Comparative analysis of cell culture and prediction algorithms for phenotyping of genetically diverse HIV-1 strains from Cameroon

Background  

With the advent of entry inhibitors, monitoring of viral tropism in the clinical setting is important. Conventional methods are cell-based and lengthy, therefore V3 sequence based prediction algorithms are becoming increasingly attractive as monitoring tools. Here we report a comparative analysis of viral tropism of strains circulating in Cameroon where diverse and emerging variant strains are prevalent.     

Mutation of the Cyba gene encoding p22phox causes vestibular and immune defects in mice

In humans, hereditary inactivation of either p22(phox) or gp91(phox) leads to chronic granulomatous disease (CGD), a severe immune disorder characterized by the inability of phagocytes to produce bacteria-destroying ROS. Heterodimers of p22(phox) and gp91(phox) proteins constitute the superoxide-producing cytochrome core of the phagocyte NADPH oxidase. In this study, we identified the nmf333 mouse strain as what we believe to be the first animal model of p22(phox) deficiency. Characterization of nmf333 mice revealed that deletion of p22(phox) inactivated not only the phagocyte NADPH oxidase, but also a second cytochrome in the inner ear epithelium. As a consequence, mice of the nmf333 strain exhibit a compound phenotype consisting of both a CGD-like immune defect and a balance disorder caused by the aberrant development of gravity-sensing organs. Thus, in addition to identifying a model of p22(phox)-dependent immune deficiency, our study indicates that a clinically identifiable patient population with an otherwise cryptic loss of gravity-sensor function may exist. Thus, p22(phox) represents a shared and essential component of at least 2 superoxide-producing cytochromes with entirely different biological functions. The site of p22(phox) expression in the inner ear leads us to propose what we believe to be a novel mechanism for the control of vestibular organogenesis.     

Excretion of methamphetamine and amphetamine in human sweat following controlled oral methamphetamine administration

BACKGROUND: Understanding methamphetamine (MAMP) and amphetamine (AMP) excretion in sweat is important for interpreting sweat and hair testing results in judicial, workplace, and drug treatment settings. METHODS: Participants (n = 8) received 4 10-mg (low) oral doses of sustained-release S-(+)-MAMP HCl (d-MAMP HCl) within 1 week in a double-blind, institutional review board-approved study. Five participants also received 4 20-mg (high) doses 3 weeks later. PharmChek sweat patches (n = 682) were worn for periods of 2 h to 1 week during and up to 3 weeks after dosing. The mass of MAMP and AMP in each patch was measured by GC-MS, with a limit of quantification of 2.5 ng/patch. RESULTS: MAMP was measurable in sweat within 2 h of dosing. After low and high doses, 92.9% and 62.5% of weekly sweat patches were positive, with a median (range) MAMP of 63.0 (16.8-175) and 307 (199-607) ng MAMP/patch, respectively; AMP values were 15.5 (6.5-40.5) and 53.8 (34.0-83.4) ng AMP/patch. Patches applied 2 weeks after the drug administration week had no measurable MAMP following the low doses, and only 1 positive result following the high doses. Using criteria proposed by the Substance Abuse Mental Health Services Administration, 85.7% (low) and 62.5% (high) weekly sweat patches from the dosing week were positive for MAMP, and all patches applied after the dosing week were negative. CONCLUSIONS: These data characterize the excretion of MAMP and AMP after controlled MAMP administration and provide a framework for interpretation of MAMP sweat test results in clinical and forensic settings.     

Treatment paradigm shift may improve survival of patients with high risk superficial bladder cancer

