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Randomized trial of salbutamol in acute bronchiolitis.

To test whether nebulized salbutamol (albuterol) is safe and efficacious for the treatment of young children with acute bronchiolitis, we enrolled 83 children (median age 6 months, range 1 to 21 months) in a randomized, double-blind clinical trial. Participants received two treatments at 30-minute intervals of either nebulized salbutamol (0.10 mg/kg in 2 ml 0.9% saline solution) or a similar volume of 0.9% saline solution placebo. Outcome measures were the respiratory rate, pulse oximetry, and a clinical score based on the degree of wheezing and retractions. Patients in the salbutamol arm had significantly greater improvement in clinical scores after the initial treatment (p = 0.04). There was no difference between the groups in oxygen saturation (p = 0.74); patients treated with salbutamol had a small increase in heart rate after two treatments (159 +/- 16 vs 151 +/- 16; p = 0.03). We conclude that salbutamol is safe and effective for the initial treatment of young children with acute bronchiolitis.

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Adjuvant chemotherapy for stage II and III breast carcinoma.

Stage II or III breast carcinoma patients were assigned to one of three adjuvant chemotherapy groups after mastectomy. The efficacy of melphalan, vs cyclophosphamide, fluorouracil, and prednisone (CFP), vs CFP plus BCG vaccine was compared in 173 patients treated for five days every six weeks for the first postoperative year. Tumor size, unfavorable local signs, extent of axillary nodal involvement, menopausal status, and participating hospital were considered in assigning patients to treatment groups. The median follow-up time was 26 months; 24.2% of the patients were studied for more than three years. Recurrent disease occurred in 31.6% of the patients in the melphalan group and in 13.4% and 13.2% in the other two groups. Six patients died of metastatic tumor; three others died of other causes. A favorable significant difference exists for polychemotherapy in prolonging disease-free interval in our series.

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An Unprecedented High Incidence of Leptospirosis in Futuna, South Pacific, 2004 - 2014, Evidenced by Retrospective Analysis of Surveillance Data.

Futuna is a small Polynesian island in the South Pacific with a population of 3,612 in 2013. The first human leptospirosis case was confirmed in 1997. Active surveillance started in 2004. Cases were confirmed by PCR or real time PCR, or by serology using MAT or a combination of IgM-ELISA and MAT. A retrospective analysis of surveillance data shows that the disease was endemic with a mean annual incidence of 844 cases per 100,000 over an 11-year period from 2004 to 2014. An epidemic peak as high as 1,945 cases per 100,000 occurred in 2008. Serogroup Australis was predominant until 2007, Icterohaemorrhagiae was dominant afterwards. Cluster analysis revealed different hot spots over time. Lifestyle habits, such as walking barefoot in irrigated taro fields or pig pens probably contributed to contamination from the swine and rodent reservoirs to humans. Severe forms were rare, and the case fatality rate was 0.5%. The medical community and general population were aware of leptospirosis and rapid treatment with amoxycillin was the main treatment, probably contributing to this low fatality rate.

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Comparison of telmisartan versus losartan: meta-analysis of titration-to-response studies.

To compare the ability of telmisartan and losartan to reduce mean diastolic blood pressure (DBP) during the last 6 h of the 24-h dosing interval in a prospectively planned meta-analysis of ambulatory blood pressure monitoring (ABPM) data from two independent studies. Data were from two independent randomized, double-blind, double-dummy, titration-to-response studies conducted in patients with mild-to-moderate hypertension (seated cuff DBP 95-109 mmHg, 24-h mean ambulatory DBP >or=85 mmHg). After a 4-week placebo run-in period, patients received once-daily telmisartan 40 mg or losartan 50 mg, with up-titration after 4 weeks to telmisartan 80 mg or losartan 100 mg, respectively, if seated trough cuff DBP >or=90 mmHg. Blood pressures were recorded using ABPM immediately before randomization and after 8 weeks of active treatment. In addition, seated trough cuff blood pressures were measured at baseline and after 4 and 8 weeks of active treatment. Titration to the higher dose was required in 60.1% of telmisartan patients and 69.5% of losartan patients (P=0.01). Reductions from baseline in the last 6 h mean ambulatory DBP with telmisartan and losartan were 6.6+/-0.4 and 5.1+/-0.4 mmHg, respectively (P<0.01, adjusted for baseline and study); the effects were homogeneous across the two studies. During the last 6 h of the 24-h dosing interval, telmisartan produced greater reductions in each of the observed hourly mean ambulatory DBP values. Telmisartan-induced reductions were also greater for the majority of the observed hourly mean ambulatory DBP values over the entire 24-h dosing interval. Reductions from baseline in the last 6 h adjusted mean ambulatory systolic blood pressure (SBP) for telmisartan and losartan were 9.9+/-0.6 and 7.8+/-0.6 mmHg, respectively (P=0.01). The 24-h profiles of ambulatory SBP hourly mean reductions were similar to those for DBP. Both telmisartan and losartan were found to be safe and well tolerated. Telmisartan 40/80 mg is superior to losartan 50/100 mg in controlling DBP and SBP during the last 6 h of the 24-h dosing interval.

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[Clinical analysis of 140 cases of mantle cell lymphoma].

<b>Objective:</b> To study the clinical features, therapeutic effects, prognostic factors of 140 patents with mantle cell lymphoma (MCL). <b>Methods:</b> Clinical data of 140 MCL patients admitted from June 2009 to January 2016 in our hospital were retrospectively analyzed. <b>Results:</b> The median age of 140 patients was 59 years with a ratio of 6∶1 for men and women. There were 134 cases (95.7%) in Ann-Arbor stage Ⅲ-Ⅳ, 37 cases (26.4%) with B symptoms, 61 cases (43.6%) with bone marrow involvement and 38 cases (27.1%) with enlarged spleen. The overall response rate (ORR), 3-year survival rate and progression-free survival rate in the treatment group with rituximab were 87.1%, 68.1% and 59.5% respectively, which were significantly higher than those in the rituximab-free treatment group (66.6%, 51.5% and 31.7%, respectively). The difference was statistically significant (all <i>P</i><0.05). Among patients treated with rituximab, the complete remission rates (70.8% and 77.8%) of R-HyperCVAD/MA and VcR-CAP regimens were higher than those of R-CHOP regimen (39.0%, both <i>P</i><0.05). However, there was no significant difference in the overall response rate, overall survival rate and progression-free survival rate (all <i>P</i>>0.05). Univariate analysis showed that age, Ki-67 index, B symptoms, bone marrow invasion, platelet count, LDH, β(2)-MG and MIPI scores were associated with overall survival (all <i>P</i><0.05). Multivariate analysis showed that age (<i>HR</i>=4.940, 95% <i>CI:</i> 2.347 to 10.397), B symptom (<i>HR</i>=2.900, 95% <i>CI:</i> 1.517-5.544), β(2)-MG (<i>HR</i>=2.945, 95% <i>CI:</i> 1.656-5.238), Ki-67 index (<i>HR</i>=4.915, 95% <i>CI:</i> 2.554-9.456) and treatment with rituximab-containing regimen (<i>HR</i>=2.450, 95% <i>CI:</i> 1.352-4.440) were independent factors for OS. <b>Conclusions:</b> Most patients with MCL were older adults and usually had bone marrow involvement and spleen involvement. Rituximab combined with chemotherapy (especially R-HyprCVAD/MA and VcR-CAP) had better clinical efficacy than conventional chemotherapy.

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Impact of the CYP2D6 genotype on the clinical effects of metoprolol: a prospective longitudinal study.

After administration of metoprolol, plasma concentrations of the drug are markedly higher in CYP2D6 poor metabolizers (PMs) than in non-PMs. In a prospective double-blind 3-month study, we investigated whether this translates into differences in metoprolol's effects after initiation of therapy. Despite administering equal doses to PMs and non-PMs, metoprolol plasma concentrations were 4.9-fold higher in the PM group. Metoprolol evoked significantly and persistently greater reductions in heart rate, diastolic blood pressure, and mean arterial pressure in PMs than in non-PMs. It appears, therefore, that the CYP2D6 genotype contributes to interindividual differences in metoprolol response.

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[The influence of simvastatin on hsCRP and some paramneters of hemostasis in patients with ischemic heart disease].

Inflammation and disturbances of the hemostatic system may play a role in pathogenesis and complications of ischemic heart disease. More and more reports indicate that apart from their cholesterol-lowering effect statins also exert other beneficial effects in cardiovascular diseases. Taking this into consideration, the aim of the study was to assess the influence of simvastatin (20 mg per day) on a marker of inflammation - CRP and some parameters of coagulation and fibrinolysis in 22 patients with ischaemic heart disease. Serum lipids, levels of hsCRP, thrombomodulin (TM), vWF, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), thrombin activatable fibrinolysis inhibitor (TAFI), t-PA, plasmin-antiplasmin complex (PAP) and TAFI activity were assessed before and after one, three and six months simvastatin treatment. After one month therapy of simvastatin, there have been significant reduction of levels of total cholesterol, LDL-cholesterol and triglycerides and these values have remained until the end of the study. No influence on the level of HDL-cholesterol has been observed. After 6 months of treatment significant decrease in the level of hsCRP and increase of the levels TM and vWF with reference to baselines results have been observed. After a 1-and 6-month therapy, the level of TAFI have been significantly increased. Other hemostatic parameters, i.e. levels of F1+2, TAT, t-PA, PAP and TAFI activity have not changed significantly. This prospective study has confirmed high efficacy of lipid-lowering effect and anti-inflammatory properties of simvastatin. Simvastatin influenced some hemo-static parameters, however, these effects were not, in majority, significant.

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Drug therapy of the idiopathic inflammatory myopathies: predictors of response to prednisone, azathioprine, and methotrexate and a comparison of their efficacy.

To identify factors associated with responses to treatment with prednisone, methotrexate, or azathioprine in patients with idiopathic inflammatory myopathy, and to compare the efficacy of these drugs. Data were collected on 113 adult patients meeting criteria for definite idiopathic inflammatory myopathy in this retrospective cohort study. Patients were categorized as responding completely, partially, or not at all to each therapeutic trial based upon clinical and laboratory criteria. Clinical group, presence of certain myositis-specific autoantibodies, and time from disease onset to diagnosis influenced rates of complete clinical response to these therapeutic agents. Patients with inclusion body myositis responded comparatively poorly to prednisone and the other drugs: 43% had no clinical response to prednisone and none responded completely to any medication. Patients with autoantibodies to aminoacyl-tRNA synthetases or to signal recognition particle proteins were likely to respond partially, but not completely, to prednisone. No patient with a long delay to diagnosis (greater than 18 months) responded completely, compared with 34% of those with a short delay (less than 3 months). A patient's response to the first course of prednisone predicted subsequent responses to prednisone and to azathioprine better than response to methotrexate. Men responded to methotrexate better than women. Among certain subgroups of patients, responses to methotrexate were better than to either azathioprine or retreatment with prednisone. Determining the clinical group, autoantibody status, and time from disease onset to diagnosis of patients with myositis provides useful information in predicting clinical responses to therapy, and these factors should be considered in designing future therapeutic trials. Methotrexate therapy may be superior to either azathioprine or further steroid treatment alone in certain patients who do not respond completely to an initial adequate course of prednisone.

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Prevalence and nature of statin drug-drug interactions in a university hospital by electronic health record mining.

Our aim was to describe prevalence, nature, and level of severity of potential statin drug-drug interactions in a university hospital. In a cross-sectional study, statin drug-drug interactions were screened from medical record of 10,506 in-patients treated stored in the clinical data warehouse "eHOP." We screened drug-drug interactions using Theriaque and Micromedex drug databases. A total of 22.5% of patients were exposed to at least one statin drug-drug interaction. Given their lipophilicity and CYP3A4 metabolic pathway, atorvastatin and simvastatin presented a higher prevalence of drug-drug interactions while fluvastatin presented the lowest prevalence. Up to 1% of the patients was exposed to a contraindicated drug-drug interaction, the most frequent drug-drug interaction involving influx-transporter (i.e., OATP1B1) interactions between simvastatin or rosuvastatin with cyclosporin. The second most frequent contraindicated drug-drug interaction involved CYP3A4 interaction between atorvastatin or simvastatin with either posaconazole or erythromycin. Furthermore, our analysis showed some discrepancies between Theriaque and Micromedex in the prevalence and the nature of drug-drug interactions. Different drug-drug interaction profiles were observed between statins with a higher prevalence of CYP3A4-based interactions for lipophilic statins. Analyzing the three most frequent DDIs, the more significant DDIs (level 1: contraindication) were reported for transporter-based DDI involving OATP1B1 influx transporter. These points are of concern to improve prescriptions of statins.

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Gabapentin in the treatment of neuropathic pain after spinal cord injury: a prospective, randomized, double-blind, crossover trial.

Neuropathic pain is a common complaint after traumatic spinal cord injury (SCI). Gabapentin, a synthetic structural analogue of GABA, has been shown to have beneficial effects in the treatment of neuropathic pain in other diagnostic groups; however, no standardized clinical trial has been performed to evaluate its efficacy after SCI. A 10-week, prospective, randomized, double-blind, crossover, and placebo-controlled clinical trial. To determine the efficacy of gabapentin in the treatment of SCI-related neuropathic pain. Seven subjects with neuropathic pain, who were more than 30 days post-SCI, completed the study. Two groups received a 4-week course of gabapentin and placebo in a randomized crossover design with a 2-week washout period. The Neuropathic Pain Scale was used to record daily pain levels. Data were analyzed using the Wilcoxon signed rank test. Gabapentin has some beneficial effects on certain types of neuropathic pain. There was a significant decrease of "unpleasant feeling" and a trend toward a decrease in both the "pain intensity" and "burning sensation" at the fourth week of gabapentin treatment compared with those on the placebo. No significant difference was found among other pain descriptors during the gabapentin and placebo treatment, although this may have been limited by the small sample size and low maximum dosage of gabapentin. Gabapentin reduces certain types of neuropathic pain in the SCI population. Future studies with larger sample sizes, higher dosages, and quicker titration will help further determine the efficacy of gabapentin in the treatment of SCI-related neuropathic pain.

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Stanford V regimen and concomitant HAART in 59 patients with Hodgkin disease and HIV infection.

A phase 2 prospective study was performed to evaluate the feasibility and activity of a short, dose-intensive chemotherapy regimen and radiotherapy (the Stanford V regimen) plus highly active antiretroviral therapy (HAART) and granulocyte colony-stimulating factor (G-CSF) support in patients with Hodgkin disease and HIV infection. Fifty-nine patients were enrolled. Stanford V was well tolerated and 69% of the patients completed treatment with no dose reduction or delayed chemotherapy administration. The most important dose-limiting side effects were bone marrow toxicity and neurotoxicity. Complete remission was achieved by 81% of the patients, and after a median follow-up of 17 months 33 patients (56%) were alive and disease-free. The estimated 3-year overall survival (OS), disease-free survival (DFS), and freedom from progression (FFP) were 51%, 68%, and 60%, respectively. Probability of FFP was significantly (P =.02) higher among patients with an International Prognostic Score (IPS) of 2 or lower than in those with an IPS higher than 2, and the percentages of FFP at 2 years in these groups were 83% and 41%, respectively. Similarly, the probability of OS was significantly (P =.0004) different in the 2 groups, and the percentages of OS at 3 years were 76% and 33%, respectively. Our data confirm that the Stanford V regimen with concomitant HAART is feasible and active in an HIV setting. However, a more intensive approach should be considered in patients with high IPSs.

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Serotonin transporter polymorphism and fluoxetine effect on impulsiveness and aggression in borderline personality disorder.

Impulsiveness and aggressiveness are characteristics of borderline personality disorder and are associated to a serotoninergic system dysfunction. Serotonin transporter polymorphisms have been linked to aggressive and impulsive behaviors. The short allele (S) in depression is associated to a worse response to selective serotonin reuptake inhibitors (SSRI). This study aims to study these polymorphisms to predict the response of aggressive and impulsive behaviors to SSRIs in borderline personality disorder. Fifty-nine patients with DSM-IV borderline personality disorder in accordance with the International Personality Disorder Examination (IPDE) and without axis 1 disease were treated with flexible doses of fluoxetine for 12 weeks. The patients were evaluated with the Overt Aggression Scale Modified (OAS-M) at the beginning and at 2, 4, 8 and 12 weeks of treatment. Polymorphisms L and S of the serotonin transporter promoter region were determined. Response to fluoxetine of the LL carriers versus the S carriers (LS+SS) was compared. LL carriers had a better response than S carriers in the reduction of total OAS-M scores and on the aggressiveness and irritability components of the OAS-M. L-allele carriers responded better to fluoxetine than S carriers, in a similar way as in depression. The S allele may represent a common factor of bad response to SSRI in diseases associated to serotoninergic system dysfunction.

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[The effectiveness of carvedilol in heart failure].

The third generation beta-blocker (carvedilol) is effective in reduction of hypertension, and of mortality and morbidity as a supplement to conventional drugs of heart failure therapies (diuretics, ACE inhibitors), based on randomized controlled trials and retrospective analysis. To analyse the efficacy of carvedilol in the treatment of heart failure with special focused on morbidity, mortality endpoints. We assessed the multicenter, randomised, double-blind studies involving more than 150 patients (1995-2005) from MEDLINE database, in which carvedilol was used in the case of moderate to severe heart failure. We also present the results of health-economic publications (2000-2005). In U.S. Carvedilol Heart Failure Study (n 1096) the mortality declined by 65% (3.2% vs. 7.8%; p <0.001) with carvedilol vs. placebo, while the cardiovascular hospitalization decline was 27% (14.1% vs. 19.6%; p = 0.036) in heart failure (LVEF < or = 5%) applied together with the basic therapy (diuretic and ACE-inhibitor). In the COPERNICUS trial the efficacy of carvedilol was compared to placebo in the case of severe HF patients (LVEF < 25%, n = 2889). The annual mortality risk declined by 35% (19.7% vs. 12.8%, 95% CI 19-48%, p = 0.00013) while the risk of mortality or any risk of hospitalisation by 24% (p = 0.00004) in the active group. The CAPRICORN study (LVEF < or = 0%, n=1959) showed that carvedilol is efficacious in reduction of total (HR: 0.77; 95% CI 0.60-0.98; p = 0.031) and cardiovascular mortality (HR: 0.75; 95% CI 0.58-0.96; p = 0.024) as far as high-risk patients are concerned. The effectiveness of carvedilol is certified in reduction of mortality and hospitalization in the treatment of moderate-severe heart-failure as part of the combination therapy. The benefits of use of the drug are well measurable not only on the level of patients but on the suppliers and the financer as well, thanks to the decline of resource utilization.

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[Intensified insulin therapy plus antineuritic medication is more effective than antineuritics alone in painful diabetic neuropathy].

