Antibodies to hepatitis C virus in autologous blood donors

Hepatitis C virus (HCV) is the major cause of posttransfusion hepatitis. Two anti-HCV enzyme immunoassay (EIA) kits and one recombinant immunoblot assay (RIBA) were used to test serum samples of 1476 donations from 692 autologous blood donors to assess the prevalence of anti-HCV and its relationship to transfusion history. Of all autologous blood donations, 23 (1.6%) reacted when tested with one EIA kit and 29 (2.0%) reacted when tested by the other EIA kit. Of the autologous donors, 12 (1.78%) reacted by the first EIA kit and 14 (2.02%) by the second. Discrepancies in the EIA results from different donations by the same donor were seen in seven donors. The RIBA was positive or indeterminate in 33 percent of the EIA-reactive donations and in 41 percent of EIA-reactive donors. All RIBA-positive and -indeterminate samples reacted with both EIA kits. There was no significant difference in the EIA-reactive rates of autologous and first-time homologous blood donors. Previously transfused autologous blood donors had a higher anti-HCV EIA-reactive rate than nontransfused autologous donors, but the difference was not significant. In regard to hepatitis C, the use of autologous blood for homologous transfusion appears to be as safe as the use of blood from first-time homologous donors. Universal testing of previously transfused patients for hepatitis C appears premature at this time. Discrepant anti-HCV EIA results from different donations from the same individual have implications regarding donor deferral.     

Current knowledge and future research on infant feeding in the context of HIV: basic, clinical, behavioral, and programmatic perspectives

In 2008, between 129,000 and 194,000 of the 430,000 pediatric HIV infections worldwide were attributable to breastfeeding. Yet in many settings, the health, economic, and social consequences of not breastfeeding would have dire consequences for many more children. In the first part of this review we provide an overview of current knowledge about infant feeding in the context of HIV. Namely, we describe the benefits and risks of breastmilk, the evolution of recommended infant feeding modalities in high-income and low-income countries in the last two decades, and contextualize the recently revised guidelines for infant feeding in the context of HIV current knowledge. In the second section, we suggest areas for future research on the postnatal prevention of mother-to-child transmission of HIV (PMTCT) in developing and industrialized countries. We suggest two shifts in perspective. The first is to evaluate PMTCT interventions more holistically, to include the psychosocial and economic consequences as well as the biomedical ones. The second shift in perspective should be one that contextualizes postnatal PMTCT efforts in the cascade of maternal health services. We conclude by discussing basic, clinical, behavioral, and programmatic research questions pertaining to a number of PMTCT efforts, including extended postnatal ARV prophylaxis, exclusive breastfeeding promotion, counseling, breast milk pasteurization, breast milk banking, novel techniques for making breast milk safer, and optimal breastfeeding practices. We believe the research efforts outlined here will maximize the number of healthy, thriving, HIV-free children around the world.     

Population pharmacokinetics of enfuvirtide in HIV-1-infected pediatric patients over 48 weeks of treatment

The objective of this study was to characterize the population pharmacokinetics of enfuvirtide in HIV-1-infected children and adolescents. HIV-infected patients received combination antiretroviral therapy, including enfuvirtide 2.0 mg/kg subcutaneously, twice daily. Serial and trough blood samples were collected up to 48 weeks. NONMEM was used for population pharmacokinetic analysis. Enfuvirtide exposure was calculated from individual parameter estimates derived from the final model. A total of 218 samples from 43 patients were included in the analysis. Enfuvirtide plasma concentration-time data were described by a 1-compartment model with first-order absorption and elimination. The addition of each subject's actual body weight as a covariate affected CL/F but not V/F or K(a). The population CL/F, V/F, and K(a) for a 33-kg reference patient was 1.31 L/h, 2.31 L, and 0.105 h(-1), respectively. The final model was CL/F (L/h) = 1.31 . (body weight/33 [kg])(0.721). Age did not affect enfuvirtide exposure. These results confirm the appropriateness of body weight-based pediatric enfuvirtide dosing.     

NEW INVESTIGATOR AWARD FINALISTSNIA0001Induction of differentiation in human preadipocytes may contribute to adipogenic effect of human adenovirus Ad-36

