The duration of viral suppression during protease inhibitor therapy for HIV-1 infection is predicted by plasma HIV-1 RNA at the nadir

OBJECTIVE: To determine markers that are associated with the durability of virologic response to therapy with HIV protease inhibitors in HIV-infected individuals. DESIGN: This study encompassed two retrospective analyses of the duration of virologic response to protease inhibitor therapy. The first analysis included 29 patients receiving either monotherapy or combination therapy with the protease inhibitor ritonavir whose plasma HIV RNA levels rebounded from the point of greatest decline with mutations associated with resistance to ritonavir. The second analysis included a cohort of 102 patients who initially responded to randomized treatment with either monotherapy with ritonavir or combination therapy with ritonavir and zidovudine. METHODS: Durability of response was defined as the time from the initiation of therapy to the point at which plasma HIV RNA displayed a sustained increase of at least 0.6 log10 copies/ml from the nadir value. In the first analysis, durability of response was analyzed with respect to baseline HIV RNA, HIV RNA at the nadir, and the drop in HIV RNA from baseline to the nadir. In the second analysis, time to rebound was examined using Kaplan-Meier analysis, stratifying by either baseline HIV RNA or HIV RNA at the nadir. RESULTS: In both analyses, the durability of response was not highly associated with either baseline RNA or the magnitude of RNA decline from baseline. Instead, a strong relationship was observed between the durability of response and the nadir plasma HIV-1 RNA value (P < 0.01). The nadir in viral load was generally reached after 12 weeks of randomized therapy. CONCLUSIONS: Viral RNA determinations at intermediate timepoints may be prognostic of impending virologic failure of protease inhibitor therapy. Therapeutic strategies that allow intensification of initial antiretroviral regimens in the subset of patients with incomplete virological response before the emergence of high level resistance should be investigated.     

Complete physical map of the common deletion region in Williams syndrome and identification and characterization of three novel genes

Williams syndrome (WS) is a contiguous gene deletion disorder caused by haploinsufficiency of genes at 7q11.23. We have shown that hemizygosity of elastin is responsible for one feature of WS, supravalvular aortic stenosis (SVAS). We have also implicated LIM-kinase 1 hemizygosity as a contributing factor to impaired visual-spatial constructive cognition in WS. However, the common WS deletion region has not been completely characterized, and genes for additional features of WS, including mental retardation, infantile hypercalcemia, and unique personality profile, are yet to be discovered. Here, we present a physical map encompassing 1.5 Mb DNA that is commonly deleted in individuals with WS. Fluorescence in situ hybridization analysis of 200 WS individuals shows that WS individuals have the consistent deletion interval. In addition, we identify three novel genes from the common deletion region: WS-betaTRP, WS-bHLH, and BCL7B. WS-betaTRP has four putative beta-transducin (WD40) repeats, and WS-bHLH is a novel basic helix-loop-helix leucine zipper (bHLHZip) gene. BCL7B belongs to a novel family of highly conserved genes. We describe the expression profile and genomic structure for each of these genes. Hemizygous deletion of one or more of these genes may contribute to developmental defects in WS.     

Dorsalis pedis flap donor site: acceptable or not?

The dorsalis pedis flap has been used successfully for 20 years, both as a pedicled transfer for local foot reconstruction and as a free microvascular transfer. Proponents cite the reliable vascularity, versatility, ease of harvest, and thinness. Although significant donor-site morbidity has been recognized previously, published reports have inadequately documented the long-term effects of dorsalis pedis flap harvest. The purpose of the present study was to obtain long-term follow-up data regarding the donor site on a total of 10 male patients who underwent dorsalis pedis flap harvest during the period from 1982 to 1984. Standardized questionnaires and chart reviews were completed, and physical examinations and photographs of each patient were carried out when possible. Eight patients were reviewed, and seven of them were examined and photographed (mean follow-up 13 years). All patients had initially experienced delayed donor-site healing (mean 18 months; range 3 to 36 months). In addition, soft-tissue infections (five of eight cases), osteomyelitis (one of eight cases), wound breakdown (seven of eight cases), scarring and contracture (four of seven cases), pain or other uncomfortable sensations in the foot (six of seven cases), and requirement for reoperation (three of eight cases) were significant complications of the procedure. Most patients were able to attain their preoperative level of physical activity (five of eight cases). Although generally favorable reconstructive results were obtained in this series, the long-term follow-up of donor-site healing indicates that this flap should be used with caution. In particular, delayed donor-site healing, need for wound revision, and long-term and possibly permanent donor-site symptoms are common.     

Effectiveness of a worksite smoking cessation program in the military. Program evaluation

1. A program evaluation was conducted to evaluate the effectiveness of the smoking cessation program. Substantiating data enhances the value of health promotion programs as key components of the health care delivery system. 2. Persons enrolled in the 8 week smoking cessation program and members of a comparison group were administered an evaluation tool prior to participating in the program, with a second evaluation tool upon completion of the program. Afterward, the smoking status of the members of both groups was evaluated at 3 month intervals for a period of 1 year. 3. Of the participants, 26.7% were not smoking 12 months after the program, compared to 6.9% of the comparison group. Of those participants who resumed smoking, 64% smoked less than half the amount they smoked before taking the class.     