The basis of the treatment of painful diabetic neuropathy is the use of drugs that block the transmission of pain (antineuritics) and a good metabolic control of underlying disease. To describe the outcomes of 17 type-2 diabetics with painful neuropathy, treated between 1988 and 2005 with symptomatic therapy plus intensified insulin. Review of medical records of 17 type-2 diabetic patients, aged 63+/-11 years and a duration of diabetes of 15+/-8 years. All patients received intensified insulin therapy with 0.35 units/kg of NPH insulin (2/3 before breakfast and 1/3 evening meal), plus capillary glucose measurements and regular insulin (with sliding-scale centered in approximately 0.1 units/kg) before the 3 main meals. All patients were also treated with gabapentin, nortriptyline or clomipramine. Pain was assessed using a visual analog score of 10 points. After 1 year, glycosilated hemoglobin decreased from 10.0+/-1.4% to 7.7+/-1.2% (p approximately =0.003). Pain decreased from 10 to 5.1+/-3.3 at one month, 2.3+/-3.2 at six months, and 3.1+/-3.6 at 1 year (p <0.01). There was a direct statistical correlation between the reduction of HbA1C and pain decline (r =0.736; p =0.037). Pain scores were lower than those reported elsewhere for Pregabalin (n =76; p =0.05), Lamotrigine (n =27; p <0.0005), Topiramate (n =208; p <0.005), and Gabapentin (n =84; p <0.025). The lack of difference to Sodium Valproate (n =21; p =0.07) had borderline significance. The addition of intensified insulin therapy to the symptomatic treatment of painful neuropathy in type-2 diabetics, significantly enhanced the reduction of pain. The lowering of glycosilated hemoglobin was a significant predictor of success in pain reduction.

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Effects of Statin Therapy on Plasma Proprotein Convertase Subtilisin/kexin Type 9 and Sortilin Levels in Statin-Naive Patients with Coronary Artery Disease.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of serum low-density lipoprotein (LDL) cholesterol levels, and sortilin is linked to lipoprotein metabolism. Although statin therapy increases PCSK9 levels, effects of this therapy on plasma sortilin levels have not been evaluated. The purpose of the present study was to examine the effects of statins on plasma PCSK9 and sortilin levels, and association of statin-induced increase in PCSK9 levels with sortilin. Serum lipid levels and plasma PCSK9 and sortilin levels were measured at baseline and 8 months after statin therapy in 90 statin-naive patients with coronary artery disease (CAD). Pitavastatin 4 mg/day was used to treat 44 patients and pravastatin 20 mg/day to treat the remaining 46 patients. For both statin groups, significant increases in hetero-dimer PCSK9 levels (pitavastatin: 31%, p＜0.0001; pravastatin: 34%, p=0.03) and decreases in sortilin levels (pitavastatin: －8%, p=0.02; pravastatin: －16%, p=0.002) were observed. Although a reduction in LDL cholesterol was greater in the pitavastatin group than in the pravastatin group, no significant differences were observed in percentage changes in hetero-dimer PCSK9 and sortilin levels. A significant positive correlation was observed between percentage changes in hetero-dimer PCSK9 levels and those in sortilin levels (pitavastatin: r=0.359, p=0.02; pravastatin: r=0.276, p=0.06). Use of pitavastatin and pravastatin increased plasma PCSK9 and decreased sortilin levels. Statin-induced increases in PCSK9 were associated with changes in sortilin in statin-naive patients with CAD.

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Therapeutic efficacy of allopurinol in patients with chronic Chagas' disease.

Laboratory and animal studies have demonstrated that pyrazolopyrimidines have significant activity against Trypanosoma cruzi. This clinical investigation was to ascertain the efficacy of allopurinol in the treatment of chronic Chagas' disease. Of 307 patients studied, 91 were untreated; the remaining 216 were divided into 4 treatment groups. These corresponded to 600 or 900 mg/day of allopurinol for 60 days and benznidazole or nifurtimox at conventional dosage regimens. Patients were evaluated clinically, serologically, and parasitologically. Allopurinol was found to be as efficacious as the conventional therapeutic modalities in eliminating the parasitemia and rendering patients seronegative. Adverse reactions occurred in 11% of patients who received allopurinol and in 30% of those receiving nitrofurans. Reactions with the conventional therapy were more frequent and of a more serious nature. Oral allopurinol is as effective as the nitrofurans, but has none of the side effects.

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Effects of aspirin and clopidogrel on plasma brain natriuretic peptide in patients with heart failure receiving ACE inhibitors.

By inhibiting prostaglandins, aspirin may be deleterious in heart failure (HF) and/or may counteract angiotensin-converting enzyme (ACE) inhibitor efficacy. Conversely, clopidogrel has no effect on prostaglandin metabolism. To investigate the effect of aspirin and clopidogrel on brain natriuretic peptide (BNP) levels in HF patients treated with ACE inhibitors. 36 patients with stable HF (65+/-13 years, 24 males/12 females, NYHA class II to IV, ejection fraction <40%, 13 with coronary disease, all treated with ACE inhibitors) were enrolled in this prospective, double-blind study and randomised to aspirin 325 mg/day or clopidogrel 75 mg/day for 14 days. BNP was determined at day 0 and day 14. 19 patients were randomised to aspirin and 17 to clopidogrel. Baseline characteristics were similar in both groups. BNP levels increased in the aspirin group from day 0 to day 14 (107+/-103 to 144+/-149 pg/ml, p=0.04) whereas clopidogrel had no effect (104+/-107 and 97+/-99 pg/ml respectively, p=0.61). This study demonstrates an adverse effect of aspirin 325 mg/day on BNP plasma levels in HF patients treated with ACE inhibitors. In contrast clopidogrel 75 mg/day had no effect.

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Efficacy of reduced-intensity allogeneic stem cell transplantation in chemotherapy-refractory non-hodgkin lymphoma.

Chemotherapy sensitivity has been identified as an important prognostic factor in reduced-intensity allogeneic stem cell transplantation (RIST) for non-Hodgkin lymphoma (NHL). However, the effect of uniform salvage chemotherapy before RIST has not been studied prospectively. We examined whether the response to prospectively administered uniform salvage therapy (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and fludarabine) influenced the subsequent outcome of RIST in 28 patients with relapsed or refractory NHL. After RIST, overall survival (OS) at 36 months is 49%, whereas event-free survival (EFS) is 32%. In Cox model analyses, the response to chemotherapy was the best predictor of OS (P = .0006) and EFS (P = .0006) after RIST. Differentiating stable disease from progressive disease after salvage chemotherapy strengthened the association with survival. Among chemotherapy-sensitive patients, the median OS and EFS have not been reached. In patients with stable disease, OS and EFS at 24 months are 50% and 25%, respectively. In contrast, only 1 patient with progressive disease during salvage therapy survived longer than 12 months. These prospective data confirm the favorable prognosis for chemotherapy-sensitive NHL after RIST and suggest that chemotherapy resistance is not an absolute contraindication to RIST for NHL patients with stable disease during salvage therapy.

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Predictive modeling of long-term opioid and benzodiazepine use after intradural tumor resection.

Despite increased awareness of the ongoing opioid epidemic, opioid and benzodiazepine use remain high after spine surgery. In particular, long-term co-prescription of opioids and benzodiazepines have been linked to high risk of overdose-associated death. Tumor patients represent a unique subset of spine surgery patients and few studies have attempted to develop predictive models to anticipate long-term opioid and benzodiazepine use after spinal tumor resection. The IBM Watson Health MarketScan Database and Medicare Supplement were assessed to identify admissions for intradural tumor resection between 2007 and 2015. Adult patients were required to have at least 6 months of continuous preadmission baseline data and 12 months of continuous postdischarge follow-up. Primary outcomes were long-term opioid and benzodiazepine use, defined as at least 6 prescriptions within 12 months. Secondary outcomes were durations of opioid and benzodiazepine prescribing. Logistic regression models, with and without regularization, were trained on an 80% training sample and validated on the withheld 20%. A total of 1,942 patients were identified. The majority of tumors were extramedullary (74.8%) and benign (62.5%). A minority of patients received arthrodesis (9.2%) and most patients were discharged to home (79.1%). Factors associated with postdischarge opioid use duration include tumor malignancy (vs benign, B=19.8 prescribed-days/year, 95% confidence interval [CI] 1.1-38.5) and intramedullary compartment (vs extramedullary, B=18.1 prescribed-days/year, 95% CI 3.3-32.9). Pre- and perioperative use of prescribed nonsteroidal anti-inflammatory drugs and gabapentin/pregabalin were associated with shorter and longer duration opioid use, respectively. History of opioid and history of benzodiazepine use were both associated with increased postdischarge opioid and benzodiazepine use. Intramedullary location was associated with longer duration postdischarge benzodiazepine use (B=10.3 prescribed-days/year, 95% CI 1.5-19.1). Among assessed models, elastic net regularization demonstrated best predictive performance in the withheld validation cohort when assessing both long-term opioid use (area under curve [AUC]=0.748) and long-term benzodiazepine use (AUC=0.704). Applying our model to the validation set, patients scored as low-risk demonstrated a 4.8% and 2.4% risk of long-term opioid and benzodiazepine use, respectively, compared to 35.2% and 11.1% of high-risk patients. We developed and validated a parsimonious, predictive model to anticipate long-term opioid and benzodiazepine use early after intradural tumor resection, providing physicians opportunities to consider alternative pain management strategies.

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The effects of steroid therapy on pulmonary hypertension secondary to fibrosing mediastinitis.

Mediastinal fibrosis, a rare cause of pulmonary hypertension, may produce cough, dyspnea, and hemoptysis. Steroid therapy has been suggested for individuals with progressive symptoms, but data demonstrating the efficacy of such therapy are lacking. We present a case of pulmonary hypertension secondary to fibrosing mediastinitis. Hemodynamic and scintigraphic studies performed before and after a trial of corticosteroid therapy were unable to demonstrate any therapeutic benefit from the corticosteroids. In order to achieve better use of steroids for the treatment of this disease, we suggest that similar determinations be made on other patients with mediastinal fibrosis who receive such treatment.

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Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization.

The clinical benefits of lipid lowering with statins are attributed to changes in plaque composition leading to lesion stability, but supporting clinical data from human studies are lacking. Therefore, we investigated the effect of 3 months of pravastatin treatment on composition of human carotid plaques removed during carotid endarterectomy. Consecutive patients with symptomatic carotid artery stenosis received 40 mg/d pravastatin (n=11) or no lipid-lowering therapy (n=13; control subjects) for 3 months before scheduled carotid endarterectomy. Carotid plaque composition was assessed with special stains and immunocytochemistry with quantitative image analysis. Plaques from the pravastatin group had less lipid by oil red O staining (8.2+/-8.4% versus 23.9+/-21.1% of the plaque area, P<0.05), less oxidized LDL immunoreactivity (13.3+/-3.6% versus 22.0+/-6.5%, P<0.001), fewer macrophages (15.0+/-10.2% versus 25.3+/-12.5%, P<0.05), fewer T cells (11.2+/-9.3% versus 24.3+/-13.4%, P<0.05), less matrix metalloproteinase 2 (MMP-2) immunoreactivity (3.6+/-3.9% versus 8.4+/-5.3%, P<0.05), greater tissue inhibitor of metalloproteinase 1 (TIMP-1) immunoreactivity (9.0+/-6.2% versus 3.1+/-3.9%, P<0.05), and a higher collagen content by Sirius red staining (12.4+/-3.1% versus 7.5+/-3.5%, P<0.005). Cell death by TUNEL staining was reduced in the pravastatin group (17.7+/-7.8% versus 32.0+/-12.6%, P<0.05). -Pravastatin decreased lipids, lipid oxidation, inflammation, MMP-2, and cell death and increased TIMP-1 and collagen content in human carotid plaques, confirming its plaque-stabilizing effect in humans.

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The effect of the CYP2D6 genotype on the maintenance dose of metoprolol in a chronic Dutch patient population.

Metoprolol is among the most frequently prescribed β-blockers for the treatment of various cardiovascular diseases. Genetic polymorphism within CYP2D6 has been shown to affect the rate of metabolism of metoprolol. Whether metoprolol dose adjustments are indicated in CYP2D6 poor metabolizers (PMs) has thus far not well been studied. The aim of this study was to determine the effect of the CYP2D6 genotype on the metoprolol maintenance dose in a chronic Dutch patient population. Patients were included if they were treated with metoprolol and in whom CYP2D6 genotype status was known. Patient and treatment characteristics were obtained retrospectively from the electronic healthcare records. Metoprolol maintenance dose was the primary endpoint and was defined as the last known dose that the patients had been treated with. Genotype data were categorized into four phenotypes, that is, PMs, intermediate metabolizers, extensive metabolizers, and ultra-rapid metabolizers (UMs). The endpoints were analyzed as PM versus non-PM. A total of 105 patients were included. The mean ± SD maintenance dose in PMs (n = 12) was significantly lower compared with non-PMs (n = 93), that is, 48 ± 20 versus 84 ± 53 mg, respectively (P = 0.019). No association of the CYP2D6 genotype with the incidence of side effects was observed, although there was a trend for increased risk of drowsiness (P = 0.053). The results of this study show that the CYP2D6 genotype is associated with the maintenance dose of metoprolol. Patients with the CYP2D6 PM phenotype may benefit from a lower metoprolol starting dose, followed by further dose titration to provide patient-tailored therapy and thereby increase the effectiveness of treatment.

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The early anti-oxidant effect of carvedilol predicts the clinical course in congestive heart failure patients.

Carvedilol, a beta1 and beta2 as well as an alpha1 adrenoreceptor antagonist with multiple hemodynamic, anti-ischemic and anti-oxidant properties, is widely accepted for the treatment of hypertension and congestive heart failure (CHF). It has been shown to improve morbidity and mortality in CHF. To assess whether the anti-oxidant effect of carvedilol has an impact on the clinical course in post-myocardial infarction (MI) CHF. Thirty-nine recent MI patients, aged 60.5 +/- 7 years, New York Heart Association functional class (FC) II-III, and left ventricular ejection fraction (LVEF) 29 +/- 3.8%, underwent oxygen free radical (OFR) assessment using the thiobarbituric acid reactive substances, thermochemoluminescence and conjugated dienes methods. OFR was determined at baseline, 1, 3, 12, and 24 h after 3.125, 6.25 and 12.5 mg carvedilol, and after 6 months of treatment. Brain natriuretic peptide (BNP), LVEF, FC change, 6-min walk test (6MW) and quality of life scores were evaluated before and after 6 months. Two patterns of OFR activity were found. In 29 patients (group 1) a significant and consistent reduction in OFR following administration of each dose of carvedilol was found, significantly correlating with each of the outcome parameters. In ten patients (group 2), no change in OFR was found, nor in any of the other outcomes. At 6 months, FC improved in 23 patients from group 1 (79.3%) and only in one (10%) from group 2 (P<0.01). 6MW increased by more than 10% in group 1 with no change in group 2 (P<0.05). BNP decreased from 397 +/- 36 pg/ml to 171 +/- 15.9 pg/ml (P<0.01) in group 1 compared to 381 +/- 32.5 pg/ml and 405 +/- 36 pg/ml, respectively (P=not significant) in group 2. One year hospital admissions and death rate were significantly higher in group 2. The early anti-oxidative effect of carvedilol correlates well with the clinical course and probably predicts it.

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Prospective single-arm protocol of carvedilol in children with ventricular dysfunction.

The objective of this study was to evaluate the safety and efficacy of carvedilol in pediatric patients with stable moderate heart failure. We performed a single-arm prospective drug trial at three academic medical centers and the results were compared to historical controls. Patients were 3 months to 17 years old with an ejection fraction <40% in the systemic ventricle for at least 3 months on maximal medical therapy including ACE inhibitors. Treated patients were started on 0.1 mg/kg/day and uptitrated to 0.8 mg/kg/day or the maximal tolerated dose. Echocardiographic parameters of function were prospectively measured at entry and at 6 months. Two composite endpoints were recorded: severe decline in status and significant clinical change. Adverse events were reviewed by a safety committee. Data were also collected from untreated controls with dilated cardiomyopathy meeting entry criteria, assessed over a similar time frame. Twenty patients [12 dilated cardiomyopathy (DCM) and 8 congenital] with a median age of 8.4 years (range, 8 months to 17.8 years) were treated with carvedilol. Three patients discontinued the drug during the study. At entry, there was no statistical difference in age, weight, or ejection fraction between the treated group and controls. The ejection fraction of the treated DCM group improved significantly from entry to 6 months (median, 31 to 40%, p = 0.04), with no significant change in ejection fraction in the control group [median, 29 to 27%, p = not significant (NS)]. The median increase in ejection fraction was larger for the treated DCM group than for the untreated DCM controls (7 vs 0%, p = 0.05). By Kaplan-Meier analysis, time to death or transplant tended to be longer in treated patients (p = 0.07). The difference in the proportion of patients with severe decline in status or significant clinical change in the treated group was not significant compared to the controls (5 vs 12%, p = NS). We conclude that in this prospective protocol of pediatric patients, the use of adjunct carvedilol in the DCM group improved ejection fraction compared to untreated controls and trended toward delaying time to transplant or death.

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Adjunctive therapy with pregabalin in generalized anxiety disorder patients with partial response to SSRI or SNRI treatment.

This study evaluated the efficacy of adjunctive pregabalin versus placebo for treatment of patients with generalized anxiety disorder (GAD) who had not optimally responded to previous or prospective monotherapies. This was a phase 3, randomized, double-blind, placebo-controlled study. Patients diagnosed with GAD who had a historical and current lack of response to pharmacotherapy [Hamilton Anxiety Rating Scale (HAM-A) of ≥ 22 at screening] were randomized to adjunctive treatment with either pregabalin (150-600 mg/day) or placebo. The primary outcome measure was the change in HAM-A total scores after 8 weeks of combination treatment. Adverse events were regularly monitored. Randomized patients (N=356) were treated with pregabalin (n=180) or placebo (n=176). Mean baseline HAM-A scores were 20.7 and 21.4, respectively. After treatment, the mean change in HAM-A was significantly greater for pregabalin compared with placebo (-7.6 vs. -6.4, respectively; P<0.05). HAM-A responder rates (≥ 50% reduction) were significantly higher for pregabalin (47.5%) versus placebo (35.2%; P=0.0145). The time-to-sustained response favored pregabalin over placebo (P=0.014). Adverse events were consistent with previous studies and discontinuations were infrequent for pregabalin (4.4%) and placebo (2.3%). The study was discontinued early after an interim analysis. The results indicate that adjunctive pregabalin is an efficacious therapy for patients with GAD who experience an inadequate response to established treatments.

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Non-steroidal anti-inflammatory drugs and colorectal cancer risk in a large, prospective cohort.

Use of non-steroidal anti-inflammatory drugs (NSAIDs) has been inversely associated with colorectal cancer; however, the association within colorectal subsites or among higher risk individuals is understudied. We investigated NSAID use and colorectal adenocarcinoma by subsite, and among individuals with a family history of colon cancer in the National Institutes of Health-AARP Diet and Health Study. Using Cox proportional hazards regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for colorectal cancer incidence among 301,240 men and women (mean age 62.8 years); including 26,994 individuals with a first-degree relative with a history of colon cancer. We accrued 3,894 colorectal cancer cases during 10 years of follow-up; 372 cases had a first-degree relative with colon cancer. Both aspirin and non-aspirin NSAID use reduced colorectal cancer risk (HR for users compared with non-users=0.91, 95% CI: 0.85, 0.98; HR=0.82, 95% CI: 0.77, 0.87, respectively). Daily aspirin use reduced the risk of cancer in the distal colon (HR=0.84, 95% CI: 0.71, 0.99) and rectum (HR=0.76, 95% CI: 0.64, 0.90); daily non-aspirin NSAID use reduced the risk of both proximal (HR=0.65, 95% CI: 0.54, 0.78) and distal colon cancer (HR=0.69, 95% CI: 0.55, 0.87), but not rectal cancer. Among participants with a first-degree relative with colon cancer, daily use of aspirin was associated with a decreased risk of rectal cancer (HR=0.38, 95% CI: 0.19, 0.78), and daily use of non-aspirin NSAIDs was associated with a decreased risk of colon cancer (HR=0.49, 95% CI: 0.29, 0.82). No protective benefit for daily aspirin use and colon cancer or daily non-aspirin NSAID use and rectal cancer was observed in this higher risk subgroup, although power was limited by small case numbers. NSAID use was associated with a reduced colorectal cancer risk; the magnitude of this association differed between aspirin and non-aspirin NSAIDs. Daily aspirin and non-aspirin NSAID use by individuals with a family history of colon cancer significantly reduced the risk of rectal and colon cancer, respectively.