PURPOSE: Historically patients with recurrent T1 bladder tumors after bacillus Calmette-Guerin have been treated with bladder sparing approaches. Recently a paradigm shift has occurred since patients are increasingly offered radical cystectomy before disease progression to muscle invasion. In this study we explored the effect of this paradigm shift on progression rates and disease specific survival. MATERIALS AND METHODS: The historical cohort consisted of 307 patients from 3 prospective intravesical bacillus Calmette-Guerin protocols from 1980 to 1989. An institutional review board approved review identified 589 patients treated with bacillus Calmette-Guerin in a contemporary cohort from 1992 to 2004. RESULTS: In the historical cohort the 85 patients with documented T1 recurrence were initially treated with repeat transurethral resection and intravesical bacillus Calmette-Guerin. Of these 85 patients 60 had progression to muscle invasive disease. At 5 years after T1 recurrence, the cumulative incidence of progression to T2 disease was 71% (95% CI 61%, 81%) and the cumulative incidence of death from disease was 48% (95% CI 39%, 60%). In the contemporary cohort 129 patients had documented T1 recurrence. In this cohort 65 of the 129 patients with recurrent T1 underwent immediate radical cystectomy. At 5 years after T1 recurrence, the cumulative incidence of progression to muscle invasive disease was 28% (95% CI 20%, 38%) and the cumulative incidence of death from disease was 31% (95% CI 22%, 42%). CONCLUSIONS: Preemptive radical cystectomy performed for recurrent T1 disease following intravesical bacillus Calmette-Guerin therapy may be associated with better disease specific survival.     

Anti-CD40L monoclonal antibody treatment induces long-term, tissue-specific, immunologic hyporesponsiveness to peripheral nerve allografts

The CD40/CD40L costimulatory pathway plays a crucial role in allograft rejection. The purpose of this study was to determine the effectiveness of anti-CD40L monoclonal antibody (mAb) treatment as a method to induce long-term, tissue-specific, immunologic hyporesponsiveness to peripheral nerve allografts. Sciatic nerve allografts were performed from BALB/c donor mice into C57BL/6 recipients. Anti-CD40L mAb (1 mg) was administered intraperitoneally to recipient mice on postoperative days 0, 1, and 2. After a 14-, 28-, or 60-day recovery period, the mice were rechallenged with either a BALB/c cardiac or peripheral nerve allograft. Rejection was assessed by measuring the production of interferon gamma (IFN-gamma), interleukin (IL)-2, -4, and -5, and alloantibodies immunoglobulin (Ig) M and IgG. IFN-gamma, IL-2, IL-4, IL-5, IgM, and IgG responses were much lower in the anti-CD40L mAb group compared with controls. Nerve allograft and nerve isograft rechallenge 60 days following the original nerve allotransplantation produced low cytokine responses, whereas cardiac allograft rechallenge produced high cytokine production, indicative of acute rejection. Short-term anti-CD40L treatment may cause long-term, tissue-specific, immunologic hyporesponsiveness. This may allow time for native axons to traverse the transplanted nerve allograft and replace the graft with autogenous peripheral nerve tissue.     

Partial splenectomy for children with congenital hemolytic anemia and massive splenomegaly

Partial splenectomy is an alternative to total splenectomy for the treatment of congenital hemolytic anemias (CHAs) in children, although the feasibility of this technique in the setting of massive splenomegaly is unknown. This study was designed to evaluate the safety and efficacy of partial splenectomy in children with CHAs and massive splenomegaly. This retrospective study examined 29 children with CHAs who underwent partial splenectomy. Children were divided into 2 groups based on splenic size: 8 children had splenic volumes greater than 500 mL, whereas 21 children had splenic volumes less than 500 mL. Outcome variables included perioperative complications, transfusion requirements, hematocrits, reticulocyte counts, bilirubin levels, splenic sequestration, and splenic regrowth. All 29 children underwent successful partial splenectomy with 0.02 to 10 years of follow-up. After partial splenectomy, children overall had decreased transfusion requirements, increased hematocrits, decreased bilirubin levels, decreased reticulocyte counts, and elimination of splenic sequestration. Children with massive splenomegaly had similar outcomes compared with children without massive splenomegaly. Long-term complications included 3 mild infections, 4 cases of gallstones requiring cholecystectomy, and 1 child who required completion splenectomy. Partial splenectomy is a safe, effective, and technically feasible option for children with various CHAs, even in the setting of massive splenomegaly.     

