Emerging human papillomavirus vaccines

Human papillomavirus (HPV) infections are a leading cause of virus-associated cancers of the anogenital, oropharyneal and cutaneous epithelium. The most prevalent of these is cervical cancer, which is responsible for approximately 500,000 deaths annually worldwide. A group of about 15 serologically unrelated 'high-risk' HPV types are responsible for almost all HPV-associated cancers. Prevention of papillomavirus infection can be achieved by induction of capsid-specific neutralising antibodies in preclinical animal papillomavirus models and in recent human clinical trials. High titres of conformationally-dependent, type-specific HPV-neutralising antibodies are triggered by HPV virus-like particle (VLP) vaccines. Overcoming the problems of type-specificity of the responses to these VLP vaccines is a potentially important area of current HPV vaccine research, with an emphasis on induction of more broadly cross-protective neutralising responses. Viral oncogenes E6 and E7 are continuously present in HPV-associated cancers and are prime targets for HPV therapeutic vaccines. A variety of approaches are being tested in therapeutic vaccine clinical trials and in various preclinical animal papillomavirus models for efficacy. Approaches include genetic vaccines, recombinant virus vaccines, dendritic cell-based strategies, immunomodulatory strategies and various combination strategies to maximise cell-mediated immunity to papillomavirus proteins present in HPV infections and cancers. The success of preventive HPV VLP vaccines in clinical trials is clear. However, current therapeutic vaccine trials are less effective with respect to disease clearance. Nevertheless, a series of combination approaches have shown significant therapeutic enhancement in preclinical papillomavirus models and await testing in patient populations to determine the most effective strategy. There is much encouragement that HPV vaccines will be the most effective approach to prevention and cure of infections caused by this group of viruses, which re-present a significant human pathogen.     

Idiosyncratic drug hepatotoxicity

The occurrence of idiosyncratic drug hepatotoxicity is a major problem in all phases of clinical drug development and the most frequent cause of post-marketing warnings and withdrawals. This review examines the clinical signatures of this problem, signals predictive of its occurrence (particularly of more frequent, reversible, low-grade injury) and the role of monitoring in prevention by examining several recent examples (for example, troglitazone). In addition, the failure of preclinical toxicology to predict idiosyncratic reactions, and what can be done to improve this problem, is discussed. Finally, our current understanding of the pathophysiology of experimental drug hepatotoxicity is examined, focusing on acetaminophen, particularly with respect to the role of the innate immune system and control of cell-death pathways, which might provide targets for exploration and identification of risk factors and mechanisms in humans.     

Prolonged exposure of rats to intravenous methamphetamine: behavioral and neurochemical characterization

The translational value of preclinical models of methamphetamine abuse depends in large part on the degree to which the drug regimens used in animals produce methamphetamine exposure patterns similar to those experienced by human methamphetamine abusers. To approximate one common form of methamphetamine abuse, we studied the effects of a schedule of intravenous methamphetamine administration in rats which included 2 weeks of progressively more frequent drug injections (0.125 mg/kg/injection) followed by 40 maintenance days during which animals received 40 daily injections (at 15-min intervals), with the dose gradually increasing (0.125–0.25 mg/kg per injection) every 5–10 days. This treatment produced an emerging behavioral profile characterized by gradually more continuous periods of activation consisting of progressively more intense, focused stereotypy interrupted by episodic bursts of locomotion. We also assessed markers of dopamine neurotransmission (dopamine transporter, vesicular monoamine transporter, and dopamine D1 and D2 receptors) at 15 min and (including dopamine levels) at 6 and 30 days following cessation of methamphetamine treatment. All dopamine components measured in caudate–putamen were significantly reduced at 15 min and 6 days after the final methamphetamine injection. Dopamine D1 and D2 receptors fully recovered after 30 days of drug abstinence, whereas dopamine and the dopamine transporter exhibited significant but incomplete recovery by this time point. In contrast, only the vesicular monoamine transporter exhibited no evidence of recovery over the 30-day withdrawal period. These data are discussed in terms of damage to dopamine terminals and compensatory adjustments in mechanisms maintaining functional dopaminergic transmission.     

Can we evaluate population screening strategies in UK general practice? A pilot randomised controlled trial comparing postal and opportunistic screening for genital chlamydial infection

STUDY OBJECTIVE: To assess whether opportunistic and postal screening strategies for Chlamydia trachomatis can be compared with usual care in a randomised trial in general practice. DESIGN: Feasibility study for a randomised controlled trial. SETTING: Three West of Scotland general medical practices: one rural, one urban/deprived, and one urban/affluent. PARTICIPANTS: 600 women aged 16-30 years, 200 from each of three participating practices selected at random from a sample of West of Scotland practices that had expressed interest in the study. The women could opt out of the study. Those who did not were randomly assigned to one of three groups: postal screening, opportunistic screening, or usual care. RESULTS: 38% (85 of 221) of the approached practices expressed interest in the study. Data were collected successfully from the three participating practices. There were considerable workload implications for staff. Altogether 124 of the 600 women opted out of the study. During the four month study period, 55% (81 of 146) of the control group attended their practice but none was offered screening. Some 59% (80 of 136) women in the opportunistic group attended their practice of whom 55% (44 of 80) were offered screening. Of those, 64% (28 of 44) accepted, representing 21% of the opportunistic group. Forty eight per cent (59 of 124) of the postal group returned samples. CONCLUSION: A randomised controlled trial comparing postal and opportunistic screening for chlamydial infection in general practice is feasible, although resource intensive. There may be problems with generalizing from screening trials in which patients may opt out from the offer of screening.     