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Comparison between fenoterol/ipratropium bromide combinations and salbutamol administered as nebulizer solution assessing dose-response and duration of action.

The study was performed to assess the efficacy of three ipratropium/fenoterol combinations and salbutamol when administered as nebulizer solution to patients with reversible airway obstruction. 11 patients, of whom 10 completed, aged 18 years or over, were chosen. For inclusion they were required to demonstrate a 15% improvement in absolute FEV1 within 10 min of administering an inhaled beta-adrenergic agonist. The study consisted of a randomised, double-blind, cross-over comparison between three combinations of ipratropium/fenoterol and salbutamol: ipratropium 0.5 mg/fenoterol 1.25 mg; iptratropium 0.5 mg/fenoterol 2.5 mg; ipratropium 0.5 mg/fenoterol 5.0 mg, and salbutamol 5.0 mg. In this relatively small number of patients there was no overall significant difference between the three doses of combination when PEFR, FEV1 and FVC were considered. However, the results for each of the three combinations were better than those for salbutamol and these reached the level of statistical significance (p less than 0.01) for the medium and high doses. PEFR measured between 3 and 8 h again demonstrated improved results for the three combinations compared with salbutamol reaching a level of statistical significance (p less than 0.01) for the high and medium doses.

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[Characteristic features of proton pump inhibitors in the inhibition of gastric acid secretion: long-acting and complete inhibition].

Proton pump inhibitor is a compound recently applied for the treatment of peptic ulcers for its strong action to inhibit the gastric acid secretion. It works through inhibition of H+, K(+)-ATPase, so called proton pump, on the luminal surface of secretory canaliculi in the parietal cells, showing remarkable characteristics in the inhibition of gastric acid secretion; e.g., the long-acting and complete inhibition. At neutral pH, the unionized form of this compound as a weak base is lipophilic, and passes through the cell membrane to accumulate as the ionized form in an acidic environment in the secretory canaliculi of parietal cells, where it is transformed to an active molecule which binds covalently to the active site of H+, K(+)-ATPase, forming a highly stable complex. The long-acting and complete inhibition of gastric acid secretion by this compound is derived from this physico-chemical nature. The above characteristics of the proton pump inhibitor have been confirmed with the basal, stimulated and nocturnal gastric acid secretion and the 24-hour intragastric pH of healthy volunteers by several investigators prior to its nation-wide clinical trial in Japan. On the other hand, the increased endocrine and exocrine secretion, such as pepsin secretion and gastrin release, and the increased turnover of gastrointestinal endocrine cells by this compound have been reported in animal models, probably due to its accumulation in the acidic environment.(ABSTRACT TRUNCATED AT 250 WORDS)

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Aspirin use, cancer, and polyps of the large bowel.

The effect of aspirin use on 490 patients with cancer of the colon, 340 with cancer of the rectum as the first primary site, and 212 patients with polyps having no coexisting malignancies was compared with that of two groups of control subjects that consisted of 524 hospital patients having no cancers and no diseases of the digestive organs and 1138 healthy visitors to the screening clinic. All subjects entered Roswell Park Cancer Institute between 1982 and 1991. After adjustment for adulthood lifetime duration of aspirin use, sex, age, residence, and education, the risk of having cancers and polyps of the colon or the rectum among people who had been using aspirin at least for 1 year before the illness relative to that of nonusers was estimated using multiple logistic regression procedure. The odds ratio estimates showed that the risk of colorectal cancers declined progressively as the frequency of aspirin use increased compared with control groups. Among patients reporting use of aspirin two or more times a day, the odds ratio estimates for colorectal cancers were 0.33 (95% confidence interval [CI], 0.72-0.15) and 0.44 (95% CI, 1.10-0.18) compared with those of screening clinic visitors and hospital control subjects, respectively. The odds ratio for patients with polyps who had used aspirin less than once a day relative to that of nonusers was 0.28 (95% CI, 0.62-0.13) and 0.43 (95% CI, 1.09-0.17) compared with screening clinic visitors and hospital control subjects, respectively. There is a risk reduction effect of aspirin use on the incidence of colorectal cancers and polyps, and this effect is dose related.

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The effect of oral corticosteroid dosage on CT enhancing multiple sclerosis plaques.

Fifty high-dose delayed CT scans were performed on 36 patients with definite MS within 4 months of a clinical relapse. The number of enhancing lesions visualized was compared in patients being treated with high- or low-dose oral corticosteroids and untreated controls. High-dose oral corticosteroid treatment significantly but incompletely reduced enhancement of MS plaques. Lower doses were less effective, especially when the latter were given on alternate days.

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Prednisone therapy for children with newly diagnosed idiopathic thrombocytopenic purpura. A randomized clinical trial.

The efficacy of corticosteroids in childhood acute idiopathic thrombocytopenic purpura (ITP) is controversial and has infrequently been evaluated in a controlled randomized fashion. We administered prednisone (2 mg/kg/day for 14 days with subsequent tapering and discontinuation by day 21) or placebo to 27 children, aged 10 years or less, with newly diagnosed ITP. Platelet count, bleeding time (a test of the integrity of the platelet-microvasculature interaction), and clinical bleeding score (based on a 0-4 scale) were determined before (day 0) and six times following initiation of drug therapy (days 1-2, 3-5, 7, 14, 21, and 28). There were no statistically significant (p less than 0.05) differences between the two treatment groups in any of the three study parameters except on day 7 of therapy when children receiving prednisone had higher platelet counts and lower bleeding scores and bleeding times than those taking placebo. Bleeding time correlated inversely with the platelet count in both treatment groups. Prednisone did not appear to influence bleeding time independent of its effect on platelet count. This treatment regimen of prednisone did not clearly improve hemostasis in childhood acute ITP except transiently at the end of 1 week of treatment.

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Eradication of Helicobacter pylori abolishes 24-hour hypergastrinaemia: a prospective study in healthy subjects.

In a prospective study, eight young healthy subjects (five with an active H. pylori infection in the antral mucosa) were treated with a course of tripotassium dicitrato bismuthate, amoxycillin and metronidazole. The triple therapy eradicated infection when assessed 20-24 weeks later by antral biopsy (urease, histology, and 13C urea breath test [4 out of 5 subjects]). Twenty-four hour intragastric acidity and plasma gastrin concentration were measured before treatment, and 4-6 weeks and 20-24 weeks post-treatment. Treatment did not affect acidity in either the H. pylori-positive or H. pylori-negative groups, nor did it affect the plasma gastrin profile in the H. pylori-negative group. Eradication of H. pylori infection in five subjects caused a drop of the median integrated 24-hour plasma gastrin concentration from 558 pmol.h/L before treatment to 307 and 289 pmol.h/L at 4-6 and 20-24 weeks post-treatment, respectively. It is concluded that H. pylori infection is associated with 24-hour hypergastrinaemia, and that in apparently healthy subjects normal gastric physiology can be restored by eradication of the infection.

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Comparative effects of candesartan and enalapril on left ventricular hypertrophy in patients with essential hypertension: the candesartan assessment in the treatment of cardiac hypertrophy (CATCH) study.

A limited number of studies have evaluated the effect of angiotensin II receptor antagonists (AIIAs) on left ventricular hypertrophy (LVH) in comparison with other antihypertensive drugs, and no large study has compared AIIAs with angiotensin-converting enzyme inhibitors (ACEIs). The CATCH (Candesartan Assessment in the Treatment of Cardiac Hypertrophy) study was a multicenter prospective randomized double-blind trial comparing the effects of candesartan cilexetil (8-16 mg once daily) and enalapril (10-20 mg once daily) with possible addition of hydrochlorothiazide (12.5-25 mg once daily) on echocardiographic left ventricular mass index (LVMI), in 239 hypertensives with LVH (LVMI 120 g/m2 in men and 100 g/m2 in women). Two-dimensionally guided M-mode echocardiograms were carried out at screening (recruiting scan), randomization (baseline scan) and after 24 and 48 weeks of treatment. Baseline and treatment echocardiograms were read at two central labs without knowledge of the scan time sequence. In intention-to-treat (ITT) analyses (196 patients), systolic and diastolic blood pressures (SBP, DBP) were significantly and equally reduced by the two treatments. Candesartan and enalapril reduced LVMI to the same extent, i.e. by 15.0 and 13.1 g/m2 (-10.9 and -8.4%; P<0.001 for both). The proportion of patients achieving normalization of LVMI was non-significantly higher with candesartan (36.3 versus 28.6%). Similar results were obtained in per-protocol (PP) analyses. Cough incidence was lower with candesartan ( P<0.03). CATCH is the first large study comparing the effects of an AIIA and an ACEI on LVMI. Candesartan cilexetil was found to be equally effective as enalapril in reducing SBP, DBP and LVMI in hypertensives with LVH, according to both ITT and PP analyses.

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Intracoronary Imaging, Cholesterol Efflux, and Transcriptomes After Intensive Statin Treatment: The YELLOW II Study.

Despite extensive evidence demonstrating the beneficial effects of statins on clinical outcomes, the mechanisms underlying these effects remain elusive. This study assessed changes in plaque morphology using intravascular imaging, with a comprehensive evaluation of cholesterol efflux capacity (CEC) and peripheral blood mononuclear cell (PBMC) transcriptomics in patients receiving high-dose statin therapy. In a prospective study, 85 patients with stable coronary artery disease underwent percutaneous coronary intervention for a culprit lesion, followed by intracoronary multimodality imaging, including optical coherence tomography (OCT) of an obstructive nonculprit lesion. All subjects received 40 mg of rosuvastatin daily for 8 to 12 weeks, when the nonculprit lesion was reimaged and intervention performed. Blood samples were drawn at both times to assess CEC and transcriptomic profile in PBMC. Baseline OCT minimal fibrous cap thickness (FCT) was 100.9 ± 41.7 μm, which increased to 108.6 ± 39.6 μm at follow-up, and baseline CEC was 0.81 ± 0.14, which increased at follow-up to 0.84 ± 0.14 (p = 0.003). Thin-cap fibroatheroma prevalence decreased from 20.0% to 7.1% (p = 0.003). Changes in FCT were independently associated with CEC increase by multivariate analysis (β: 0.30; p = 0.01). PBMC microarray analysis detected 117 genes that were differentially expressed at follow-up compared to baseline, including genes playing key roles in cholesterol synthesis (SQLE), regulation of fatty acids unsaturation (FADS1), cellular cholesterol uptake (LDLR), efflux (ABCA1 and ABCG1), and inflammation (DHCR24). Weighted coexpression network analysis revealed unique clusters of genes associated with favorable FCT and CEC changes. The study demonstrated an independent association between fibrous cap thickening and improved CEC that may contribute to morphological changes suggesting plaque stabilization among patients taking intensive statin therapy. Furthermore, the significant perturbations in PBMC transcriptome may help determine the beneficial effects of statin on plaque stabilization. (Reduction in Coronary Yellow Plaque, Lipids and Vascular Inflammation by Aggressive Lipid Lowering [YELLOW II]; NCT01837823).

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Genetic variant showing a positive interaction with beta-blocking agents with a beneficial influence on lipoprotein lipase activity, HDL cholesterol, and triglyceride levels in coronary artery disease patients. The Ser447-stop substitution in the lipoprotein lipase gene. REGRESS Study Group.

Lipoprotein lipase (LPL) is the rate-limiting enzyme in the lipolysis of triglyceride-rich lipoproteins, and the gene coding for LPL is therefore a candidate gene in atherogenesis. We previously demonstrated that two amino acid substitutions in LPL, the Asn291-Ser and the Asp9-Asn, are associated with elevated triglycerides and lower HDL cholesterol and are present with greater frequency in coronary artery disease (CAD) patients than in normolipidemic control subjects. Conversely, a third frequent mutation in this gene, the Ser447-Stop, is reported by some investigators to underlie higher HDL cholesterol levels and would represent a beneficial genetic variant in lipoprotein metabolism. We therefore sought conclusive evidence for these allegations by investigating the effects of the LPL Ser447-Stop mutation on LPL and hepatic lipase (HL) activity, HDL cholesterol, and triglycerides in a large group of CAD patients (n = 820) with normal to mildly elevated total and LDL cholesterol levels. Carriers of the Ser447-Stop allele (heterozygotes and homozygotes) had significantly higher postheparin LPL activity (P = .034), normal postheparin HL activity (P = .453), higher HDL cholesterol levels (P = .013), and lower triglyceride levels (P = .044) than noncarriers. The influence of the Ser447-Stop allele on LPL activity was pronounced in patients using beta-blockers (P = .042) and not significant in those not using them (P = .881), suggesting a gene-environment interaction between the Ser447-Stop mutation and beta-blockers. We conclude that the LPL Ser447-Stop mutation has a significant positive effect on LPL activity and HDL cholesterol and triglyceride levels and that certain subgroups of CAD patients carrying the Ser447-Stop mutation will have less adverse metabolic effects when placed on beta-blockers. The LPL Ser447-Stop mutation therefore should have a protective effect against the development of atherosclerosis and subsequent CAD.

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Acupuncture effectiveness as a complementary therapy in functional dyspepsia patients.

Functional dyspepsia represents a frequent gastrointestinal disorder in clinical practice. According to the Roma III criteria, functional dyspepsia can be classified into two types as the predominant symptom: epigastric pain and postprandial discomfort. Even though the pathophysiology is still uncertain, the functional dyspepsia seems to be related to multiple mechanisms, among them visceral hypersensitivity, changes in the gastroduodenal motility and gastric accommodation and psychological factors. Evaluate the effectiveness of acupuncture as a complementary to conventional treatment in functional dyspepsia patients. Randomized clinical trial in which were enrolled patients with functional dyspepsia patients in according with Rome III criteria. One group was submitted to drug therapy and specific acupuncture (GI) and the other to drug therapy and non-specific acupuncture (GII). The gastrointestinal symptoms, presence of psychiatric disorders and quality of life were evaluated, at the end and three months after treatment. After 4 weeks of treatment there was improvement of gastrointestinal symptoms in Group I (55 ± 12 vs 29 ± 8.8; P = 0.001) and Group II (50.5 ± 10.2 vs 46 ± 10.5; P = 0.001). Quality of life was significantly better in Group I than group II (93.4 ± 7.3 vs 102.4 ± 5.1; P = 0.001). Anxiety (93.3% vs 0%; P = 0.001) and depression (46.7% vs 0%; P = 0.004) were significantly lower in Group I than group II. When comparing the two groups after 4 weeks of treatment, gastrointestinal symptoms (29 ± 8.8 vs 46 ± 10.5; P<0.001) and quality of life (102.4 ± 5.1 vs 96 ± 6.1; P = 0.021) were significantly better in Group I than group II. Three months after the treatment, gastrointestinal symptoms remained better only in Group I, when compared to the pre-treatment values (38 ± 11.3 vs 55 ± 12; P = 0.001). In patients with functional dyspepsia the complementary acupuncture treatment is superior to conventional treatment. Further studies with more patients are needed to confirm these findings.

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Trazodone conventional and controlled-release formulations: pharmacodynamic effects after single and repeated administration.

In a double-blind study, the pharmacodynamic effects of single and repeated doses of two formulations of trazodone were compared in 14 healthy young volunteers (6 men and 8 women). They received either 100 mg trazodone conventional capsules or 150 mg controlled-release tablets daily at 08.00 hours for two 7-day periods separated by a 'wash-out' period of 2 weeks. Blood pressure standing and lying, critical flicker fusion frequency and manual dexterity were measured on Days 1 and 7 of each session before and at intervals up to 8 hours after the dose. Manual dexterity was tested by measuring the time taken to drop 50 airgun pellets down a narrow tube. A daily pre-dose blood sample was also taken for measurement of trazodone to check compliance and to confirm that steady state had been achieved. Steady state plasma concentrations were reached by Day 2 of repeated dosing on both treatments. There was a trend towards shorter duration of the expected depressant effect of trazodone on critical flicker fusion frequency and manual dexterity on Day 7 for both treatments, which was significantly different between treatments for manual dexterity (p less than 0.001): for the controlled-release tablet, manual dexterity performance was better on Day 7 than on Day 1 at all times after dosing, whereas for the conventional capsule manual dexterity was worse on Day 7 than on Day 1 until 4 and 8 hours after dosing, when performance was better than on Day 1. In this study, both formulations of trazodone caused the expected negative effects on psychomotor function. Further studies would be required to confirm the apparent advantage of the controlled-release tablet in the test of manual dexterity.

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Effects of pimobendan on myocardial perfusion and pulmonary transit time in dogs with myxomatous mitral valve disease: a pilot study.

To describe pulmonary transit time (nPTT) and myocardial perfusion (nMP) normalised to heart rate in dogs with stable ACVIM stage C myxomatous mitral valve disease (MMVD) and to assess short-term effects of pimobendan on these variables. We hypothesised that nPTT and nMP would increase in dogs with MMVD compared with normal dogs. Additionally, we hypothesised that treatment with pimobendan would decrease nMP and nPTT in dogs with MMVD. Prospective, single-blind study involving 6 normal dogs and 12 dogs with MMVD. Dogs with MMVD were treated with enalapril and furosemide for at least 1 month prior to examination. All dogs underwent standard and contrast echocardiographic examinations at the beginning of the study (T0). At this time, MMVD dogs were randomly assigned to receive either pimobendan (0.4-0.6 mg/kg) or not. All dogs with MMVD were re-evaluated by standard and contrast echocardiography after 1 week (T1) and nPTT and nMP were measured. nPTT was significantly increased in dogs with MMVD (P = 0.0063), compared with normal dogs. It was significantly decreased at T1 in dogs receiving pimobendan (P = 0.0250). The nMP was not significantly different in dogs with MMVD, compared with healthy dogs (P = 0.2552), and it was not significantly different at T1 in the treatment group (P = 0.8798). Contrast echocardiography was a valid, complementary tool for echocardiographic analysis of dogs with MMVD. Pimobendan decreased nPTT in dogs affected by MMVD. Myocardial perfusion was not different in dogs with severe MMVD.

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Video capsule endoscopy to prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and placebo.

