For the total 41 patients, median overall survival (OS) was 18 mo (95% confidence interval, 11-25 mo). For patients with a TD of less than 205 Gy, median OS was 4.3 mo (3.7-5 mo), versus 18.2 mo (8.5-28.7 mo) for those with a TD of 205 Gy or more (P = 0.005). Median OS was 20.9 mo for patients with a TD of 205 Gy or more and good PVT targeting (n = 36). OS was 12 mo (3 mo to ∞) for patients with main PVT, versus 21.5 mo (12-28.7 mo) for those with segmental or lobar PVT (not statistically significant). For the 5 patients with complete portal vein revascularization who underwent lobar hepatectomy, median OS was not reached yet exceeded 24.5 mo and was significantly higher than that of other patients (P = 0.0493). Using a (99m)Tc-macroaggregated albumin SPECT/CT personalized dosimetry and intensification concept with (90)Y-loaded glass microspheres induced prolonged OS for PVT patients as compared with the standard of care (sorafenib), without increasing liver toxicity. Prospective randomized studies are therefore warranted.

Modulatory effects of regional cortical activation on the onset responses of the cat medial geniculate neurons. Corticofugal modulation on activity of the medial geniculate body (MGB) was examined by locally activating the primary auditory cortex (AI) and looking for effects on the onset responses of MGB neurons to acoustic stimuli. Of 103 MGB neurons recorded from 13 hemispheres of 11 animals, 91 neurons (88%) showed either a facilitatory or inhibitory effect or both; of these neurons, 72 showed facilitatory effects and 25 inhibitory effects. The average facilitatory effect was large, with a mean increase of 62.4%. Small inhibitory effects (mean: -16.2%) were obtained from a few neurons (6 of 103) when a pure tone stimulus was used, whereas the effect became larger and more frequent when a noise burst stimulus was used (mean: -27.3%, n = 22 of 27 neurons). Activation of an AI site having the same best frequency (BF) as the MGB neuron being recorded from produced mainly a facilitatory effect on MGB neuronal responses to pure tones. Activation of AI at a site neighboring the BF site produced inhibitory effects on the MGB response when noise burst stimuli were used. We found that the effective stimulation sites in AI that could modulate MGB activity formed patchlike maps with a diameter of 1.13 +/- 0.09 (SE) mm (range 0.6-1.9 mm, n = 15) being larger than the patches of thalamocortical terminal fields. Examining the effects of sound intensities, of 18 neurons tested 9 neurons showed a larger effect for low-sound-intensity stimuli and small or no effects for high-sound-intensity stimuli. These were named low-sound-intensity effective neurons. Five neurons showed high sound intensity effectiveness and four were non-intensity specific. Most low-sound-intensity effective neurons were monotonic rate-intensity function neurons. The AI cortical modulatory effect was frequency specific, because 15 of 27 neurons showed a larger facilitatory effect when a BF stimulus was used rather than a stimulus of any other frequency. The corticothalamic connection between the recording site in MGB and the most effective stimulation site in AI was confirmed by injecting wheat germ agglutinin-horseradish peroxidase tracer at the stimulation site and producing a small lesion in the recording site. The results suggest that 1) the large facilitation effects obtained by AI activation at the region that directly projected to the MGB could be the result mainly of the direct projection terminals to the MGB relay neurons; 2) the large size patches of the effective stimulation site in AI could be due to widely ramifying corticothalamic projections; and 3) the corticofugal projection selectively gates auditory information mainly by a facilitatory effect, although there is also an inhibitory effect that depends on the sound stimulus used.

The Impact of Caregivers' Anxiety on Patients' Anxiety before Fast-Track Knee Arthroplasty. PURPOSE OF THE STUDY Anxiety may have negative repercussions on the surgery including poorer outcomes. On the other hand, the majority of patients reporting preoperative anxiety fear not receiving enough attention from a caregiver. In patients undergoing fast-track knee arthroplasty, we determined the relationship between patients' preoperative anxiety and the anxiety the patient's caregiver. We also analyzed the influence of selected psychosocial and demographic variables on the relationship between caregivers' and patients' anxiety. MATERIAL AND METHODS We conducted a prospective, descriptive study in which baseline assessments of patients scheduled to undergo fast-track total knee arthroplasty between 1st November 2014 and 30th April 2015 were compared with those of their caregivers. Patients were recruited from a large teaching hospital through the orthopedics joint replacement clinic. Information on sex, age, body mass index (BMI), educational status, employment status, marital status, and living status was recorded for all patients. Patients and their caregivers completed the Spielberger State-Trait Anxiety Inventory. Baseline trait anxiety was assessed with STAI scores in the initial interview, 2 weeks before hospitalization, and state anxiety was assessed the day before the surgery. The patients' caregivers were contacted during a scheduled postoperative clinic visit and asked to complete the STAI and to provide information on their age, degree of consanguinity with patient, and living status. RESULTS The mean age was 66.4 years for the 118 patients and 55.7 years for the 93 caregivers. In male caregivers, caregiver anxiety and patient anxiety were positively related but not statistically so, and in women was not significant. In male patients, a relationship between caregiver's anxiety and patient's anxiety was positive, although not statistically significant, and in women was neither present nor significant. DISCUSSION Given the widespread impacts of anxiety before knee arthroplasty, it is critical for surgeons to gain a better understanding of how to identify and reduce preoperative anxiety in operated patients. We found that male sex among caregivers was associated with more preoperative anxiety among patients than was female sex and that male patients more quickly accepted anxiety from their caregivers than did female patients. CONCLUSIONS Anxious male caregivers appear to impart their anxiety to male patients but not to female patients. The anxiety of unrelated caregivers is associated with low preoperative anxiety among patients. Preoperative interventions should focus on caregivers, especially male caregivers, and to related caregivers to help patients cope with anxiety before knee arthroplasty. Key words: knee arthroplasty. knee replacement. fast track, anxiety, caregiver, preoperative stress.

Vascular surgery and the Internet: a poor source of patient-oriented information. Increasing numbers of patients use the Internet to obtain medical information. The Internet is easily accessible, but available information is under no guidelines or regulations. We sought to evaluate the type, quality, and focus of vascular disease information presented on the Internet and the role in patient education with simple search techniques. The arbitrarily chosen search phrases "abdominal aortic aneurysm (AAA)," "carotid surgery (CEA)," "claudication surgery," and "leg gangrene surgery" were entered into five common Internet search engines. No attempt was made to refine searches. As indicated by the search engines, the 50 most commonly encountered web sites for both AAA and CEA were reviewed. The first 25 claudication sites and the first 25 gangrene sites were combined for a total of 50 leg ischemia (LIS) sites. An information score (IS) was developed as a weighted score ranging from 0 (poor) to 100 (outstanding) and was designed to assess how well the web page educated the patient about the disease, the treatment options, and the medical and surgical complications. Each vascular surgery web site was classified according to the author, the referenced information source, and the therapeutic recommendations. This was followed by an evaluation of each web site with the IS independently scored by two observers. Of the 150 web sites, 146 were accessible. Ninety-six sites (65.8%) had no useful patient-oriented information (IS < 10). The mean IS and the ranges were: AAA, 14.9 (0 to 72.0); CEA, 17.5 (0 to 77.0); and LIS, 12.2 (0 to 44.5; P =.9). The mean IS of the 59 sites with scores of more than 10 were: AAA, 39.8 (n = 17); CEA, 44.8 (n = 19); and LIS, 24.8 (n = 23; P <.01, as compared with LIS scores). Differences in IS between observers were not significant (P =.9). Misleading or unconventional care recommendations were recognized in one AAA site (1 of 47, 2.1%), two CEA sites (2 of 49, 4.1%), and 13 LIS sites (13 of 50, 26.0%). The Joint Vascular Societies web page was identified only as a tertiary link. Patient-oriented vascular surgery information, for common vascular diseases, is difficult to find on the Internet. The overall quality is poor, and information is difficult to obtain in part because of the large number of irrelevant sites. Of the sites that were relevant to patient education (33%), one third presented information that was classified by the authors as misleading or unconventional. This was most apparent in the leg ischemia sites. The Internet is a poor overall source of patient-oriented vascular surgery information and education. Focused and refined searches and improvements in search engines and educational web sites may yield improved information. Public and medical community awareness needs to be improved regarding the severe limitations of the Internet as an information resource.

The biology of some intraerythrocytic parasites of fishes, amphibia and reptiles. Fishes, amphibia and reptiles, the ectothermic vertebrates, are hosts for a variety of intraerythrocytic parasites including protists, prokaryotes, viruses and structures of uncertain status. These parasites may experience host temperature fluctuations, host reproductive strategies, population genetics, host habitat and migratory behaviour quite unlike those of endothermic hosts. Few blood infections of fishes, amphibia and reptiles have proven pathogenicity, in contrast to the many intraerythrocytic parasites of mammals and some birds which harm their hosts. Although not given the attention afforded to intraerythrocytic parasites of endotherms, those of ectotherms have been studied for more than a century. This review reports on the diversity, general biology and phylogeny of intraerythrocytic parasites of ectotherms. The existence of taxonomic confusion is emphasized and the main taxonomic features of most of the 23 better characterized genera, particularly the kinetoplastid and apicomplexan protists, are summarized. Transmission of protistan infections of aquatic ectotherms is also discussed. Leeches can transfer sporozoties or merozoites to the vertebrate host during feeding. Dormant sporozoites of Lankesterella may permit transmission of species of this genus between vertebrates by predation. The fish haemogregarine, Haemogregarina bigemina, probably has gnathiid isopods, rather than leeches, as its definitive hosts. Hepatozoon spp. in aquatic hosts, and Progarnia of caiman, may also use invertebrate hosts other than leeches. Protistan infections of terrestrial or semi-terrestrial hosts are transmitted by a variety of arthropods, or, in some cases, leeches, contaminated paratenic hosts, or sporocysts free in water. Transfer of protists between vertebrates by predation and congenitally may also occur. The biology of the host cells of these infections, the red blood cells of ectotherm vertebrates, is summarized and compared with that of mammalian erythrocytes. Erythropoiesis, the nature of the surface molecules (especially the possible existence of a major histocompatibility complex), the haemoglobins, and the shape and size of erythrocytes are discussed. The exoerythrocytic sites in which protists, prokaryotes, viruses and structures of uncertain status exist before erythrocyte entry are described. Tissue merogony, tissue cysts and invasion of the white cell series occur in a variety of protistan infections. Intraerythrocytic stages of protistan infections are also discussed, including modes of entry to erythrocytes, survival mechanisms, and multiplication. The impact of infection on host populations is difficult to assess, in part because there is no agreement in the literature on the criteria used to evaluate parasite-induced cost to the host. Almost all studies have been on haemogregarine and Plasmodium infections in, mainly, lizards, but also fishes and snakes. Some infections may be responsible for mortality in their hosts, but hosts themselves may be short-lived, or have a limited ability to recover from infection.

Boosted neural networks scoring functions for accurate ligand docking and ranking. Predicting the native poses of ligands correctly is one of the most important steps towards successful structure-based drug design. Binding affinities (BAs) estimated by traditional scoring functions (SFs) are typically used to score and rank-order poses to select the most promising conformation. This BA-based approach is widely applied and some success has been reported, but it is inconsistent and still far from perfect. The main reason for this is that SFs are trained on experimental BA values of only native poses found in co-crystallized structures of protein-ligand complexes (PLCs). However, during docking, they are needed to discriminate between native and decoy poses, a task for which they have not been specifically designed. To overcome this limitation, we propose to build task-specific SFs that model binding affinities (scoring task) as well as conformations (docking task) using the root mean square deviation (RMSD) of a ligand pose from the native pose. Our models are based on boosted ensembles of neural networks and other state-of-the-art machine learning (ML) algorithms in conjunction with multi-perspective interaction modeling techniques for accurate characterization of PLCs. We assess the docking and scoring/ranking accuracies of the proposed ML SFs as well as three conventional SFs in the context of the 2014 CSAR benchmark exercise that encompasses three high-quality protein systems and a diverse set of drug-like molecules. Our proposed docking-specific SFs provide a substantial improvement in the docking task. We find that RMSD-based SFs for BsN, an ensemble neural networks (NN) model based on boosting, and six other ML models provide more than 120% improvement, on average, over their BA-based counterparts. In terms of scoring/ranking accuracy, we find that the approach of using RMSD-based BsN to select the top ligand pose followed by applying BA-based BsN to rank ligands using predicted BA scores leads to consistent and correctly ranked ligands for the two protein targets Spleen Tyrosine Kinase (SYK) and tRNA (m1G37) methyltransferase (TrmD). In addition, the ensemble NN SF BsN is at least 250% more accurate than a single neural network (SNN) model. We further find that ensemble models based on NNs surpass SFs based on other state-of-the-art ML algorithms such as BRT, RF, SVM, and [Formula: see text]NN. Finally, our RF model fitted to PLCs characterized by multiple sets of descriptors from four different sources (X-Score, AffiScore, RF-Score, and GOLD) substantially outperforms the SF RF-Score that uses only one set of features, underlining the value of multi-perspective modeling.

Correlation between NDI, PROMIS and SF-12 in cervical spine surgery. As the focus in spine surgery has shifted from radiographic to patient-centric outcome, patient-reported outcomes measures (PROMs) are becoming increasingly important. They are linked to patient satisfaction, and are used to assess healthcare expenditure, determine compensation and evaluate cost-effectiveness. Thus, PROMs are important to various stakeholders, including patients, physicians, payers, and healthcare institutions. Thus, it is vital to establish methods to interpret and evaluate these outcome measures. To evaluate the correlation between Neck Disability Index (NDI), Patient Reported Outcome Measurement Information System Physical Function (PROMIS-PF) and Short Form-12 Physical Health Score (SF-12 PHS) in cervical spinal surgery in order to determine the validity of PROMIS-PF in these patients. Retrospective review of prospectively collected data. Consecutive patients who underwent cervical surgery for degenerative spinal pathology with a minimum of 3 months follow-up. Self-reported measures that is, PROMs including NDI, PROMIS-PF, and SF-12 PHS. No funding was received for this study. The authors report no relevant conflict of interest. PROM collected preoperatively and at each follow-up were analyzed using Pearson product-moment correlation. Of the 121 patients included, 66 underwent anterior cervical discectomy and fusion, 42 cervical disc replacement, 13 posterior cervical decompression with or without fusion. A statistically significant improvement was achieved in all PROMs by 6 weeks and maintained at 1 year. Furthermore, the percentage of patients achieving an improvement greater than minimum clinically important difference was similar for NDI and PROMIS-PF, particularly at a follow-up of 3 months or more. A statistically significant negative correlation was seen between NDI and PROMIS-PF, which was moderate preoperatively and in the early postoperative period (r=-0.565 to -0.600), and strong at 3 months or longer follow-up (r=-0.622 to -0.705). A statistically significant, negative correlation was also seen between SF-12 PHS and NDI, which was moderate preoperatively and at 6 weeks (r=-0.5551 to -0.566); and strong at all other time-points (r=-0.678 to -0.749). There was a statistically significant positive correlation between SF-12 PHS and PROMIS-PF, which was strong to very-strong at all time-points (r=0.644-0.822), except at 2 weeks (r=0.570). Although NDI and SF-12 have been used for several years, PROMIS is a new outcome measure that is increasingly being implemented. The results of our study demonstrate the convergent and discriminant validity of PROMIS-PF, supported by the strong correlation between SF-12 PHS and PROMIS-PF at all time-points and the moderate correlation between NDI and PROMIS-PF preoperatively and in the early postoperative period, respectively. Thus, while PROMIS-PF may not be a good surrogate for disease-specific outcome measures, it may extend value as a precise and efficient general health tool.

Continuous positive airway pressure in older people with obstructive sleep apnoea syndrome (PREDICT): a 12-month, multicentre, randomised trial. The therapeutic and economic benefits of continuous positive airway pressure (CPAP) for moderate to severe obstructive sleep apnoea (OSA) syndrome have been established in middle-aged people; however, the benefits in older people are unknown. This trial was designed to address this evidence gap. This 12-month, multicentre, randomised trial enrolled patients across 14 National Health Service sleep centres in the UK. Consecutive patients aged 65 years or older with newly diagnosed OSA syndrome were eligible to join the trial. Patients were randomly assigned (1:1) into parallel groups to receive either CPAP with best supportive care (BSC) or BSC alone for 12 months. Randomisation was done by the Medical Research Council Clinical Trials Unit with computer-generated randomisation. The main investigator at each centre was masked to the trial randomisation. Coprimary endpoints were Epworth sleepiness score (ESS) at 3 months and cost-effectiveness over the 12-month trial period. Secondary outcomes were subjective sleepiness at 12 months, plus objective sleepiness, quality of life, mood, functionality, nocturia, mobility, accidents, cognitive function, and cardiovascular risk factors and events at 3 months and 12 months. The analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN90464927. Between Feb 24, 2010, and May 30, 2012, 278 patients were randomly assigned to the trial, of whom 231 (83%) completed the trial. 140 patients were allocated to and received CPAP plus BSC and 138 were allocated to and received BSC only. CPAP reduced ESS by 2·1 points (95% CI -3·0 to -1·3; p<0·0001) at 3 months for 124 (89%) of 140 patients compared with 124 (90%) of 138 patients given BSC, and by 2·0 points (-2·8 to -1·2; p<0·0001) at 12 months for 116 patients compared with 122 patients given BSC. The effect was greater in patients with higher CPAP usage or higher baseline ESS. Quality-adjusted life-years were similar between the groups (treatment effect 0·01 (95% CI -0·03 to 0·04; p=0·787) and health-care costs were marginally reduced with CPAP (-£35, -390 to 321; p=0·847). CPAP improved objective sleepiness (p=0·024), mobility (p=0·029), total cholesterol (p=0·048), and LDL cholesterol (p=0·042) at 3 months, but these were not sustained at 12 months. Measures of mood, functionality, nocturia, accidents, cognitive function, and cardiovascular events remained unchanged. Systolic blood pressure fell in the BSC group. 37 serious adverse events occurred in the CPAP group, and 22 in BSC group; all were independently classified as being unrelated to the trial and no significant harm was attributed to CPAP use. In older people with OSA syndrome, CPAP reduces sleepiness and is marginally more cost effective over 12 months than is BSC alone. On the basis of these results, we recommend that CPAP treatment should be offered routinely to older patients with OSA syndrome. National Institute of Health Research (NIHR) Health Technology Assessment, NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.