A phosphoinositide-linked dopamine D1 receptor mediates repetitive jaw movements in rats

BACKGROUND: We have demonstrated that rats injected with D1 agonists SKF 38393 or A68930 demonstrate repetitive jaw movements (RJM). These agonist-induced movements in rats are similar in their appearance to those induced in rats by long-term treatment with antipsychotic drugs. Over recent years D-1 receptors were discovered which showed linkage not only to c-AMP but also to PI hydrolysis. We examined the effect of EEDQ inactivation of D1 receptors on D-1 mediated PI hydrolysis and RJM. METHODS: Twenty four hours following EEDQ or vehicle administration D-1 agonists or vehicle were administered. The number of RJM episodes was assessed in EEDQ and vehicle treated rats. D-1 receptor density and inositol phosphate formation were determined in the striata. RESULTS: EEDQ administration resulted, 24 hours later, in 70-80% selective depletion of D-1 receptors in the striata but did not modify the rate of RJM induced by D-1 agonists. There was no significant difference in D-1 mediated PI hydrolysis in EEDQ treated rats when compared to vehicle treated group. CONCLUSIONS: The present data support the earlier demonstration of D-1 agonist induced RJM, an effect mediated by a subpopulation of a D-1 receptor subtype and constitute the first behavioral evidence for the existence of a behavioral response mediated by D-1 like dopamine receptors linked to an alternate second messenger system-PI hydrolysis.     

Outcome measures for low back pain research. A proposal for standardized use

STUDY DESIGN: An international group of back pain researchers considered recommendations for standardized measures in clinical outcomes research in patients with back pain. OBJECTIVES: To promote more standardization of outcome measurement in clinical trials and other types of outcomes research, including meta-analyses, cost-effectiveness analyses, and multicenter studies. SUMMARY OF BACKGROUND DATA: Better standardization of outcome measurement would facilitate comparison of results among studies, and more complete reporting of relevant outcomes. Because back pain is rarely fatal or completely cured, outcome assessment is complex and involves multiple dimensions. These include symptoms, function, general well-being, work disability, and satisfaction with care. METHODS: The panel considered several factors in recommending a standard battery of outcome measures. These included reliability, validity, responsiveness, and practicality of the measures. In addition, compatibility with widely used and promoted batteries such, as the American Academy of Orthopaedic Surgeons Lumbar Cluster were considered to minimize the need for changes when these instruments are used. RESULTS: First, a six-item set was proposed, which is sufficiently brief that it could be used in routine care settings for quality improvement and for research purposes. An expanded outcome set, which would provide more precise measurement for research purposes, includes measures of severity and frequency of symptoms, either the Roland or the Oswestry Disability Scale, either the SF-12 or the EuroQol measure of general health status, a question about satisfaction with symptoms, three types of "disability days," and an optional single item on overall satisfaction with medical care. CONCLUSION: Standardized measurement of outcomes would facilitate scientific advances in clinical care. A short, 6-item questionnaire and a somewhat expanded, more precise battery of questionnaires can be recommended. Although many considerations support such recommendations, more data on responsiveness and the minimally important change in scores are needed for most of the instruments.     

Effects of short-term treatment of hyperlipidemia on coronary vasodilator function and myocardial perfusion in regions having substantial impairment of baseline dilator reverse

BACKGROUND: We tested the hypothesis that correction of hyperlipidemia improves coronary vasodilator response and maximal perfusion in myocardial regions having substantial impairment of pretreatment vasodilator capacity. METHODS AND RESULTS: Measurements of myocardial blood flow were made with PET [13N]ammonia in 12 patients with ischemic heart disease (11 men; age, 65+/-8 years [mean+/-SD]) at rest and during adenosine at 70 and then 140 microg . kg-1 . min-1 for 5 minutes each before and approximately 4 months after simvastatin treatment (40 mg daily). Simvastatin reduced LDL (171+/-13 before versus 99+/-18 mg/dL after simvastatin, P<0.001) and increased HDL (39+/-8 versus 45+/-9 mg/dL, P<0.05). Myocardial segments were classified on the basis of pretreatment blood flow response to 140 microg . kg-1 . min-1 adenosine as normal (flow >/=2 mL . min-1 . g-1) or abnormal (flow <2 mL . min-1 . g-1). In normal segments, baseline myocardial blood flow (0.95+/-0.32) increased (P<0.001) at both low- (1.62+/-0.81) and high- (2.63+/-0.41) dose adenosine and was unchanged both at rest and with adenosine after simvastatin. In abnormal segments, myocardial blood flow at rest (0. 73+/-0.19) increased at low- (1.06+/-0.59, P<0.02) and high- (1. 29+/-0.33, P<0.01) dose adenosine. After simvastatin, myocardial blood flow increased more compared with pretreatment at both low- (1. 37+/-0.66, P<0.05 versus pretreatment) and high- (1.89+/-0.79, P<0. 01 versus pretreatment) dose adenosine. CONCLUSIONS: Short-term lipid-lowering therapy increases stenotic segment maximal myocardial blood flow by approximately 45%. The mechanism involves enhanced, flow-mediated dilation of stenotic epicardial conduit vessels and may account at least in part for the efficacy of lipid lowering in secondary prevention trials and in reducing ischemic episodes in ambulatory patients.