Data indicate that cyclooxygenase-2-specific inhibitors cause less gastroduodenal mucosal damage than nonspecific NSAIDS, but their effects on the small bowel mucosa are less well recognized. In a multicenter, double-blind, placebo-controlled trial with video capsule endoscopy (VCE) we prospectively evaluated the incidence of small bowel injury in healthy subjects treated with celecoxib compared to naproxen plus omeprazole. We randomly assigned subjects with normal baseline VCEs to celecoxib 200 mg twice daily (n = 120), naproxen 500 mg twice daily plus omeprazole 20 mg once daily (n = 118), or placebo (n = 118) for 2 weeks. The primary end point was the mean number of small bowel mucosal breaks per subject. Baseline VCE found small bowel lesions in 13.8% (57/413) of screened subjects, who became ineligible for randomization. The mean number of small bowel mucosal breaks per subject and the percentage of subjects with these mucosal breaks were 2.99 +/- 0.51, 55% for naproxen/omeprazole compared to 0.32 +/- 0.10, 16% for celecoxib and 0.11 +/- 0.04, 7% for placebo (P < .001, both comparisons). The magnitude of the difference between celecoxib and placebo was small but statistically significant (P = .04). Among healthy subjects with lesion-free baseline VCEs, celecoxib was associated with significantly fewer small bowel mucosal breaks than naproxen plus omeprazole. This study also showed that the background incidence of small bowel lesions in healthy adults is not insignificant and should be considered in future trials with VCE.

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A comparative study of a BCNU containing 4-drug program versus MOPP versus 3-drug combinations in advanced Hodgkin's disease: a cooperative study by the Cancer and Leukemia Group B.

A prospective randomized trial by CALGB examined the relative value of four chemotherapy regimens in 537 patients with stage III B and IV Hodgkin's disease. A new combination BOPP, derived by substitution of BCNU for nitrogen mustard in the MOPP regimen, was compared to MOPP and to two 3-drug regimens, derived by removing the procarbazine in BOPP (BOP) or removing the alkylating agent (OPP). The 4-drug programs gave significantly higher frequency of complete remissions (BOPP 67%, MOPP 63%) than the 3-drug regimens (BOP 40%, OPP 42%), and significantly longer duration of remission and survival. BOPP had a therapeutic activity equal to MOPP, and was accompanied by less toxicity. After 6 cycles of induction chemotherapy, responding patients, both CR and PR, were continued on maintenance chemotherapy for 3 years. No significant difference in relapse rate was demonstrated following maintenance treatment with either vinblastine, chlorambucil, or chlorambucil plus monthly vincristine + prednisone doses. Nor could a reinforcement phase late in the maintenance program be shown to influence the relapse rate. The median survival for all patients entered on the 4-drug programs was 5 years, while the median has not yet been reached at 6 years for those patients, who obtained CR.

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Efficacy and safety of quinapril in the elderly hypertensive patient.

The efficacy and safety of once-daily administration of the new angiotensin-converting enzyme inhibitor quinapril or quinapril plus hydrochlorothiazide (HCTZ) were assessed in 64 older (greater than 65 years) patients with mild to moderate hypertension in an uncontrolled, open-label study. Treatment was initiated with 20 mg of quinapril once daily and titrated upward to 40 mg of quinapril or 40 mg of quinapril combined with 25 mg of HCTZ according to efficacy. At the end of the 12-week active-treatment phase, 43 patients received 20 mg of quinapril once daily, 12 patients received 40 mg of quinapril once daily, and 4 patients received 40 mg of quinapril combined with 25 mg of HCTZ once daily. Of 48 patients evaluable for efficacy, the mean decrease from baseline in sitting diastolic blood pressure (DBP) was 12.8 mm Hg; 96% of the patients had a blood pressure reduction of greater than or equal to 10 mm Hg, and 98% had a sitting DBP of less than or equal to 90 mm Hg 20 to 28 hours after administration. The decrease in sitting DBP was significant after 1 week and continued for the entire study, as did corresponding changes in sitting systolic blood pressure. We conclude that quinapril administered once daily is well tolerated and effective for the treatment of mild to moderate hypertension in elderly patients.

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A comparison of the efficacy and safety of alprazolam and desipramine in depressed outpatients.

Fifty-two adult depressed outpatients fulfilling Research Diagnostic Criteria for Definite Major Depressive Disorder were enrolled in a double-blind study comparing the antidepressant effects of alprazolam versus desipramine. Twenty-nine patients completed the seven week (one week placebo followed by six weeks of active drug) study. The mean daily dose of alprazolam and desipramine at study termination was 3.34 mg and 192 mg respectively. Based on psychometric ratings of depression (Hamilton Scale) and severity of illness (Clinical Global Impressions) there was no significant difference between alprazolam and desipramine at the end of six weeks of active drug treatment. Both medications were well tolerated with drowsiness being the most common side effect of alprazolam, and insomnia, dry mouth, and constipation, the complaints most associated with desipramine.

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Do diuretics have antihypertensive properties independent of natriuresis?

To ascertain whether diuretics have an antihypertensive effect independent of natriuresis, 12 stable patients on maintenance hemodialysis underwent a crossover evaluation with hydrochlorothiazide, 50 mg daily, metolazone, 5 mg daily, or placebo in 4-wk treatment periods for 6 mo. Compliance was assured by pill counts and serum drug concentrations. All patients had daily urine less than 100 ml. Pre- and postdialysis blood pressure, body weight, plasma volume, and plasma renin activity were monitored. Over the 6-mo study period there were no statistically significant changes in any parameter related to diuretic therapy. It is concluded that a functioning kidney with the ability to respond to diuretics with a natriuresis is necessary for the antihypertensive action of diuretics. Direct vascular effects of diuretics to lower peripheral resistance could not be demonstrated in this unique patient population.

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Comparison of terbutaline via the Nebuhaler and salbutamol via the Volumatic: theory and practice.

The bronchodilating efficacy of terbutaline (250 micrograms.puff) inhaled via the Nebuhaler and salbutamol (100 micrograms.puff) inhaled via the Volumatic has been studied in 30 patients with reversible obstructive airways disease in a randomized crossover study. The salbutamol/Volumatic combination produced significantly greater bronchodilatation than terbutaline/Nebuhaler (one puff, p less than 0.001; eight puffs, p less than 0.01). The findings are discussed with particular reference to the theories of spacer action.

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[Comparison on the effects of clopidogrel, statins combination in treating coronary artery disease among the elderly patients: a retrospective cohort study].

To compare the effects of clopidogrel with or without combined with CYP3A4-metabolized statin in treating coronary artery disease (CAD) among the elderly patients. The study cohort was defined as all patients were over 60 years of age and hospitalized for CAD who were prescribed clopidogrel between January 2000 and February 2011. A total of 1021 patients were enrolled, with 178 of them prescribed clopidogrel and 843 patients were administrated clopidogrel combined with statins (CYP3A4-metabolized statins 636 and non CYP3A4-metabolized statins 207). The primary endpoint was all cause of death and the second endpoint were non-fatal myocardial infarction (MI), but hospitalized for unstable angina, stroke, transient ischemic attack, or repeated revascularization (PCI or coronary artery bypass graft). Among the clopidogrel group and the clopidogrel plus statins group, the incidence density of death was 6.86/1000 and 3.18/1000 respectively, with crude RR as 2.15 (95%CI: 1.39-3.33) and statistically significant (χ2=3.53, P<0.01). The incidence density of composite thromboembolic events did not show statistical significance (P>0.05). The two groups were 1:1 matched, after propensity score matching, clopidogrel coadministrated with statins group showed significant decrease in all cause of death, with RR as 0.42 (95%CI: 0.19-0.93), χ2=7.23, P<0.01. No significant difference was observed in deaths or composite thromboembolic events between statins via different cytochrome P450 pathways. Clopidogrel with statin could reduce the mortality of elderly CAD patients compared with clopidogrel without statin. The result did not show statistical significance between CYP3A4-metabolized statins or non CYP3A4-metabolized statins regarding the mortality or composite endpoint events.

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Antithymocyte globulin, cyclosporine, and prednisone for the treatment of severe aplastic anemia in children. A pilot study.

The aim of the therapeutic trial was to try to optimize the treatment of severe and moderate aplastic anemia in children who lack a suitable bone marrow donor using the most successful available drugs, with the least amount of side effects. A pilot study for the treatment of severe aplastic anemia in children was conducted by four institutions. The treatment protocol included antithymocyte globulin (ATG), prednisone, and cyclosporine A. Twelve patients were enrolled, and 11 were evaluable. All patients had severe aplastic anemia (SAA); three had hepatitis-induced severe aplastic anemia (HI-SAA). Of 11 evaluable patients, eight have responded with normalization of their blood counts. Two of the three patients with HI-SAA responded to the therapy. The results of our pilot study compare favorably with previous therapeutic trials. All the patients who responded achieved complete response, i.e., restoration of blood counts to within the normal range.

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Rapid recovery of spermatogenesis after mitoxantrone, vincristine, vinblastine, and prednisone chemotherapy for Hodgkin's disease.

Because the effects of mitoxantrone on human male fertility were unknown, we determined prospectively the effects of three courses of mitoxantrone (Novantrone), vincristine (Oncovin), vinblastine, prednisone (NOVP) chemotherapy on the potential for fertility of men with Hodgkin's disease (HD). Semen analyses were performed on 58 patients with stages I-III HD before, during, and after chemotherapy and after the sperm count recovered from the effects of abdominal radiotherapy that was given after chemotherapy. Before the initiation of treatment, 84% of the patients were normospermic. Sperm counts declined significantly within 1 month after the start of NOVP chemotherapy. In the month after chemotherapy, 38% of patients were azoospermic, 52% had counts < 1 million/ mL, and 10% had counts between 1 and 3 million/mL. Between 2.6 and 4.5 months after the completion of chemotherapy, sperm counts recovered rapidly to normospermic levels in 63% of patients. In the remaining patients who were followed up for at least 1 year after standard upper abdominal radiotherapy, counts also recovered to normospermic levels. NOVP chemotherapy, like most other regimens, produced marked temporary effects or spermatogenesis. However, sperm production recovered very rapidly, within 3 to 4 months after the end of NOVP chemotherapy. This pattern was caused by killing differentiating spermatogenic cells, but there was little cytotoxicity or inhibition of stem cells from mitoxantrone or the other drugs. After the combination of NOVP plus abdominal radiotherapy, sperm counts and motility were restored in most patients to pretreatment levels, which were compatible with normal fertility.

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Controlled trial of intravenous hyperalimentation and total bowel rest as an adjunct to the routine therapy of acute colitis.

Thirty-six patients (27 with ulcerative colitis and 9 with Crohn's disease) completed a prospective controlled therapeutic trial of intravenous hyperalimentation (IVH) and total bowel rest in acute colitis. All patients received prednisone 40 mg/day which was reduced every 3 days or more depending on the response to treatment. The trial was completed either when the prednisone was reduced to 10 mg/day or when the patient came to colectomy. In the control group (5 males, 12 females; mean age 44.7 yr), 6 came to surgery and 11 responded medically in a mean time of 23.7 days. In the IVH group (8 males, 11 females; mean age 37.4 yr) 9 came to surgery and 10 responded medically in a mean time of 21.2 days. The results of this trial show that IVH with total bowel rest has no primary therapeutic effect in acute colitis.

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Alternating chemotherapy with cyclophosphamide/adriamycin/vincristine (CAV) and cisplatin/etoposide (PVP) against small cell lung cancer. Eastern Shikoku Lung Cancer Chemotherapy Group.

Seventy-four confirmed small cell lung cancer (SCLC) patients received alternating combination chemotherapy with CAV and PVP. The CAV comprised of cyclophosphamide 800 mg/m2 on day 1, adriamycin 50 mg/m2 on day 1 and vincristine 1.4 mg/m2 on day 1, administered every 3-4 weeks. The PVP comprised cisplatin 80 mg/m2 on day 1 and etoposide 75 mg/m2 on day 1-5 administered every 3-4 weeks. Of these 74 patients, 63 (85.1%) achieved complete or partial responses with 16 (21.6%) obtaining a complete response. The median survival time was 13.2 months: 10.4 months in patients with extensive disease (ED), 16.3 months in those with limited disease (LD). A three-year disease-free period was achieved in eight patients (11.2%: 4.8% with ED, 16.8% with LD). The median duration of response was 28.3 weeks: 20.1 weeks with ED and 44.0 weeks with LD. The most commonly encountered side effects were nausea, vomiting, alopecia and myelosuppression but all were tolerable. We consider CAV-PVP to be an effective combination regimen for treating SCLC.

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Enantioselective pharmacokinetics of tramadol in CYP2D6 extensive and poor metabolizers.

To describe in detail the intravenous, single oral and multiple oral dose enantioselective pharmacokinetics of tramadol in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs). Eight EMs and eight PMs conducted three phases as an open-label cross-over trial with different formulations; 150 mg single oral tramadol hydrochloride, 50 mg single oral tramadol hydrochloride every 8 h for 48 h (steady state), 100 mg intravenous tramadol hydrochloride. Urine and plasma concentrations of (+/-)-tramadol and (+/-)-M1 were determined for 48 h after administration. In all three phases, there were significant differences between EMs and PMs in AUC and t(1/2) of (+)-tramadol (P< or =0.0015), (-)-tramadol (P< or =0.0062), (+)-M1 (P< or =0.0198) and (-)-M1 (P< or =0.0370), and significant differences in C(max) of (+)-M1 (P<0.0001) and (-)-M1 (P< or =0.0010). In Phase A and C, significant differences in t(max) were seen for (+)-M1 (P< or =0.0200). There were no statistical differences between the absolute bioavailability of tramadol in EMs and PMs. The urinary recoveries of (+)-tramadol, (-)-tramadol, (+)-M1 and (-)-M1 were statistically significantly different in EMs and PMs (P<0.05). Median antimodes of the urinary metabolic ratios of (+)-tramadol / (+)-M1 and (-)-M1 were 5.0 and 1.5, respectively, hereby clearly separating EMs and PMs in all three phases. The impact of CYP2D6 phenotype on tramadol pharmacokinetics was similar after single oral, multiple oral and intravenous administration displaying significant pharmacokinetic differences between EMs and PMs of (+)-tramadol, (-)-tramadol, -(+)-M1 and (-)-M1. The O-demethylation of tramadol was catalysed stereospecific by CYP2D6 in the way that very little (+)-M1 was produced in PMs.

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Aproach to the risk of delirium in an orthogeriatric unit.

The objective of this study is to evaluate the efficacy of a change in the management of the risk of delirium in an orthogeriatric unit. Prospective, comparative, non-randomised study of two cohorts of patients. One cohort (control group) treated with standard therapy with tramadol rescue and diazepam and another cohort (experimental group) treated with rescue with morphine at low doses and short half-life benzodiazepines as well as preventive treatment with neuroleptics in patients at high risk. Eighty-five patients were included (42 in the control group and 43 in the experimental group). Mean age: 85 (71-105). Twenty-nine patients (34%) had an episode of delirium during the current admission, 16 patients (38%) in the control group and 13 patients (30%) in the experimental group respectively (P=.498). The mean duration of delirium in the 29 patients who presented it was 5.3 days. This duration in the control group was 6.6 days and in the experimental group 3.8 days (P=.031). In the group of patients who had previous delirium, a lower incidence of delirium was seen during the current admission in the experimental group (80% vs 17% P=.036). Experimental treatment has been effective since a trend to a lower incidence of delirium has been observed. In the patients who have suffered an episode of delirium, the treatment served to decrease its duration with statistically significant differences.

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[Ranitidine and amoxicillin for eradication of Helicobacter pylori in patients with duodenal ulcer].

The results of many clinical studies have indicated that the eradication of Helicobacter pylori leads to a reduction in ulcer relapse. The aim of this double-blind, randomized, multicenter comparative study in 196 patients with H. pylori positive duodenal ulcer was to examine the efficacy and safety of two eradication therapies with ranitidine. The patients were treated daily with 4 x 150 mg ranitidine (CAS 66357-35-5, Sostril, Zantic) combined with 4 x 500 mg amoxicillin (CAS 26787-78-0, Amoxypen) (group 1) or 4 x 300 mg ranitidine (Sostril 300, Zantic 300) combined with 4 x 500 mg amoxicillin (group 2) for two weeks and during next two weeks with 300 mg ranitidine only. The final endoscopic investigation 6 weeks yielded healing rates of 90% (group 1) or 96% (group 2). Histopathological examination/urease test of biopsy showed successful eradication of H. pylori in 65%/60% (group 1) or 63%/69% (group 2) of patients. The treatment therapies were generally well or very well tolerated. Adverse events required drug withdrawal only in 3 patients (1.5%). A combination with ranitidine and amoxicillin is an effective and well tolerated therapy in H. pylori infected duodenal ulcer patients. The eradication rate does not seem to be further improved by a ranitidine dose higher than 600 mg daily.

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The effect of COX-2-selective meloxicam on the myocardial, vascular and renal risks: a systematic review.

Non-steroidal anti-inflammatory drugs (NSAIDs) are known to increase the risk of cardiovascular (CV) and renal incidences, especially at higher doses and upon long term use. However, the available reports are criticized for lack of specificity, grouping of vastly different outcomes together and ignoring the heterogeneity among NSAIDs. In this systematic review, we are reporting CV/renal risks associated with meloxicam, stratified into myocardial, vascular, renal risk categories, to address the differential nature of NSAIDs effects on different body systems. We are also reporting composite CV/renal risk to present overall risk associated with various covariates. We searched the online healthcare databases for observational studies or randomized controlled trials, reporting myocardial or all-cause mortality outcome (>90 days exposure) and/or vascular/renal outcomes (any exposure) after meloxicam use, published until April 2014. The combined odd ratio values (OR'; 95% CI) were calculated using the random effect inverse variance model. We found 19 eligible studies out of 2,422 reports. Meloxicam demonstrated a low increase in composite risk (OR' 1.14; CI 1.04-1.25) which was mainly vascular in nature (OR' 1.35; CI 1.18-1.55] as it did not elevate myocardial (OR' 1.13; CI 0.98-1.32) or renal (OR', 0.99; CI 0.72-1.35) risks. Relative to meloxicam, other NSAIDs increased the composite risk, in a dose-dependent fashion, in the following order: rofecoxib > indomethacin > diclofenac > celecoxib > naproxen > ibuprofen. OR' was also influenced by type of disease and the comparator used, and acetylsalicylic acid. NSAIDs are heterogeneous in increasing CV/renal risks. The low increased risk associated with meloxicam is mainly vascular in origin.

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Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial.

Incidence of end-stage renal disease due to hypertension has increased in recent decades, but the optimal strategy for treatment of hypertension to prevent renal failure is unknown, especially among African Americans. To compare the effects of an angiotensin-converting enzyme (ACE) inhibitor (ramipril), a dihydropyridine calcium channel blocker (amlodipine), and a beta-blocker (metoprolol) on hypertensive renal disease progression. Interim analysis of a randomized, double-blind, 3 x 2 factorial trial conducted in 1094 African Americans aged 18 to 70 years with hypertensive renal disease (glomerular filtration rate [GFR] of 20-65 mL/min per 1.73 m(2)) enrolled between February 1995 and September 1998. This report compares the ramipril and amlodipine groups following discontinuation of the amlodipine intervention in September 2000. Participants were randomly assigned to receive amlodipine, 5 to 10 mg/d (n = 217), ramipril, 2.5 to 10 mg/d (n = 436), or metoprolol, 50 to 200 mg/d (n = 441), with other agents added to achieve 1 of 2 blood pressure goals. The primary outcome measure was the rate of change in GFR; the main secondary outcome was a composite index of the clinical end points of reduction in GFR of more than 50% or 25 mL/min per 1.73 m(2), end-stage renal disease, or death. Among participants with a urinary protein to creatinine ratio of >0.22 (corresponding approximately to proteinuria of more than 300 mg/d), the ramipril group had a 36% (2.02 [SE, 0.74] mL/min per 1.73 m(2)/y) slower mean decline in GFR over 3 years (P =.006) and a 48% reduced risk of the clinical end points vs the amlodipine group (95% confidence interval [CI], 20%-66%). In the entire cohort, there was no significant difference in mean GFR decline from baseline to 3 years between treatment groups (P =.38). However, compared with the amlodipine group, after adjustment for baseline covariates the ramipril group had a 38% reduced risk of clinical end points (95% CI, 13%-56%), a 36% slower mean decline in GFR after 3 months (P =.002), and less proteinuria (P<.001). Ramipril, compared with amlodipine, retards renal disease progression in patients with hypertensive renal disease and proteinuria and may offer benefit to patients without proteinuria.