Modified ultrafiltration improves left ventricular systolic function in infants after cardiopulmonary bypass. Our objective was to test the hypothesis that use of modified ultrafiltration after cardiopulmonary bypass improves intrinsic left ventricular systolic function in children. Twenty-one infants undergoing cardiopulmonary bypass were instrumented with ultrasonic dimension transducers, to measure the anteroposterior minor axis diameter, and a left ventricular micromanometer. Patients were randomized to modified ultrafiltration (n = 11, age 226 +/- 355 days, weight 6.7 +/- 3.1 kg) or control (n = 10, age 300 +/- 240 days, weight 7.0 +/- 2.5 kg) (all differences p > 0.05 between groups). Left ventricular systolic function was assessed by means of the slope of the preload-recruitable stroke work index. Myocardial cross-sectional area was measured by echocardiography. Data were acquired immediately after separation from bypass, at steady state, and during transient vena caval occlusion. Data acquisition was repeated after 13 +/- 5 minutes of modified ultrafiltration or after 12 +/- 5 minutes without modified ultrafiltration in the control group. Inotropic drug support was the same at both study points. In the modified ultrafiltration group, the filtrate volume was 363 +/- 262 ml. The hematocrit value increased from 26.0% +/- 2.7% to 36.7% +/- 9.5% (p = 0.018), myocardial cross-sectional area decreased from 3.72 +/- 0.35 cm2 to 3.63 +/- 0.36 cm2 (p = 0.04), end-diastolic length increased from 25.6 +/- 9.0 mm to 28.8 +/- 9.9 mm (p = 0.01), and end-diastolic pressure fell from 5.6 +/- 0.8 mm Hg to 4.2 +/- 0.8 mm Hg (p = 0.005), suggesting an improved diastolic compliance. In the control group, the hematocrit value, myocardial cross-sectional area, end-diastolic length, and pressure did not change (all p > 0.05). Mean ejection pressure increased in the ultrafiltration group (p = 0.001) but did not change in the control group (p = 0.22). The slope of the preload-recruitable stroke work index increased after ultrafiltration from 52.3 +/- 52.0 to 74.2 +/- 66.0 (10[3] erg/cm3) (p = 0.02) but did not change in the control group (p = 0.07). One patient from each group died in the postoperative period. Patients in the ultrafiltration group received less inotropic drug support in the first 24 hours after the operation (156.62 +/- 92.31 microg/kg in 24 hours) than patients in the control group (865.33 +/- 1772.26 microg/kg in 24 hours, p = 0.03). Use of modified ultrafiltration after cardiopulmonary bypass improves intrinsic left ventricular systolic function, improves diastolic compliance, increases blood pressure, and decreases inotropic drug use in the early postoperative period.

Examination of the effects of cholecystokinin 26-33 and neuropeptide Y on responses of visual cortical neurons of the cat. Extracellular recordings were made from 160 neurons in area 17 (n = 120) and area 18 (n = 40) of the visual cortex of anesthetized cats. Cells were classified according to their receptive field properties and their intracortical positions were evaluated histologically. Cholecystokinin 26-33, antagonists, (cholecystokinin 27-32, cholecystokinin 27-33 and proglumide), amino acids, neuropeptide Y and solvent vehicle (control), were administered to cells by microiontophoresis (cholecystokinin and neuropeptide Y) or by pressure (neuropeptide Y). The results of the tests with cholecystokinin 26-33 fell into four categories: enhancement (31%), suppression (24%), mixed, i.e. either biphasic responses or dose-related alterations in the direction of effect (20%), and no effect (25%). Enhancements of the visually elicited response were more prevalent in simple (43%) and unimodal/movement-sensitive (34%) cells than in complex (7%) cells. The converse was true for suppressions: 19% of simple cells, 24% of unimodal/movement-sensitive cells, and 31% of complex cells were suppressed. Thirty per cent of the unaffected cells were complex or unimodal/movement-sensitive; only 14% were simple. Cells in layers II-IV were more likely to have firing enhanced than suppressed by cholecystokinin 26-33. The converse was true for cells in layers V and VI, where 50% of responses were suppressed and only 22% were enhanced. Unaffected cells were found predominantly in layer III of areas 17, and the lower part of layer III and layer IV of area 18. Cholecystokinin 26-33 sometimes exerted delayed, response-suppressant effects; it also occasionally elevated responsiveness preferentially within the upper ranges (10-20 degrees/s) of velocity tuning curves. Cholecystokinin 26-33 altered the response-suppressant action of GABA in 11 of 19 visually sensitive cells. The peptide potentiated the visual responsiveness in half of the cells where cholecystokinin 26-33 diminished the GABA-induced suppressions (n = 8). The presumed antagonists either exerted no effect on firing or on cholecystokinin 26-33-induced effects, or had cholecystokinin 26-33-like actions themselves. There was a reversible partial antagonism of the effects of cholecystokinin 26-33 on only two of 11 cells tested. Neuropeptide Y injected by pressure or administered iontophoretically had variable and inconsistent effects on the visually evoked responses of 29 additional neurons from those described above. These effects were indistinguishable from those of the vehicle whether spontaneous activity, magnitude of the visually elicited response, spatial integrity of the RF substructure, orientation or velocity tuning was assessed.(ABSTRACT TRUNCATED AT 400 WORDS)

5-Aminolevulinic acid-based photodynamic therapy. Clinical research and future challenges. Photodynamic therapy (PDT) for cancer patients has developed into an important new clinical treatment modality in the past 25-years. PDT involves administration of a tumor-localizing photosensitizer or photosensitizer prodrug (5-aminolevulinic acid [ALA], a precursor in the heme biosynthetic pathway) and the subsequent activation of the photosensitizer by light. Although several photosensitizers other than ALA-derived protoprophyrin IX (PpIX) have been used in clinical PDT, ALA-based PDT has been the most active area of clinical PDT research during the past 5 years. Studies have shown that a higher accumulation of ALA-derived PpIX in rapidly proliferating cells may provide a biologic rationale for clinical use of ALA-based PDT and diagnosis. However, no review updating the clinical data has appeared so far. A review of recently published data on clinical ALA-based PDT and diagnosis was conducted. Several individual studies in which patients with primary nonmelanoma cutaneous tumors received topical ALA-based PDT have reported promising results, including outstanding cosmetic results. However, the modality with present protocols does not in general, appear to be superior to conventional therapies with respect to initial complete response rates and long term recurrence rates, particularly in the treatment of nodular skin tumors. Topical ALA-PDT does have the following advantages over conventional treatments: it is noninvasive; it produces excellent cosmetic results; it is well tolerated by patients; it can be used to treat multiple superficial lesions in short treatment sessions; it can be applied to patients who refuse surgery or have pacemakers and bleeding tendency; it can be used to treat lesions in specific locations, such as the oral mucosa or the genital area; it can be used as a palliative treatment; and it can be applied repeatedly without cumulative toxicity. Topical ALA-PDT also has potential as a treatment for nonneoplastic skin diseases. Systemic administration of ALA does not seem to be severely toxic, but the advantage of using this approach for PDT of superficial lesions of internal hollow organs is still uncertain. The ALA-derived porphyrin fluorescence technique would be useful in the diagnosis of superficial lesions of internal hollow organs. Promising results of ALA-based clinical PDT and diagnosis have been obtained. The modality has advantages over conventional treatments. However, some improvements need to be made, such as optimization of parameters of ALA-based PDT and diagnosis; increased tumor selectivity of ALA-derived PpIX; better understanding of light distribution in tissue: improvement of light dosimetry procedure; and development of simpler, cheaper, and more efficient light delivery systems.

[Lipoprotein (a)--a mysterious factor in atherogenesis]. Etiopathogenesis of arterial hypertension and coronary disease involves interaction of numerous exogenous factors which determine the clinical course and therapeutic response in genetically predisposed individuals. The role of numerous cardiovascular risk factors has been reevaluated during the past few years, yet some unresolved issues and gaps still remain. One of the still insufficiently studied factors is lipoprotein (a) [Lp (a)] which belongs to a subclass of LDL lipoproteins. Its important component is apolipoprotein (a) which is structurally similar to plasminogen. This characteristic can be followed through evolution and is probably crucial for its physiologic but also pathophysiologic role. Actually, through its competition with plasminogen, Lp (a) interferes with the process of fibrinolysis and may contribute to tissue healing and restoration but also support and accelerate atherothrombotic process. Lp (a) concentration is stable and genetically determined in an individual and the indication that persons with elevated levels are permanently exposed to increased risk is supported by the data on twofold incidence of myocardial infarction in mothers of children with highest Lp (a) concentrations. Apart from competing with plasminogen via apolipoprotein (a), Lp (a) increases the activity of inhibitors of plasminogen-I activator and reduces the activity of transforming growth factor-beta. This results both in the absence of fibrinolysis and promotion of migration and proliferation of media smooth muscle cells, which are important in the onset of atherosclerotic process. Lp (a) binds to elastin via apolipoprotein B, resulting in oxidation and facilitated entry into macrophages and their transition into the so-called foam cells, also an important sign of early atherosclerosis. Although many pathophysiologic processes by which Lp (a) contributes to atherosclerosis have also been confirmed by animal experiments as well as by the presence of histologic evidence, clinical significance of elevated Lp (a) concentration is still questionable. However, results of prospective studies and metaanalyses were published few months ago and identified decisively Lp (a) as a factor that increases cardiovascular risk primarily in patients in whom other risk factors were also present. According to currently prevailing attitude, routine determination of Lp (a) is not justified and, according to most authors, its determination is useful in patients who had a cardiovascular incident at the age under 55 years, in those with recurrent coronary stenosis, or those with positive family history of such incidents. As Lp (a) is genetically determined, its detection in the early stages of essential hypertension might be a useful prognostic marker but a period of observation is still necessary for correct selection of hypertensive patients. Apart from the observation that hormone replacement therapy significantly decreases the Lp (a) level, there is currently no information on the effectiveness of either dietary or drug therapy. Due to Lp (a) antifibrotic effects, small aspirin doses may be beneficial to these patients, as well as B complex vitamins since hyperhomocysteinemia enhances atherogenicity of Lp (a). Therapeutic approach to patient with increased Lp (a) levels is currently based on as strict regulation of arterial pressure, glycemia and other dislipidemias as possible. In the present clinical practice, the elevated level of this lipoprotein indicates a patients with elevated cardiovascular risk, regardless of the fact whether Lp (a) is only a marker or an active factor of pathophysiologic process. Increased Lp (a) concentration may refer to the need for therapy, frequent monitoring and determination of even stricter aims for these individuals by selecting metabolically neutral and best tolerated drugs.

Using Campylobacter spp. and Escherichia coli data and Bayesian microbial risk assessment to examine public health risks in agricultural watersheds under tile drainage management. Human campylobacteriosis is the leading bacterial gastrointestinal illness in Canada; environmental transmission has been implicated in addition to transmission via consumption of contaminated food. Information about Campylobacter spp. occurrence at the watershed scale will enhance our understanding of the associated public health risks and the efficacy of source water protection strategies. The overriding purpose of this study is to provide a quantitative framework to assess and compare the relative public health significance of watershed microbial water quality associated with agricultural BMPs. A microbial monitoring program was expanded from fecal indicator analyses and Campylobacter spp. presence/absence tests to the development of a novel, 11-tube most probable number (MPN) method that targeted Campylobacter jejuni, Campylobacter coli, and Campylobacter lari. These three types of data were used to make inferences about theoretical risks in a watershed in which controlled tile drainage is widely practiced, an adjacent watershed with conventional (uncontrolled) tile drainage, and reference sites elsewhere in the same river basin. E. coli concentrations (MPN and plate count) in the controlled tile drainage watershed were statistically higher (2008-11), relative to the uncontrolled tile drainage watershed, but yearly variation was high as well. Escherichia coli loading for years 2008-11 combined were statistically higher in the controlled watershed, relative to the uncontrolled tile drainage watershed, but Campylobacter spp. loads for 2010-11 were generally higher for the uncontrolled tile drainage watershed (but not statistically significant). Using MPN data and a Bayesian modelling approach, higher mean Campylobacter spp. concentrations were found in the controlled tile drainage watershed relative to the uncontrolled tile drainage watershed (2010, 2011). A second-order quantitative microbial risk assessment (QMRA) was used, in a relative way, to identify differences in mean Campylobacter spp. infection risks among monitoring sites for a hypothetical exposure scenario. Greater relative mean risks were obtained for sites in the controlled tile drainage watershed than in the uncontrolled tile drainage watershed in each year of monitoring with pair-wise posterior probabilities exceeding 0.699, and the lowest relative mean risks were found at a downstream drinking water intake reference site. The second-order modelling approach was used to partition sources of uncertainty, which revealed that an adequate representation of the temporal variation in Campylobacter spp. concentrations for risk assessment was achieved with as few as 10 MPN data per site. This study demonstrates for the first time how QMRA can be implemented to evaluate, in a relative sense, the public health implications of controlled tile drainage on watershed-scale water quality.

Pertuzumab for the Neoadjuvant Treatment of Early-Stage HER2-Positive Breast Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. As part of its single technology appraisal process, the National Institute for Health and Care Excellence invited the manufacturer of pertuzumab (Perjeta®; Roche Products Limited) to submit evidence of its clinical and cost- effectiveness for the neoadjuvant treatment of women with high-risk, early-stage, HER2-positive breast cancer when used in combination with trastuzumab and chemotherapy. High-risk women included those with locally advanced (including inflammatory) breast cancer and women with high-risk early-stage breast cancer (classified as T2/3 or N1). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group. This article presents the critical review of the company's submission by the Evidence Review Group and the outcome of the National Institute for Health and Care Excellence guidance. The clinical data were mainly taken from a phase II, randomised, open-label, active controlled study (NeoSphere), which reported a significant advantage in terms of pathological complete response rates of pertuzumab in combination with trastuzumab and chemotherapy, compared with trastuzumab alone with chemotherapy (45.8 vs. 29.0%, p = 0.0141). The company did not make any indirect comparisons. A meta-analysis of 12 neoadjuvant studies investigating the relationship between pathological complete response and event-free survival was used to extrapolate the outcomes reported in the NeoSphere study. A cardiac safety study (TRYPHAENA) demonstrated the safety of pertuzumab. The company undertook a model-based economic evaluation of neoadjuvant pertuzumab plus trastuzumab and docetaxel compared with neoadjuvant trastuzumab and docetaxel over a lifetime horizon from the National Health Service and Personal Social Services perspective. The probabilistic incremental cost-effectiveness ratio was estimated to be £20,104 per quality-adjusted life-year gained for pertuzumab alongside trastuzumab and docetaxel compared with trastuzumab and docetaxel, which was revised to £21,869 per quality-adjusted life-year gained following the clarification process. The Evidence Review Group corrected an error in the digitisation of the survivor functions and modified the clinically inappropriate assumption that recurrence is zero after 7 years. The Evidence Review Group's probabilistic base case was £23,962 per quality-adjusted life-year gained. During the appraisal, to mitigate the uncertainties associated with the evidence, the company offered a patient access scheme, which led to the National Institute for Health and Care Excellence Appraisal Committee recommending pertuzumab in this patient group, subject to the company providing the agreed discount in the patient access scheme.

Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. To investigate the potential gain of the concomitant use of radiotherapy and chemotherapy in improving local control and reducing the need for colostomy, a randomized phase III trial was performed in patients with locally advanced anal cancer. From 1987 to 1994, 110 patients were randomized between radiotherapy alone and a combination of radiotherapy and chemotherapy. The patients had T3-4NO-3 or T1-2N1-3 anal cancer. Radiotherapy consisted of 45 Gy given in 5 weeks, with a daily dose of 1.8 Gy. After a rest period of 6 weeks, a boost of 20 or 15 Gy was given in case of partial or complete response, respectively. Surgical resection as part of the primary treatment was performed if possible in patients who had not responded 6 weeks after 45 Gy or with residual palpable disease after the completion of treatment. Chemotherapy was given during radiotherapy: 750 mg/m2 daily fluorouracil as a continuous infusion on days 1 to 5 and 29 to 33, and a single dose of mitomycin 15 mg/m2 administered on day 1. The addition of chemotherapy to radiotherapy resulted in a significant increase in the complete remission rate from 54% for radiotherapy alone to 80% for radiotherapy and chemotherapy, and from 85% to 96%, respectively, if results are considered after surgical resections. This led to a significant improvement of locoregional control and colostomy-free interval (P = .02 and P = .002, respectively), both in favor of the combined modality treatment. The locoregional control rate improved by 18% at 5 years, while the colostomy-free rate at that time increased by 32% by the addition of chemotherapy to radiotherapy. No significant difference was found when severe side effects were considered, although anal ulcers were more frequently observed in the combined-treatment arm. The survival rate remained similar in both treatment arms. Skin ulceration, nodal involvement, and sex were the most important prognostic factors for both local control and survival. These remained significant after multivariate analysis. The improvement seen in local control by adding chemotherapy to radiotherapy also remained significant after adjusting for prognostic factors in the multivariate analysis. Event-free survival, defined as free of locoregional progression, no colostomy, and no severe side effects or death, showed significant improvement (P = .03) in favor of the combined-treatment modality. The 5-year survival rate was 56% for the whole patient group. The concomitant use of radiotherapy and chemotherapy resulted in a significantly improved locoregional control rate and a reduction of the need for colostomy in patients with locally advanced anal cancer without a significant increase in late side effects.

Results of radiation therapy for unresected soft-tissue sarcomas. Definitive radiotherapy is uncommonly used in the management of soft-tissue sarcoma (STS). The purpose of the study was to evaluate the results of radiotherapy for unresected STSs treated in a single institution. Between 1970 and 2001, 112 patients with STSs underwent radiotherapy for gross disease. Locations of the tumor were 43% in the extremities, 26% retroperitoneal, 24% in the head and neck, and 7% in the truncal wall. Histologic grades were 11% G1 and 89% G2 to G3. Median size of tumor at radiotherapy was 8 cm (range, 1-30 cm). Median radiation dose was 64 Gy (range, 25-87.5 Gy). Twenty percent of patients received chemotherapy. Local control (LC), disease-free survival (DFS), and overall survival (OS) rates were evaluated in univariate (log-rank) and then multivariate (Cox model) analysis to determine prognostic factors for STS. Median follow-up for patients is 139 months (range, 30-365 months). The 5-year actuarial LC, DFS, and OS were 45%, 24%, and 35%, respectively. Tumor size at radiotherapy and radiation dose influenced LC, DFS, and OS in univariate analysis. LC at 5 years was 51%, 45%, and 9% for tumors less than 5 cm, 5 to 10 cm, and greater than 10 cm, respectively. Patients who received doses of less than 63 Gy had 5-year LC, DFS, and OS rates of 22%, 10%, and 14%, respectively, compared with 5-year LC, DFS, and OS rates of 60%, 36%, and 52%, respectively, for patients who received doses of 63 Gy or more. AJCC stage was related to the OS and DFS without statistically significant influence on LC. Use of chemotherapy, histologic grade, age, and location did not influence results. In multivariate analysis, LC was related to total dose (p = 0.02), T size at radiotherapy (p = 0.003), and AJCC stage (p = 0.04); DFS was related to total dose (p = 0.007), T size at radiotherapy (p = 0.01), and AJCC stage (p < 0.0001); and OS was related to AJCC stage (p = 0.0001) and total dose (p = 0.002), but not to T size, at radiotherapy. Major radiotherapy complications were noted in 14% of patients; 27% of patients who received doses of 68 Gy or more had these complications compared with 8% of patients treated with doses of less than 68 Gy. Definitive radiotherapy for STS should be considered in clinical situations where no acceptable surgical option is available. Higher radiation doses yield superior tumor control and survival. A rise in complications occurs in patients who receive doses of 68 Gy or more, which provides a therapeutic window for benefit in these patients.