Arteriovenous fistula outcomes in the era of the elderly dialysis population

BACKGROUND: The growth of patients > or =65 years on hemodialysis is increasing. Guidelines recommend arteriovenous fistula (AVF) access but their outcomes in elderly patients are controversial. This study compared the outcomes of AVF in patients <65 years old (65- group) versus those > or =65 years old (65+ group). METHODS: This retrospective analysis of prospectively collected data included 444 incident, first-time AVF created in a large dialysis center between January 1, 1995 and July 1, 2003. The primary outcome of AVF cumulative patency was evaluated using Kaplan-Meier survival analysis with log-rank test comparison. A Cox model determined factors associated with AVF loss. RESULTS: One hundred ninety-six patients (44%) were in the 65+ group. In total, there were 230 (52.2%) radiocephalic, 186 (42.2%) brachiocephalic, and 25 (5.6%) basilic vein transposed AVF. The one-year AVF cumulative survival was 75.1% (65+ group) and 79.7% (65- group); the five-year survival was 64.7% (65+ group) and 71.4% (65- group). The overall total procedure, angioplasty, thrombolysis, and revision rates per access-year were 0.83, 0.30, 0.66, and 0.16, respectively. The 65+ group had a relative risk of 1.7 of their AVF failing to mature compared with the 65- group. Multivariate analysis yielded these variables significant for AVF loss: male sex HR 0.63 (95% CI 0.44-0.91), coronary artery disease HR 2.1 (95% CI 1.5-3.0), and Caucasian ethnicity HR 0.63 (95% CI 0.44-0.91). CONCLUSION: Age should not be a limiting factor when determining candidacy for AVF creation due to equivalent survival and procedural rates. Failure of fistula maturation is a primary concern to patients of all ages and demands further study.     

Combined helium-3/proton magnetic resonance imaging measurement of ventilated lung volumes in smokers compared to never-smokers

PURPOSE: To use a combination of helium-3 (3-He) magnetic resonance imaging (MRI) and proton single-shot fast spin echo (SSFSE) to compare ventilated lung volumes in groups of "healthy" smokers, smokers diagnosed with moderate chronic obstructive pulmonary disease (COPD), and never-smokers. MATERIALS AND METHODS: All study participants were assessed with spirometry prior to imaging. 3-He images were collected during an arrested breath hold, after inhaling a mixture of 200 mL of hyperpolarized 3-He/800 mL of N2. Proton SSFSE images were acquired after inhaling 1 liter of room air. The ventilated volume for each study participant was calculated from the 3-He images, and a ratio was calculated to give a percentage ventilated lung volume. RESULTS: Never-smokers exhibited a 90% mean ventilated volume. The mean ventilated lung volumes for healthy smokers and smokers diagnosed with COPD were 75.2% and 67.6%, respectively. No correlation with spirometry was demonstrated for either of the smoking groups. CONCLUSION: Combined 3-He/Proton SSFSE MRI of the lungs is a noninvasive method, using nonionizing radiation, which demonstrates ventilated airspaces and enables the calculation of ventilated lung volumes. This method appears to be sensitive to early obstructive changes in the lungs of smokers.     

Accuracy of computed tomographic intravenous cholangiography (CT-IVC) with iotroxate in the detection of choledocholithiasis

To determine the accuracy of computed tomographic intravenous cholangiography (CT-IVC) for detection of choledocholithiasis. Sixty-five patients undergoing endoscopic retrograde cholangiography (ERC) underwent CT-IVC prior to ERC, using a single detector helical CT following intravenous infusion of 100 ml iotroxate. Patients with bilirubin levels >3 times normal were excluded. ERC was indeterminate in three patients (4.7%) and CT-IVC in four (6.3%). Twenty-three patients had ductal calculi at ERC, and CT-IVC was positive in 22, with two false positives and one false negative: sensitivity 95.6%, specificity 94.3%. Stones were multiple in nine and solitary in 14. Of the 14 solitary stones, ten were 5 mm and eight were 4 mm. The bilirubin level in positive cases was within normal in 20. Maximum intensity projection (MIP) reformats showed stones in only 27% of cases and surface rendered (SR) reformats in none. CT-IVC is highly accurate for detection of ductal calculi, including single small calculi, with a normal or near normal serum bilirubin. Axial images should be used for interpretation rather than MIP or SR reformats.     

Compensatory stepping in response to waist pulls in balance-impaired and unimpaired women

An effective stepping response is often critical in avoiding a fall. Our objective was to study the effects of age and balance impairment on anterior and posterior compensatory stepping strategies in response to waist pull perturbations of 1-5% body weight (BW). Based on maximal unipedal stance time (UST), we tested 15 balance-impaired old (BI, UST < 10s, mean age = 76 years), 12 healthy old (O, UST>30s, mean age = 71 years), and 13 healthy young women (Y, UST >30s, mean age=23 years). Randomized anterior and posterior pulls of 1-5% body weight (BW) were applied to the waist while kinematic and kinetic recovery responses were recorded. Results show that O and BI required 0.5 more steps than Y to recover balance for posterior pulls of 4-5% BW (P < 0.01). For anterior pulls of 4-5% BW, only BI had a greater probability of step initiation (P相似文献