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Pre-emptive meloxicam for postoperative analgesia in piglets undergoing surgical castration.

To investigate the effect of preoperative meloxicam administration on postoperative stress and pain induced by surgical castration in piglets. Prospective, blinded, randomized clinical trial. One hundred and eighty male piglets of <1 week of age. Castration was performed on 150 piglets which had received either an intramuscular injection of 0.4 mg kg(-1) meloxicam or a placebo 10-30 minutes before the procedure. Blood cortisol and ACTH concentrations were determined at 30 minutes post-castration and haptoglobin was measured at 24 hours post-castration. Presence or absence of foreleg movements, hind leg movements, urine or faeces emission, tremors or other body movements were recorded during the castration procedure. Scores for presence or absence of prostration, tremors, tail movements and isolation were recorded at 30 minutes, and at 1, 2, 4 and 24 hours post-castration and combined in a global behaviour score (GBS). Blood samples were taken from a further 30 piglets which did not undergo castration. Mean blood cortisol and ACTH concentrations at 30 minutes post-castration were both significantly lower in the meloxicam group than in the placebo group (p < or = 0.01). The mean haptoglobin concentration at 24 hours was not significantly reduced (p = 0.178). The distribution of the GBS during castration was similar in both groups. There were significant differences in the GBS after castration at both 2 and 4 hours post-castration with a greater proportion of piglets in the meloxicam group showing no behavioural alterations (82.7%versus 68.0% at both time points). The score distribution was similar in both groups at 30 minutes, 1 and 24 hours after castration. This study suggests that pre-emptive administration of meloxicam is able to produce some postoperative analgesia after surgical castration of young piglets.

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Association between focused cardiac ultrasound and time to furosemide administration in acute heart failure.

Heart failure (HF) is a global health burden, and its management in the emergency department (ED) is important. This study aimed to evaluate the association between focused cardiac ultrasound (FoCUS) and early administration of diuretics in patients with acute HF admitted to the ED. This retrospective observational study was conducted at a tertiary academic hospital. Patients with acute HF patients who were admitted to the ED and receiving intravenous medication between January 2018 and December 2019 were enrolled. The main exposure was a FoCUS examination performed within 2 h of ED triage. The primary outcome was the time to furosemide administration. Of 1154 patients with acute HF, 787 were included in the study, with 116 of them having undergone FoCUS. The time to furosemide was significantly shorter in the FoCUS group (median time (q1-q3), 112 min; range, 65-163 min) compared to the non-FoCUS group (median time, 131 min; range, 71-229 min). In the multivariable logistic regression analysis adjusting for age, sex, chief complaint, mode of arrival, triage level, shock status, and desaturation at triage, early administration of furosemide within 2 h from triage was significantly higher in the FoCUS group (adjusted odds ratio, 1.63; 95% confidence intervals, 1.04-2.55) than in the non-FoCUS group. Early administration of intravenous furosemide was associated with FoCUS examination in patients with acute HF admitted to the ED. An early screening protocol could be useful for improving levels in clinical practice at EDs.

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Fluticasone propionate in clinically suspected asthma patients with negative methacholine challenge test.

Despite reports of response to steroid inhaler in some clinically suspected asthma patients with negative methacholine challenge test (CSA/MCT-), treatment in these patients has not been prospectively studied. We studied the role of a 12 week high dose inhaled fluticasone trial in CSA/MCT- patients. After a 2 week run-in period, CSA/MCT-patients were treated with 12 weeks of Fluticasone propionate 1000 µg/day. The Asthma Control Test (ACT), numeric cough score (NCS) and bronchodilator use were compared with their pretreatment values. Thirty-four of 42 CSA/MCT-patients completed the study. Mean pretreatment ACT score (pACT) was significantly increased after treatment (14.7 ± 3.37 to 20.9 ± 3.1, P < 0.001). Posttreatment values of daytime (1.0 ± 1.0) and night-time (0.6 ± 0.9) NCS decreased compared to their pretreatment values (2.8 ± 1.1 and 1.9 ± 1.3, respectively; P < 0.001). ACT score change (ΔACT) were significantly greater in those with pACT < 15 than in those ≥15 (P < 0.001) . Fifteen of 21 patients with ΔACT > 5 did not need to use bronchodilator for their symptom relief. Wheeze disappeared in all six patients with ΔACT > 5 after the trial. Six months after the study, steroid inhaler continued to be used by 72.2% of patients. A significant portion of CSA/MCT- (especially those with pretreatment ACT score <15) respond to high dose fluticasone inhaler in terms of symptoms relief, disappearance of wheeze and need to bronchodilator use. ΔACT could not be predicted with any individual symptoms or signs before MCT, % FEV1 decline or symptoms during MCT and exhaled nitric oxide.

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Catechol-O-methyltransferase Val158Met polymorphism is associated with methylphenidate response in ADHD children.

Methylphenidate is the most frequently prescribed drug in the treatment of attention deficit hyperactivity disorder (ADHD) but it is not effective in every case. Therefore, identifying genetic and/or biological markers predicting drug-response is increasingly important. Here we present a case-control study and pharmacogenetic association analyses in ADHD investigating three dopaminergic polymorphisms. Previous studies suggested variable number of tandem repeats (VNTR) in the dopamine D4 receptor (DRD4) and the dopamine transporter (DAT1) genes as genetic risk factors for ADHD and as possible markers of methylphenidate response. Our results did not indicate substantial involvement of these two VNTRs in ADHD, however, both the case-control and the pharmacogenetic analyses showed significant role of the high activity Val-allele of cathecol-O-methyltransferase (COMT) Val158Met polymorphism in our ADHD population. The Val-allele was more frequent in the ADHD group (n = 173) compared to the healthy population (P = 0.016). The categorical analysis of 90 responders versus 32 non-responders showed an association between the Val-allele or Val/Val genotype and good methylphenidate response (P = 0.009 and P = 0.034, respectively). Analyzing symptom severity as a continuous trait, significant interaction of COMT genotype and methylphenidate was found on the Hyperactivity-Impulsivity scale (P = 0.044). Symptom severity scores of all three genotype groups decreased following methylphenidate administration (P < 0.001), however Val/Val homozygote children had significantly less severe symptoms than those with Met/Met genotype after treatment (P = 0.015). This interaction might reflect the regulatory effect of COMT dominated prefrontal dopamine transmission on subcortical dopamine systems, which are the actual site of methylphenidate action.

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Efficacy and safety of manual acupuncture manipulations with different frequencies on epigastric pain syndrome (EPS) in functional dyspepsia (FD) patients: study protocol for a randomized controlled trial.

Manual acupuncture (MA) manipulations are one of the key factors influencing acupuncture effects in traditional Chinese medicine theory. Different MA manipulations contain different stimulating parameters, thus generating different acupuncture responses or effects. Evidence has demonstrated that acupuncture is effective for functional dyspepsia (FD). However, the effects of different stimulating parameters of MA manipulations on FD remain unclear. This study is a randomized controlled trial with a four-arm, parallel-group structure. Patients with FD with epigastric pain syndrome (EPS) will be included and randomly allocated into four groups: three MA manipulation groups (separately treated with a frequency of 1 Hz, 2 Hz, or 3 Hz) and a control group. All groups will receive omeprazole as a basic treatment and acupuncture: in the MA manipulation groups, the needles will be manipulated manually with three different frequencies on the basis when de qi is reached, while in the control group, the needles will be inserted without any manipulation. All patients will receive acupuncture treatment of five consecutive sessions per week for 2 weeks and be followed up at 4, 8, and 12 weeks. The primary outcomes of the study include patients' response to the treatment. The secondary outcomes include dyspeptic symptoms, quality of life, mental status, fasting serum gastrin, motilin, and ghrelin concentrations, and adverse events. The protocol was approved by the Ethics committee of the First Affiliated Hospital of Zhejiang Chinese Medical University (2016-K-057-01). The aim of this study is to evaluate the efficacy and safety of MA manipulations with different stimulating parameters (different frequencies) on EPS in patients with FD. Chinese Clinical Trial Registry, ChiCTR-IOR-16008189 . Registered on 30 March 2016.

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R-CHOP versus dose-adjusted R-EPOCH in frontline management of primary mediastinal B-cell lymphoma: a multi-centre analysis.

Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is an uncommon subtype of non-Hodgkin lymphoma (NHL) that presents with a mediastinal mass and has unique clinicopathological features. Historically, patients with PMBCL were treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy ± involved field radiation. Since a phase II trial, published in April 2013, demonstrated excellent results using dose-adjusted (DA) R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), this treatment has gained popularity. We performed a retrospective, multicentre analysis of patients aged ≥18 years with PMBCL since January 2011. Patients were stratified by frontline regimen, R-CHOP versus DA-R-EPOCH. 132 patients were identified from 11 contributing centres (56 R-CHOP and 76 DA-R-EPOCH). The primary outcome was overall survival. Secondary outcomes included progression-free survival, complete response (CR) rate, and rates of treatment-related complications. Demographic characteristics were similar in both groups. DA-R-EPOCH use increased after April 2013 (79% vs. 45%, P < 0·001), and there was less radiation use after DA-R-EPOCH (13% vs. 59%, P < 0·001). While CR rates were higher with DA-R-EPOCH (84% vs. 70%, P = 0·046), these patients were more likely to experience treatment-related toxicities. At 2 years, 89% of R-CHOP patients and 91% of DA-R-EPOCH patients were alive. To our knowledge, this represents the largest series comparing outcomes of R-CHOP to DA-R-EPOCH for PMBCL.

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Risk factors for stent thrombosis after implantation of sirolimus-eluting stents in diabetic and nondiabetic patients: the EVASTENT Matched-Cohort Registry.

We sought to assess the frequency and causes of stent thrombosis in diabetic and nondiabetic patients after implantation of sirolimus-eluting stents. Safety concerns about late stent thrombosis have been raised, particularly when drug-eluting stents are used in less highly selected patients than in randomized trials. The EVASTENT study is a matched multicenter cohort registry of 1,731 patients undergoing revascularization exclusively with sirolimus stents; for each diabetic patient included (stratified as single- or multiple-vessel disease), a nondiabetic patient was subsequently included. Patients were treated with aspirin + clopidogrel for at least 3 months and were followed for 465 (range 0 to 1,062) days (1-year follow-up in 98.5%). The primary end point was a composite of stent thrombosis (according to Academic Research Consortium definitions), cardiovascular death, and nonfatal myocardial infarction (major adverse cardiac events [MACE]). During follow-up, MACE occurred in 78 patients (4.5%), cardiac death in 35 (2.1%), and stent thrombosis in 45 (2.6%): 30 definite, 23 subacute, and 22 late, including 9 at >6 months. In univariate analysis, the 1-year stent thrombosis rate was 1.8 times higher in diabetic than in nondiabetic patients (3.2% vs. 1.7%; log rank p = 0.03), with diabetic patients with multiple-vessel disease experiencing the highest rate and nondiabetic single-vessel disease patients the lowest (4.3% vs. 0.8%; p < 0.001). In multivariate analysis, in addition to the interruption of antithrombotic treatment, independent stent thrombosis predictors were previous stroke, renal failure, lower ejection fraction, calcified lesion, length stented, and insulin-requiring diabetes. The risk of sirolimus stent thrombosis is higher for multiple-vessel disease diabetic patients.

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A shift toward T helper 2 responses and an increase in modulators of innate immunity in depressed patients treated with escitalopram.

Depression is hypothesized to involve inflammatory processes, and identifying the key cytokines targeted by antidepressant drugs is critical for tailoring treatment to specific cases. However, investigating a limited number of cytokines at one time cannot provide a broad picture of antidepressant-associated immunomodulation. Cytokines act in a network where one could demonstrate pleiotropism, redundancy, synergy, and antagonism with other cytokine functions. This study was aimed at determining whether escitalopram functions as an anti-inflammatory agent and, if so, how it influences cytokine networks. A total of 24 healthy controls and 26 patients with clinical depression requiring inpatient treatment were recruited. A multiplex assay, an efficient tool to simultaneously measure 27 cytokines, was applied in patients with depression before and after 4-week escitalopram treatment. Healthy controls did not take escitalopram and completed cytokine analyses once. We demonstrated that escitalopram increased the levels of interleukin (IL)-1 receptor antagonist and IL-2. Moreover, escitalopram contributed to a shift toward T helper 2 responses and an increase in modulators of innate immunity, leading to a decrease of immune system activation, both innate and adaptive. We suggest that escitalopram modulates the balance of IL-1 and IL-1 receptor antagonist and improves the function and number of T regulatory cells. However, diverse conclusions could be drawn if only a few cytokines were assessed or different significance levels were used. Further studies should investigate a wide range of cytokines in a reliable and valid way, which is key to disentangling the effects of different antidepressants on inflammatory processes.

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A randomized, placebo-controlled trial of corticosteroids for hyperemesis due to pregnancy.

Hyperemesis gravidarum, a severe form of nausea and vomiting due to pregnancy for which there is no proven pharmacological treatment, is the third leading cause for hospitalization during pregnancy. Corticosteroids are commonly used for the treatment of nausea and vomiting due to cancer chemotherapy-induced emesis and might prove useful in hyperemesis gravidarum. A randomized, double-blind, placebo-controlled trial was conducted in 126 women who previously had not responded to outpatient therapy for hyperemesis gravidarum during the first half of pregnancy. Intravenous methylprednisolone (125 mg) was followed by an oral prednisone taper (40 mg for 1 day, 20 mg for 3 days, 10 mg for 3 days, 5 mg for 7 days) versus an identical-appearing placebo regimen. All women also received promethazine 25 mg and metoclopramide 10 mg intravenously every 6 hours for 24 hours, followed by the same regimen administered orally as needed until discharge. The primary study outcome was the number of women requiring rehospitalization for hyperemesis gravidarum. A total of 110 women delivered at our hospital and had pregnancy outcomes available for analysis; 56 were randomized to corticosteroids and 54 were administered placebo. Nineteen women in each study group required rehospitalization (34% versus 35%, P =.89, for corticosteroids versus placebo, respectively). The addition of parenteral and oral corticosteroids to the treatment of women with hyperemesis gravidarum did not reduce the need for rehospitalization later in pregnancy.

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Glucocorticoid-induced osteoporosis: is the bone density decrease the only explanation?

Glucocorticoids may increase bone fragility via mechanisms independent from their bone mass reducing effect. To study relationships between osteoporotic fractures and bone mineral density in patients on long-term glucocorticoid therapy. We studied 121 women with a mean age of 60.4 +/- 14.3 years on long-term glucocorticoid therapy (cumulative dose > or = 1 g of prednisone equivalent, duration > or = 6 months) for rheumatoid arthritis (n = 38), polymyalgia rheumatica or giant cell arteritis (n = 26), connective tissue disease (n = 15), asthma (n = 14), another inflammatory joint disease (n = 14), or another condition (n = 14). The control group was composed of 125 subjects who had the same mean age and met the same exclusion criteria as the case group. Bone mineral density was measured at the lumbar spine and femoral neck using a Hologic QDR 4500 unit. In subjects with back pain, radiographs of the thoracic and lumbar spine were obtained to look for fractures. The odds ratio for a bone mineral density decrease of one standard deviation at the femoral neck was 1.68 (1.20-2.35) in patients with a cumulative glucocorticoid dose of 10 g of prednisone equivalent and 1.67 (1.22-2.29) in those with a glucocorticoid therapy duration of 2 years. Sixty-eight fractures were recorded in 56 patients (46% of the overall patient group). Even after adjustment on age, glucocorticoid therapy duration, and dose, mean bone mineral density values at the lumbar spine and femoral neck were significantly lower in the subgroup of patients with fractures than in the subgroup without fractures. Sensitivity and specificity of bone mineral density at the femoral neck and/or lumbar spine for the diagnosis of vertebral fracture and/or peripheral fracture were 73% and 51%, respectively. In the stepwise logistic regression model, factors explaining the presence of fractures were as follows, in hierarchical order: age; absence of calcium/vitamin D supplementation, femoral neck T-score, and glucocorticoid dose. Our data are compelling evidence that bone mineral density is a major determinant of the fracture risk in patients with glucocorticoid-induced osteoporosis.

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A randomized controlled trial of oral albuterol in acute cough.

Beta-agonist agents have been used for bronchospasm and cough in a variety of settings. We sought to evaluate the efficacy of oral albuterol for acute cough in ambulatory adults. We performed a prospective, randomized, controlled, double-blind clinical trial comparing albuterol 4 mg by mouth three times daily for 7 days with placebo in 104 adults. Subjects had cough of less than 4 weeks' duration and no evidence of pneumonia, asthma, or chronic obstructive pulmonary disease. All subjects were enrolled at the walk-in clinic of a rural academic medical center. There was no significant difference between treated and control subjects in any measure of efficacy including cough severity score, reduction in sleepless nights, utilization of health care, or return to full activity. There were significantly more reports of "shakiness" and "nervousness" among albuterol-treated subjects than among controls. Oral albuterol should not be used in unselected patients with acute, nonspecific cough.

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Remission and residual symptoms after short-term treatment in the Treatment of Adolescents with Depression Study (TADS).

To ascertain remission rates in depressed youth participating in the Treatment for Adolescents With Depression Study (TADS), a multisite clinical trial that randomized 439 adolescents with major depressive disorder (MDD) to a 12-week treatment of fluoxetine (FLX), cognitive-behavioral therapy (CBT), their combination (COMB), or clinical management with pill placebo (PBO). Using an end-of-treatment Children's Depression Rating Scale-Revised (CDRS-R) total score of 28 or below as the criterion for remission, rates of remission were examined with logistic regression, controlling for site. Loss of MDD diagnosis and residual symptoms in responders (defined as Clinical Global Impressions-Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved) were also examined across treatment groups. After 12 weeks of treatment, 102 (23%) of 439 youths had reached remission. The remission rate was significantly higher in the COMB group (37%) relative to the other treatment groups (FLX, 23%; CBT, 16%; PBO, 17%), with odds ratios of 2.1 for COMB versus FLX, 3.3 for COMB versus CBT, and 3.0 for COMB versus PBO. In addition, 71% of subjects across treatment groups no longer met criteria for MDD at the end of acute treatment. Fifty percent of the youths who responded by CGI-I criteria continued to have residual symptoms, such as sleep or mood disturbances, fatigue, and poor concentration. The combination of FLX and CBT was superior to both monotherapy and PBO in terms of remission rates, but overall rates of remission remain low and residual symptoms are common at the end of 12 weeks of treatment.