An intelligent model for liver disease diagnosis. Liver disease, the most common disease in Taiwan, is not easily discovered in its initial stage; early diagnosis of this leading cause of mortality is therefore highly important. The design of an effective diagnosis model is therefore an important issue in liver disease treatment. This study accordingly employs classification and regression tree (CART) and case-based reasoning (CBR) techniques to structure an intelligent diagnosis model aiming to provide a comprehensive analytic framework to raise the accuracy of liver disease diagnosis. Based on the advice and assistance of doctors and medical specialists of liver conditions, 510 outpatient visitors using ICD-9 (International Classification of Diseases, 9th Revision) codes at a medical center in Taiwan from 2005 to 2006 were selected as the cases in the data set for liver disease diagnosis. Data on 340 patients was utilized for the development of the model and on 170 patients utilized to perform comparative analysis of the models. This paper accordingly suggests an intelligent model for the diagnosis of liver diseases which integrates CART and CBR. The major steps in applying the model include: (1) adopting CART to diagnose whether a patient suffers from liver disease; (2) for patients diagnosed with liver disease in the first step, employing CBR to diagnose the types of liver diseases. In the first phase, CART is used to extract rules from health examination data to show whether the patient suffers from liver disease. The results indicate that the CART rate of accuracy is 92.94%. In the second phase, CBR is developed to diagnose the type of liver disease, and the new case triggers the CBR system to retrieve the most similar case from the case base in order to support the treatment of liver disease. The new case is supported by a similarity ratio, and the CBR diagnostic accuracy rate is 90.00%. Actual implementation shows that the intelligent diagnosis model is capable of integrating CART and CBR techniques to examine liver diseases with considerable accuracy. The model can be used as a supporting system in making decisions regarding liver disease diagnosis and treatment. The rules extracted from CART are helpful to physicians in diagnosing liver diseases. CBR can retrieve the most similar case from the case base in order to solve a new liver disease problem and can be of great assistance to physicians in identifying the type of liver disease, reducing diagnostic errors and improving the quality and effectiveness of medical treatment.

Orofacial pain emerging as a dental specialty. The emerging field of orofacial pain was considered by the American Dental Association for full status as a new dental specialty. While the recognition of orofacial pain as a specialty was denied, the American Academy of Orofacial Pain plans to continue its efforts. Many recent advances in the neuroscience of orofacial pain have led to treatments that provide significant relief for patients with chronic orofacial pain disorders. However, access to this care has been limited, leaving many patients to suffer. Dentists are generally supportive of the efforts to develop oral pain treatment into a specialty because the field will provide benefits for both dentists and their patients. A recent survey of 805 individuals who reported having a persistent pain disorder revealed that more than four out of 10 people have yet to find adequate relief, saying their pain is out of control--despite having the pain for more than five years and switching doctors at least once. "This survey suggests that there are millions of people living with severe uncontrolled pain," says Russell Portenoy, MD, president of the American Pain Society. "This is a great tragedy. Although not everyone can be helped, it is likely that most of these patients could benefit if provided with state-of-the-art therapies and improved access to pain specialists when needed." Development of the field of orofacial pain into a dental specialty has been moved primarily by the fact that historically, patients with complex chronic orofacial pain disorders have not been treated well by any discipline of healthcare. Recent studies of chronic orofacial pain patients have found that these patients have a higher number of previous clinicians and have endured many years with pain prior to seeing an orofacial pain dentist (see Figure 1). Complex pain patients and the clinicians who see them are often confused about who they should consult for relief of the pain. Treatment for those patients within the existing structure of dental or medical specialties has been inadequate, with millions of patients left suffering. Insurers are also confused with regard to reimbursement and may make decisions to exclude treatment for orofacial pain disorders under both dental and medical policies. However, dentistry has taken a leading role in healthcare to address the national problem of developing the field of orofacial pain into a dental specialty. A study of dentists and dental specialists has shown that there is a recognized need and broad support for developing this field into a specialty.

[Application of dental floss traction-assisted endoscopic submucosa dissection to rectal neuroendocrine neoplasm]. Objective: To evaluate the safety and efficacy of dental floss traction-assisted endoscopic submucosal dissection (DFS-ESD) for rectal neuroendocrine neoplasm (NEN). Methods: A retrospective cohort study was performed. Clinical data of rectal NEN patients undergoing ESD at Endoscopy Center of Zhongshan Hospital, Fudan University from January 2016 to December 2017 were retrospectively analyzed. Inclusion criteria: 1) age of 18 to 80 years old; 2) maximal diameter of lesions <1.5 cm; 3) tumor locating in the submucosa without invasion into the muscularis propria; 4) no enlarged lymph nodes around bowel and in abdominal cavity; 5) ESD requested actively by patients. A total of 37 patients were enrolled, including 23 male and 14 female cases with mean age of (56.0±11.3) years. All the lesions were single tumor of stage T1, and the mean size was 0.8±0.2(0.5-1.2) cm. Postoperative pathology revealed all samples as neuroendocrine tumors (NET). Seventeen patients received DFS-ESD treatment (DFS-ESD group) and 20 patient received conventional ESD treatment (conventional ESD group). In DFS-ESD group, after the mucosa was partly incised along the marker dots, the endoscopy was extracted, and the dental floss was tied to one arm of the metallic clip. When the endoscope was reinserted, the hemoclip was attached onto the incised mucosa; another hemoclip was attached onto normal mucosa opposite to the lesion in the same way. The submucosa was clearly exposed with the traction of dental floss and the resection could proceed. The conventional ESD group received the traditional ESD operation procedure. The operation time, modified operation time (remaining time after excluding the assembly time of dental floss traction in DFS-ESD group), en bloc resection rate, R0 resection rate, morbidity of operative complication, recurrence and metastasis were compared between two groups. Results: The average tumor size was (0.8±0.2) cm in DFS-ESD group and (0.7±0.2) cm in conventional ESD group (t=0.425, P=0.673). According to postoperative pathological grading of rectal neuroendocrine neoplasm, 13 were G1 and 4 were G2 in DFS-ESD group, while 17 cases were G1 and 3 cases were G2 in conventional ESD group without significant difference (P=0.680). There were no significant differences in baseline data between in the two groups (all P>0.05). All the basal resection margins were negative, the en bloc resection rate was 100% and the R0 resection rate was 100%. Pathological results showed tumor tissue close to the burning margin in 5 cases of conventional ESD group and in 2 cases of DFS-ESD group (P=0.416). The operation time was (17.9±6.6) minutes in conventional ESD group and (14.7±3.3) minutes in DFS-ESD group (t=1.776, P=0.084). The modified operation time of DFS-ESD group was (11.9±2.8) minutes, which was significantly shorter than (17.9±6.6) minutes in conventional ESD group (t=3.425, P=0.002). The hospital stay was (2.3±0.6) days and (2.0±0.5) days in conventional ESD group and DFS-ESD group, respectively, without significant difference (t=1.436, P=0.160). No patient was transferred to surgery, and no delayed bleeding or perforation occurred in either group. There was no recurrence or primary tumor-related death, and all the patients recovered well during a follow-up period of 14(1-24) months. Conclusion: Dental floss traction-assisted ESD for rectal neuroendocrine neoplasm can simplify operation and ensure negative basal margin.

First Report of Root Rot of Watermelon Caused by Ceratobasidium sp. in Sonora, Mexico. Watermelon is one of the major crops grown in Mexico and represents 4% of the total cultivated area with fruits in this country. In 2013, Sonora State was ranked second in the production of watermelon at a national level. Fungal and oomycete diseases are among the main biotic factors affecting watermelon production, particularly those caused by species of the genera Fusarium, Phytophthora, Pythium, and Rhizoctonia. During the spring of 2013, wilting or death symptoms were confirmed in approximately 50% of ungrafted watermelon plants grown in four sampled fields along the coast of Hermosillo and Guaymas Valley in Sonora, Mexico. On both roots and stems of infected plants, localized lesions were found that were 0.2 to 2.0 cm long, reddish brown, and slightly sunken on the stem base. In some cases, the discolorations encompassed nearly 90% of the root system. One-centimeter pieces from the edge of lesions on stems and roots were superficially disinfected with 1% sodium hypochlorite, then rinsed with sterile distilled water, placed onto petri dishes containing potato dextrose agar (PDA), and incubated at 25°C for 3 days. Fungal colonies were white initially, then turned brown, and septate hyphae were 3.7 to 4.3 μm in diameter and branched at right angles with a constriction at the origin of the branch point. These characteristics are typical of the genus Rhizoctonia. Binucleate cells from five isolates were observed using a lactophenol aniline blue solution stain, according to Ceratobasidium morphological descriptions. Mycelia from five isolates grown on PDA was used for DNA extraction. The rDNA-ITS region was amplified using PCR with the universal fungal primers ITS1 and ITS4 (3). The purified products were separately sequenced in both directions using the same primer pair. The sequences obtained were 99% similar to those of Ceratobasidium sp. AG-F and AG-Fa isolates (accessions KC193238.1 on Tagetes erecta, HQ168370.1 on Musa spp., and JX913821.1 on soy-rice-weeds, respectively) from GenBank (2,4). The pathogenicity of the fungus was tested under growth chamber conditions. Sets of seven healthy watermelon seedlings of the Sugar red variety were inoculated with five isolates of Ceratobasidium. Three disks (8 mm in diameter) of mycelia grown on PDA were placed around the roots of each plantlet. The pots were maintained at 27 ± 0.1°C for 14 days with a photoperiod of 12 h. Seven uninoculated seedlings were used as a control. Initial symptoms showing water-soaked lesions developed on all inoculated seedlings within 6 to 7 days, while typical disease symptoms appeared after 10 to 14 days after inoculation. Seedlings without inoculum were free from infection. The fungus was re-isolated from the inoculated seedlings on PDA, and identified as Ceratobasidium sp., confirmed using morphological characteristics. A similar disease has been reported recently in Italy and Arizona (1); however, this report is the first description of a Ceratobasidium sp. causing root rot of watermelon in Sonora, Mexico. Agricultural areas where the study was carried represent 90% of the total area cultivated with watermelon in this state, so it is necessary to evaluate the impact of this pathogen in the crop. References: (1) C. Nischwitz et al. APS joint meeting, 2013. (2) A. Saroj et al. Plant Dis. 97:1251, 2013. (3) T. J. White et al. PCR Protocols: A Guide to Methods and Applications. Academic Press, San Diego, CA, 1990. (4) J. Yin et al. Plant Dis. 95:490, 2011.

[The mechanism of signal extension in Haoqin Qingdan decoction immunity activity in Damp-heat syndrome of pneumonia disease infected by influenza virus]. To explore the immunoregulation existing signal transduction mechanism, to evaluate the role of lay its experimental basis By using Haoqin Qingdan decoction for treatments on the mouse models. A total of 40 NIH Mice were randomly divided into five groups: control group, virus group (infecting by influenza virus), complex model group (richly fatty and sweet diet + Humid heat environment + infecting by influenza virus), virazole group (mouse of model group was treated by virazole), and Haoqin Qingdan decoction group (mouse of complex model group was treated by decoction of Haoqin Qingdan). When the complex model was established, determination of the mice lung indexes in each group and calculate the inhibition of lung indexes. The level of TLR2 mRNA and NF-κB mRNA expressions of peritoneal macrophages in each group of mice were quantitated by reverse transcription-polymerase chain reaction (RT-PCR). The level of IL-4 and IFN-γ in mouse serum was detected by ELISA to calculate the Th1/Th2 (IFN-γ/IL-4). The lung index of control group, virus group, complex model group, virazole group and Haoqin Qingdan decoction group were separately: (0.79 ± 0.11)%, (1.93 ± 0.38)%, (1.41 ± 0.26)%, (1.10 ± 0.26)% and (1.02 ± 0.16)%; The mice of virazole group and Haoqin Qingdan decoction group lung index were decreased (t = 0.322, P < 0.05). TLR2 mRNA expression The results showed that the control group, virus group, complex model group, virazole group and Haoqin Qingdan decoction group were: 0.145 ± 0.017, 0.991 ± 0.149, 0.903 ± 0.124, 0.257 ± 0.03 and 0.413 ± 0.031; Compared to the complex model group, Haoqin Qingdan decoction group and virazole group were decreased (t = 0.422, F = 112.834, P < 0.05). Control group, virus group, complex model group, virazole group and Haoqin Qingdan decoction group NF-κB mRNA expression were separately: 0.075 ± 0.148, 0.379 ± 0.019, 0.291 ± 0.012, 0.169 ± 0.026 and 0.175 ± 0.033; the expression in virazole group and Haoqin Qingdan decoction group were decreased (t = 0.422, F = 112.834, P < 0.05). The level of IFN-γ in mice serum of control group, virus group, complex model group, virazole group and Haoqin Qingdan decoction group were: (7434.06 ± 323.27) pg/ml, (8679.77 ± 198.70) pg/ml, (8068.78 ± 113.8) pg/ml, (7454.66 ± 301.30) pg/ml and (7484.56 ± 229.85) pg/ml respectively; the IFN-γ level in serum of Haoqin Qingdan decoction group and virazole group were decreased (t = 0.201, F = 5.390, P < 0.05). Each group of mice IL-4 contents were (3701.74 ± 256.00) pg/ml, (3569.64 ± 161.35) pg/ml, (3530.88 ± 334.63) pg/ml, (3481.84 ± 282.25) pg/ml and (3618.00 ± 262.16) pg/ml; there were no significant difference between each group (t = 0.414, F = 0.505, P > 0.05). Th1/Th2 type cells in state of equilibrium (means IFN-γ/IL-4) were: 2.02 ± 0.19, 2.38 ± 0.10, 2.36 ± 0.14, 2.22 ± 0.17 and 2.07 ± 0.15; and complex model group Haoqin Qingdan decoction group and virazole group were decreased, and there was no significant difference observed (t = 0.587, F = 3.684, P > 0.05). The effect of Haoqin Qingdan decoction on treatment of damp-heat syndrome of pneumonia infected by influenza virus was observed. Through reducing the expressions of TLR2, it decreases the levels of NF-κB mRNA and the proportionality of Th1/Th2 are obviously descend (P < 0.05). Haoqin Qingdan decoction can reduce the lung index and relieve the pathogenic changes.

Thyroid toxicity due to subchronic exposure to a complex mixture of 16 organochlorines, lead, and cadmium. The human population in the industrialized world is ubiquitously exposed to complex mixtures of persistent pollutants that contaminate food, water, and air. A large number of these contaminants have been shown to cause significant toxicity to the hypothalamic-pituitary-thyroid (HPT) axis in laboratory animal studies, through a variety of mechanisms, although these effects occur at levels of exposure greatly in excess of common human exposure. While many of the mechanisms of thyroid toxicity of these substances are potentially complementary, little is known of the degree of interaction of common persistent contaminants on responses of the HPT axis. To investigate the potential effects of a complex, environmentally relevant mixture on the HPT axis, sexually mature male rats were administered a mixture of 16 common organochlorines (dichlorodiphenoxytrichloroethane [DDT], p,p'-dichlorodiphenoxydichloroethylene [p,p'-DDE], hexachlorobenzene [HCB], tetrachlorodibenzo-p-dioxin [TCDD], polychlorinated biphenyls [PCBs], methoxychlor, endosulfan, heptachlor, hexachlorocyclohexane, dieldrin, aldrin, mirex, and several chlorinated benzenes, and metal contaminants [lead, cadmium]). The doses of the mixture that were administered were related to minimum risk levels or tolerable daily intakes of these substances, as derived by risk assessment with the 1x, 10x, 100x, and 1000x groups receiving mixture components at doses equivalent to 1x, 10x, 100x, or 1000x the minimum risk level (or tolerable daily intake, reference dose), respectively. After 70 daily treatments by gavage, endpoints related to circulating thyroid hormone (serum thyroxine [T(4)], triiodothyronine [T(3)], thyroid stimulating hormone [TSH], and serum T(3) uptake [T(3)-up]), thyroid gland histomorphology (thyroid follicle cross sectional area, epithelial height, follicle roundness or aspect ratio, colloid/epithelial ratio) and hepatic metabolism of thyroid hormone (UDP-glucuronyl transferase [UGT] and outer-ring deiodinase [ORD]) were assessed. All examined endpoints were significantly altered by the mixture albeit with great variability between endpoints in the sensitivity. While most endpoints examined did not show significant changes at mixture doses below 1000x, 2 endpoints, TSH and hepatic outer ring deiodinase activity, were significantly increased and decreased, respectively, by 1x dose and showed dose-related increases in severity with increasing dose. Median thyroid follicle cross sectional area was also increased by the lowest dose of the mixture but decreased with subsequent increases in dose until, at the highest dose, this parameter was significantly reduced relative to control. The relative sensitivity of endpoints of thyroid function in detecting toxicity of the mixture was TSH = ORD = median follicle area >> T(3) > all other endpoints. These results demonstrate that low doses of ubiquitous environmental contaminants can alter HPT physiology in sexually mature males.

[Conventional transrectal ultrasound guided biopsy. Current role, indications, techniques and limitations]. The objective of this work is to evaluate the current role of conventional transrectal ultrasound guided biopsy of the prostate in the diagnosis of cancer. With this aim we review its indications, the various techniques, associated complications and limitations of this test. We performed a bibliographic review through NCBI-PUBMED. We also evaluated the information and recommendations of the available clinical guidelines with their respective evidence levels. Lastly, some of the appraisals included are based on our group's personal experience that has performed more than 7000 prostate biopsies with various protocols and methodologies over two decades of health care practice. Conventional prostatic biopsies lack precision; they are not close to reality in terms of tumor amount, localization and grading. The number and localization of the cores to be taken is not clear; there are too many biopsy schemes, making it less reliable and reproducible than expected. Although it is a good tool, there is an obvious risk of over diagnosis of clinically non-significant tumors. The lack of standardization of the various biopsy schemes has clear prognostic and decision-making implications. Another limitation is the scarce number of results attributable to biopsies targeted at ultrasound visible lesions. Obviously, the complications, discomfort, and distress generated by conventional biopsy and repeated biopsy programs are some of their limitations and the reasons for patient rejection. We are in a crossroad where multiple groups try to demonstrate the sensitivity and reproducibility of targeting the biopsy, by means of various techniques, to the lesions found in multiparametric MRI. Ultrasound guided prostatic biopsy is the main diagnostic method for prostate cancer yet. The information it gives is greatly relevant for staging, prognostic evaluation and therapeutic decision-making. Nevertheless, its limitations are evident: low sensitivity, overdiagnosis, complicacions, patient's distress, etc. There are two lines of development to improve its efficiency. The one aiming to reduce the number of biopsies and cores by selectively targeting the findings of the MRI and the one that continues systematizing schemes with increasing number of cores to achieve the optimal sampling. Technical advances, such as image fusion, will maybe allow us in the future to translate the MRI findings into verified and reproducible clinical results. We must standardize the conventional techniques of prostate biopsy in our centers, using protocols and making them safe for patients. We must review our results to ensure reasonable detection rates, as well as our indications, considering patient's age, comorbidities and expectations about therapy. We must include, as far as possible, other tools, such as multiparametric MRI to enable biopsy rationalization and improve their efficacy.