Human adenovirus Ad-36 causes adiposity in animal models and shows association with human obesity. The mechanism involved is unknown. We previously reported that Ad-36 enhances differentiation of 3T3-L1 preadipocytes and E4orf-1 gene of the virus is responsible for the adipogenic effect in the rodent cell line. We undertook a three-step approach to investigate the role of preadipocyte differentiation in adipogenic effect of Ad-36. First, we showed that the viral mRNA is expressed in adipose-derived stem cells (ASC) of animals experimentally infected with Ad-36. Infection of rats with Ad-36 resulted in increased epididymal fat pad weight and the expression of Ad-36 E4orf-1 mRNA was detected in ASC isolated from the fat pads. Next, we determined if humans naturally infected with Ad-36 will show greater preadipocyte differentiation. Subcutaneous adipose-tissue samples from 33 Pima Indian subjects were screened by nested-PCR specific for Ad-36 DNA. Nine subjects (27%) had Ad-36 DNA. A blinded comparison of their ASC showed greater differentiation to adipocytes for the Ad-36 DNA positive subjects ( P =  0.06) compared to the Ad-36 DNA negative group. Finally, we used a direct approach. Human-ASC when infected with Ad-36 showed spontaneous replication, differentiation, and lipid accumulation, which was significantly greater than the uninfected controls ( P  < 0.01). Ad-36 induced lipid accumulation in human-ASC increased in response to the viral load and the lipogenic response was observed regardless of the donor gender and over an age range of 22–57 years. These results suggest that ability of Ad-36 to induce preadipocyte differentiation may play a role in human adiposity.     

Cyclin-dependent kinase inhibitor Dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models

Pancreatic cancer is one of the most lethal of human malignancies, and potent therapeutic options are lacking. Inhibition of cell cycle progression through pharmacological blockade of cyclin-dependent kinases (CDK) has been suggested as a potential treatment option for human cancers with deregulated cell cycle control. Dinaciclib (SCH727965) is a novel small molecule multi-CDK inhibitor with low nanomolar potency against CDK1, CDK2, CDK5 and CDK9 that has shown favorable toxicity and efficacy in preliminary mouse experiments, and has been well tolerated in Phase I clinical trials. In the current study, the therapeutic efficacy of SCH727965 on human pancreatic cancer cells was tested using in vitro and in vivo model systems. Treatment with SCH727965 significantly reduced in vitro cell growth, motility and colony formation in soft agar of MIAPaCa-2 and Pa20C cells. These phenotypic changes were accompanied by marked reduction of phosphorylation of Retinoblastoma (Rb) and reduced activation of RalA. Single agent therapy with SCH727965 (40 mg/kg i.p. twice weekly) for 4 weeks significantly reduced subcutaneous tumor growth in 10/10 (100%) of tested low-passage human pancreatic cancer xenografts. Treatment of low passage pancreatic cancer xenografts with a combination of SCH727965 and gemcitabine was significantly more effective than either agent alone. Gene Set Enrichment Analysis identified overrepresentation of the Notch and Transforming Growth Factor-β (TGFβ) signaling pathways in the xenografts least responsive to SCH727965 treatment. Treatment with the cyclin-dependent kinase inhibitor SCH727965 alone or in combination is a highly promising novel experimental therapeutic strategy against pancreatic cancer.Key words: pancreatic cancer, xenograft mouse models, cyclin-dependent kinases, SCH727965, dinaciclib, cell cycle, translational research     

高位胸段硬膜外麻醉下清醒病人的冠状动脉搭桥手术

目的　了解在高位胸段硬膜外麻醉下避免全麻行非体外循环心脏跳动下冠状动脉搭桥手术的可行性。方法　硬膜外麻醉下对 2 5例清醒病人行非体外循环心脏跳动下冠状动脉搭桥手术 ,没有气管插管全麻 ,所有病人在手术前晚行硬膜外置管。结果　总共搭桥 71支 (1支 11例 ,2支 5例 ,3支 6例 ,4支 3例 )。除 1例因为术中出现室颤转为全麻和体外循环外 ,2 4例在硬外麻作为唯一麻醉下完成非体外循环心脏跳动下冠状动脉搭桥手术。除 2例行左胸小切口外其余行正中切口 ;其中 6例为再次手术 ;平均每例搭桥2 8支 ,没有手术死亡。术后在复苏室和病房住院时间分别为 (16 2± 4 2 )h和 (3 2 4± 1 2 )d。结论　本组的早期经验提示在没有气管插管全麻、病人清醒下可以行多支冠状动脉搭桥术     

Effects on growth of single short courses of fluoroquinolones

The aim of the study was to document the effects of short courses of fluoroquinolones given during an outbreak of multidrug resistant typhoid fever in southern Viet Nam on the growth of children over a period of two years. In a prospective cohort study, 326 Vietnamese children aged between 1 and 14 years were followed up for two years after receiving either ciprofloxacin (70 mg/kg given over 7 d) (n = 173) or ofloxacin (45-50 mg/kg given over 3-5 d) (n = 153) for suspected typhoid fever. Growth velocity and weight for height were compared with an age matched control group of children from the same locality (n = 223) who had not contracted typhoid or received any fluoroquinolones. In the ofloxacin and ciprofloxacin treated patients there was no evidence of acute joint toxicity, nor of any joint symptoms attributable to either of the fluoroquinolones. There was no difference in expected weight for height measurements between the three groups of children over the two year period. During the first year, height velocity in ciprofloxacin treated children was greater than in either ofloxacin treated children or untreated controls. Height velocity in the latter two groups was not significantly different. After two years height velocity was similar in the three groups. The results support the use of short course fluoroquinolone treatment in childhood typhoid, especially when caused by strains resistant to other antibiotics.