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Do Stimulants Reduce the Risk for Alcohol and Substance Use in Youth With ADHD? A Secondary Analysis of a Prospective, 24-Month Open-Label Study of Osmotic-Release Methylphenidate.

The purpose of this study was to examine the impact of stimulant treatment on risk for alcohol and illicit drug use in adolescents with ADHD. Analysis of data derived from a prospective open-label treatment study of adolescent ADHD ( n = 115, 76% male), and a historical, naturalistic sample of ADHD ( n = 44, 68% male) and non-ADHD youth ( n = 52, 73% male) of similar age and sex. Treatment consisted of extended-release methylphenidate in the clinical trial or naturalistic stimulant treatment. Self-report of alcohol and drug use was derived from a modified version of the Drug Use Screening Inventory. Rates of alcohol and drug use in the past year were significantly lower in the clinical trial compared with untreated and treated naturalistic ADHD comparators, and similar to rates in non-ADHD comparators. Well-monitored stimulant treatment may reduce the risk for alcohol and substance use in adolescent ADHD.

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Excellent long-term survival in patients with early-stage primary bone lymphoma treated with doxorubicin-based chemotherapy and local radiotherapy.

Primary bone lymphoma accounts for less than 5% of primary extranodal presentations, and the majority are of the diffuse, large cell, B-cell type. The study presents the authors' 21 years of experience (1979-2000) in ten patients with early stage (IE-IIE) primary bone lymphoma. All patients were treated with doxorubicin-based chemotherapy. Seven received consolidation radiotherapy to an area encompassing the primary tumor with generous margins, including the adjacent soft tissues, and in two stage IIE patients also to the regional lymph nodes. Mean total dose was 3989 cGy. Nine patients are alive with no evidence of recurrent disease. There are no severe late side effects, and only one patient died due to therapy-resistant small cell lung cancer (second primary), while in complete remission from his primary lymphoma. Albeit retrospective in nature with a small patient accrual, this study demonstrates that primary bone lymphoma is a curable disease following aggressive doxorubicin-based chemotherapy. The exact rule of radiation therapy is yet to be determined.

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[Toxic food infection caused by Shigella flexneri in a military unit].

Food borne disease outbreaks have increased in France, but outbreaks caused by Shigella are rare, accounting for only 73 cases (1.62%) in 1993. We report a food borne outbreak of Shigella flexneri strain 3 infection in a fire fighting unit in Paris between July 13th and 17th 1995. Forty of the 127 firemen suffered symptoms including acute diarrhea (80%), fever (50%) and blood and mucus in stools (1 case, 2.5%). Epidemiological investigation generated an unimodal epidemic curve suggesting a single source of contamination with no secondary cases. The median incubation period was between 43 hours 30 minutes and 51 hours 30 minutes. This is consistent with food borne Shigella infection. Statistical analysis of a case-control study implicated a mixed salad containing frozen shellfish from Asia (shrimps and mussels), served at lunch and dinner on July 13th 1995. Shigella was not detected in this salad by microbiological methods. However, inoculation with as little as 100 organisms can cause symptoms. There was low-level contamination with Escherichia coli (940 cfu/g) due to cross-contamination. Shigella flexneri strain 3 was isolated from 11 of 18 stool cultures, but was never isolated from cultures of stools provided by the cooks. All isolates had identical antibiotic resistance profiles. They were resistant to ampicillin and ticarcillin, moderately sensitive to amoxicillin-clavulanic acid, highly sensitive to aminosides, erythromycin and quinolones. This identical pattern in all isolates suggests a common source of contamination. Plasmid-based multiple resistance is common in this organism. Therefore, antibiotics should only be given to patients with evident clinical signs of infection. Treatment was symptom-based in all but 4 patients, who had acute diarrhea and were treated with ciprofloxacin. This antibiotic is well tolerated, has rapid bactericidal action and significantly reduces the duration of the symptoms and excretion of Shigella, thus preventing secondary contamination with this highly infectious bacterium. Thus, food borne outbreaks of Shigella can occur in countries with a high standard of living because of the increase in mass catering (e.g. fast food restaurants) and importation of foodstuffs from developing countries with endemic shigellosis. This is a public health problem because of the morbidity and absenteeism due to illness, particularly when the patients are firemen responsible for emergency management.

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The effect of statins on mortality in patients with bacteremia.

The statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, act to regulate the biosynthesis of cholesterol. Statins also deplete nonsterol cholesterol precursors, the isoprenoids, which are necessary for prenylation of critical membrane proteins that regulate cellular communication, including the inflammatory response. In a retrospective review of 388 bacteremic infections due to aerobic gram-negative bacilli and Staphylococcus aureus, there was a significant reduction in both overall (6% vs. 28%; P=.002) and attributable (3% vs. 20%; P=.010) mortality among patients taking statins compared with patients not taking statins. This reduction in mortality persisted in a multivariate analysis (odds ratio, 7.6; 95% confidence interval, 1.01-57.5). Among the statin group, diabetes, hypertension, and coronary artery disease were more prevalent (P<.001), and there were more skin and soft tissue infections identified as sources of bacteremia (P=.008). These data suggest a potential clinical role of statins in bacteremic infection; however, the mechanism by which mortality is reduced remains undefined.

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Effect on blood pressure control of switching from valsartan monotherapy to losartan/hydrochlorothiazide in Asian patients with hypertension: results of a multicentre open-label trial.

An open-label, multicentre study was conducted to evaluate the antihypertensive efficacy of a 4-week course of losartan 50 mg plus hydrochlorothiazide 12.5 mg in Asian patients with essential hypertension whose blood pressure had previously been treated with but not controlled by valsartan 80 mg. A total of 237 eligible patients with mean trough sitting diastolic blood pressure (SiDBP) 95-115 mmHg and a mean trough sitting systolic blood pressure (SiSBP) < 190 mmHg entered the baseline period of treatment with valsartan 80 mg/day for 4 weeks. Those (n = 165) whose SiDBP remained > 90 mmHg and who were not excluded for other reasons were then switched to a single-tablet formulation of losartan 50 mg/hydrochlorothiazide 12.5 mg combination once daily for a further 4 weeks. Mean SiDBP (study primary endpoint) at the end of combination therapy was reduced to 86.9 mmHg from 95.2 mmHg. SiSBP (study secondary endpoint) was reduced to 132.6 mmHg from 140.7 mmHg. Mean reductions after switching from valsartan 80 mg to losartan 50 mg/hydrochlorothiazide 12.5 mg were thus 8.3 and 8.1 mmHg for SiDBP and SiSBP, respectively (p < or = 0.001 for both outcomes). The goal of SiDBP < or = 90 mmHg was attained in 72% of the patients previously not controlled to the same level by valsartan 80 mg/day. Combination therapy with losartan 50 mg/hydrochlorothiazide 12.5 mg was generally well tolerated. Mean compliance with the losartan 50 mg/hydrochlorothiazide 12.5 mg combination was > 99%. These results demonstrate that in Asian patients who do not reach the goal of mean trough SiDBP < or = 90 mmHg with valsartan monotherapy at 80 mg once-daily, switching to a single-tablet combination of losartan 50 mg/hydrochlorothiazide 12.5 mg once-daily is well tolerated, provides effective control of blood pressure and is an excellent choice to achieve blood pressure reduction goals.

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Evaluation of serum eosinophil cationic protein as a predictive marker for asthma exacerbation in patients with persistent disease.

Eosinophilic inflammation is a feature of asthma. However, serological markers to indicate eosinophil activation in this process are not fully defined. To evaluate the relationship of serum eosinophil cationic protein (ECP) to asthma worsening and a marker for treatment effectiveness, 26 adult patients with an asthma exacerbation were identified. Identified asthma subjects were treated with oral corticosteroids (prednisone) for 14 days. The lung function variables, forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF), were determined as percentage of predicted and the blood total eosinophil count and serum ECP levels were measured. Patients were re-evaluated after 14 days of corticosteroid treatment and then every 3 months thereafter during a 12-month period. Eighteen patients responded to prednisone treatment, whereas eight did not, assessed as improvement of their lung function parameters. Different serum ECP patterns could be seen in the responders compared with the non-responders. All 18 responders had considerably increased serum ECP at the time of exacerbation, whereas the non-responders had lower serum ECP levels. The serum ECP levels decreased to a greater extent in the responder patient group than in the non-responder patients following prednisone treatment. This difference in patterns was not seen with total blood eosinophil counts. Our findings suggest that serum ECP may be used to predict a response to corticosteroid therapy in adult patients with asthma.

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Effect of drug transporter genotypes on pravastatin disposition in European- and African-American participants.

Our aims were to evaluate the effects of polymorphisms in the hepatic drug uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1, SLCO1B1) and efflux transporters multidrug resistance-associated protein 2 (MRP2, ABCC2), bile salt export pump (BSEP, ABCB11), and breast cancer-related protein (BCRP, ABCG2) on single-dose pravastatin pharmacokinetics in healthy European- and African-American participants. The pharmacokinetics of a single oral 40 mg dose of pravastatin was determined in 107 participants (69 European-Americans and 38 African-Americans). Participants were genotyped for known OATP1B1, MRP2, BSEP, and BCRP polymorphisms. Baseline serum total and unconjugated plasma bilirubin concentrations were also determined. OATP1B1 genotypes were ethnicity-dependent with a 521C allele frequency of approximately 15% in European-Americans and approximately 1% in African-Americans. SLCO1B1 521TC genotype was associated with significantly higher pravastatin area under the curve [AUC(0-5)] (P=0.01) and Cmax values (P<0.05). When analyzed by diplotype, SLCO1B1*1a/*15 (N=8) participants exhibited 45 and 80% higher AUC values than SLCO1B1*1a/*1a (N=29) (P=0.013) and SLCO1B1*1b/*1b (N=34) (P=0.001) carriers, respectively. SLCO1B1*15/*15 (N=2) participants exhibited 92 and 149% higher AUC values than SLCO1B1*1a/*1a (P=0.017) and SLCO1B1*1b/*1b (P=0.011) carriers, respectively. European-Americans had significantly higher plasma pravastatin AUC(0-5) (P=0.01) and Cmax values (P=0.009) than African-Americans. Neither ABCC2, ABCB11, nor ABCG2 genotypes were associated with differences in pravastatin pharmacokinetics. We did not observe an effect of SLCO1B1 genotype on baseline total or unconjugated bilirubin levels. SLCO1B1 genotype, in particular the 521C allele, had a significant effect on the pharmacokinetics of pravastatin. Even when adjusted for the presence of the SLCO1B1 521C or 388G variant allele, European-Americans demonstrated significantly higher pravastatin AUC and Cmax values than African-Americans.

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Prescription of antibiotics in the medical care of newly arrived refugees and migrants.

Unnecessary and inappropriate use of antibiotics is a widespread problem in primary care. However, current data on the care of refugees and migrants in initial reception centers is pending. This article provides data on prescription frequencies of various antibiotics and associated diagnoses. In this retrospective observational study, patient data of 3255 patients with 6376 medical contacts in two initial reception centers in Germany were analyzed. Patient data, collected by chart review, included sociodemographic characteristics, diagnoses, and prescriptions. Antibiotic prescription behavior and corresponding physician-coded diagnoses were analyzed. Nineteen percent of all patients in our study received systemic antibiotics during the observation period, with children below the age of 10 years receiving antibiotics most frequently (24%). The most commonly prescribed antibiotics were penicillins (65%), macrolides (12%), and cephalosporins (7%). The most frequent diagnoses associated with antibiotic prescription were acute tonsillitis (26%), bronchitis (21%), infections of the upper respiratory tract (14%), and urinary tract infections (10%). In case of acute bronchitis 74% of the antibiotic prescriptions were probably not indicated. In addition, we found a significant number of inappropriate prescriptions such as amoxicillin for tonsillitis (67%), and ciprofloxacin and cotrimoxazol for urinary tract infections (49%). Regarding inappropriate prescription of antibiotics in refugee healthcare, this study shows a rate ranging from 8% for upper respiratory tract infections to 75% for acute bronchitis. Unnecessary use of antibiotics is a global problem contributing to gratuitous costs, side effects, and antimicrobial resistance. This research contributes to the development of stringent antibiotic stewardship regiments in the particularly vulnerable population of migrants and refugees.

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Effects of simvastatin on plasma lipoprotein subfractions, cholesterol esterification rate, and cholesteryl ester transfer protein in type II hyperlipoproteinemia.

We investigated the effects of simvastatin on plasma levels of lipoprotein subfractions, cholesterol esterification rates and activities of cholesteryl ester transfer protein in 28 patients with type II hyperlipoproteinemia (i.e., nonfamilial hyperlipoproteinemia type IIa and type IIb, and heterozygous familial hypercholesterolemia (FH)). Plasma levels of VLDL-cholesterol (C) and VLDL-triglyceride (TG) were significantly reduced overall by 12.9 +/- 58.0% (mean +/- S.D.; P < 0.05) and 4.2 +/- 54.2% (P < 0.05) respectively, but not in FH. Plasma levels of IDL-C and IDLT-G were decreased overall by 23.2 +/- 47.5% (P < 0.001) and 12.3 +/- 49.7% (P < 0.05), respectively, again mainly due to decreases seen in nonfamilial type II hyperlipoproteinemia. Plasma levels of LDL1 (1.019 < d < 1.045)-C and LDL1-TG were significantly reduced by 33.1 +/- 12.9% (P < 0.001) and 23.3 +/- 24.7% (P < 0.001), respectively. Plasma levels of LDL2 (1.045 < d < 1.063)-C were significantly reduced by 22.9 +/- 18.1% (P < 0.001) overall but not in FH. Gradient PAGE showed no consistent changes in the distribution of LDL particles. Thus, plasma levels of all apo B-containing lipoprotein subfractions were reduced by simvastatin, but its effects varied among the three subgroups. Cholesterol esterification rates were suppressed by 9.3 +/- 19.7% (P < 0.01) and activities of cholesteryl ester transfer protein were reduced by 30.6 +/- 21.5% (P < 0.001). Changes in CETP activity and in plasma levels of cholesterol in lipoprotein subfractions were not correlated. Thus, the changes in distribution of lipoprotein subfractions were not due mainly to CETP suppression.

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Children with ADHD treated with long-term methylphenidate and multimodal psychosocial treatment: impact on parental practices.

To test the hypothesis that multimodal psychosocial intervention, which includes parent training, combined with methylphenidate significantly enhances the behavior of parents of children with attention-deficit/hyperactivity disorder (ADHD), compared with methylphenidate alone and compared with methylphenidate and nonspecific psychosocial treatment (attention control). One hundred three children with ADHD (ages 7-9), free of conduct and learning disorders, who responded to short-term methylphenidate therapy were randomized for 2 years to receive either (1) methylphenidate treatment alone; (2) methylphenidate plus psychosocial treatment that included parent training and counseling, social skills training, academic assistance, and psychotherapy; or (3) methylphenidate plus attention control treatment. Parents rated their knowledge of parenting principles and negative and positive parenting behavior. Children rated their parents' behavior. Psychosocial treatment led to significantly better knowledge of parenting principles but did not enhance parenting practices, as rated by parents and children. Significant improvement in mothers' negative parenting occurred across all treatments and was maintained. In nonconduct-disordered, stimulant-treated children with ADHD, parent training does not improve self-rated parental behavior. The benefits of brief stimulant treatment for negative parental behavior are sustained with extended treatment.

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Effects of amlodipine and fosinopril on heart rate variability and left ventricular mass in mild-to-moderate essential hypertension.

The differences between long-acting dihydropyridines and angiotensin-converting enzyme inhibitors with regard to their long-term effects on 24-h heart rate variability (HRV) and left ventricular (LV) mass are less clear in mild-to-moderate essential hypertension. We studied the long-term effects of amlodipine and fosinopril on 24-h HRV and LV mass in mild-to-moderate essential hypertension. In this study, 27 patients with never treated mild-to-moderate essential hypertension were randomised to receive either amlodipine or fosinopril once daily as monotherapy. At baseline and at the end of the third and sixth months, each of the patients underwent 24-h HRV and ambulatory systolic (SBP) and diastolic (DBP) blood pressure analysis. LV mass index was calculated from echocardiographic examination at baseline and at the end of the sixth month. In amlodipine group (n = 14), 24-h SBP/DBP (mmHg) decreased from 144 +/- 8/94 +/- 4 to 128 +/- 6/83 +/- 3 at the end of the third month and to 125 +/- 5/81 +/- 2 at the end of the sixth month (p < 0.0001). In fosinopril group (n = 13), the respective changes were 143 +/- 9/97 +/- 7, 132 +/- 6/87 +/- 5 and 127 +/- 6/82 +/- 3 (p < 0.0001). At the end of the sixth month, LV mass index (g/m(2)) decreased from 122 +/- 26 to 105 +/- 21 in amlodipine group (p < 0.0001) and from 118 +/- 23 to 101 +/- 14 in fosinopril group (p < 0.0001). There were no significant changes in HRV parameters in both the groups. It was concluded that both drugs caused significant decrease in SBP and DBP, and LV mass in patients with mild-to-moderate essential hypertension did not have significant long-term effects of either amlodipine or fosinopril on 24-h HRV parameters reflecting sympathetic or parasympathetic activity in these patients.

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A phase III randomized, double-blind, placebo-controlled trial of gabapentin in the management of hot flashes in men (N00CB).

Hot flashes represent a significant problem in men undergoing androgen deprivation therapy. Via a prospective, double-blind, placebo-controlled clinical trial, men with hot flashes, on a stable androgen deprivation therapy program for prostate cancer, received a placebo or gabapentin at target doses of 300, 600, or 900 mg/day. Hot flash frequencies and severities were recorded daily during a baseline week and for 4 weeks while the patients took the study medication. In the 214 eligible patients who began the study drug on this trial, comparing the fourth treatment week to the baseline week, mean hot flash scores decreased in the placebo group by 4.1 units and in the three increasing dose gabapentin groups by, 3.2, 4.6, and 7.0 units. Comparing the three combined gabapentin arms to the placebo arm did not result in significant hot flash differences. Wilcoxon rank-sum P values for change in hot flash scores and frequencies after 4 weeks of treatment were 0.10 and 0.02, comparing the highest dose gabapentin arm to the placebo arm, respectively. The gabapentin was well tolerated in this trial. These results support that gabapentin decreases hot flashes, to a moderate degree, in men with androgen ablation-related vasomotor dysfunction.

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Central neurochemical ultradian variability in depression.