Biochemical analyses of proteolytic nicking of the human glycoprotein hormone alpha-subunit and its effect on conformational epitopes. Conformational features of two epitopes on the glycoprotein hormone alpha-subunit were investigated using two antihuman FSH (anti-hFSH) monoclonal antibodies (mAbs) 3A and 5F that recognize different epitopes and are specific for alpha-subunit. These mAbs were used to investigate whether the conformation of these epitopes was different in heterodimeric hFSH, hTSH, hLH, or hCG. Any differences in the mass of hormone in each preparation were accounted for by sodium dodecyl sulfate-polyacrylamide gel electrophoresis/Western blot analysis of all hormone preparations used in this study. Rabbit anti-hFSH alpha-(11-27) antipeptide antisera and [125I]protein-G were used in the Western blot analysis. Radioactivity associated with each band was determined and used to normalize the mass of alpha-subunit in each reference preparation used in the displacement assays. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis was also performed in order to examine the integrity of each of the hormone reference preparations. hTSH alpha and, to a lesser extent, hLH alpha preparations contained an internal nick in the polypeptide chain. RIA analysis performed using heterodimeric glycoprotein hormones as competitors revealed that an average 100-fold difference in the ED50 values for hFSH compared to the other glycoprotein hormones was seen with mAb 3A. Therefore, the conformation of 3A epitope appeared to be different in hFSH than in hTSH, hLH, or hCG. In comparison, the epitope recognized by mAb 5F only had an average 7-fold difference in reactivity (ED50 values) for hFSH compared to hTSH, hLH, and hCG. Likewise, competition assays using the respective alpha-subunits and mAb 5F revealed a pattern of competition similar to that observed with heterodimers, with an average 4-fold difference in the ED50 values for hFSH alpha compared to those for hTSH alpha, hLH alpha, and hCG alpha. Therefore, the conformation of the 5F epitope appears unaffected by association of alpha-subunit with beta-subunit. Accordingly, any differences in the conformation of the four alpha-subunits, as demonstrated by these small differences in ED50 values, appear to be inherent to each alpha-subunit. In fact, the 5F epitope appears to be quite rigid, since nicked alpha-subunit preparations could compete with [125I]hFSH for binding to 5F with comparable potency to non-nicked alpha-subunits. These findings support the concept that epitopes on heterodimeric hFSH alpha may have different conformational features. Some are specific for heterodimeric hFSH alpha, and we refer to these as conformationally active (flexible). Others are common to the four human glycoprotein hormone alpha-subunits, suggesting that they are conformationally constrained (rigid).

The Marburg-Münster Affective Disorders Cohort Study (MACS): A quality assurance protocol for MR neuroimaging data. Large, longitudinal, multi-center MR neuroimaging studies require comprehensive quality assurance (QA) protocols for assessing the general quality of the compiled data, indicating potential malfunctions in the scanning equipment, and evaluating inter-site differences that need to be accounted for in subsequent analyses. We describe the implementation of a QA protocol for functional magnet resonance imaging (fMRI) data based on the regular measurement of an MRI phantom and an extensive variety of currently published QA statistics. The protocol is implemented in the MACS (Marburg-Münster Affective Disorders Cohort Study, http://for2107.de/), a two-center research consortium studying the neurobiological foundations of affective disorders. Between February 2015 and October 2016, 1214 phantom measurements have been acquired using a standard fMRI protocol. Using 444 healthy control subjects which have been measured between 2014 and 2016 in the cohort, we investigate the extent of between-site differences in contrast to the dependence on subject-specific covariates (age and sex) for structural MRI, fMRI, and diffusion tensor imaging (DTI) data. We show that most of the presented QA statistics differ severely not only between the two scanners used for the cohort but also between experimental settings (e.g. hardware and software changes), demonstrate that some of these statistics depend on external variables (e.g. time of day, temperature), highlight their strong dependence on proper handling of the MRI phantom, and show how the use of a phantom holder may balance this dependence. Site effects, however, do not only exist for the phantom data, but also for human MRI data. Using T1-weighted structural images, we show that total intracranial (TIV), grey matter (GMV), and white matter (WMV) volumes significantly differ between the MR scanners, showing large effect sizes. Voxel-based morphometry (VBM) analyses show that these structural differences observed between scanners are most pronounced in the bilateral basal ganglia, thalamus, and posterior regions. Using DTI data, we also show that fractional anisotropy (FA) differs between sites in almost all regions assessed. When pooling data from multiple centers, our data show that it is a necessity to account not only for inter-site differences but also for hardware and software changes of the scanning equipment. Also, the strong dependence of the QA statistics on the reliable placement of the MRI phantom shows that the use of a phantom holder is recommended to reduce the variance of the QA statistics and thus to increase the probability of detecting potential scanner malfunctions.

The effect of high-dose fluticasone propionate and budesonide on lung function and asthma exacerbations in patients with severe asthma. The purpose of this study was to investigate the comparative efficacy and safety of equal doses of inhaled fluticasone propionate (FP) and inhaled budesonide (BUD) using their respective dry powder inhalers in a population of severe asthmatics requiring high doses of inhaled corticosteroid. This double-blind double-dummy parallel-group study compared the effects of 24 weeks of treatment with FP (2000 micrograms daily via a Diskhaler inhaler; Glaxo Wellcome, Evreux, France) and BUD (2000 micrograms daily via a Turbuhaler inhaler; Astra Pharmaceuticals, Rijswijka, Netherlands) on lung function and asthma exacerbations in 395 patients with asthma. FP was statistically significantly superior to BUD with respect to the percentage of symptom-free days (P = 0.02), the incidence of days free from rescue bronchodilator usage (P = 0.02) and the distribution of change in peak expiratory flow (PEF) expressed as a percentage of the predicted PEF (P = 0.04). During the treatment period FP was statistically significantly superior to BUD for change in forced expiratory volume in 1 sec (FEV1) at 8, 16 and 24 weeks, change in the median daytime symptom score during weeks 5-16, for incidence of symptom-free days and incidence of days free from rescue bronchodilator usage during weeks 17-24. There was no significant difference between FP and BUD with respect to the number of patients experiencing one or more asthma exacerbation (33.8 and 28.4% of patients, respectively). There was, however, evidence that the exacerbations were clinically less severe in patients treated with FP, in that the time to resolution was quicker (11.0 vs. 14.7 days; P = 0.035), mean duration of all exacerbations (for an individual patient) tended to be shorter (18.5 vs. 23.6 days; P = 0.12), the time off work was reduced (4.2 vs. 7.6 days; P = 0.012) and the lowest PEF recorded during the exacerbation was higher (301 vs. 263 l min-1; P = 0.07). There were no clinically relevant differences in the safety (serum cortisol levels, markers of bone turnover, adverse events) of FP and BUD at these microgram equivalent doses. The patients recruited into this study, in retrospect, probably had no need for such high doses of inhaled corticosteroid but, irrespective of this, FP at microgram equivalent doses showed evidence of superior efficacy to BUD with respect to lung function and severity of asthma exacerbations without producing any greater adverse systemic effect.

[Clinicopathologic and molecular characteristics of malignant gastrointestinal neuroectodermal tumors]. Objective: To investigate the clinicopathologic and molecular characteristics, diagnostic, differential diagnostic and prognostic features of malignant gastrointestinal neuroectodermal tumor. Methods: Two cases of malignant gastrointestinal neuroectodermal tumor were retrieved; the clinical and radiologic features, histomorphology, immunophenotype, molecular genetics and prognosis were analyzed and the relevant literature reviewed. Results: Case 1 was a 57-year-old male, presented with recurrent abdominal pain and melena. Pelvic imaging showed a circumscribed thickening of the wall of a small intestinal segment, and a malignant lymphoma was favored. Case 2 was a 24-year-old male, presented with recurrent small intestinal malignancy. Imaging demonstrated multiple masses in the peritoneal and pelvic cavities, and a malignant gastrointestinal stromal tumor with multiple metastases was suspected. Grossly both tumors were located mainly in the muscularis propria of small intestine. Case 1 showed a single 5.5 cm tumor; and case 2 consisted of two tumors measuring 4 cm and 6 cm respectively. Microscopic examination of both tumors showed small round blue, but focally spindled or clear tumor cells in solid pattern. The tumor cells had scanty cytoplasm, indistinctive nucleoli and brisk mitoses. Osteoclast-like giant cells were dispersed within the stroma. In case 1 rosette-like and pseudo-papillary growth patterns were noted, and in case 2 there were variable-sized hemorrhagic cysts. By immunohistochemistry, both tumors showed strong and diffuse expression of SOX10 and S-100, and focal to diffuse expression of neuroendocrine markers (CD56 or synaptophysin). Case 2 exhibited focal reactivity to pan-cytokeratin. Both tumors lacked expression of markers associated with gastrointestinal stromal tumor, smooth muscle tumor, melanoma (HMB45 or Melan A), dendritic cell tumor and Ewing sarcoma. Fluorescence in situ hybridization analysis demonstrated EWSR1 rearrangement in both tumors and the next generation sequencing confirmed EWSR1-ATF1 gene fusion in case 2. At follow-up of 16 months, case 1 was recurrence or metastasis free; whereas case 2 showed multiple recurrences and metastases within 19 months although stable disease was transiently achieved when treated with combinations of multidrug and targeted chemotherapy. Conclusions: Malignant gastrointestinal neuroectodermal tumor is a rare and aggressive soft tissue sarcoma with a predilection for small intestine. It has distinctive morphologic, immunohistochemical and molecular characteristics and needs to be distinguished from other small blue round and spindle cell tumors that occur in the gut. Careful attentions to its characteristic histomorphology with the judicious use of immunohistochemistry and molecular genetics can help to distinguish this tumor from its many mimickers.

111In-cetuximab-F(ab')2 SPECT and 18F-FDG PET for prediction and response monitoring of combined-modality treatment of human head and neck carcinomas in a mouse model. Treatment of head and neck squamous cell carcinomas with radiotherapy and the epidermal growth factor receptor (EGFR) inhibitor cetuximab shows an improved response in a subgroup of patients. The aim of this study was to noninvasively monitor treatment response by visualizing systemically accessible EGFR with (111)In-cetuximab-F(ab')2 while simultaneously evaluating tumor metabolism with (18)F-FDG PET during combined-modality treatment. Eighty mice with patient-derived head and neck squamous cell carcinomas xenografts, SCCNij202 or SCCNij185, were imaged with SPECT/CT using (111)In-cetuximab-F(ab')2 (5 μg, 28 ± 6.1 MBq, 24 h after injection), followed by PET imaging with (18)F-FDG (9.4 ± 2.9 MBq, 1 h after injection). Scans were acquired on mice 10 d before treatment with either single-dose irradiation (10 Gy), cetuximab alone, or cetuximab-plus-irradiation combined or on untreated control mice. Scans were repeated 18 d after treatment. Tumor growth was monitored up to 120 d after treatment. EGFR expression was evaluated immunohistochemically. SCCNij202 responded to combined treatment (P < 0.01) and cetuximab treatment alone (P < 0.05) but not to irradiation alone (P = 0.13). SCCNij185 responded to combined treatment (P < 0.05) and irradiation (P < 0.05) but not to cetuximab treatment alone (P = 0.34). (111)In-cetuximab-F(ab')2 uptake (tumor-to-liver ratio, scan 2 - scan 1) predicted response to therapy. A positive response to treatment significantly correlated with a reduced tracer uptake in the tumor in the second SPECT scan, compared with the first scan (P < 0.005 and <0.05 for SCCNij202 and SCCNij185, respectively). Resistance to therapy was characterized by a significantly increased (111)In-cetuximab-F(ab')2 tumor uptake; tumor-to-liver ratio was 2.2 ± 0.6 to 3.5 ± 1.2, P < 0.01, for (irradiated) SCCNij202 and 1.4 ± 0.4 to 2.0 ± 0.3, P < 0.05, for (cetuximab-treated) SCCNij185, respectively. (18)F-FDG PET tumor uptake (maximum standardized uptake value, scan 2 - scan 1) correlated with tumor response for SCCNij202 (P < 0.01) but not for SCCNij185 (P = 0.66). EGFR fractions were significantly different: 0.9 ± 0.1 (SCCNij202) and 0.5 ± 0.1 (SCCNij185) (P < 0.001). The EGFR fraction was significantly lower for irradiated SCCNij202 tumors than for controls (P < 0.005). (111)In-cetuximab-F(ab')2 predicted and monitored the effects of EGFR inhibition or irradiation during treatment in both head and neck carcinoma models investigated, whereas (18)F-FDG PET only correlated with tumor response in the SCCNij202 model. Thus, the additional value of the (111)In-cetuximab-F(ab')2 tracer is emphasized and the tracer can aid in evaluating future treatments with EGFR-targeted therapies.

Increased parenteral amino acid administration to extremely low-birth-weight infants during early postnatal life. Early administration of parenteral amino acids to infants with extremely low birth weight (birth weight < or = 1,000 g) has been encouraged to foster growth. However, excessive intravenous intake of amino acids may cause metabolic acidosis and uremia in extremely low birth weight infants. The hypothesis for this study was that extremely low birth weight infants would tolerate slightly increased early postnatal parenteral amino acid administration and benefit. The peak daily parenteral amino acid dosage was increased from 3 g/kg (standard group) to 4 g/kg (modified group). The corrected parenteral amino acid dosage was computed to account for enteral protein intake and keep the combined daily intravenous amino acid and enteral protein intake at or below 3 g . kg -1 . d -1 in the standard group and 4 g . kg -1 . d -1 in the modified group. The primary outcome measure was plasma bicarbonate concentration as an indicator of acid-base status. Data were collected for patient demographics, nutritional intake, serum bicarbonate and serum urea nitrogen concentrations, and outcome. The corrected parenteral amino acid intake of the modified group was 16% greater at postnatal week 1 (3.30 +/- 0.83 g . kg -1 . d -1; mean, +/-1 SD) and 18% greater (3.86 +/- 0.94 g . kg -1 . d -1 ) at postnatal week 2 than the parenteral amino acid intake of the standard group. In the modified group, the mean serum bicarbonate concentration was 19.1 +/- 1.8 mEq/dL at week 1 and 23.9 +/- 2.9 mEq/dL at week 2, with no difference between the groups. At week 1, serum urea nitrogen concentrations were the same in both groups. The mean serum urea nitrogen concentration of the modified group at postnatal week 2 (18.2 +/- 8.8 mg/dL) was unchanged from postnatal week 1, but was greater than that of the standard group at postnatal week 2. Weight gain was the same in both groups. Corrected parenteral amino acid intake at postnatal week 1 correlated directly with weight gain from birth to postnatal week 2 ( P < 0.03) in both groups. Infants with extremely low birth weight tolerated parenteral amino acid intake of approximately 4 g . kg -1 . d -1. Mild increases of mean serum urea nitrogen concentration and mean weight gain were associated with increased parenteral amino acid administration without significant acidosis.

Supplementation with wine phenolic compounds increases the antioxidant capacity of plasma and vitamin E of low-density lipoprotein without changing the lipoprotein Cu(2+)-oxidizability: possible explanation by phenolic location. To evaluate the effect of the red wine phenolic compound (RWPC) dietary supplementation without alcohol interference on: (1) some of the biochemical characteristics of LDL, (2) the oxidative susceptibility of LDL and (3) the antioxidant capacity of total plasma (Pl-AOC). In order to account for discrepancies between the three series of data, the in vitro stability of the association of phenolic compounds and LDL was tested. An intervention study with 20 volunteers. Each served as his own control. Cu(2+)-oxidizability of LDL and Pl-AOC were tested on blood samples before and after dietary supplementation. Cu(2+)-oxidizability of LDL was also tested by co-incubation in the presence of RWPC or phenolic acids with or without extensive dialysis. The Laboratory of Lipid Biochemistry and Biology, School of Medicine, and the Laboratory of Metabolic Diseases, Lapeyronie Hospital, University of Montpellier, France. Healthy males, nonsmokers and moderate drinkers, submitted to a dietary regimen deprived of vitamin E and C for a period of 10 d before supplementation. They also abstained from alcohol, wine, fruit juices, coffee, tea and cola beverages during this period. Six 0.33 g capsules/d (namely two capsules at each meal) of a preparation of red wine phenolic compounds in a dry powder form were given to the volunteers over a period of two weeks. Blood samples were drawn in fasting conditions at day 0 and day 14 of the supplementation period. Supplementation led to: (1) in LDL, a significant increase in vitamin E content (n = 20, P = 0.01) or vitamin E/total fatty acid bis-allylic carbon number ratio (n = 20, P = 0.006) without modification in the other biochemical characteristics or Cu(2+)-oxidizability; (2) in plasma, a significant increase in the antioxidant capacity (n = 11, P = 0.01). In vitro studies showed that RWPC or sinapic, caffeic or ferulic acids incubated in the presence of LDL increased the protection of the lipoparticle against oxidation (caffeic > sinapic > ferulic). This effect, however, was totally lost after extensive dialysis. The enhancing effect of the RWPC supplementation on Pl-AOC may be due to a phenolic-compound action both in the aqueous phase of plasma and at the surface of lipoprotein particles. Surface location possibly explains the enhancing-sparing effect of supplementation on LDL vitamin E and the absence of effect on dialysed-LDL oxidizability.

Experimental reproduction of itai-itai disease, a chronic cadmium poisoning of humans, in rats and monkeys. To establish a useful animal model of Itai-Itai disease (IID) of humans, we conducted the following experiments. Experiment 1: Toxic effects of Cd were compared between ovariectomized (OX) and non-OX rats after daily, intravenous injection of cadmium (Cd) chloride for 14 days. In this experiment, we demonstrated that OX rats were more susceptible to Cd-induced nephrotoxicity and hepatotoxicity than non-OX rats. Experiment 2: OX rats were injected with Cd at doses of 1.0 and 2.0 mg/kg, 5 days a week, for 13 weeks. The bone Cd content was gradually increased for 13 weeks in a dose-dependent manner. Calcium and phosphorus contents in the bone and serum levels of parathyroid hormone and osteocalcin were not significantly different between Cd-treated and control rats. Mild osteomalacic lesions in the cortical bones of the midshaft haversian canals as well as chronic nephropathy appeared in the rats of the 2.0 mg/kg group. Experiment 3: OX rats were treated with Cd at doses of 0.5 and 0.05 mg/kg for 70 weeks. The rats of the 0.05 mg/kg group showed slight anemia and mild degeneration of tubular epithelium after 50 weeks of treatment. In the 0.5 mg/kg group, the rats showed definite osteomalacia of bones and nephrosclerosis. The Cd concentration in the bones increased for the first 25 weeks, but was replaced gradually with iron at from 50 to 70 weeks of the administration period. Iron deficiency anemia appeared in the 0.5 mg/kg group at from 12 to 25 weeks, and changed to renal anemia after 50 weeks of administration. The anemia at 50 and 70 weeks was normocytic and normochromic, and serum erythropoietin levels were not elevated in response to the decrease of hemoglobin concentrations of red blood cells. Experiment 4: Ten, OX cynomolgus monkeys were given intravenous injections of 0, 1.0 or 2.5 mg/kg/day Cd, 2 or 3 days per week, for 13 to 15 months. Normocytic and normochromic anemia, renal lesions characterized by tubular atrophy and interstitial fibrosis (Cd nephropathy), and bone lesions characterized by an increase of osteoid and osteopenia (Cd osteopathy) were induced in the monkeys treated with Cd. These results demonstrated that chronic cadmium toxicosis similar to IID of humans was reproducible in rats and monkeys by repeated intravenous injection of Cd and that a disease entity closely resembling IID of humans could be induced in experimental animals by chronic Cd toxicosis without participation of malnutrition, vitamin D deficiency, impaired absorption at the intestinal mucosa or multiparous birth.

