Anti-tumor necrosis factor (TNF) therapy in rheumatoid arthritis: correlation of TNF-alpha serum level with clinical response and benefit from changing dose or frequency of infliximab infusions

OBJECTIVE: To determine the relationship between serum TNF-alpha level and clinical response in rheumatoid arthritis patients treated by infliximab. This could be of value to predict clinical response to infliximab and to determine the optimal dose and interval between dosing of infliximab. RA patients who did not respond adequately to conventional doses (3 mg/kg) of infliximab were studied to see if increasing the dose or frequency of infliximab infusions would be more effective. METHODS: Fifty-five RA patients who fulfilled the American College of Rheumatology criteria and were receiving treatment by anti-TNF-alpha (infliximab 3 mg/kg body weight every 8 weeks) were evaluated by: clinical disease activity using the Richie score index before receiving their scheduled infliximab infusion. Serum level of TNF-alpha, as measured by competitive ELISA assay, was determined immediately before and 9-11 days after receiving infliximab. RA patients who did not respond adequately to treatment with infliximab were given either a larger dose of infliximab or given the infusion at six-week intervals. Their clinical response was then evaluated sixteen months later. RESULTS Patients were divided into 2 groups according to Richie score, active group with score > 10 (score 20.3 +/- 7.7 mean +/- standard deviation, n = 25) and inactive group with scores < or = 10 (score 4.1 +/- 3.2, n = 30). TNF-alpha serum levels pre-infliximab infusion were significantly higher in the active group 76.1 pg/ml than the inactive group 38.0 pg/ml (P < 0.02). Whereas TNF serum level significantly dropped post infliximab in the inactive group (P < 0.05), it did not drop in the active group. The mean level of the post-infusion TNF-alpha serum level was higher (76.6 +/- 93.4 ng/ml) in the-active than the mean level of the post-infusion serum TNF-alpha levels in the inactive group (26.4 ng/ml +/- 7.9) P < 0.01 using the t-test. Increasing the frequency was superior in RA patients' clinical outcome than increasing the dose of infliximab infusions. CONCLUSION: RA patients who responded well to infliximab and had inactive disease at the time of the study have lower levels of serum TNF-alpha which could be further suppressed by the recommended doses of infliximab. RA patients with active disease have higher serum levels of TNF-alpha which could not be suppressed after the recommended doses of infliximab infusion. Changing the frequency of infliximab infusions in the active group was more effective than increasing the dose of infliximab in inducing improved clinical outcome. We suggest that the lack of suppression of TNF-alpha in the active group could be due to inadequate dosing of infliximab or to the presence of a neutralizing antibody directed against infliximab. It remains to be seen if serum TNF-alpha levels could be used as a guide in determining the dose and intervals between dosing of anti-TNF therapy in RA in order to achieve the desired clinical response.     

NMR based CSF metabolomics in tuberculous meningitis: correlation with clinical and MRI findings

Metabolic Brain Disease - We report the potential role of 1H Nuclear Magnetic Resonance (NMR) based metabolomics in tuberculous meningitis (TBM). We also correlate the significant metabolites with...     

A prospective study on clinical outcome following pleurotomy during cardiac surgery

BACKGROUND: Due to conflicting reports on pleurotomy-associated morbidity following internal mammary artery (IMA) harvesting, we conducted a prospective study to assess the clinical significance and outcome of pleurotomy during cardiac surgery. METHODS: We included patients undergoing cardiac surgery from November 2000 until January 2001. Participants were divided into two groups: one with routine or incidental left pleurotomy and the other with intact left pleurae. RESULTS: Of the 218 patients registered for this study, 12 were excluded (7 deaths occurred, 5 patients were transferred prior to study completion). Of the 206 remaining, 138 had isolated CABG, 39 had valve surgery and 29 had a combined procedure. Although patients with a left pleurotomy (n= 164) had a higher incidence of left lung atelectasis (67.7% vs. 45.2%; p = 0.007), neither radiographic consolidation (7.5% vs. 7.3%; p = 0.96), effusion (42.5%vs. 46.3%; p - 0.66), nor hospital stay (9 days in both groups; p - 0.83) increased. CONCLUSIONS: Left pleurotomy was found to increase the rate of atelectasis. However, this was not associated with an adverse clinical outcome. Pleurotomy during IMA harvesting can be performed according to operator preference.     

Development of an opinion leader-led HIV prevention intervention among alcohol users in Chennai, India.

In 1999, we began a community-based randomized controlled prevention trial in Chennai, which aims to test the efficacy of HIV prevention messages disseminated through members of an individual's social group called community popular opinion leaders, or CPOLs. We targeted patrons of 100 bars or wine shops in the city of Chennai, India. In this article we report on the process of development of an HIV prevention intervention for wine shop patrons. First, we conducted detailed ethnography to understand social norms and CPOL and social network characteristics, including 41 in-depth interviews among wine shop patrons and gatekeepers. Second, we tailored a generic HIV education training manual to appropriately address the needs of Chennai wine shop patrons. Field-testing involved 16 focus groups with wine shop patrons and 12 sessions of participant observations in wine shops. Finally, we piloted the intervention to determine the appropriateness of the training program and its content among wine shop patrons. Our ethnographic data indicated that wine shops are a common meeting place for men. We were able to identify CPOLs influential in these settings and train them to deliver appropriate prevention messages to their close friends and associates. We found that HIV prevention messages in this population need to dispel misperceptions about HIV transmission, provide strategies and skills to adopt and sustain condom use, and target the role of alcohol in sexual behavior. We outline specific lessons we learned in intervention development in this population.     