Response to the 2004-2005 influenza vaccine shortage in veterans with spinal cord injuries and disorders and their providers

BACKGROUND/OBJECTIVES: To assess patient and provider behaviors regarding influenza vaccination, diagnosis, and testing strategies and the availability of influenza vaccine during the 2004-2005 nationwide influenza vaccine shortage. DESIGN/METHODS: Multisite, anonymous, cross-sectional surveys of patients and providers and qualitative interviews after the 2004-2005 influenza season. SETTING: Department of Veterans Affairs (VA) health care facilities with spinal cord injury centers or clinics. PARTICIPANTS: Stratified random sample of 3,958 veterans with spinal cord injuries and disorders (SCI & D; 31% response rate), 177 providers who treat persons with SCI&D, and 17 key informants. RESULTS: Most patient respondents (96.1%) reported awareness of a vaccine shortage (n = 938). When asked whether the shortage affected their ability to get the vaccine, 64.8% said they had no problem, whereas 12.1% reported an inability to get the vaccine. The vaccination rate was 71.8%; most veterans received the vaccine early (October-November) at the VA, and vaccination rates increased with age (P < 0.0001). Although vaccine shortages were reported by 47.5% of provider survey respondents (n = 177), most reported that the vaccine shortage did not affect availability of vaccine for patients with SCI&D. Few clinicians conducted diagnostic tests for influenza more often than in past years (4.9%). Although providers reported shortages at 12 centers (n = 23), patients with SCI&D had priority at 11 of 12 centers. CONCLUSIONS: Most patients were aware of the vaccine shortage, and the vaccination rate remained high and comparable with previous years. VA providers and facilities targeted SCI&D as a high-risk group and prioritized use of the limited vaccine supply for them.     

Emergency Department Presentation of Superior Mesenteric Artery Syndrome: Two Cases in Marine Corps Recruits

Background: Superior mesenteric artery (SMA) syndrome is a relatively rare etiology of proximal intestinal obstruction. Obstruction results from marked narrowing of the angle between the SMA and aorta, causing compression of the third portion of the duodenum, most commonly as a result of precipitous weight loss. Intermittent non-specific symptoms at presentation often result in a delayed diagnosis, thus the importance of being aware of this condition. Objective: To familiarize emergency physicians with the presentation of SMA syndrome and discuss its diagnosis and management in the emergency department (ED). Case Report: We present two cases of SMA syndrome identified in Marine Corps recruits presenting to our ED. Conclusion: Emergency physicians should include SMA syndrome in the differential diagnosis of abdominal pain and vomiting in individuals with predisposing factors.     

Ontogeny of Vestibular Compound Action Potentials in the Domestic Chicken

Compound action potentials of the vestibular nerve were measured from the surface of the scalp in 148 chickens (Gallus domesticus). Ages ranged from incubation day 18 (E18) to 22 days posthatch (P22). Responses were elicited using linear acceleration cranial pulses. Response thresholds decreased at an average rate of –0.45 dB/day. The decrease was best fit by an exponential model with half-maturity time constant of 5.1 days and asymptote of approximately –25.9 dB re:1.0 g/ms. Mean threshold approached within 3 dB of the asymptote by ages P6–P9. Similarly, response latencies decreased exponentially to within 3% of mature values at ages beyond P9. The half-maturity time constant for peripheral response peak latencies P1, N1, and P2 was comparable to thresholds and ranged from approximately 4.6 to 6.2 days, whereas central peaks (N2, P3, and N3) ranged from 2.9 to 3.4 days. Latency-intensity slopes for P1, N1, and P2 tended to decrease with age, reaching mature values within approximately 100 hours of hatching. Amplitudes increased as a function of age with average growth rates for response peaks ranging from 0.04 to 0.09 μV/day. There was no obvious asymptote to the growth of amplitudes over the ages studied. Amplitude-intensity slopes also increased modestly with age. The results show that gravity receptors are responsive to transient cranial stimuli as early as E19 in the chicken embryo. The functional response of gravity receptors continues to develop for many days after all major morphological structures are in place. Distinct maturational processes can be identified in central and peripheral neural relays. Functional improvements during maturation may result from refinements in the receptor epithelia, improvements in central and peripheral synaptic transmission, increased neural myelination, as well as changes in the mechanical coupling between the cranium and receptor organ.