Fish oil for kidney transplant recipients. Calcineurin inhibitors used in kidney transplantation for immunosuppression have adverse effects that may contribute to nephrotoxicity and increased cardiovascular risk profile. Fish oils are rich in very long chain omega-3 fatty acids, which may reduce nephrotoxicity by improving endothelial function and reduce rejection rates through their immuno-modulatory effects. They may also modify the cardiovascular risk profile. Hence, fish oils may potentially prolong graft survival and reduce cardiovascular mortality. This review aimed to look at the benefits and harms of fish oil treatment in ameliorating the kidney and cardiovascular adverse effects of CNI-based immunosuppressive therapy in kidney transplant recipients. We searched the Cochrane Kidney and Transplant Specialised Register (up to 17 March 2016) through contact with the Information Specialist using search terms relevant to this review. All randomised controlled trials (RCTs) and quasi-RCTs of fish oils in kidney transplant recipients on a calcineurin inhibitor-based immunosuppressive regimen. RCTs of fish oil versus statins were included. Data was extracted and the quality of studies assessed by two authors, with differences resolved by discussion with a third independent author. Dichotomous outcomes were reported as risk ratio (RR) and continuous outcome measures were reported as the mean difference (MD) with 95% confidence intervals using the random effects model. Heterogeneity was assessed using a Chi(2) test on n-1 degrees of freedom and the I(2) statistic. Data not suitable for pooling were tabulated and described. Fifteen studies (733 patients) were suitable for analysis. All studies were small and had variable methodology. Fish oil did not significantly affect patient or graft survival, acute rejection rates, or calcineurin inhibitor toxicity when compared to placebo. Overall SCr was significantly lower in the fish oil group compared to placebo (5 studies, 237 participants: MD -30.63 µmol/L, 95% CI -59.74 to -1.53; I(2) = 88%). In the subgroup analysis, this was only significant in the long-course (six months or more) group (4 studies, 157 participants: MD -37.41 µmol/L, 95% CI -69.89 to -4.94; I(2) = 82%). Fish oil treatment was associated with a lower diastolic blood pressure (4 studies, 200 participants: MD -4.53 mm Hg, 95% CI -7.60 to -1.45) compared to placebo. Patients receiving fish oil for more than six months had a modest increase in HDL (5 studies, 178 participants: MD 0.12 mmol/L, 95% CI 0.03 to 0.21; I(2) = 47%) compared to placebo. Fish oil effects on lipids were not significantly different from low-dose statins. There was insufficient data to analyse cardiovascular outcomes. Fishy aftertaste and gastrointestinal upset were common but did not result in significant patient drop-out. There is insufficient evidence from currently available RCTs to recommend fish oil therapy to improve kidney function, rejection rates, patient survival or graft survival. The improvements in HDL cholesterol and diastolic blood pressure were too modest to recommend routine use. To determine a benefit in clinical outcomes, future RCTs will need to be adequately powered with these outcomes in mind.

Insights into infant neuroblastomas based on an analysis of neuroblastomas detected by mass screening at 6 months of age in Japan. Mass screening (MS) for neuroblastoma (NB) at 6 months of age in Japan was discontinued in 2004. We have previously reported that the majority of NB detected by MS showed a good prognosis, with only a few cases demonstrating an unfavorable outcome (J Pediatr Surg 2002, Cancer 2001). This study aims to provide insights into infant NB by assessing the details of the clinical courses in patients treated with a standard regimen and the biological features of such cases using highly sensitive methods at one institution in Japan. In 76 NB detected through MS treated at Kyushu University Hospital, the clinical features and MYCN amplification, 1p deletion, 17q gain, the expression level of TRKA using FISH and the quantitative PCR were analyzed. Of these 76 persons with NB treated at one institution, 97 % are still alive, while 2 cases died from other diseases. Three patients experienced a recurrence after complete remission (CR), and 2 patients demonstrated refractory disease since the initial diagnosis. Two of the 3 NB patients with recurrence have demonstrated a 2nd CR, while one case still has multiple active diseases. Regarding the findings of highly sensitive biological analyses, 5/74 (7 %) showed MYCN amplification, 2/24 (8 %) cases had a 1p deletion, 3/33 (9 %) cases had a 17q gain, 5/50 (10 %) cases had diploidy, 1/25 (4 %) cases had a low expression of TRKA, and 2/76 (3 %) cases had an unfavorable histology. Of the 76 NB, 13 tumors (17 %) had one or more unfavorable factors (UF). Of the 5 refractory NB, 1 case had 3 UF, 1 case had 2 UF, 1 case had 1 UF, and 2 cases had no UF. As a result, 60 % of the refractory NB had one or more UF. Of the NB detected by MS at one institution in Japan, 17 % had one or more unfavorable factors (UF) and might have a higher risk of recurrence than the patients with no UF, although the unfavorable biology of several refractory cases is still unclear even after highly sensitive analyses. At least one-fifth of the NB cases detected by MS are anticipated cases. In infantile neuroblastomas, it may therefore be most important to analyze biologically prognostic factors using highly sensitive methods followed by immediate surgical intervention. Since the MS program has been discontinued in Japan, it will be necessary in future to assess the mortality and characteristics of NB detected clinically.

The generalized anxiety spectrum: prevalence, onset, course and outcome. Generalized anxiety disorder (GAD) is generally considered to be a chronic condition, waxing and waning in severity; however prospective investigation of the course of GAD in community samples is lacking. This study seeks to fill that gap, by identifying the whole spectrum of generalized anxiety syndromes, sub-typing them according to their duration and frequency of occurrence, and evaluating their long-term course and outcome in the community. The prospective Zurich Study assessed psychiatric and somatic syndromes in a community sample of young adults (N = 591) (aged 20 years at first interview) by six interviews over a period of 20 years (1979-1999). GAD syndromes were defined by DSM-III symptom criteria without applying any exclusion criteria. A spectrum of generalized anxiety was defined by duration: 6 months (DSM-IV), 1 month (DSM-III), < or = 2 weeks (with weekly occurrence over one year), and anxiety symptoms. From 1978 (screening) to 1999 the annual presence of symptoms and treatment was assessed. Persistence of anxiety was defined by the almost daily presence of symptoms over the previous 12 months. The annual incidence of DSM-III GAD increased considerably between the ages of 20 and 40. The average age of onset of symptoms was 15.6 years; in 75% of cases it occurred before the age of 20. 75 of 105 DSM-III GAD cases had at least one follow-up. At their individual last follow-up, 12 of those 75 subjects (16%) were re-diagnosed as having GAD, 22 (29%) manifested subthreshold syndromes or anxiety symptoms, while 39 cases, the majority, (52%) were symptom-free; 5 of the 12 re-diagnosed GAD cases were persistent (corresponding to 7% of all 75 initial GAD cases). In their twenties they were treated at some time in 6% of all years, but in their thirties this figure rose to 12%. At their individual last follow-up 26% of 6-month GAD subjects and 22% of 1-month GAD subjects were still being treated. Treated vs. non-treated subjects did not differ in terms of gender but did differ in severity, persistence and in comorbidity with bipolar-II disorder, social phobia, obsessive-compulsive syndromes and substance-use disorders. Results are based on a relatively small sample and cannot be generalized to adults aged over 40 years. The course of DSM-III-defined GAD may not be chronic, as previously suggested, but mainly recurrent with intervening symptom-free periods of recovery in about half of cases. Over a period of 20 years there was more improvement than progression within the anxiety spectrum.

Double-blind trial of the efficacy and tolerability of doxazosin in the gastrointestinal therapeutic system, doxazosin standard, and placebo in patients with benign prostatic hyperplasia. The alpha(1)-blocker doxazosin mesylate is an established efficacious and welltolerated treatment for benign prostatic hyperplasia (PBH). However, its clinical utility can be limited by the need for multiple titration steps, starting at an initial dose of 1 mg, increased up to 8 mg once daily, to achieve optimal therapeutic response. A new controlled-release gastrointestinal therapeutic system (GITS) formulation of doxazosin mesylate enhances the pharmacokinetic profile and drug delivery rate, reducing the plasma doxazosin mesylate peak-to-trough ratio and minimizing the need for titration. A study was conducted to assess the effects of doxazosin GITS 4 or 8 mg once daily, doxazosin standard 1 mg to 8 mg once daily, and placebo, in 795 men with BPH. This randomized, double-blind, multicenter Scandinavian study included a 2-week washout period, 2-week single-blind placebo run-in phase, and 13-week double-blind treatment phase. Doxazosin GITS was initiated at 4 mg once daily and titrated to 8 mg once daily after 7 weeks, if indicated, and doxazosin standard was initiated at 1 mg once daily, titrated to 2 mg after 1 week, to 4 mg at 3 weeks, and to 8 mg at 7 weeks if indicated, to achieve symptom control. The primary outcome measures were mean changes from baseline to the final visit for International Prostate Symptom Score (I-PSS) and maximum urinary flow rate adjusted for baseline values. Both doxazosin GITS and doxazosin standard significantly improved the symptoms of BPH, as evidenced by least-squares mean reductions in total I-PSS of -8.0+/-0.3 and -8.4+/-0.3 from baseline, respectively, compared with a reduction of -6.0+/-0.4 in patients on placebo. Doxazosin GITS and doxazosin standard produced clinically comparable improvements in maximum urinary flow rates, with a greater improvement observed earlier following treatment with doxazosin GITS than with doxazosin standard. Both active treatments produced significantly greater increases in maximum urinary flow rate compared with placebo. Nearly half of the patients on doxazosin GITS achieved symptom relief at the 4-mg starting dose. A similar number of patients in both doxazosin groups were titrated to the maximum dose of 8 mg for both formulations. The overall incidence of adverse events was similar among patients treated with doxazosin GITS and placebo, and slightly higher in those on doxazosin standard. There was no apparent difference in the type of adverse events reported for the two formulations of doxazosin, although most adverse events were reported at a lower frequency with doxazosin GITS. Doxazosin GITS is significantly more effective than placebo in reducing the clinical symptoms of BPH and improving maximum urinary flow rate, and as effective as doxazosin standard. A therapeutic effect equivalent to that of doxazosin standard was achieved with doxazosin GITS with fewer titration steps, in a manner that appeared to be better tolerated. Because treatment with doxazosin GITS starts with an effective dose for many patients, it is likely that this clinical profile will result in the need for fewer patient visits than with doxazosin standard therapy.

Disinfection of biologically treated wastewater and prevention of biofouling by UV/electrolysis hybrid technology: influence factors and limits for domestic wastewater reuse. Reuse of wastewater contributes significantly to an efficient and sustainable water usage. However, due to the presence of a multitude of pathogens (e.g. bacteria, viruses, worms, protozoa) in secondary effluents, disinfection procedures are indispensable. In decentralized wastewater treatment, UV irradiation represents one of the most common disinfection methods in addition to membrane processes and to a certain extent electrochemical procedures. However, the usage of UV disinfected secondary effluents for domestic (sanitary) or irrigation purposes bears a potential health risk due to the possible photo and dark repair of reversibly damaged bacteria. Against this background, the application of the UV/electrolysis hybrid technology for disinfection and prevention of bacterial reactivation in biologically treated wastewater was investigated in view of relevant influence factors and operating limits. Furthermore, the influence of electrochemically generated total oxidants on the formation of biofilms on quartz glass surfaces was examined, since its preventive avoidance contributes to an enhanced operational safety of the hybrid reactor. It was found that reactivation of bacteria in UV irradiated, biologically treated wastewater can be prevented by electrochemically produced total oxidants. In this regard, the influence of the initial concentration of the microbiological indicator organism Escherichia coli (E. coli) (9.3*10(2)-2.2*10(5) per 100 mL) and the influence of total suspended solids (TSS) in the range of 11-75 mg L(-1) was examined. The concentration of total oxidants necessary for prevention of bacterial regrowth increases linearly with the initial E. coli and TSS concentration. At an initial concentration of 933 E. coli per 100 mL, a total oxidants concentration of 0.4 mg L(-1) is necessary to avoid photo reactivation (at 4200 Lux), whereas 0.67 mg L(-1) is required if the E. coli concentration is enhanced by 2.4 log levels (cTSS = constant = 13 mg L(-1)). The prevention of dark repair is ensured with 25-50% lower concentration of total oxidants. An increase of the TSS concentration from 11 mg L(-1) to 75 mg L(-1) leads to a triplication of the need of total oxidants from 0.6 mg L(-1) to 1.8 mg L(-1) (3*10(5)E. coli per 100 mL). The energy consumption of the hybrid reactor varies from 0.17 kWh m(-3) to 0.94 kWh m(-3) depending on the TSS concentration (11-75 mg L(-1)). Furthermore, biofilm formation on quartz glass surfaces, of which the sleeves of UV lamps consist, can be suppressed by electrochemically produced total oxidants at a concentration of at least 1 mg L(-1) which ensures high operational safety of the hybrid reactor combined with large maintenance intervals.

[Imaging study of ankle injury in professional soccer player of males]. To analyze the imaging abnormal findings of ankle injuries in professional soccer player of males. The thirty-two professional soccer players in local region soccer club had been selected as research objects from March 2014 to January 2015, and all were men. Average age was 22.03±3.0 years old (19-33 years); the average age was 8.6±2.0 years old that began to engage in professional football training, and average time of engaged in football sports was 13±4 years (7-27 years). X-ray examination was used VM DR (Philips Co.), anteroposterior and lateral position of ankle joints. CT scan was used MSCT of 64 rows detector (Aquilion 64, TOSHIBA Co.). After routine scan, raw data was transmitted to the workstation and then reconstructed to be axial, sagittal, coronal imaging. MR examination was used 1.5 T superconducting equipment system (Achieva Dual, Philips Co.) and with ankle joint special phased array coil. TSE sequence be used to scan routine axial T2-weighted imaging; coronal T1-weighted imaging; coronal PWI; and sagittal T2-weighted imaging with fat suppressed. The sagittal PWI scan was used with Isotropic with fat suppressed FFE sequence. The X-ray examination was finished for 28 person and 51 ankle joints. 26 person and 52 ankle joints were completed CT scan and reconstructed imaging for all joints. MR examination was finished in 30 person and 51 ankle joints. On X-ray and CT display that the abnormal changes of the talus is most commonly found that the incidence of "dolphin mouth" like protrusion at posterior edge was 35 ankles (rate of occurrence was 68.6%), the triangle prominence at out edge was 45 ankles (rate of occurrence was 88.2%). It also was found that 8 lateral malleolus have osteophytes, 5 ankles have medial malleolus osteophytes and 12 ankles have loose bodies at posterior ankle. MRI showed that 30 ankles were the anterior talofibular ligaments injury and incidence was 58.82%, 26 ankles were posterior talofibular ligaments injury (incidence was 51.0%), 25 ankles were calcanofibular ligaments injury (incidence was 49.0%), 29 ankles was the synovitis and local effusion at posterior ankle (incidence was 56.9%), the partial ligaments injured of deltoid ligaments were usually found and entirely torn were very rare (only three ankles). The former groups and shallow ligaments of deltoid ligaments were prone to injury. The common tendon disease of injury was tenosynovitis, 18 flexor hallucis longus tenosynovitis, 13 posterior tibialis tenosynovitis,7 flexor digitorium tenosynovitis, 5 peroneus longus tenosynovitis, 2 peroneus brevis tenosynovitis and 6 Achilles tendinopathy. Tendinosis and tendon degeneration was relatively rare. The professional soccer players have been easily lead to the anatomic abnormal and pathological changes in the bones, ligaments and tendons due to long-term training and competition. The majority changes were chronic injury. Imaging examination can be found the abnormal changes of ankle and could help athletes, coachs, doctors to understand and assess the ankle structure and functional status.

Effect of CSN1S1 genotype and its interaction with diet energy level on milk production and quality in Girgentana goats fed ad libitum. A study was carried out to evaluate how the energy level of the diet can affect milk production and quality in Girgentana lactating goats in relation to polymorphism at the alphas1-casein (CSN1S1) genotype locus. Twenty-seven goats, homogeneous for milk production (1.5+/-0.3 kg/d), days of lactation (90+/-10 d) and body weight (35.8+/-5.5 kg) were selected on the basis of their CSN1S1 genotype, as follows: nine goats homozygous for strong (AA) alleles, nine goats homozygous for weak alleles (FF) and nine goats heterozygous (AF). The goats were used in a 3x3 factorial arrangement of treatments, with three genotypes (AA, FF, AF) and three diets at different energy levels (100%, 65% and 30% of hay inclusion). The experiment consisted of three simultaneous 3x3 Latin squares for the three genotypes, with one square for each level of hay inclusion in the diet. All the animals were housed in individual pens. Each experimental period lasted 23 d and consisted of 15 d for adaptation and 8 d for data and sample collection, during which the goats received the scheduled diet ad libitum. The animals were fed three different diets designed to have the same crude protein content (about 15%) but different energy levels: a pelleted alfalfa hay (H100) and two feeds including 65% (H65) and 30% (H30) of alfalfa hay (respectively 1099, 1386 and 1590 kcal NE for lactation/kg DM). All the diets were ground and pelleted (6 mm diameter). AA goats were more productive than AF and FF goats (respectively: 1419 v. 1145 and 1014 g/d; P=0.002). Indeed the interaction energy levelxgenotype was significant (P=0.018): in fact AA goats showed their milk increase only when fed with concentrates. Differences in protein and in casein levels between the three genotypes were in line with results expected from the different allele contribution to alphas1-casein synthesis. Milk urea levels were significantly lower in AA goats compared with AF and FF genotypes (respectively 32.7 v. 40.4 and 40.4 mg/dl; P=0.049) and significantly lower when goats were fed with 65H and 30H diets than with 100H diet (respectively 37.4 and 34.3 v. 41.7 mg/dl; P<0.001). Indeed, a significant interaction genotypexdiet (P=0.043) occurred for milk urea, which was significantly lower in AA goats but only when fed with concentrates (65H and 30H). Blood concentrations of energy indicators (glucose, non-esterified fatty acids and beta-hydroxybutyric acid) were not influenced by genotype. The results confirm that strong alleles are associated with a greater efficiency of feed utilization and seem to show that a high energy level of the diet can further improve this efficiency.