Depression is characterized by blunted behavior and neuroendocrine function that generally improve with antidepressant treatment. This study examined intrinsic variability in brain neurotransmitter function, since it may be a source of blunted behavior and neuroendocrine function in depression and a marker for the illness, and has not previously been analyzed using wavelet decomposition. To measure variability in monoamine metabolites, lumbar cerebrospinal fluid (CSF) was collected in serial samples in depressed patients before and after treatment. We hypothesized that changes in variability would be observed after treatment. Mechanisms that control such variability may be critical to the pathophysiology of depression. Time series data was obtained from serial ten-min sampling over a 24-hr period (N=144) from thirteen depressed patients, with a repeat collection after 5 weeks of antidepressant (sertraline or bupropion) treatment. Concentrations of tryptophan (TRP), the monoamine metabolites 5-HIAA (metabolite of serotonin) and HVA (metabolite of dopamine), and the HVA:5HIAA ratio were transformed to examine power in slowly (160 min/cycle) to rapidly (20 min/cycle) occurring events. Power, the sum of the squares of the coefficients in each d (detail) wavelet, reflects variability within a limited frequency bandwidth for that wavelet. Pre-treatment to post-treatment comparisons were conducted with repeated measures ANOVA. Antidepressant treatment was associated with increased power in the d2 wavelet from the HVA (p=0.03) and the HVA:5-HIAA ratio (p=0.03) series. The d1 and d3 wavelets showed increased power following antidepressant treatment for the ratio series (d1, p=0.01; d3, p=0.05). Significant changes in power were not observed for the 5-HIAA data series. Power differences among analytes suggest that the findings are specific to each system. The wavelet transform analysis shows changes in neurochemical signal variability following antidepressant treatment. Patterns or degrees of variability may be as important as, or possibly more important than, the mean levels of monoamine transmitters. Studies of variability observed in healthy individuals and a larger depressed sample will be needed to verify a relationship with mood and treatment response. Neurochemical measures of time-variability may be a pivotal marker in depression.

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Predischarge two-dimensional echocardiographic evaluation of left ventricular thrombosis after acute myocardial infarction in the GISSI-3 study.

Left ventricular (LV) thrombosis can be found in patients with acute myocardial infarction (AMI). No wide multicenter trial on AMI has provided information about LV thrombosis until now. The protocol of the GISSI-3 study included the search for the presence of LV thrombosis in patients from 200 coronary care units that did not specifically focus on LV thrombosis. We examined the GISSI-3 database results related to 8,326 patients at low to medium risk for LV thrombi in which a predischarge echocardiogram (9 +/- 5 days) was available. LV thrombosis was found in 427 patients (5.1%): 292 of 2,544 patients (11.5%) with anterior AMI and in 135 of 5,782 patients (2.3%) with AMI in other sites (p <0.0001). The incidence of LV thrombosis was higher in patients with ejection fraction < or = 40% (151 of 1,432 [10.5%] vs 276 of 6,894 [4%]; p <0.0001) both in the total population and in the subgroup with anterior AMI (106 of 597 [17.8%] vs 186 of 1,947 [9.6%]; p <0.0001). Multivariate analysis showed that only the Killip class > I and early intravenous beta-blocker administration were independently associated with higher LV thrombosis risk in the subgroup of patients with anterior AMI (odds ratio 1.75, 95% confidence interval 1.28 to 2.39; odds ratio 1.32, 95% confidence interval 1.02 to 1.72, respectively). In patients with anterior AMI, oral beta-blocker therapy given or not given after early intravenous beta-blocker administration does not influence the occurrence of LV thrombosis. The rate of LV thrombosis was similar in patients treated or not treated with nitrates and lisinopril both in the total population and in patients with anterior and nonanterior AMI. In conclusion, in the GISSI-3 population at low to medium risk for LV thrombi, the highest rate of occurrence of LV thrombosis was found among patients with anterior AMI and an ejection fraction < 40%. Killip class > I and the early intravenous beta-blocker administration were the only variables independently associated with a higher predischarge incidence of LV thrombosis after anterior AMI.

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Losartan improves diastolic ventricular filling of hypertensive patients with diastolic dysfunction.

To evaluate the role of losartan on left ventricular (LV) function of hypertensive patients. Hypertensive patients (n = 19) underwent evaluation of systolic and diastolic LV function, using radionuclide ventriculography (RVG), before and at 3 mo into the treatment with the angiotensin II antagonist losartan. All patients underwent a baseline 12 lead ECG and an echocardiogram (ECHO), which was also repeated at 3 mo into treatment. Results are expressed as mean +/- SEM and statistics were performed using paired t-test. A p value < or = 0.05 was considered significant. Treatment with losartan for 3 mo had no effect on LV mass measured by echo (141+/-5 vs. 139+/-6 g/m2). The LV ejection fraction, measured by RVG, was unchanged by treatment when compared to the baseline study (58+/-2% vs. 57+/-2%, respectivelly, p = 0.49). Considering all patients involved in the study (n = 19), the LV "Peak Filling Rate" (PFR), a parameter of diastolic function measured by RVG, was also unchanged by treatment when compared to baseline (2.5+/-0.2 EDV/s vs. 2.5+/-0.3 EDV/s, respectively, p = 0.9). However the analysis of those patients with evidence of diastolic dysfunction (n = 12) on the baseline RVG (PFR < 2.5 EVD/s), demonstrated significant improvement of LV filling after therapy with losartan (PFR = 1.8+/-0.1 EDV/s vs. 2.3 +/-0.2 EDV/s, respectively, p = 0.05). This change was associated with improvement of symptoms. Our results demonstrated that hypertensive patients with diastolic dysfunction on radionuclide ventriculography have significant improvement of ventricular filling at 3 mo into treatment with losartan.

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Improved analgesia and reduced post-operative nausea and vomiting after implementation of an enhanced recovery after surgery (ERAS) pathway for total mastectomy.

Enhanced Recovery After Surgery (ERAS) pathways have been shown in multiple surgical disciplines to improve outcomes, including reduced opioid consumption, length of stay, and post-operative nausea and vomiting (PONV). However, very few studies describe the application of ERAS to breast surgery and even fewer describe ERAS for outpatient surgery. We describe the implementation and efficacy of an Enhanced Recovery After Surgery (ERAS) pathway for total skin-sparing mastectomy with immediate reconstruction in an outpatient setting. We implemented an evidence-based, multimodal ERAS pathway for all patients undergoing total skin-sparing mastectomy surgery with immediate reconstruction at a single 23-h stay surgery center. Highlights of the ERAS pathway included: preoperative acetaminophen, gabapentin, and scopolamine; regional anesthesia for the breast (Pectoral blocks type 1 and 2 or paravertebral block); and intraoperative dexamethasone and ondansetron. This retrospective study included all American Society of Anesthesiology (ASA) Class 1-3 patients undergoing total skin-sparing mastectomy surgery with immediate reconstruction between July 2013 and April 2016. We compared 96 patients who were in the ERAS pathway (ERAS group) to a retrospective cohort of 276 patients (Pre group). The primary outcome was total perioperative opioid consumption. Secondary outcomes were highest postoperative pain scores, incidence of PONV, and length of stay. Patients in the ERAS group had significantly lower total perioperative opioid consumption compared to the Pre group (mean (SD): 111.4 mg (46.0) vs. 163.8 mg (73.2) oral morphine equivalents, p < 0.001). Patients in the ERAS group also had a lower incidence of PONV (28% vs. 50%, p < 0.001). Patients in the ERAS group reported less pain in the recovery room, with a two-point decrease in highest pain score (median [interquartile range (IQR)]: 4 [2,6] in ERAS group vs. 6 [4,7] in Pre group, p < 0.001). There was no clinically significant difference in length of stay (median [IQR]: 1144 min [992, 1259] in ERAS group vs. 1188 [1058, 1344] in Pre group, p = 0.006). Implementation of an ERAS pathway for total skin-sparing mastectomy with reconstruction that incorporates regional anesthesia is feasible in a 23-h-stay hospital. Patients in the ERAS pathway had improved post-operative analgesia and reduced post-operative nausea and vomiting.

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Low-dose prednisone inclusion in a methotrexate-based, tight control strategy for early rheumatoid arthritis: a randomized trial.

Treatment strategies for tight control of early rheumatoid arthritis (RA) are highly effective but can be improved. To investigate whether adding prednisone, 10 mg/d, at the start of a methotrexate (MTX)-based treatment strategy for tight control in early RA increases its effectiveness. A 2-year, prospective, randomized, placebo-controlled, double-blind, multicenter trial (CAMERA-II [Computer Assisted Management in Early Rheumatoid Arthritis trial-II]). (International Standard Randomised Controlled Trial Number: ISRCTN 70365169) 7 hospitals in the Netherlands. 236 patients with early RA (duration <1 year). Patients were randomly assigned to an MTX-based, tight control strategy starting with either MTX and prednisone or MTX and placebo. Methotrexate treatment was tailored to the individual patient at monthly visits on the basis of predefined response criteria aiming for remission. The primary outcome was radiographic erosive joint damage after 2 years. Secondary outcomes included response criteria, remission, and the need to add cyclosporine or a biologic agent to the treatment. Erosive joint damage after 2 years was limited and less in the group receiving MTX and prednisone (n = 117) than in the group receiving MTX and placebo (n = 119). The MTX and prednisone strategy was also more effective in reducing disease activity and physical disability, achieving sustained remission, and avoiding the addition of cyclosporine or biologic treatment. Adverse events were similar in both groups, but some occurred less in the MTX and prednisone group. A tight control strategy for RA implies monthly visits to an outpatient clinic, which is not always feasible. Inclusion of low-dose prednisone in an MTX-based treatment strategy for tight control in early RA improves patient outcomes. Catharijne Foundation.

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Eltrombopag increases plasma rosuvastatin exposure in healthy volunteers.

OATP1B1 is important for hepatic uptake of rosuvastatin and BCRP is important for rosuvastatin absorption and elimination. Eltrombopag inhibits OATP1B1 and BCRP in vitro at clinically relevant concentrations. Inhibition of these transporters could change cholesterol-lowering efficacy and increase the risk of exposure-dependent toxicities. To determine if co-administration of eltrombopag with rosuvastatin alters plasma rosuvastatin exposure, an open-label study was conducted in 42 healthy adult subjects. Concomitant administration of eltrombopag with rosuvastatin was associated with increased rosuvastatin exposure via inhibition of drug transporters. The therapeutic index of HMG Co-A reductase inhibitors may be reduced by the concomitant use of eltrombopag. In subjects taking eltrombopag, a reduced dose of HMG Co-A reductase inhibitors may be needed. Eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist, inhibits the organic anion transporting polypeptide 1B1 (OATP1B1) and breast cancer resistance protein (BCRP) in vitro. OATP1B1 is important for hepatic uptake of rosuvastatin and inhibition of this transporter could reduce cholesterol-lowering efficacy and increase the risk of exposure-dependent toxicities. In contrast, BCRP is an efflux transporter and inhibition of this transporter could increase both hepatic and plasma rosuvastatin concentrations, resulting in increased efficacy and toxicity. To determine if co-administration of eltrombopag with rosuvastatin alters plasma rosuvastatin exposure, an open-label study was conducted in 42 healthy adult subjects. Subjects received rosuvastatin and eltrombopag orally: day 1, rosuvastatin 10 mg single dose; days 6 to 9, eltrombopag 75 mg once daily; day 10, eltrombopag 75 mg once daily and rosuvastatin 10 mg single dose. Adverse event assessments were performed daily and at the follow-up visit. Plasma samples for pharmacokinetic analysis were collected days 1 to 5 and days 10 to 14. Co-administration of eltrombopag with rosuvastatin increased geometric mean (90% confidence interval) plasma rosuvastatin AUC(0,∞) by 55% (42%, 69%) and C(max) by 103% (82%, 126%) in the overall study population, with a larger interaction in the non-Asian compared with Asian subjects. Concomitant administration of eltrombopag with rosuvastatin was associated with increased rosuvastatin exposure. The therapeutic index of HMG Co-A reductase inhibitors may be reduced by the concomitant use of eltrombopag. In subjects taking eltrombopag, a reduced dose of HMG Co-A reductase inhibitors may be needed.

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Periendoscopic management of antiplatelet therapy: Prospective evaluation of adherence to guidelines.

INTRODUCCIóN: Adherence to guidelines on the periendoscopic management of antiplatelet therapy (APT) has not been analyzed in detail. Our aim was to assess adherence to guidelines in patients referred to our Endoscopy Unit on a case-by-case basis, describing in detail the detected deviations and identifying areas of improvement. Cross-sectional study of outpatients consecutively scheduled for an unsedated upper or lower gastrointestinal endoscopy between January and June 2015. Patients on anticoagulant therapy were excluded. 675 patients were evaluated, including 91 (13.5%) patients on APT [upper GI endoscopy 25 (27.5%), lower GI endoscopy 66 (72.5%)]. Contrary to the clinical guidelines, aspirin was discontinued in 25 of the 77 patients previously prescribed the drug (32.5%) but this modification was patient's own decision in 11 cases. Most of the apparent deviations in the management of clopidogrel and dual antiplatelet therapy (DAPT) were not true non-adherence cases. The Primary Care physician modified an APT prescribed by another physician in 8 of 9 cases (88.9%), always in cases with aspirin. No relationship was found between the endoscopic procedure's predicted risk of bleeding or the patient's thrombotic risk and modification of therapy. In many patients, the peri-procedural management of APT goes against current guidelines, but some of these inconsistencies cannot be considered true deviations from practice. Identified areas for improvement are increasing patient awareness about APT, disseminating the guidelines in Primary Care, and underscoring the significance of thrombotic risk related to APT withdrawal.

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Incidence of Stevens-Johnson syndrome following combination drug use of allopurinol, carbamazepine and phenytoin in Taiwan: A case-control study.

The goal of our study was to investigate the incidence of Stevens-Johnson syndrome (SJS), the frequency of SJS diagnosis, and the association between SJS and prior use of allopurinol, carbamazepine or phenytoin. This case-control study utilized data from the National Health Insurance Research Database (NHIRD) of Taiwan. Controls visited the emergency department of the same hospital for trauma or fractures (excluding burns) and used allopurinol, carbamazepine or phenytoin during the past 3 months. We determined whether patients were prescribed a combination of drugs in addition to allopurinol, carbamazepine or phenytoin within the last 3 months. We identified 1 853 985 controls and 7327 SJS-diagnosed patients using the Taiwan NHIRD records for 2000-2008. Higher use of allopurinol (49.8%), carbamazepine (39.1%) or phenytoin (21.3%) was observed among patients (n = 3131) than among controls (n = 2858). The overall SJS incidence rate was 3.6/1 000 000. Drug combinations were uncommon (<10%) in patients or controls taking allopurinol. However, combination drug use exceeded 10% in patients taking carbamazepine or phenytoin. Logistic regression analysis of recent combination drug use revealed that phenobarbital, valproate, non-steroidal anti-inflammatory drugs (NSAIDs) including piroxicam and tenoxicam, and antibiotics including amoxicillin and cephalexin were strongly associated with SJS. Patients with gout or epilepsy taking allopurinol, carbamazepine or phenytoin should be evaluated carefully by physicians. Concurrent use of piroxicam, tenoxicam, phenobarbital, valproate, amoxicillin or cephalexin, in addition to carbamazepine or phenytoin, may increase the incidence of SJS.

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Increasing aclarubicin dose in low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor (CAG regimen) is efficacious as salvage chemotherapy for relapsed/refractory mixed-phenotype acute leukemia.

We treated 60 relapsed/refractory mixed-phenotype acute leukemia patients (MPAL-1) with increasing the aclarubicin dose in CAG regimen (HD-CAG, cytarabine (10 mg/m(2)/12 h, days 1-14), aclarubicin (5-7 mg/m(2)/day, days 1-14), granulocyte colony-stimulating factor (200 μg/m(2)/day, days 1-14). This was compared to 64 relapsed/refractory MPAL patients (MPAL-2) treated with DOAP regimen (daunorubicin, vincristine/vindesine, cytarabine and prednisone), 113 relapsed/refractory acute myeloid leukemia (AML) patients and 78 acute lymphocytic leukemia (ALL) patients treated with HD-CAG regimen. After one course, complete remission (CR) and overall response [OR, CR+partial remission (PR)] rates for MPAL-1 exceeded MPAL-2 (CR, 61.02% vs. 28.13%, P=0.000; OR, 72.88% vs. 34.38%, P=0.000), but these data were similar to AML and ALL (P>0.05). In MPAL-1 group, CR and OR rates of T-lymphoid+myeloid immunophenotype were higher than B-lymphoid+myeloid immunophenotype (CR, 81.82% vs. 44.12%, P=0.005; OR, 90.91% vs. 58.82%, P=0.009). The overall survival at 3 years in MPAL-1, MPAL-2, AML and ALL groups were 14.2%±6.8%, 14.1%±6.4%, 17.3%±5.0% and 15.0%±5.3% (P>0.05). Side effects were similar between HD-CAG and DOAP (P>0.05). HD-CAG regimen is efficacious for relapsed/refractory MPAL, especially for T+My patients.

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Inhaled flunisolide for acute severe asthma.

This randomized, double-blind trial was designed to determine the benefit of high and cumulative doses of flunisolide added to salbutamol in patients with acute asthma in the emergency room (ER). Ninety-four patients who presented to an ER for treatment of an acute exacerbation of asthma were assigned in a randomized, double-blind fashion to receive salbutamol and placebo (n = 47) or salbutamol combined with flunisolide (n = 47). Both drugs were administered successively through a metered-dose inhaler and spacer at 10-min intervals for 3 h (400 microg of salbutamol and 1 mg of flunisolide every 10 min). In both groups, FEV1 and peak expiratory flow rate (PEFR) improved significantly over baseline values (p < 0.01). Results in the flunisolide group were significantly different from those in the placebo group at 90, 120, 150, and 180 min. Data analyzed separately in accord with the duration of the attack before presenting at the ER (< 24 or > or = 24 h) showed that the placebo > or = 24 h group produced a significantly lower FEV1 at 120, 150, and 180 min (p = 0.041) than did the remaining groups. Our data support the theory that high and cumulative doses of inhaled flunisolide administered by metered-dose inhaler with spacer and added to salbutamol are an effective therapy for patients with acute asthma and a prolonged duration of symptoms before ER presentation.

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Cefpodoxime proxetil. An appraisal of its use in antibacterial cost-containment programmes, as stepdown and abbreviated therapy in respiratory tract infections.

Cefpodoxime proxetil is an orally administered prodrug which is converted in vivo to the third generation cephalosporin cefpodoxime. Cefpodoxime has a similar spectrum of antibacterial activity to the parenteral cephalosporins ceftriaxone and cefotaxime and a long elimination half-life, which allows once- or twice-daily administration. Cefpodoxime proxetil has proven efficacy in the treatment of community-acquired pneumonia and upper respiratory tract, skin and soft tissue and urinary tract infections. It has been evaluated for use in cost-containment programmes, as stepdown (parenteral-to-oral conversion) therapy in the treatment of community-acquired pneumonia and as abbreviated therapy in upper respiratory tract infections. Substituting oral for parenteral therapy can achieve considerable savings (in acquisition, delivery and labour costs). Moreover, oral administration has advantages for the patient in terms of comfort and mobility, avoids the hazards of parenteral delivery and may allow earlier discharge from hospital, or even allow home treatment from the outset in low-risk patients. As hospitalisation is usually the major cost component in treating serious infections, considerable savings can be made in this way. Pharmacy-driven stepdown programmes in 2 US hospitals have achieved cost savings by targeting patients with community-acquired pneumonia for early conversion from intravenous ceftriaxone therapy to oral cefpodoxime proxetil. Costs were compared with those from a control group of patients who continued to receive intravenous ceftriaxone until physicians deemed that oral therapy (with various agents) was appropriate. In one study, duration of parenteral therapy in the cefpodoxime proxetil group was reduced from 6.18 to 3.82 days and duration of hospitalisation was reduced from 10.06 to 6.23 days (p < 0.02), with corresponding hospitalisation cost reductions of $US7300 per patient. However, clinical trial data relating to the efficacy of cefpodoxime proxetil as stepdown therapy in patients initially requiring parenteral antibacterials are lacking. Abbreviated (4-to 7-day) cephalosporin regimens appear to be as effective as traditional 10-day penicillin regimens in the treatment of upper respiratory tract infections. Short regimens may improve patient compliance and tolerability, thereby reducing the costs of adverse effects and treatment failures. Data from preliminary clinical studies suggest that a 5-day course of cefpodoxime proxetil is as effective as an 8-day course of amoxicillin/clavulanic acid in treating either acute otitis media or sinusitis, and as effective as a 10-day course of amoxicillin/ clavulanic acid and more effective than a 10-day course of phenoxymethyl- penicillin in the treatment of pharyngotonsillitis. Cefpodoxime proxetil tended to be better tolerated and was associated with better compliance than penicillin-based regimens. Indeed, a pharmacoeconomic study showed that a 10-day regimen of cefpodoxime proxetil was associated with lower costs for treating adverse effects and treatment failures than a 10-day regimen of amoxicillin/clavulanic acid in the treatment of acute otitis media in children. A 5-day course of cefpodoxime proxetil had a lower cost per patient treated per month free of recurrence than a 10-day course of phenoxymethylpenicillin (non-generic) or amoxicillin/clavulanic acid in the treatment of recurrent pharyngotonsillitis. Thus, evidence to date suggests that cefpodoxime proxetil has potential for use as stepdown therapy in community-acquired pneumonia and in abbreviated therapy courses in upper respiratory tract infections. These preliminary observations require confirmation in well designed studies.

