Domain communication in the dynamical structure of human immunodeficiency virus 1 protease.

A dynamical model for the structure of the human immunodeficiency virus 1 (HIV-1) protease dimer in aqueous solution has been developed on the basis of molecular dynamics simulation. The model provides an accurate account of the crystal geometry and also a prediction of the structural reorganization expected to occur in the protein in aqueous solution compared to the crystalline environment. Analysis of the results by means of dynamical cross-correlation coefficients for atomic displacements indicates that domain-domain communication is present in the protein in the form of a molecular "cantilever" and is likely to be involved in enzyme function at the molecular level. The dynamical structure also suggests information that may ultimately be useful in understanding and further development of specific inhibitors of HIV-1 protease.     

The Effects of 10 Weeks Military Training on Heel Ultrasound and Bone Turnover

To measure the physiological changes in bone in response to strenuous exercise we performed a prospective study of male army recruits over 10 weeks of basic training. Measurements performed at the start and completion of training consisted of ultrasound (US) measurements of the heel: velocity of sound (VOS in m/seconds) and broadband ultrasound attenuation (BUA in dB/MHz) and bone turnover markers; osteocalcin (OC), bone-specific alkaline phosphatase (BALP), and tartrate-resistant acid phosphatase (TRAP). Forty subjects were recruited for the study and 26 completed training. Over the 10-week study period there was a significant 1.7% fall in mean VOS [mean paired difference (mpd) 27.2 m/second, SEM 9.5 (95% CI 7.5–46.8) P= 0.009] and a nonsignificant 3.4% increase in BUA (P= 0.159). There were significant falls in markers of bone formation OC [11.6%, mpd 0.11 μg/liter (95% CI 0.07–0.14) P < 0.001] and BALP [13.3%, mpd 3.49 U/liter (CI 0.80–6.18) P= 0.013] and a nonsignificant 9.5% fall in TRAP a marker of bone resorption. The 10 recruits subsequently injured had a significantly lower VOS on entry [mean difference 24.2 m/seconds (95% CI 4.6–43.7) P= 0.017] and nonsignificantly raised BUA and baseline levels of all bone markers. The ultrasound changes may be accounted for by increase in trabecular separation and a fall in trabecular connectivity due to microfracture. The decrease in bone markers implies a fall in bone turnover. Received: 26 June 1997 / Accepted: 26 August 1998     

Allogeneic vaccination with a B7.1 HLA-A gene-modified adenocarcinoma cell line in patients with advanced non-small-cell lung cancer.

PURPOSE: To determine the safety, immunogenicity, and clinical response to an allogeneic tumor vaccine for non-small-cell lung cancer, we conducted a phase I trial in patients with advanced metastatic disease. PATIENTS AND METHODS: We treated 19 patients with a vaccine based on an adenocarcinoma line (AD100) transfected with B7.1 (CD80) and HLA A1 or A2. Patients were vaccinated intradermally with 5 x 10(7) cells once every 2 weeks. Three vaccinations represented one course of treatment. If patients had complete response, partial response, or stable disease, they continued with the vaccinations for up to three courses (nine vaccinations). Immune response was assessed by a change between pre-study and postvaccination enzyme-linked immunospot frequency of purified CD8 T-cells secreting interferon-gamma in response to in vitro challenge with AD100. RESULTS: Four patients experienced serious adverse events that were unrelated to vaccine. Another four patients experienced only minimal skin erythema. All but one patient had a measurable CD8 response after three immunizations. The immune response of six surviving, clinically responding patients shows that CD8 titers continue to be elevated up to 150 weeks, even after cessation of vaccination. Overall, one patient had a partial response, and five had stable disease. Median survival for all patients is 18 months (90% CI, 7 to 23 months), with corresponding estimates of 1-year, 2-year, and 3-year survival of 52%, 30%, and 30%, respectively. HLA matching of vaccine, age, sex, race, and pathology did not bear a significant relation to response. CONCLUSION: Minimal toxicity and good survival in this small population suggest clinical benefit from vaccination.     

Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients

Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients. BACKGROUND: In hypertensive type 2 diabetic patients, treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with a lower incidence of cardiovascular events than those treated with calcium channel-blocking agents. However, the long-term renal effects of ACE inhibitors in these patients remain inconclusive. In 1989, we commenced a placebo-controlled, double-blind, randomized study to examine the anti-albuminuric effects of enalapril versus nifedipine (slow release) in 102 hypertensive, type 2 diabetic patients. These patients have been followed up for a mean trial duration of 5.5 +/- 2.2 years. We examined the determinants, including the effect of ACE inhibition on clinical outcomes in these patients. METHODS: After a six-week placebo-controlled, run-in period, 52 patients were randomized double-blind to receive nifedipine (slow release) and 50 patients to receive enalapril. After the one-year analysis, which confirmed the superior anti-albuminuric effects of enalapril (-54%) over nifedipine (+11%), all patients were continued on their previously assigned treatment with informed consent. They were subdivided into normoalbuminuric (N = 43), microalbuminuric (N = 34), and macroalbuminuric (N = 25) groups based on two of three 24-hour urinary albumin excretion (UAE) measurements during the run-in period. Renal function was shown by the 24-hour UAE, creatinine clearance (CCr), and the regression coefficient of the yearly plasma creatinine reciprocal (beta-1/Cr). Clinical endpoints were defined as death, cardiovascular events, and/or renal events (need for renal replacement therapy or doubling of baseline plasma creatinine). RESULTS: In the whole group, patients treated with enalapril were more likely to revert to being normoalbuminuric (23.8 vs. 15.4%), and fewer of them developed macroalbuminuria (19.1 vs. 30.8%) compared with the nifedipine-treated patients (P < 0.05). In the microalbuminuric group, treatment with enalapril (N = 21) was associated with a 13.0% (P < 0.01) reduction in 24-hour UAE compared with a 17.3% increase in the nifedipine group (N = 13). In the macroalbuminuric patients, enalapril treatment (N = 11) was associated with stabilization compared with a decline in renal function in the nifedipine group, as shown by the beta-1/Cr (0.65 +/- 4.29 vs. -1.93 +/- 2.35 1/micromol x 10-3, P < 0.05) after adjustment for baseline values. Compared with the normoalbuminuric and microalbuminuric patients, those with macroalbuminuria had the lowest mean CCr (75.5 +/- 24.1 vs. 63.5 +/- 21.3 vs. 41.9 +/- 18.5 mL/min, P < 0.001) and the highest frequency of clinical events (4.7 vs. 5.9 vs. 52%, P < 0. 001). On multivariate analysis, beta-1/Cr (R2 = 0.195, P < 0.001) was independently associated with baseline HbA1c (beta = -0.285, P = 0.004), whereas clinical outcomes (R2 = 0.176, P < 0.001) were independently related to the mean low-density lipoprotein cholesterol (beta = 2.426, P = 0.018), high-density lipoprotein cholesterol (beta = -8.797, P = 0.03), baseline UAE (beta = 0.002, P = 0.04), and mean CCr during treatment (beta = -0.211, P = 0.006). CONCLUSION: In this prospective cohort analysis involving 102 hypertensive, type 2 diabetic patients with varying degrees of albuminuria followed up for a mean duration of five years, we observed the importance of good metabolic and blood pressure control on the progression of albuminuria and renal function. Treatment with enalapril was associated with a greater reduction in albuminuria than with nifedipine in the entire patient group, and especially in those with microalbuminuria. In the macroalbuminuric patients, the rate of deterioration in renal function was also attenuated by treatment with enalapril.     

Glycosylated hemoglobin-defined prediabetes and cardiovascular risk markers in rural India: the Nallampatti noncommunicable disease study

The aim of this study is to assess the associations between glycosylated hemoglobin in the prediabetes range and cardiovascular risk markers in a rural South Indian population. Local Ethics Committee approval and informed consent was obtained from all participants. Inclusion criteria were participants, aged ≥20 and ≤85 years, from Nallampatti, a classical farming village from Tamil Nadu State, India. Those with known history of diabetes were excluded from this analysis. All participants were administered a detailed questionnaire, had anthropometric measurements including height, weight, and waist circumference. Bloods were drawn for random blood glucose, glycosylated hemoglobin, nonfasting lipid profile, cystatin C, uric acid, and hemoglobin. All participants had carotid intima thickness done by high-resolution B-mode carotid ultrasound. Progressive hyperglycemia across the glucose tolerance continuum based on glycosylated hemoglobin levels in a rural South Indian population seems to be associated with worsening cardiovascular risk markers. A cut-off value of ≥6% (42 mmol/mol) seems to herald a much more significant increase in such markers. Long-term follow-up of this cohort for incident cardiovascular disease will help to substantiate the associations between glycosylated hemoglobin levels within the prediabetes range and cardiovascular disease in an Indian population. Evidence-based race-specific criteria for diagnosis of prediabetes and diabetes are the need of the hour for risk stratification and appropriate management.     

Setting priorities for a research agenda to combat drug-resistant tuberculosis in children

Setting: Numerous knowledge gaps hamper the prevention and treatment of childhood drug-resistant tuberculosis (TB). Identifying research priorities is vital to inform and develop strategies to address this neglected problem.Objective: To systematically identify and rank research priorities in childhood drug-resistant TB.Design: Adapting the Child Health and Nutrition Research Initiative (CHNRI) methodology, we compiled 53 research questions in four research areas, then classified the questions into three research types. We invited experts in childhood drug-resistant TB to score these questions through an online survey.Results: A total of 81 respondents participated in the survey. The top-ranked research question was to identify the best combination of existing diagnostic tools for early diagnosis. Highly ranked treatment-related questions centred on the reasons for and interventions to improve treatment outcomes, adverse effects of drugs and optimal treatment duration. The prevalence of drug-resistant TB was the highest-ranked question in the epidemiology area. The development type questions that ranked highest focused on interventions for optimal diagnosis, treatment and modalities for treatment delivery.Conclusion: This is the first effort to identify and rank research priorities for childhood drug-resistant TB. The result is a resource to guide research to improve prevention and treatment of drug-resistant TB in children.