Effect of HLA mismatching and antibody status on "homovital" aortic valve homograft performance. Recipients of "homovital" aortic valve homografts are known to produce specific antibodies to human leukocyte antigen (HLA) determinants present on the cellular compartment of the valve tissue; however, the clinical significance of these antibodies is unknown. Data from 182 patients receiving homovital aortic valve homografts has been analyzed to determine the impact of HLA disparity and HLA antibody production on survival and function of the homograft. Human leukocyte antigen mismatch data were available for 127 patients (mean follow-up, 6.02+/-0.26 years). Two patients were considered well matched for HLA A+B antigens (zero or one mismatch) compared with 125 poorly matched (two to four mismatches). Nine patients had a zero HLA-DR mismatch compared with 52 with one mismatch and 59 patients completely mismatched for DR antigens. There was no significant association between the degree of HLA mismatch for either class I or class II antigens whether the loci were considered alone or in combination (ie, A, B, DR, AB, or ABDR mismatching) with markers of long-term valve function including patient mortality, reoperation, valve degeneration, valve stenosis, presence of regurgitation, and postoperative New York Heart Association class. One hundred thirty-six of 167 (82%) were found to have produced antibodies after operation (mean time after operation, 6.42+/-0.58 years). In 61 cases both antibody specificity and donor HLA typing was available. In 92% of these, the antibodies were of the IgG subclass and were specific for the HLA class I molecules of the donor. The presence of HLA antibodies was associated with an increase in the frequency of mild valve stenosis (not significant) compared with those patients who did not develop HLA antibodies (antibody negative = 9.7%; panel reactive antibodies <50% = 29.1%; and panel reactive antibodies >50% = 22.2%; not significant). There was also an increased prevalence of valve degeneration associated with HLA antibodies. The actuarial freedom from valve degeneration for the 35 HLA antibody-negative patients was 100% at 1, 5, and 10 years compared with 100% at 1 year, 97% at 5 years, and 92% at 10 years for 55 patients with panel reactivity less than 50%, and 98% at 1 year, 94% at 5 years, and 88% at 10 years for the 77 patients who were highly sensitized (not significant). There was no correlation with other markers of long-term valve function. The influence of the immune response on valve function requires further studies involving large numbers of patients followed for a longer period of time. We believe prospective matching for HLA antigens is warranted to produce a well-matched cohort of patients for analysis and to reduce antibody sensitization, which would help to clarify this issue.

Effect of a high nutrient density diet on long-term weight loss: a retrospective chart review. A high nutrient density (HND) vegetable-based diet offers a dietary model extremely low in saturated fat as well as refined carbohydrates and emphasizes a liberal intake of fresh fruits, vegetables, beans, and nuts. We conducted a retrospective chart review of patients who came to a family practice office seeking nutritional counseling for weight loss. All of these patients were prescribed an HND diet in an extended counseling session with a family physician. A convenience sample (N = 56) of all patients seeking dietary counseling for weight loss from a family practice physician in a 3-year period was included in the chart review. No personal identifying data were recorded. The initial counseling sessions averaged 1 hour in length. Patients were provided with a sample HND daily meal plan and recipes and with verbal and written information about the rationale for the diet. Data recorded from patients' charts at 6-month intervals for up to 2 years of follow-up (when available) included weight, blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and cholesterol:HDL ratio. Non-parametric statistical testing using the Friedman rank order (exact) test for k-related samples was conducted. A follow-up survey on adherence and medication use was completed by 38 patients. Of the 33 patients who returned for follow-up after 1 year, the mean weight loss was 31 lbs (P = .000). Of the 19 patients who returned after 2 years, the mean weight loss was 53 lbs (P = .000), mean cholesterol fell by 13 points, LDL by 15 points, triglycerides by 17 points, and cardiac risk ratio dropped from 4.5 to 3.8. Changes in systolic and diastolic blood pressure were highly significant at all follow-up time intervals (P < or = .001). There was a significant correlation between adherence and degree of weight loss (P = .011). Weight loss was sustained in patients who returned for follow-up and was more substantial in those who reported good adherence to the recommendations. However, many patients were lost to follow-up. Favorable changes in lipid profile and blood pressure were noted. An HND diet has the potential to provide sustainable, significant, long-term weight loss and may provide substantial lowering of cardiac risk in patients who are motivated and provided with extended one-on-one counseling and follow-up visits. Development of tools to aid in patient retention is an area for possible further study. Clinical trials with long-term follow-up are needed to further test the therapeutic potential and to examine adherence and follow-up issues related to this dietary approach. An HND diet as demonstrated with this group may be the most health-favorable and effective way to lose weight for appropriately motivated patients.

[Studies of cerebral blood flow and metabolism in patients with senile dementia of the Alzheimer's type and diagnostic evaluation of the dementing illnesses by positron emission tomography]. This study was designed to estimate cerebral dysfunction in senile dementia of the Alzheimer's type (SDAT). Regional cerebral blood flow (rCBF), oxygen extraction fraction (rOEF) and cerebral oxygen consumption (rCMRO2) were studied in 16 patients with SDAT and 5 age-matched normal elderly people by positron emission tomography (PET), using the 15O labeled CO2 and O2 inhalation technique. This technique was also applied to the evaluation of PET in diagnosing the dementing illnesses. In this study, a total of 19 pairs of bilateral cerebral regions were analyzed and the reductions of rCBF and rCMRO2 in each region were compared with those of the primary sensorimotor cortex to demonstrate any significant localized difference between each clinical stage of the SDAT and normal controls. In the mild SDAT group, CMRO2 of the temporal cortex was significantly reduced, as compared with that of controls. In the moderate SDAT group, CBF of the temporal cortex and CMRO2 of the temporal and parietal cortices were significantly reduced. In the severe SDAT group, CBF and CMRO2 of the frontal cortex were also reduced and those of the occipital cortex were relatively unchanged. This suggested that mildly demented patients showed a metabolic reduction in the temporal cortex and as the dementia progressed, metabolic reductions were extended to the parietal and frontal cortices. Reductions in blood flow were followed by further metabolic reductions. More detailed investigation of the PET images of SDAT revealed that relative oxygen hypometabolism of the posterior temporal and posterior parietal association cortices occurred in the mildly demented patients earlier than that of the other association cortices. These findings are consistent with neuropathological studies of SDAT. The right/left ratio of rCMRO2 was also analyzed in each region. The right/left oxygen metabolic asymmetry in the temporal and parietal cortices was correlated with the difference between speech and visuospatial functions. Namely, the patients with a lower metabolism in the left hemisphere had more disturbances in speech than visuospatial functions. In addition, the PET images of SDAT were compared with those of multi-infarct dementia (MID) and Pick disease. In patients with MID, there were reductions of CBF and CMRO2 unhomogenously all over association cortices, but the reductions were most remarkable in the frontal cortex. Patients with Pick disease showed diffuse lobar reductions of CBF and CMRO2 in the frontal and temporal cortices.(ABSTRACT TRUNCATED AT 400 WORDS)

[Interaction of Dystamycin Dimeric Analog with Poly(dA) x poly(dT), Poly[d(A-T)] x poly[d(A-T)] and Duplex O23 at Origin of Replication of the Herpes Simplex Virus]. The binding of distamycin dimeric analog (Pt-bis-Dst) to poly[d(A-T)] x poly[d(A-T)1, poly(dA) x poly(dT) and duplex O23 with the sequence 5'-GCCAATATATATATATTATTAGG-3' which is present at the origin of replication of herpes simplex virus OriS is investigated with the use of UV and CD spectroscopy. The distinction of the synthetic polyamide from a natural antibiotic lies in the fact that in the synthetic polyamide there are two distamycin moieties bound via a glycine cis-diamino platinum group. It was shown that the binding of Pt-bis-Dst to poly[d(A-T)] x poly[d(A-T)] and poly(dA) x poly(dT) reaches saturation if one molecule of the ligand occurs at approximately every 8 bp. With further increase in the ratio of the added ligand to the base pairs in CD spectra of complexes with poly[d(A-T)] x poly[d(A-T)], we observed that the maximum wavelength band tend to be shifted towards longer wavelengths, while in the spectral region of 290-310 nm a "shoulder", that was absent in the spectra of the complexes obtained at low polymer coverages by the ligand, appeared. At high molar concentration ratios of ligand to oligonucleotide Pt-bis-Dst can bind to poly[d(A-T)] x poly[d(A-T)] in the form of hairpins or may form associates by the interaction between the distamycin moieties of neighboring molecules of Pt-bis-Dst. The structure of the complexes is stabilized by interactions between pirrolcarboxamide moieties of two molecules of Pt-bis-Dst adsorbed on adjacent overlapping binding sites. These interactions are probably also responsible for the concentration-dependent spectral changes observed during the formation of a complex between Pt-bis-Dst and poly[d(A-T)] x poly[d(A-T)]. Spectral changes are almost absent in binding of Pt-bis-Dst to poly(dA) x poly(dT). Binding of Pt-bis-Dst to duplex O23 reaches saturation if two ligand molecules occur in a duplex that contains a cluster of 18 AT pairs. With increasing the molar concentration ratio of the ligand to the duplex CD spectra undergo concentration-dependent changes similar to those observed during binding of Pt-bis-Dst to poly [d(A-T)] x poly[d(A-T)]. Testing for antiviral efficacy of Pt-bis-Dst showed that the concentration, at which the cytopathic effect produced by the herpes simplex virus in cell culture Vero E6 halved, is equal to 1.5 μg/ml and the selectivity index for evaluating antiviral activity is 65 at a relatively low cytotoxicity. The concentration of Pt-bis-Dst, at which approximately half the cells are killed, is equal to 100 μg/ml.

A review of thyroid cancer with intermediate differentiation. Tall cell (TCV), columnar cell (CCV), insular (IC), diffuse sclerosing (DSPTC) and solid/trabecular are uncommon subtypes of thyroid cancer, which have generally been described in case reports or small series in the world literature. Due to the rarity of these thyroid cancers, their clinical behavior remains incompletely understood. The aim of this review was to pool the currently available clinical information regarding these uncommon thyroid cancers so as to gain a better understanding of their clinical aspects and natural history. A computer-aided search of MEDLINE (1966-2001, PUBMED website) and CINAHL (1982-2001) databases was performed, as well as a review of the reference section of each primary study was done. All cases of TCV, CCV, DSPTC, solid/trabecular, and IC described in the English medical literature were identified. For the subtypes DSPTC, TCV, and IC, clinical data from the published case series were combined in a weighted analysis. Weighting was based on the number of cases per series. For the CCV and the solid/trabecular variant, due to the small number of cases, raw figures for the clinical features were obtained. DSPTC (n = 65) appeared to have a tendency for intra-thyroidal extension (40%) and a high propensity for nodal metastates (68%). The mean overall tumor related mortality was similar to well differentiated thyroid cancer (WDTC) at only 2% at 8 years follow-up. The solid/trabecular variant was seen in 37% of the radiation induced thyroid tumors of the Chernobyl accident. It had a high propensity for extrathyroidal extension, and cervical lymph node metastases were found in up to 83% of patients. Unlike WDTC, TCV (n = 209) was a more aggressive tumor, associated with distant metastases in 22% of cases and had a mean tumor related mortality of 16%. The histological diagnosis of TCV was a poor prognostic factor regardless of patient age or tumor size. The CCV (n = 41) had a high overall mortality rate of 32%. When encapsulated, however, CCV had an excellent prognosis similar to that found in WDTC. In contrast, CCV tumors that were not encapsulated had extrathyroidal spread in 67% and had distant metastases in 87% of patients. The variant of IC (n = 213) appeared to be an aggressive subtype of thyroid cancer. The mean loco-regional recurrence and/or distant metastases rate was 64% and tumor related mortality was high at 32%. DSPTC, TCV, CCV, and IC are thyroid cancer subtypes, which have a biological aggressiveness, which appear to be intermediate between that of WDTC and poorly differentiated anaplastic thyroid cancer. J. Surg. Oncol. 2004;86:44-54.

Effects of 3 surface types on dairy cattle behavior, preference, and hygiene. Muddy surfaces have negative effects on the health and welfare of dairy cattle, and if possible, cows will avoid this surface. However, it is unclear whether it is the moisture content or the contamination with manure that is aversive to the cows. This study aimed to assess the use and preference for different wood chip (0.4 m deep) surface types: (1) clean and dry (clean, dry matter content, DM: 44 ± 2.8%), (2) dirty (dirty, contaminated with manure, DM: 40 ± 3.7%), and (3) clean and wet (wet, wetted by water, DM: 23 ± 3.3%). Eighteen nonlactating, pregnant cows were tested individually (mean 24-h temperature: 9.9 ± 4.46°C, mean ± standard deviation for all preceding values). Cows were kept indoors in test pens for 18 h on wood chip without feed and 6 h on pasture to allow for daily feed intake. To ensure cows made informed choices and to measure changes in behavior and hygiene associated with each option, they were first exposed to each surface for 5 d (n = 12 cows per surface type when they were restricted on one surface; i.e., each cow was exposed to 2 treatment surfaces only). Cows on the wet surface spent the least amount of time lying when restricted to one surface for 18 h (wet: 21%, dirty: 57%, clean: 64%) and spent more time lying when on pasture for 6 h (wet: 13%, dirty: 4%, clean: 3%). The total lying times during the 5-d surface exposure were wet: 4.6 ± 1.04 h, dirty: 10.6 ± 0.25 h, and clean: 11.7 ± 0.25 h per 24 h. Cows restricted on the wet surface for 18 h had fewer bouts (no.) of lateral lying (wet: 0.9 ± 1.36, dirty: 6.3 ± 1.36, clean: 8.4 ± 1.38), spent less time lying with their heads supported (wet: 18.9 ± 7.17 min, dirty: 36.7 ± 7.17 min, clean: 39.1 ± 7.26 min), and spent less time with the front legs tucked (wet: 16 ± 4.3%, dirty: 41 ± 4.3%, clean: 50 ± 4.3% of time spent lying, mean ± standard error of the mean for all preceding values), than cows on the other surfaces. Cows on the dirty surface were less clean compared with the other treatment groups (0.6 of a score on a 5-point scale; standard error of the differences of means: 0.11 for both comparisons). They were then given a free choice between 2 known surfaces for 2 consecutive days (n = 6 per pairwise choice). Cows ranked the surfaces as clean > dirty > wet. In summary, there is compelling evidence that wet surfaces impair the welfare of dairy cattle by affecting the quantity and quality of rest. Rebound responses indicate that the motivation to rest is not fulfilled on wet surfaces. Finally, when given a choice, they show clearly that they will avoid wet and dirty surfaces. The combined results indicate that changes in affective state likely underlie these behavioral responses.

Femoral neck response to exercise and subsequent deconditioning in young and adult rats. Aged bones have been considered to have reduced capacity to respond to changes in incident loading. By subjecting young and adult rats to increased loading and subsequent deconditioning, we observed quantitatively similar adaptive responses of bone in these two groups, but young skeletons adapted primarily through geometric changes and adult bones through increased volumetric density. Loss of the exercise-induced bone benefits did not depend on age. Aging has been shown to decrease the sensitivity of the mechanosensory cells of bones to loading-induced stimuli, presumably resulting in not only reduced capacity but also different adaptive mechanism of the aged skeleton to altered loading, as well as poorer capacity to preserve exercise-induced bone benefits. Fifty young (5-week-old) and 50 adult (33-week-old) male rats were randomized into control and exercise (+deconditioning) groups. After a 14-week progressively intensified running program, one-half of the exercised rats (both young and adult) were killed, and the remaining rats underwent subsequent 14-week period of deconditioning (free cage activity). A comprehensive analysis of the femoral neck was performed using peripheral quantitative computed tomography and mechanical testing. In comparison with the controls, both young and adult exercised rats had significant increases in almost all measured parameters: +25% (p < 0.001) and +10% (not significant [NS]) in the cross-sectional area; +28% (p < 0.001) and +18% (p < 0.001) in bone mineral content; +11% (p < 0.05) and +23% (p < 0.001) in bone mineral density; and +30% (p < 0.01) and +28% (p < 0.01) in the breaking load, respectively. The skeletal responses were not statistically different between the young and adult rats. After the 14-week period of deconditioning, the corresponding exercised-to-controls differences were +17% (p < 0.05) and +10% (NS), +18% (p < 0.05) and +13% (p < 0.05), +2% (NS) and +2% (NS), and +11% (NS) and +6% (NS), respectively. Again, the response differences were not significant between the age groups. Quantitatively, the capacity of the young and adult skeleton to adapt to increased loading was similar, but the adaptive mechanisms appeared different: growing bones seemed to primarily display geometric changes (increase in bone size), whereas the adult skeleton responded mainly through an increase in density. Despite this apparent difference in the adaptive mechanism, aging did not modulate the ability of the skeleton to preserve the exercise-induced bone gain, because the bone loss was similar in the young and adult rats after cessation of training.

A two- and five-year follow-up of clinical outcome after ACL reconstruction using BPTB or hamstring tendon grafts: a prospective intervention outcome study. The aim of the present study was to evaluate and compare objective and subjective outcome in patients 2 and 5 years after anterior cruciate ligament (ACL) reconstruction with either bone-patellar tendon-bone (BPTB) or hamstring grafts. The second aim was to report the prevalence of re- and contralateral ACL ruptures. Sixty-eight patients (BPTB, n = 34 and hamstring graft, n = 34) were evaluated preoperatively, 2 and 5 years after ACL reconstruction. Anterior knee laxity and rotational knee joint stability, muscle torque, hop length, anterior knee pain, activity level and self-reported knee function and quality of life were evaluated within and between groups. The prevalence of re- and contralateral ACL ruptures was also recorded. No significant difference in anterior knee laxity, rotational knee joint stability, hop length anterior knee pain or knee function and quality of life were noted at the 5-year follow-up. No significant differences in concentric or eccentric quadriceps torque at 90°/s and 230°/s were found at any of the follow-ups between and within grafts. A significant group difference in hamstring torque 1.05 (0.02) for BPTB and 0.89 (0.02) for hamstring grafts, and in hop length (leg symmetry index) follow-up 0.94 (0.07) for BPTB compared to 0.99 (0.07) for hamstring grafts (P = 0.002) was found at the 2 year follow-up in favour of the BPTB graft, but not at the 5 year follow-up. A significant improvement over time, irrespective of graft, was found in the KOOS's subscales Sport/Rec and quality of life (P < 0.001). None of the patients, irrespective of group, returned to their pre-injury level of sport (P < 0.05). Over the five postoperative years, one man and eight women (13 %) (hamstring graft, n = 5 and BPTB graft, n = 4), sustained a total of 11 (16.2 %) new ACL ruptures: seven (10.2 %) re-ruptures and four (5.9 %) ruptures of the contralateral ACL. At the 5-year follow-up, there were no significant differences in terms of anterior knee laxity, rotational knee joint stability, muscle torque, anterior knee pain, hop performance, quality of life or activity level between patients who had undergone reconstruction with BPTB or hamstring grafts. None of the patients, irrespective of group, had returned to their pre-injury level of activity. Eight out of the nine patients who had sustained a second ACL rupture were women.

Community-based adolescent health services in Israel: from theory to practice. Despite their engagement in health-risk behaviors and their health-related concerns, adolescents have the lowest rate of health service utilization of any age group. Time constraints during routine medical encounters generally leave little opportunity for professional screening for health-risk behaviors or for discussing psychosocial problems. In addition, providers express low levels of perceived competency in areas such as sexuality, eating disorders or drug abuse. To address these needs, a walk-in Adolescent Health Service was established by the Sheba Medical Center to provide diagnosis and short-term treatment for individual adolescents, as well as counseling and support for local care providers. A three-way model of cooperation and partnership was developed and implemented. A professional and financial partnership with local authorities were established to help define the particular needs of the community's youth and to improve the ability to reach youth with special health needs. The partnership along with the main medical provider (Kupat Holim Clalit) helped define local health needs, served as a referral source of patients with unmet health needs, and improved the continuity of care. The regional medical center (Sheba Medical Center) provided supervision and consultation for the medical staff of the service, as well as a referral center for patients. It was emphasized that the service staff was intended as a professional source for the primary physician and should not be considered a rival. The core staff included a specialist in adolescent medicine, gynecologist, mental health specialist and social worker. A structured intake procedure was developed for assessing health concerns and problems of adolescents in the context of a community clinic. Findings from the first years of services showed that the first 547 female adolescents demonstrated that a majority of adolescents presented with primary complaints of a somatic nature, while one third were diagnosed with psychosocial problems and one-fifth with a sexuality-related problem. A considerable percentage of those diagnosed with psychosocial or sexuality-related problems had not stated these issues as their "reason for encounter". This additional increment probably represents the contribution of the Health Concern Checklist (HCC), in which the adolescent was asked to mark each item for which she had concerns or would like to receive further information. The HCC can help primary care physicians as well as adolescent medical specialists approach the teenage patient and initiate productive communication. A practical approach to confidential health care for adolescents: The issue of confidentiality has not been sufficiently clarified by Israeli law or by the medical community. The need for confidentiality was strongly felt in the adolescent health service. A policy which provides all adolescents with the opportunity to meet with a physician and receive health guidance or advice at least once, even without parental knowledge or consent, was formulated and implemented. If parental consent was not feasible, the minor was allowed to give informed consent for medical and psychosocial care for himself/herself, with certain limitations.