Bone metabolism in adolescent boys with anorexia nervosa

BACKGROUND: Anorexia nervosa (AN) is a condition of severe undernutrition associated with low bone mineral density (BMD) in adolescent females with this disorder. Although primarily a disease in females, AN is increasingly being recognized in males. However, there are few or no data regarding BMD, bone turnover markers or their predictors in adolescent AN boys. HYPOTHESES: We hypothesized that BMD would be low in adolescent boys with AN compared with controls associated with a decrease in bone turnover markers, and that the gonadal steroids, testosterone and estradiol, and levels of IGF-I and the appetite regulatory hormones leptin, ghrelin, and peptide YY would predict BMD and bone turnover markers. METHODS: We assessed BMD using dual-energy x-ray absorptiometry and measured fasting testosterone, estradiol, IGF-I, leptin, ghrelin, and peptide YY and a bone formation (aminoterminal propeptide of type 1 procollagen) and bone resorption (N-telopeptide of type 1 collagen) marker in 17 AN boys and 17 controls 12-19 yr old. RESULTS: Boys with AN had lower BMD and corresponding Z-scores at the spine, hip, femoral neck, trochanter, intertrochanteric region, and whole body, compared with controls. Height-adjusted measures (lumbar bone mineral apparent density and whole body bone mineral content/height) were also lower. Bone formation and resorption markers were reduced in AN, indicating decreased bone turnover. Testosterone and lean mass predicted BMD. IGF-I was an important predictor of bone turnover markers. CONCLUSION: AN boys have low BMD at multiple sites associated with decreased bone turnover markers at a time when bone mass accrual is critical for attainment of peak bone mass.     

Separation and Identification of Phenolic Acid and Flavonoids from Nerium indicum Flowers

Four major compounds were separated and identified from the methanol extracts of Nerium indicum flowers (Arali) using HPLC and mass spectral data. Through mass data, the chemical structures were elucidated as: trans5-O-caffeoylquinic acid (1), quercetin-3-O- rutinoside (2), luteolin-5-O-rutinoside (3) and luteolin-7-O-rutinoside (4). In addition, the cis isomers of 5-O-caffeoylquinic acid in Nerium indicum flowers were confirmed by Mass, HPLC and UV. The structures of these compounds confirmed with the help of liquid chromatography mass spectrometry.     

Pharmacokinetics and Toxicity of Sodium Selenite in the Treatment of Patients with Carcinoma in a Phase I Clinical Trial: The SECAR Study

Background: Sodium selenite at high dose exerts antitumor effects and increases efficacy of cytostatic drugs in multiple preclinical malignancy models. We assessed the safety and efficacy of intravenous administered sodium selenite in cancer patients’ refractory to cytostatic drugs in a phase I trial. Patients received first line of chemotherapy following selenite treatment to investigate altered sensitivity to these drugs and preliminary assessment of any clinical benefits. Materials and Methods: Thirty-four patients with different therapy resistant tumors received iv sodium selenite daily for consecutive five days either for two weeks or four weeks. Each cohort consisted of at least three patients who received the same daily dose of selenite throughout the whole treatment. If 0/3 patients had dose-limiting toxicities (DLTs), the study proceeded to the next dose-level. If 2/3 had DLT, the dose was considered too high and if 1/3 had DLT, three more patients were included. Dose-escalation continued until the maximum tolerated dose (MTD) was reached. MTD was defined as the highest dose-level on which 0/3 or 1/6 patients experienced DLT. The primary endpoint was safety, dose-limiting toxic effects and the MTD of sodium selenite. The secondary endpoint was primary response evaluation. Results and Conclusion: MTD was defined as 10.2 mg/m², with a calculated median plasma half-life of 18.25 h. The maximum plasma concentration of selenium from a single dose of selenite increased in a nonlinear pattern. The most common adverse events were fatigue, nausea, and cramps in fingers and legs. DLTs were acute, of short duration and reversible. Biomarkers for organ functions indicated no major systemic toxicity. In conclusion, sodium selenite is safe and tolerable when administered up to 10.2 mg/m² under current protocol. Further development of the study is underway to determine if prolonged infusions might be a more effective treatment strategy.     

Evidence for activation of cellular immune responses in patients with acute hepatitis E.

INTRODUCTION: Although acute hepatitis E virus (HEV) infection is known to induce IgM and IgG humoral host immune responses, little is known about occurrence of cellular responses in this infection. We looked for evidence of lymphocyte sensitization to HEV peptides in patients with acute HEV infection. METHODS: peripheral blood lymphocytes were obtained from patients with acute hepatitis E and healthy controls. Proliferation of these lymphocytes in the presence of each of seven peptides with amino acid sequences corresponding to open reading frames 2 and 3 proteins of HEV (3 and 4 peptides, respectively) were studied; no peptide was added to control wells. Proliferative responses with stimulation indices exceeding 3.0 were taken as positive. RESULTS: More patients showed reactivity to two or more HEV peptides than did controls (11/21 vs 5/22, p<0.05). Reactivity to one peptide corresponding to open reading frame 2 of HEV was more frequent in patients than in controls (7/21 vs 1/22, p<0.05). CONCLUSION: Our results show that lymphocytes of patients with acute hepatitis E show sensitization to HEV peptides. This may have significance in understanding the pathogenetic mechanisms of liver injury in this infection.