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Long-term follow-up and factors predictive of recurrence in Barrett's esophagus treated by argon plasma coagulation and acid suppression.

In several series, argon plasma coagulation (APC) combined with acid suppression has led to short- or medium-term eradication of Barrett's esophagus. The present study was designed to assess the long-term outcome after this treatment. 39 patients with Barrett's esophagus, seven of them with low-grade dysplasia, underwent APC and received 40 mg omeprazole daily for eradication of the metaplastic epithelium. After the treatment period, patients were randomly assigned to receive 20 or 40 mg omeprazole daily for long-term acid suppression. Histological and endoscopic changes were evaluated annually. Univariate and multivariate analyses were used to test the following 10 variables as predictors of sustained reversal of Barrett's esophagus at the end of follow-up: age, gender, length of diseased segment, presence of hiatal hernia, circumferential nature of lesion, presence of low-grade dysplasia at initial biopsy, number of coagulation sessions, result of pH monitoring under protein pump inhibitor (PPI) treatment, omeprazole dosage, and initial response to therapy (after 1 month). The median follow-up period was 36 months (range 12 - 48). The endoscopic and histological relapse rates at 1, 12, and 24 months, and end of follow-up were, respectively, 30 % and 44 % (12/39 and 17/39), 57 % and 54 % (16/28 and 15/28), 60 % and 57 % (17/28 and 16/28), and 62 % for both rates (23/37). According to multivariate analysis, shorter length of diseased segment and normalization of pH with PPI treatment were the only independent predictors of sustained long-term re-epithelialization. Among the seven patients with low-grade dysplasia, four experienced relapse after 1 month, and during the long-term follow-up, one was lost to follow-up and all the others experienced relapse, but only one developed low-grade dysplasia again. Cancer was found in two cases after 12 and 18 months, respectively. Persistence of acid reflux and greater length of diseased segment are the major factors associated with a high relapse rate after successful initial reversal. APC for ablation of Barrett's esophagus cannot be recommended.

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Bopindolol: Czechoslovak experience with a new beta blocker in the treatment of hypertension.

Bopindolol is a nonselective beta blocker with mild intrinsic sympathomimetic activity. One of the drug's main benefits is its prolonged effect, lasting for 24 hours, which makes it possible to administer bopindolol in a single daily dose, a fact that may improve patient adherence to therapy. A double-blind study was performed in two centers, comparing bopindolol with metoprolol in 86 hypertensive patients. Baseline diastolic blood pressure (BP) was 100 to 120 mm Hg. The effects of bopindolol or metoprolol on BP and heart rate were similar: return to normal values was achieved in 70% of patients with either drug. A 6-month study at another center found that bopindolol did not affect the levels of total cholesterol, low-density and high-density lipoprotein cholesterol or triglycerides. Another 12-month study documented a decrease in total cholesterol, apolipoprotein (apo) A1 and apo B. The apo A/B ratio rose, thus improving the atherosclerotic index. No deterioration of glucose tolerance or immunoreactive insulin response to glucose was seen after 6 months of bopindolol administration. Bopindolol satisfactorily modifies not only resting but also exercise BP during isometric and isotonic load, thus reducing BP fluctuation during physical activities of the hypertensive patient. The drug exerts no effect on renal and liver function, electrolyte balance and hematologic parameters. Bopindolol is a very useful drug of first choice in mild and moderate hypertension. Bopindolol's main advantages include its prolonged action, good tolerance and a beneficial effect on risk factors of atherosclerosis (lipid and carbohydrate metabolism).

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Autonomic cardiac control. III. Psychological stress and cardiac response in autonomic space as revealed by pharmacological blockades.

Behavioral contexts can evoke a variety of autonomic modes of response, characterized by reciprocal, coactive, or independent changes in the autonomic divisions. In the present study, we investigated the reactive autonomic control of the heart in response to psychological stressors, using quantitative methods for analyzing single and double autonomic blockades, and through the use of noninvasive indices based on heart period variability and systolic time intervals. Analysis of the effects of pharmacological blockades revealed an overall pattern of increased sympathetic and decreased parasympathetic control of the heart during speech stress, mental arithmetic, and a reaction-time task. Unlike the classical reciprocal sympathetic-parasympathetic response to orthostatic challenge, however, the responses of the autonomic branches to stress were uncorrelated. This reflected notable individual differences in the mode of autonomic response to stress, which had considerable stability across stress tasks. The putative noninvasive indices of sympathetic (preejection period) and parasympathetic (respiratory sinus arrhythmia) control changed in accord with the results of pharmacological blockades. Together, these results emphasize the substantial individual differences in the mode of autonomic response to stress, the advantages of a quantitative approach to analyzing blockade data, and the importance of validity estimates of blockade data.

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Trial of Tocilizumab in Giant-Cell Arteritis.

Giant-cell arteritis commonly relapses when glucocorticoids are tapered, and the prolonged use of glucocorticoids is associated with side effects. The effect of the interleukin-6 receptor alpha inhibitor tocilizumab on the rates of relapse during glucocorticoid tapering was studied in patients with giant-cell arteritis. In this 1-year trial, we randomly assigned 251 patients, in a 2:1:1:1 ratio, to receive subcutaneous tocilizumab (at a dose of 162 mg) weekly or every other week, combined with a 26-week prednisone taper, or placebo combined with a prednisone taper over a period of either 26 weeks or 52 weeks. The primary outcome was the rate of sustained glucocorticoid-free remission at week 52 in each tocilizumab group as compared with the rate in the placebo group that underwent the 26-week prednisone taper. The key secondary outcome was the rate of remission in each tocilizumab group as compared with the placebo group that underwent the 52-week prednisone taper. Dosing of prednisone and safety were also assessed. Sustained remission at week 52 occurred in 56% of the patients treated with tocilizumab weekly and in 53% of those treated with tocilizumab every other week, as compared with 14% of those in the placebo group that underwent the 26-week prednisone taper and 18% of those in the placebo group that underwent the 52-week prednisone taper (P<0.001 for the comparisons of either active treatment with placebo). The cumulative median prednisone dose over the 52-week period was 1862 mg in each tocilizumab group, as compared with 3296 mg in the placebo group that underwent the 26-week taper (P<0.001 for both comparisons) and 3818 mg in the placebo group that underwent the 52-week taper (P<0.001 for both comparisons). Serious adverse events occurred in 15% of the patients in the group that received tocilizumab weekly, 14% of those in the group that received tocilizumab every other week, 22% of those in the placebo group that underwent the 26-week taper, and 25% of those in the placebo group that underwent the 52-week taper. Anterior ischemic optic neuropathy developed in one patient in the group that received tocilizumab every other week. Tocilizumab, received weekly or every other week, combined with a 26-week prednisone taper was superior to either 26-week or 52-week prednisone tapering plus placebo with regard to sustained glucocorticoid-free remission in patients with giant-cell arteritis. Longer follow-up is necessary to determine the durability of remission and safety of tocilizumab. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT01791153 .).

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Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen and relationship with mortality among United States Veterans after testing positive for COVID-19.

Non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen are among the most-frequently used medications. Although these medications have different mechanisms of action, they have similar indications and treatment duration has been positively correlated with cardiovascular risk although the degree of risk varies by medication. Our objective was to study treatment effects of chronic use of individual NSAID medications and acetaminophen on all-cause mortality among patients who tested positive for COVID-19 while accounting for adherence. We used the VA national datasets in this retrospective cohort study to differentiate between sporadic and chronic medication use: sporadic users filled an NSAID within the last year, but not recently or regularly. Using established and possible risk factors for severe COVID-19, we used propensity scores analysis to adjust for differences in baseline characteristics between treatment groups. Then, we used multivariate logistic regression incorporating inverse propensity score weighting to assess mortality. The cohort consisted of 28,856 patients. Chronic use of aspirin, ibuprofen, naproxen, meloxicam, celecoxib, diclofenac or acetaminophen was not associated with significant differences in mortality at 30 days (OR = 0.98, 95% CI: 0.95-1.00; OR = 0.99, 95% CI: 0.98-1.00; OR = 1.00, 95% CI: 0.98-1.01; OR = 0.99, 95% CI: 0.98-1.00; OR = 1.00, 95% CI: 0.98-1.01; OR = 0.99, 95% CI: 0.97-1.01; and OR = 1.00, 95% CI: 0.99-1.02, respectively) nor at 60 days (OR = 0.97, 95% CI: 0.95-1.00; OR = 1.00, 95% CI: 0.99-1.01; OR = 0.99, 95% CI: 0.98-1.01; OR = 0.99, 95% CI: 0.97-1.00; OR = 0.99, 95% CI: 0.97-1.01; OR = 0.99, 95% CI: 0.97-1.01; and OR = 1.01, 95% CI: 0.99-1.02, respectively). Although the study design cannot determine causality, the study should assure patients as it finds no association between mortality and chronic use of these medications compared with sporadic NSAID use among those infected with COVID-19.

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Thyroid function after surgical treatment of nontoxic goitre. A randomized study of postoperative thyroxine administration.

Following thyroid resection for nontoxic goitre, 29 euthyroid patients were randomly allocated to no medication or to 0.2 mg levothyroxine daily (17 and 12 patients). The two groups were comparable in age, sex, extent of surgery and thyroid pathology. The patients were free from other endocrine disorders and had no other medication. Serum TSH, T4 and T3 were measured and T3-resin test performed preoperatively and 14 days and 3, 6, 12 and 18 months postoperatively. All values were within normal range. Only at the 3-month follow-up could statistically significant intergroup differences be observed, with T4 higher in the thyroxine-treated and TSH higher in the untreated group, but the outset values were thereafter regained. The T3 values in both groups were slightly reduced immediately after the operation. There was no recurrence of goitre in the 18-month observation period, and none of the findings suggested that routine thyroxine treatment is of value after resection of nontoxic goitre "in Denmark".

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Pain characteristics in medication-related osteonecrosis of the jaws.

To characterise pain from medication-related osteonecrosis of the jaws (MRONJ) and the effects of antimicrobial treatment on it. Data from files of patients diagnosed with MRONJ according to the position paper of the American Association of Oral and Maxillofacial Surgeons (2014) and Multinational Association of Supportive Care in Cancer and American Society of Clinical Oncology (2019) were collected retrospectively, including gender, age, primary disease, bone-modifying agents (BMAs)/anti-angiogenics, administration route, involved jaw, location, and exposure size. The patients were treated according to the abovementioned position papers' recommendations, i.e. all patients who suffered from pain were staged as 2 or 3 and treated with systemic amoxicillin, or doxycycline or clindamycin in case of sensitivity, and local antiseptic and hygiene instructions. Data from 77 MRONJ patients (aged 65.09 ± 11.9 years old) were analysed. Most (90.1%) received bisphosphonates for cancer (79%) and osteoporosis (17%). A total of 67.5% experienced pain; 36.5% had moderate-to-severe pain. Female gender was significantly associated with the presence of pain (p = 0.002). Osteonecrosis lesions after dento-alveolar surgery had a higher risk of pain development than spontaneous lesions (p = 0.045). Medical and oncologic background, type of pharmacotherapy, lesion size, and location were not associated with pain levels. Worse initial pain was significantly associated with better relief following MRONJ treatment (p = 0.045). Meaningful pain reduction (≥ 50%) was significantly correlated with initial pain severity (p = 0.0128, OR = 4.75). Pain from infection and inflammation often accompanies MRONJ. The presence of pain is correlated with longer BMAs pre-therapy and if surgery preceded the MRONJ. Persistency of the mild pain together with a resistance to common antimicrobial treatment, although not complete, is a feature that MRONJ pain shares with neuropathic-"like" pain, and requires further study and consideration during treatment.

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Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC-II).

The Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries trial (PLAC-II) was initiated in 1987 and was the first double-blind, randomized clinical trial with progression of early extracranial carotid atherosclerosis as an outcome variable. We randomized 151 coronary patients to placebo or pravastatin and treated them for 3 years. B-mode ultrasound quantification of carotid artery intimal-medial thickness (IMT) was obtained at baseline and sequentially during this period. The primary outcome was the change in the mean of the maximum IMT measurements over time. Effects on individual carotid artery segments (common, bifurcation, internal carotid artery) and on clinical events were also investigated. During follow-up, plasma concentrations of total cholesterol were lower in pravastatin-treated patients compared with those of placebo-treated patients (4.81 vs 6.08 mmol/liter [186 vs 235 mg/dl]) as were concentrations of low density lipoprotein (LDL) cholesterol (3.10 vs 4.29 mmol/liter [120 vs 167 mg/dl]). Plasma concentrations of high density lipoprotein2 (HDL2) cholesterol were higher in pravastatin-treated patients than in placebo-treated patients (0.16 vs 0.14 mmol/liter [6.1 vs 5.5 mg/dl]). Active treatment resulted in a nonsignificant 12% reduction in progression of the mean-maximum IMT (from 0.068 mm/yr placebo to 0.059 mm/yr pravastatin) and a statistically significant 35% reduction in IMT progression in the common carotid (p = 0.03). Active treatment was also associated with a 60% reduction of nonfatal myocardial infarction plus death caused by coronary artery disease (p = 0.09), a 61% reduction of any fatal event plus any nonfatal myocardial infarction (p = 0.04), and an 80% reduction of fatal plus any nonfatal myocardial infarction (p = 0.03).

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Comparison of chlorthalidone and spironolactone in low--renin essential hypertension.

Nineteen patients with uncomplicated essential hypertension and low activity of plasma renin in response to a change from recumbency to an upright posture along with furosemide administration were given spironolactone, 400 mg/d, or chlorthalidone, 100mg/d, in a double-blind, random-sequence, crossover trial. The sequence of treatments was placebo for 2 months, one active drug for 2 months, placebo again for 1 month and the other active drug for 2 months. With both active treatments the average systolic, diastolic and mean arterial pressures decreased significantly. The two agents were equally efficacious in lowering the blood pressure regardless of the severity of hypertension during placebo treatment. Body weight, 24--hour urinary excretion of sodium, the plasma renin activity and the plasma aldosterone level at the end of the initial placebo period did not allow us to predict the response to either drug. Both drugs reduced the body weight and increased the stimulated plasma renin level activity. Chlorthalidone significantly increased the serum uric acid level and significantly reduced the serum potassium level. Three patients experienced orthostatic dizziness during spironolactone therapy, but no adverse symptoms were observed with chlorthalidone therapy. Thus, spironolactone is an effective alternative to thiazide-type drugs in patients with low-renin essential hypertension.

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Salmeterol reduces dyspnea and improves lung function in patients with COPD.

To investigate the short-term effects of inhaled salmeterol on the perception of dyspnea and lung function in patients with COPD. Double-blind, crossover, randomized trial comparing inhaled salmeterol and inhaled placebo over 4 h. Pulmonary function laboratory at university medical center. Sixteen patients with symptomatic COPD and at least 200-mL increase in FEV1 after inhalation of two puffs (180 microg) of albuterol. Visit 1 was used for familiarization. At visits 2 and 3 (2 to 3 days apart), patients inhaled either two puffs of salmeterol (42 microg) or placebo. Lung function and dyspnea were measured at 0.5, 2, and 4 h after inhalation of the study medication. Dyspnea was measured by the -5 to +5 category scale at rest and by the 0 to 10 category-ratio scale while breathing through inspiratory resistances of 5, 15, and 30 cm H20/L/s. Age was 66+/-8 years (mean+/-SD). FEV1 was 0.97+/-0.331 (51+/-13% predicted). There were significantly higher values for FEV1 and FVC (at all time periods) and lower values for functional residual capacity (at all time periods) and residual volume (at 4 h) with salmeterol than with placebo. There were significantly lower dyspnea ratings on the -5 to +5 category scale (p=0.03 at 2 h and p=0.02 at 4 h) and for the mean dyspnea scores during resistive breathing with salmeterol compared with placebo (p=0.002). Inhaled salmeterol reduced dyspnea, increased airflow, and reduced hyperinflation over 4 h in patients with symptomatic COPD.

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Respiratory response to salbutamol (albuterol) in ventilator-dependent infants with chronic lung disease: pressurized aerosol delivery versus intravenous injection.

To compare the effects of intravenously injected with inhaled salbutamol in ventilator dependent infants with chronic lung disease (CLD). Prospective randomized study which each patient served as his/her own control. Multidisciplinary neonatal and pediatric ICU. 8 ventilator dependent premature infants with CLD. Salbutamol, 10 micrograms/kg was given intravenously, and 10-19 h later, twice 100 micrograms as pressurized aerosol, or vice versa, sequence randomized. The pressurized aerosol was delivered by a metered dose inhaler into a newly developed aerosol holding chamber, integrated into the inspiratory limb of the patient circuit. Respiratory system mechanics were assessed by the single breath occlusion method before and 10 and 60 min after drug administration. Compliance improved significantly after intravenous injection (0.48 +/- 0.18 to 0.67 +/- 0.16, p < 0.01 and 0.59 +/- 0.23 ml/cmH2O/kg, NS, (mean +/- 1 SD) and after inhalation (0.46 +/- 0.19 to 0.64 +/- 0.32, p < 0.01 and 0.56 +/- 0.31 ml/cmH2O/kg, NS). Resistance decreased after iv. use (0.38 +/- 0.17 to 0.25 +/- 0.11, p < 0.001 and 0.25 +/- 0.10 cmH2O/ml/s, NS) and after inhalation (0.35 +/- 0.12 to 0.27 +/- 0.09, p < 0.01 and 0.28 +/- 0.12 cmH2O/ml/s, NS). Heart rate increased significantly after both routes of application, whereas mean arterial pressure, respirator settings, FIO2, transcutaneous SO2 and capillary PCO2 did not change. Inhaled and intravenous salbutamol improves pulmonary mechanics to the same extent with comparable side effects, and may therefore be used to facilitate weaning from respirators.

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