Outcomes following attempted en bloc resection of cervical chordomas in the C-1 and C-2 region versus the subaxial region: a multiinstitutional experience. Chordomas involving the mobile spine are ideally managed via en bloc resection with reconstruction to optimize local control and possibly offer cure. In the cervical spine, local anatomy poses unique challenges, limiting the feasibility of aggressive resection. The authors present a multi-institutional series of 16 cases of cervical chordomas removed en bloc. Particular attention was paid to clinical outcome, complications, and recurrence. In addition, outcomes were assessed according to position of tumor at the C1-2 level versus the subaxial (SA) spine (C3-7). The authors reviewed cases involving patients who underwent en bloc resection of cervical chordoma at 4 large spine centers. Patients were included if the lesion epicenter involved the C-1 to C-7 vertebral bodies. Demographic data and details of surgery, follow-up course, exposure to adjuvant therapy, and complications were obtained. Outcome was correlated with presence of tumor in C1-2 versus subaxial spine via a Student t-test. Sixteen patients were identified (mean age at presentation 55 ± 14 years). Seven cases (44%) cases involved C1-2, and 16 involved the subaxial spine. Median survival did not differ significantly different between the C1-2 (72 months) and SA (60 months) groups (p = 0.65). A combined (staged anteroposterior) approach was used in 81% of the cases. Use of the combined approach was significantly more common in treatment of subaxial than C1-2 tumors (100% vs 57%, p = 0.04). En bloc resection was attempted via an anterior approach in 6% of cases (C1-2: 14.3%; SA: 0%; p = 0.17) and a posterior approach in 13% of cases (C1-2: 29%; SA: 0%; p = 0.09). The most commonly reported margin classification was marginal (56% of cases), followed by violated (25%) and wide (19%). En bloc excision of subaxial tumors was significantly more likely to result in marginal margins than excision of C1-2 tumors (C1-2: 29%; SA: 78%; p = 0.03). C1-2 tumors were associated with significantly higher rates of postoperative complications (C1-2: 71%; SA: 22%; p = 0.03). Both local and distant tumor recurrence was greatest for C1-2 tumors (local C1-2: 29%; local SA: 11%; distant C1-2: 14%; distant SA: 0%). Statistical analysis of tumor recurrence based on tumor location was not possible due to the small number of cases. There was no between-groups difference in exposure to postoperative adjuvant radiotherapy. There was no difference in median survival between groups receiving proton beam radiotherapy or intensity-modulated radiotherapy versus no radiation therapy (p = 0.8). Compared with en bloc resection of chordomas involving the subaxial cervical spine, en bloc resection of chordomas involving the upper cervical spine (C1-2) is associated with poorer outcomes, such as less favorable margins, higher rates of complications, and increased tumor recurrence. Data from this cohort do not support a statistically significant difference in survival for patients with C1-2 versus subaxial disease, but larger studies are needed to further study survival differences.

CT energy weighting in the presence of scatter and limited energy resolution. Energy-resolved CT has the potential to improve the contrast-to-noise ratio (CNR) through optimal weighting of photons detected in energy bins. In general, optimal weighting gives higher weight to the lower energy photons that contain the most contrast information. However, low-energy photons are generally most corrupted by scatter and spectrum tailing, an effect caused by the limited energy resolution of the detector. This article first quantifies the effects of spectrum tailing on energy-resolved data, which may also be beneficial for material decomposition applications. Subsequently, the combined effects of energy weighting, spectrum tailing, and scatter are investigated through simulations. The study first investigated the effects of spectrum tailing on the estimated attenuation coefficients of homogeneous slab objects. Next, the study compared the CNR and artifact performance of images simulated with varying levels of scatter and spectrum tailing effects, and reconstructed with energy integrating, photon-counting, and two optimal linear weighting methods: Projection-based and image-based weighting. Realistic detector energy-response functions were simulated based on a previously proposed model. The energy-response functions represent the probability that a photon incident on the detector at a particular energy will be detected at a different energy. Realistic scatter was simulated with Monte Carlo methods. Spectrum tailing resulted in a negative shift in the estimated attenuation coefficient of slab objects compared to an ideal detector. The magnitude of the shift varied with material composition, increased with material thickness, and decreased with photon energy. Spectrum tailing caused cupping artifacts and CT number inaccuracies in images reconstructed with optimal energy weighting, and did not impact images reconstructed with photon counting weighting. Spectrum tailing did not significantly impact the CNR in reconstructed images. Scatter reduced the CNR for all energy-weighting methods; however, the effect was greater for optimal energy weighting. For example, optimal energy weighting improved the CNR of iodine and water compared to energy-integrating weighting by a factor of approximately 1.45 in the absence of scatter and by a factor of approximately 1.1 in the presence of scatter (8.9 degrees cone angle, SPR 0.5). Without scatter correction, the difference in CNR resulting from photon-counting and optimal energy weighting was negligible (< 15%) for cone angles greater than 4.4 degrees (SPR > 0.3). Optimal weights combined with deterministic scatter correction provided a 1.3 and 1.1 improvement in CNR compared to energy-integrating and photon-counting weighting, respectively, for the 8.9 degrees cone angle simulation. In the absence of spectrum tailing, image-based weighting demonstrated reduced cupping artifact compared to projection-based weighting; however, both weighting methods exhibited similar cupping artifacts when spectrum tailing was simulated. There were no statistically significant differences in the CNR resulting from projection an image-based weighting for any of the simulated conditions. Optimal linear energy weighting introduces artifacts and CT number inaccuracies due to spectrum tailing. While optimal energy weighting has the potential to improve CNR compared to conventional weighting methods, the benefits are reduced as scatter increases. Efficient methods for reducing scatter and correcting spectrum tailing effects are required to obtain the highest benefit from optimal energy weighting.

Morbidity and mortality of short-bowel syndrome in infants with abdominal wall defects. Total parenteral nutrition (TPN) has made survival beyond infancy possible for many infants who have sustained small intestinal loss as a result of gastroschisis or omphalocele. The length and quality of life in these patients have often been limited by the development of late sequelae secondary both to the protracted use of TPN and the long-term complications of a shortened gut. This study was undertaken to determine what factors influence the morbidity and mortality of short-bowel syndrome (SBS) due to gastroschisis or omphalocele. A retrospective chart review of 850 infants who received TPN from January 1977 through December 1999 was carried out. All infants were treated at one academic medical center; those who had received > or =3 months of TPN were further segregated and their diagnosis, surgical procedures, length of bowel, ability to wean from TPN, follow-up weight and height, and developmental progress were recorded. Seventeen children were identified with SBS and either gastroschisis or omphalocele. Tight primary or secondary closure of the abdominal wall was believed to be a major cause of bowel necrosis and SBS in at least ten of the 17 patients. Overall survival was 76 per cent (13/17); survival was correlated with length of remaining bowel and was 86 per cent in patients having more than 15 cm of small bowel remaining but only 33 per cent in patients with less than 15 cm of small bowel remaining (P = 0.05). A longer length of residual small bowel resulted in a significantly shorter duration of TPN with a mean duration of 1.0 year for survivors having >38 cm and 10.0 years for survivors with <38 cm of bowel remaining (P = 0.03). Hepatic dysfunction with progressive failure resulting from TPN was related to death in three of the four nonsurvivors. The presence or absence of an ileocecal valve appeared unrelated both to the success of TPN weaning and to the length of time on TPN (P > 0.2). Eight of the 13 survivors have no ileocecal valve; five have undergone >50 per cent colonic resection. Nine of the survivors have adapted to enteral feedings (mean 36 +/- 60 months) during which time weaning from TPN occurred. The mean age of survivors is 7.9 +/- 5.1 years. Near-normal weights (defined as exceeding the fifth percentile for weight) were achieved for 92 per cent of the patients (12/13) with 46 per cent of the patients (6/13) exceeding the 50th percentile. Near-normal heights (exceeding the fifth percentile) were achieved for 77 per cent of the patients (10/13) with 15 per cent of the patients (2/13) exceeding the 50th percentile. Quality of life was measured on the basis of return to public school: nine of ten school-age survivors attend school and eight are normal without signs of developmental delay. Tight abdominal closure of gastroschisis or omphalocele may cause bowel necrosis and SBS. TPN has improved the long-term survival and quality of life in infants with SBS.

[Dynamics of soil properties under secondary succession forest communities in Mt. Jinyun]. Mt. Jinyun is located in the north suburb of Chongqing, 30 km away from the city center. It is rich in forest plants, an epitome of forests in north tropical areas of China. Under anthropocentric disturbance, there still exist large numbers of succession communities, and the process of successive development follows the way of shrub-grassland (X1)-->coniferous forest (X2)-->coniferous-broad leaved mixed forest (X3)-->evergreen broad-leaved forest (X4). By now, soil and water conservation is very important in the Three Gorges area of Yangtze River, and the investigation on the secondary succession of the forests could help to realize the changes of the forests and soils under anthropocentric disturbance, and supply information on the protection of natural forests and the artificial reforestation of this area. In this paper, some typical and representative plant communities in different succession stages were selected to study the plant composition and type and the soil properties, with species diversity indices and canopy density investigated in many standard squares and soil physical and chemical characteristics analyzed. The results showed that there were obvious variations of soil properties with time. As the plant community developed from primary stage to climax, the contents of soil organic matter, total N, and available N and K increased in order of X1 < X2 < X3 < X4, soil pH changed from 5.23 (X1) to 4.06 (X4), soil base saturation varied from 58.3% (X1) to 37.7% (X4), and soil CEC increased with the succession. It was suggested that an intense soil acid leaching was occurred in Mt. Jinyun. The contents of soil organic matter and total N in different layers showed a trend of A>B>C, e. g., soil total nitrogen in evergreen broad leaved forest was 2.31(A), 0.66(B) and 0.12(C)g x kg(-1). Gray analysis was used to study the relationships of soil properties between the climax community and other three succession communities. The relation coefficient was 0.461 0 (X3), 0.586 2(X2) and 0.6821 (X1), respectively, indicating that soil nutrients were accumulated as the forest succession community progressed. The plant arbor species followed the sequence of 0 (X1) < 7.5 (X2) < 9.0 (X3) < 12.8 (X4), and the canopy density ranked as the same way. Plant community could affect soil nutrient reserves significantly. Multivariate variance analysis showed that soil properties varied significantly among different seasons, but this variation had no impact on the community replacement and soil development during the chronosequence of community succession. The variation of soil properties adapted well to each successive community.

Does co-morbid depression impact diabetes related costs? Evidence from a cross-sectional survey in a low-income country. The economic implications of co-morbid depression in patients with chronic medical disorders have been studied mainly in high-income countries. However, the applicability of such findings in developing countries cannot be assumed. In the present study we estimate diabetes related costs and explore the link between depression and diabetes related costs in Romania. In this former communist country, the general perception of practitioners and policy-makers is that psychological issues are far less important than medical concerns for patients with diabetes, a perception that may lead to the misallocation of already scarce resources. Data related to costs of diabetes care and to co-morbid depression were collected from a sample of 1,171 diabetes patients at the Nutrition and Diabetes Center in Cluj-Napoca, Romania, using the Diabetes Costs Questionnaire (DCQ) and the Patient Health Questionnaire 9 (PHQ9). The gathered data were subjected to a bivariate analysis of the depression-cost relationship, as well as a regression analysis in order to isolate the effect of depression on diabetes related costs from the effect of covariates. Direct and indirect diabetes related costs equally contributed to the total costs. The repartition of the cost burden between the public system and private agents is nearly equal as well. The bivariate analysis of the depression-cost relationship reveals statistically significant larger diabetes related costs for patients with major depression than for patients with minor depression, and the latter have larger diabetes related costs than patients free of depression symptoms. When the pure effect of depression on diabetes related costs was isolated by means of regression techniques, the provisional diagnosis of major depression was found to significantly increase diabetes related costs. The equal distribution of diabetes related costs between direct and indirect measures, as well as the cost burden equally split between the public system and private agents can be explained by the costs of medication and the costs associated with time lost by the non-compensated caregivers. Consistent with Romanian cultural traditions, most of the patients rely on their relatives in an informal diabetes caregiving market for assistance. Alongside depression, the multivariate analysis revealed that factors such as Hungarian ethnicity, income, and number of years since diagnosis also significantly contribute to diabetes related costs. Findings that depression increases diabetes related costs bear potential implications for health policies and health care provision (i.e., the effect of depression on costs can be minimized by adequate recognition and treatment). As such, screening and treatment of co-occurring depression in diabetes patients should become part of the diabetes treatment protocol, not only in Romania but in other Central and Eastern European countries as well.

Analysis of the individual and combined reactivities of monoclonal antibodies H25, H366, and MY9 with normal progenitor cells and blast cells from patients with acute myeloblastic leukemia. Recently we reported that two monoclonal antibodies (MoAbs), H25 and H366, which react with human natural killer cells and monocytes, also react with normal in vitro colony-forming cells including granulocyte-monocyte colony-forming units (CFU-GM), erythroid burst-forming units (BFU-E), and erythroid colony-forming units and with leukemic blasts in preliminary testing of cells from patients with myeloid leukemias and T cell acute lymphocytic leukemia. In the present studies we examined the reactivities of MoAbs H25, H366, and MY9 (singly or combined) with the total leukemic cell population and the leukemic clonogenic cells (L-CFC) from 28 patients with acute myeloblastic leukemia. Using cytofluorography, we found the extent of expression of antigen H25 comparable to MY9 in the majority of patients, and both were more highly expressed than antigen H366. Incubation with H25 and H366 MoAbs simultaneously did not increase the number of positive cells over that seen when stained with H25 alone; however, the amount of antibody fluorescence intensity (FI) was increased. Leukemic cells simultaneously stained with MoAbs H25, H366, and MY9 displayed the highest number of positive cells and FI. Using magnetic beads coated with sheep anti-mouse IgG for depleting antibody-binding cells, greater than or equal to 90% of L-CFC were depleted by a combination of H25 and H366 MoAbs in 76% of AML cases tested as compared to 41% of the cases with MoAb MY9. Using a MoAb cocktail of H25, H366, and MY9, greater than or equal to 90% of L-CFC were depleted in 94% of cases tested, and greater than or equal to 99% of L-CFC were removed in 76% of the cases. Using the same depletion methods for normal bone marrow cells, a combination of anti-H25 and anti-H366 removed 90%, 98%, and 84% of CFU-GM, BFU-E, and multipotent colony-forming units (CFU-GEM), respectively, whereas the cocktail of H25, H366, and MY9 MoAbs removed 98%, 99.5%, and 97% of CFU-GM, BFU-E, and CFU-GEM, respectively. Incubation of H25 and H366-depleted bone marrow cells for 2 weeks in the presence of irradiated adherent cell layers from long-term marrow cultures generated CFU-GM and some BFU-E, as did H25, H366, and MY9-depleted marrow cells, although to a much lesser extent. Based on the overall data, combinations of H25, H366, and MY9 MoAbs and immunomagnetic beads conceivably might have therapeutic potential for ex vivo elimination of leukemic cells from AML remission marrows prior to autologous transplantation.

The ability of the Lauge-Hansen classification to predict ligament injury and mechanism in ankle fractures: an MRI study. The Lauge-Hansen classification system was designed to predict the mechanism and ligament injury patterns of ankle fractures on the basis of x-rays. The purpose of this study was to evaluate the accuracy of these predicted injury sequences using magnetic resonance imaging (MRI) in a series of patients with ankle fractures. Retrospective cohort. Two university level 1 trauma centers. Fifty-nine patients with operative ankle fractures who were evaluated with both x-ray and MRI were included. All patients had a standard 3-view ankle x-ray series before fracture reduction, followed by an MRI. All plain x-rays were assigned to a Lauge-Hansen category by an experienced orthopedic traumatologist. MRI studies were subsequently read by an MRI musculoskeletal radiologist for the integrity of the ankle ligaments. After evaluation of the x-rays, fractures were classified according to the system of Lauge-Hansen, and the predicted presence, sequence, and mechanism of injury was determined. These were then compared to the actual injured structures on MRI in each case, and the ability of the Lauge-Hansen system to accurately predict the complete injury pattern was determined for the entire cohort. Average patient age was 59 (range: 18 to 84) years. Of the 59 ankle fractures evaluated, 37 (63%) were classified as supination external rotation, 11 (19%) were pronation external rotation, 1 (2%) was supination adduction, and 10 (17%) were not classifiable on the basis of the Lauge-Hansen system. Of the 49 fractures that fit into Lauge-Hansen categories, 26 (53%) had patterns of ligamentous injury and fracture morphology that did not coincide with the Lauge-Hansen predictions. A common fracture pattern was observed in 8 of the 10 unclassifiable fractures, which included a high spiral fracture of the fibula, vertical shear fracture of the medial malleolus, posterior malleolar fracture, and complete tears of the anterior-inferior tibiofibular ligament and the interosseous membrane. In addition, over 65% of patients in this series had complete ligamentous injury and a fracture of the malleolus to which the ligament attaches. These results demonstrate that the Lauge-Hansen classification system may have some limitations as a predictor of the mechanism of injury and the presence of soft-tissue damage associated with ankle fractures. The identification of a novel pattern of ankle fracture also illustrates how the system fails to describe all possible fracture patterns. For these reasons, we recommend that the Lauge-Hansen system be used only as a guide in the diagnosis and management of ankle fractures and not solely relied upon for treatment decisions. Although the exact clinical implications of the variety of ligamentous injuries observed on MRI are yet to be determined, this technique may be useful in individual cases in which doubt about joint stability and soft-tissue integrity exists. Additionally, MRI may be helpful in planning surgical approaches in atypical fractures in which injury patterns are less predictable solely on the basis of x-ray.

Thalidomide and the immune system. 3. Simultaneous up- and down-regulation of different integrin receptors on human white blood cells. Time-dependent changes in the surface receptor expression of various maturational and integrin receptors on peripheral blood cells were studied in two healthy human volunteers following oral applications of thalidomide (Thd). In each measurement the receptor density was quantified by prior calibration of the flow cytometer with latex beads bearing a determined number of fluorescence molecules. The effects observed in the course of the Thd-treatment were practically identical or at least very similar in both the volunteers during four different trials, and were in accord with previous results obtained in large-scale studies (68 treated animals) with non-human primates. It should be stressed that no clear-cut changes were observed in the percentage or absolute numbers of primary lymphocyte subsets such as CD3, CD4 and CD20. After the first two doses of 7 mg Thd/kg body wt the CD18 (the common beta-chain of the beta 2-integrins) marker already decreased in surface density or was no longer detectable on granulocytes, monocytes and lymphocytes. This effect persisted throughout the treatment period and slowly subsided after discontinuation of treatment. With a few days lag phase, the surface density of CD54 (ICAM-1) on granulocytes increased and many cells previously not bearing this receptor newly acquired such surface markers. On monocytes however, the CD54 receptor was lost on many cells. Within the lymphocyte fraction a loss of the CD54 marker could be noted on CD4 cells but not on CD8 cells, where an increase of the receptor expression could be observed. Other markers, such as the alpha chains of the beta 1 integrins CD49b (VLA alpha 2) and CD49d (VLA alpha 4) showed contrasting reactions to the Thd-treatment. Whereas a pronounced loss of the receptor density of CD49d was observed and only few cells with high epitope density were left in the blood at the end of the complete dosing schedule, no such effect was observable on cells bearing the CD49b epitope. A distinct reduction of the number of receptors was also noticeable on L-selectin (Leu8) bearing cells. On CD4 positive lymphocytes, the majority of the described effects on the integrin and adhesion receptors was seen on cells bearing the CD45R0 maturational epitope. This functional receptor is strongly down-regulated and the pathway of CD45RA to CD45R0 maturation is apparently altered by Thd-treatment. These multiple changes we observed may explain the large variety of therapeutic effects experienced in the treatment with Thd.

Paradoxical effects of lithium on serotonergic receptor function: an immunocytochemical, behavioural and autoradiographic study. Lithium is the preferred treatment for bipolar affective disorder, yet its mechanism of action is poorly understood. Our study was designed to investigate the effect of lithium on the 5-HT2A or 5-HT2C (5-HT2A/2C) receptor subtypes, by comparing the consequences of chronic pre-treatment of rats with lithium on 5-HT2A/2C receptor-mediated behavioural responses, Fos expression, and the density of these receptors in the brain. In addition, the time-course and persistence of the effect of chronic lithium on 5-HT2A/2C receptor-mediated Fos expression was examined. Furthermore, the acute action of lithium on Fos expression was also examined. In an investigation of the dose response of Fos to the 5-HT2A/2C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), rats received saline or 1, 2, 4, 8, 12, 16, 24 or 32 mg/kg DOI, then were sacrificed 3 h later for immunocytochemical localisation of Fos. In a chronic lithium study, rats received either control or lithium-containing (0.1% LiCO3) chow for 3 weeks prior to challenge with 8 mg/kg DOI. DOI-induced locomotor activity was measured for 30 min immediately following the drug challenge, then 150 min later, the animals were sacrificed for Fos immunocytochemistry. The brains of another group of rats, also receiving either control or lithium-containing diet for 3 weeks, were analysed for the distribution and density of 5-HT2A receptor binding sites by quantitative [3H]ketanserin autoradiography. One group of chronic lithium treated rats received ritanserin (0.4 mg/kg), a 5-HT2A/2C receptor antagonist, 40 min before DOI challenge and were sacrificed 3 h later for Fos localisation. In the time-course experiment, rats received lithium-containing diet for 3 weeks followed by normal, control diet for 48 h, 1, 2 or 4 weeks prior to DOI or saline challenge. A further group of animals received an injection of LiCl (3 mM/kg) before being challenged with DOI or saline 12, 24, 36 or 48 h later. The dose-response experiment revealed that little Fos-like immunoreactivity was evident above basal levels following administration of 1 mg/kg DOI. However, at all other doses examined, Fos-like immunoreactivity was elevated in a number of brain areas, particularly in cerebral cortex, olfactory tubercle and amygdala. Following 24 mg/kg DOI, the number of Fos-positive nuclei appeared to have reached a plateau level. Treatment of rats with chronic lithium significantly enhanced DOI-induced locomotor activity and Fos-like immunoreactivity throughout the cerebral cortex. This elevation in Fos-like immunoreactivity was completely abolished by prior treatment with ritanserin. In contrast, chronic lithium treatment had no effect on the density of [3H]ketanserin binding to 5-HT2A receptors in any brain region examined. The results of the time-course experiment demonstrated that the enhancing effect of lithium on 5-HT2A/2C receptor-mediated Fos expression was short-lived such that Fos-like immunoreactivity returned to untreated levels within 48 h. In the acute lithium experiment, administration of lithium to rats 12 or 24 h before DOI resulted in a similar elevation of Fos-like immunoreactivity to that seen in chronically treated animals. Administration of acute lithium 36 or 48 h before DOI had no effect. The effects of lithium on 5-HT2A/2C receptor function thus appear to be complex. In particular, the results of this study indicate that the enhancing effects of lithium on DOI-induced locomotor activity and Fos-like immunoreactivity are not accompanied by any alteration in the density of 5-HT2A receptor binding sites. If changes in receptor numbers therefore do not account for the physiological effect of chronic lithium, other explanations must be sought. The study also suggests that the inositol depletion hypothesis of lithium's therapeutic action does not adequately explain the mechanism of action of lithium in man.

[Effect and related mechanism of miRNA-21 on hydrogen peroxide-induced C-kit(+) cardiac stem cells apoptosis]. Objective: To explored the effect and related mechanism of miRNA-21 on hydrogen peroxide-induced C-kit(+) cardiac stem cells apoptosis. Methods: C-kit(+) cardiac stem cells were isolated from SD rats by the methods of enzyme digestion and magnetic bead. Cells were divided into the following experimental groups: (1) negative control mimics (NCM)group: cells were transfected with negative control miRNA-21 mimics for 48 hours; (2)mimics group: cells were transfected with miRNA-21 mimics for 48 hours; (3) NCM+ H(2)O(2) group: negative control miRNA-21 mimics were transfected into cells for 48 hours and then treated with 100 μmol H(2)O(2) for 2 hours; (4)mimics+ H(2)O(2) group: miRNA-21 mimics were transfected into cells for 48 hours and then treated with 100 μmol H(2)O(2) for 2 hours. mRNA of miRNA-21 was detected by RT-PCR. The apoptosis rate of C-kit(+) cardiac stem cells was determined using the annexin V-FITC/PI staining assay. Western blot was employed to measure the expression of apoptosis related proteins(Caspase-3, Bax, and Bcl-2). Results: (1) Compared with the NCM group, the mRNA expression level of miRNA-21 was significantly up-regulated in mimics group, while obviously down-regulated in NCM+ H(2)O(2) group(all P<0.05). Compared with the mimics group, the mRNA expression levels of miRNA-21 in mimics+ H(2)O(2) group was significantly downregulated (P<0.05), but remarkably upregulated compared with the NCM+ H(2)O(2) group(P<0.05). (2) Flow cytometry results indicated that the early apoptosis rates were similar between the NCM group and mimics group ((4.57±3.45)% vs. (5.13±3.21)%, P>0.05). Compared with the NCM group, the early apoptosis rates were remarkably increased ((79.07±5.75)% vs.(4.57±3.45)%, P<0.05) in NCM+ H(2)O(2) group. Compared with the mimics group, the early apoptosis was significantly up-regulated in the mimics+ H(2)O(2) group ((30.27±1.36)% vs.(5.13±3.21)%, P<0.05), which were further down-regulated in mimics+ H(2)O(2) group compared with the NCM+ H(2)O(2) group ((30.27±1.36)% vs.(79.07±5.75)%, P<0.05). (3) Western blot results showed similar protein expression of Caspase-3, Bax and Bcl-2 between NCM group and mimics group(all P>0.05). Compared with the NCM group, the Caspase-3 and Bax protein expression was significantly increased in NCM+ H(2)O(2) group (all P<0.05), but the protein expression level of Bcl-2 was similar between the 2 groups(P>0.05). The Caspase-3 and Bax protein expression was markedly decreased, while Bcl-2 apparently increased in the mimics+ H(2)O(2) group compared with the NCM+ H(2)O(2) group(all P<0.05). Conclusion: Overexpression of miRNA-21 protects the C-kit(+) cardiac stem cells from apoptosis caused by oxidative stress through downregulating proapoptotic and upregulating the antiapoptotic proteins.

The impact of isolated lesser saphenous vein system incompetence on clinical signs and symptoms of chronic venous disease. The purpose of this study was to determine the patterns of isolated lesser saphenous vein (LSV) system incompetence and correlate the distribution and extent of such reflux with symptoms and signs of chronic venous disease (CVD). During a 3-year period, 2254 limbs in 1682 patients with signs and symptoms of CVD were evaluated with color flow duplex scanning. Extremities with isolated reflux in the LSV system were selected for this study. Limbs with perforating venous reflux connected to this system only were also included. Limbs that had marked reflux in the greater saphenous or deep vein, that had a documented history of deep venous thrombosis, and that previously underwent surgery or sclerotherapy were excluded. The clinical severity of the limbs was graded with the CEAP classification system. There were 226 limbs in 200 patients with reflux in the LSV system; 61% were female patients with a mean age of 49 years (range, 18-82 years). There were 174 patients (87%) with unilateral and 26 with bilateral disease, and 41% of the limbs belonged in CVD class 2, 26% in class 3, 12% in class 4, 3.5% in class 5, and 3% in class 6. Classes 0 and 1 were present in 14.5% of the limbs. Symptoms were present in 139 limbs (61.5%). Some degree of ache or burning sensation was the most frequent symptom (41%), followed by itching (32%), heaviness (29%), cramps (24%), and restless limbs (18%). Reflux in the main trunk of the LSV was the most prevalent (177 limbs [78%]), followed by the saphenopopliteal junction (146 limbs [64.6%]), the vein of Giacomini (39 limbs [17%]) and the gastrocnemial vein (23 limbs [10%]). Reflux involving both the saphenopopliteal junction and the LSV was seen in 50% of limbs, but almost any other combination of reflux was present, which indicated the complexity of this system. Perforator vein incompetence was detected in 56 limbs (25%). We found 83 perforator veins, resulting in a mean of 1.5 veins per limb. Both the number of incompetent perforator veins and the extent of superficial reflux correlated with clinical severity. Four main types of termination of the LSV were identified with at least nine variations. The LSV was duplicated for at least half of its length in five limbs (2.2%). Nonsaphenous reflux was detected in seven limbs (3.1%). Superficial vein thrombosis in the LSV system was found in eight limbs (3.5%), and in the gastrocnemial vein it was found in four (1.8%). Isolated LSV system incompetence can cause the entire range of signs and symptoms of CVD. Clinical deterioration is associated with a longer extent of reflux and perforator incompetence. Classes 2 to 4 are the most frequent clinical presentations, whereas classes 5 and 6 are uncommon. The complex anatomy of this system and the great variation in the patterns of reflux warrant the use of color flow duplex scanning before planning treatment.

Statistical analysis of adaptive response in sister chromatid exchanges in human lymphocytes after treatment with very low and extremely low doses of N-methyl-N'-nitro-N-nitrosoguanidine using a study design to control variability. Previous studies have been interpreted as suggesting that low concentrations of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) have an adaptive effect in the cultured lymphocytes of responsive donors (that is, the cells are protected against the mutagenic effects of a subsequent challenge with a higher concentration of MNNG). The objectives of the present study were to investigate, under stringent experimental conditions, whether a protective effect exists at very low and extremely low doses of MNNG (10(-8) and 10(-24) M, respectively). Peripheral blood lymphocytes from a donor considered responsive in a previous study were stimulated to divide and were cultured under standard conditions. Pre-adaptive treatments with dilutions of MNNG were added to the cultures repeatedly before a challenge treatment with MNNG. Bromodeoxyuridine was added at the same time as the challenge treatment and, following mitotic arrest, cells were differentially stained so that the number of sister chromatid exchanges (SCEs) could be counted. The study was designed to address potential criticisms of earlier studies which did not include replicate cultures. Samples of blood were divided into two identical batches for independent processing. Five replicate cultures were prepared for each combination of pre-adaptive and challenge treatments in each batch. The complete experiment was repeated to provide a further test of the consistency of results. Five replicates per treatment combination were chosen in an attempt to provide an experiment of adequate statistical power. Considerable precautions were taken to minimise the effect of factors outside experimental control on the results. Scoring was done by three scorers. In order to minimise inter-scorer variation, 240 cells were scored at each treatment observation (five cells per-scorer, three scorers per culture, four cultures per batch, two batches per experiment and two experiments). The study was designed in this way to take account of the sources of variability to ensure that any response obtained would exceed that obtainable by experimental variability alone. A high level of quality assurance monitoring was undertaken throughout the investigation. Two measures of SCE induction were used: (i) the mean frequency of SCEs; (iii) proportion of cells with at least 20 SCEs. In both experiments, the challenge concentration of MNNG significantly increased SCE frequency. There were, however, highly significant differences between the two experiments. The proportion of high frequency cells (HFCs) in Experiment 1 was increased significantly; the proportion of HFCs was also increased in Experiment 2, but the increase was not statistically significant. The pre-adaptive concentrations of MNNG included an extremely low dilution of 6.8 x 10(-24) M and a very low dilution of 6.8 x 10(-8) M in Experiment 1 and 1.4 x 10(-7) M in Experiment 2. The various pre-adaptive concentrations used had no consistent protective effect against the SCE-inducing capacity of the challenge concentration of MNNG of 6.8 x 10(-6) M. It is concluded that an adaptive response to the alkylating agent MNNG could not be demonstrated in cultured human lymphocytes. Neither a very low nor an extremely low dilution of MNNG elicited an adaptive response in terms of SCE induction (measured either as SCE frequency or as proportion of HFCs). This is in contradiction to previous reports published by us and other groups. This study was carefully designed with large numbers of replicates, a preliminary statistical power calculation, predefined comparisons and extensive quality assurance at each treatment administration. Despite these precautions the variability between scorers and between batches was much larger than anticipated. This resulted in some statistically significant differences, but these are likely to be false positives. Our findings indicate the need for such methodological refinement in human cell adaptive response studies.

The cost of simultaneous surgical standby for percutaneous transluminal coronary angioplasty. From November, 1980, to May 1985, 699 patients have undergone percutaneous transluminal coronary angioplasty of 784 lesions at our institutions. Simultaneous surgical standby was available on all cases. One hundred twenty-four patients (18%) underwent immediate myocardial revascularization; 45 (6%) were operated on because the lesion could not be dilated. Seventy-nine patients (11%) underwent immediate operation for an acute complication of angioplasty: coronary occlusion in 45, dissection in 29, coronary perforation in three, and atrial perforation in one. Fourteen patients (18%) required cardiopulmonary resuscitation en route to the operating room, and 10 patients (20%) had insertion of an intra-aortic balloon pump in the cardiac catheterization laboratory. The average time from complication to reperfusion was 87 minutes, ranging from 40 to 165 minutes. An average of 2.0 grafts per patient (ranging from one to five grafts per patient) were performed. Of those 79 patients who underwent operation for an acute complication, one died (1.3%), 31 patients (39%) had a myocardial infarction according to enzyme criteria (creatine kinase-myocardial band greater than 40 IU), and 17 patients (22%) had new Q waves on the electrocardiogram. Good results are related to minimizing the time the myocardium is ischemic. No patient in whom reperfusion was begun in less than 75 minutes had a Q wave infarction or a creatine kinase-myocardial band level greater than 40 IU. Simultaneous surgical standby is the only method allowing immediate access to surgical facilities. A standby team of eight persons and equipment were immediately available for emergency bypass grafting for an average of 3.6 hours (range 1.3 to 5.4 hours per angioplasty attempt). The patient charges for this simultaneous standby were $632.00 per angioplasty attempt, or $442,278.00 for the entire series. The actual cost of the standby was over $1,700.00 per attempt totaling $1,188,843.00 for the 699 patients. This underestimation of the cost of surgical standby has occurred in other series, because little mention has been made of this cost in the published reports on the cost effectiveness of angioplasty. In terms of time demands, over 2,500 hours were spent by surgeons standing by for the 699 attempts. Simultaneous surgical standby is the most effective means of limiting the time the myocardium is ischemic after an angioplasty complication. However, this method is costly, necessitating more of a financial and time commitment than generally anticipated. Future studies of the cost effectiveness of angioplasty should include the cost of surgical standby with accurate per-patient cost accountability.

Haloperidol-induced catalepsy is absent in dopamine D(2), but maintained in dopamine D(3) receptor knock-out mice. We have previously found that mice homozygous for the deletion of the dopamine D(2) receptor gene (D(2)(-/-) mice) do not present spontaneous catalepsy when tested in a "bar test". In the present study, we sought to analyse the reactivity of D(2) receptor mutant mice to the cataleptogenic effects of dopamine D(2)-like or D(1)-like receptor antagonists. In parallel, we assessed the cataleptogenic effects of these antagonists in dopamine D(3) receptor mutant mice. D(2)(-/-) mice were totally unresponsive to the cataleptogenic effects of the dopamine D(2)-like receptor antagonist haloperidol (0.125-2 mg/kg i.p.), while D(2)(+/-) mice, at the highest haloperidol doses tested, showed a level of catalepsy about half that of wild-type controls. The degree of haloperidol-induced catalepsy was thus proportional to the level of striatal dopamine D(2) receptor expression (0.50, 0.30 and 0.08 pmol/mg protein as measured at 0.25 nM [3H]spiperone for D(2)(+/+), D(2)(+/-) and D(2)(-/-) mice, respectively). However, D(2)(-/-) and D(2)(+/-) mice were as sensitive as their wild-type counterparts to the cataleptogenic effects of the dopamine D(1)-like receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390: 0.03-0.6 mg/kg s.c.). Striatal dopamine D(1) receptor expression (as measured using [3H]SCH 23390 binding) was not significantly affected by the genotype. The ability of SCH 23390 to induce catalepsy in D(2)(-/-) mice suggests that their resistance to haloperidol-induced catalepsy is due to the absence of dopamine D(2) receptors, and not to the abnormal striatal synaptic plasticity that has been shown by others to occur in these mice. In agreement with the observation that dopamine D(2) and dopamine D(1) receptor expression was essentially identical in D(3)(+/+), D(3)(+/-) and D(3)(-/-) mice, dopamine D(3) receptor homozygous and heterozygous mutant mice, on the whole, did not differ from their controls in the time spent in a cataleptic position following administration of either haloperidol (0.5-2 mg/kg i.p.) or SCH 23390 (0.03-0.6 mg/kg s.c.). Also, dopamine D(3) receptor mutant mice were no more responsive than wild-type controls when co-administered subthreshold doses of haloperidol (0.125 mg/kg) and SCH 23390 (0.03 mg/kg), suggesting that dopamine D(3) receptor knock-out mice are not more sensitive than wild-types to the synergistic effects of concurrent blockade of dopamine D(2) and dopamine D(1) receptors in this model. These results suggest that the dopamine D(2) receptor subtype is necessary for haloperidol to produce catalepsy, and that the dopamine D(3) receptor subtype appears to exert no observable control over the catalepsy produced by dopamine D(2)-like, D(1)-like and the combination of D(1)-like and D(2)-like receptor antagonists.