Membrane interactions of the synthetic N-terminal peptide of HIV-1 gp41 and its structural analogs

AbstractStructural and functional studies assessed the membrane actions of the N terminus of HIV-1 glycoprotein 41 000 (gp41). Earlier site-directed mutagenesis has shown that key amino acid changes in this gp41 domain inhibit viral infection and syncytia formation. Here, a synthetic peptide corresponding to the N terminus of gp41 (FP; 23 residues, 519–541), and also FP analogs (FP520V/E with Val→Glu at residue 520; FP527L/R with Leu→Arg at 527; FP529F/Y with Phe→Tyr at 529; and FPCLP1 with FP truncated at 525) incorporating these modifications were prepared. When added to human erythrocytes at physiologic pH, the lytic and aggregating activities of the FP analogs were much reduced over those with the wild-type FP. With resealed human erythrocyte ghosts, the lipid-mixing activities of the FP analogs were also substantially depressed over that with the wild-type FP. Combined with results from earlier studies, theoretical calculations using hydrophobic moment plot analysis and physical experiments using circular dichroism and Fourier transform infrared spectroscopy indicate that the diminished lysis and fusion noted for FP analogs may be due to altered peptide-membrane lipid interactions. These data confirm that the N-terminal gp41 domain plays critical roles in the cytolysis and fusion underlying HIV-cell infection

Annular pancreas: endoscopic and pancreatographic findings from a tertiary referral ERCP center

Background and Aims Annular pancreas is a congenital anomaly whereby pancreatic tissue encircles the duodenum. Current knowledge of endoscopic findings of annular pancreas is limited to small case series. The aim of this study was to describe the endoscopic and pancreatographic findings of patients with annular pancreas at a large tertiary care ERCP center. Methods This is a retrospective observational study. Our Institutional Review Board–approved, prospectively collected ERCP database was queried for cases of annular pancreas. The electronic medical records were searched for patient and procedure-related data. Results From January 1, 1994, to December 31, 2016, 46 patients with annular pancreas underwent ERCP at our institution. Index ERCP was technically successful in 42 patients (91.3%), and technical success was achieved in all 46 patients (100%) after 2 attempts, when required. A duodenal narrowing or ring was found in most patients (n = 39, 84.8%), yet only 2 (4.3%) had retained gastric contents. Pancreas divisum was found in 21 patients (45.7%), 18 of which were complete divisum. Pancreatobiliary neoplasia was the indication for ERCP in 7 patients (15.2%). Pancreatographic findings consistent with chronic pancreatitis were noted in 15 patients (32.6%) at the index ERCP. Conclusion This is the largest series describing the endoscopic and pancreatographic findings of patients with annular pancreas. We found that 45.7% of patients had concurrent pancreas divisum. Endoscopic therapy was successful in most patients at our institution after 1 ERCP, and in all patients after a second ERCP. Nearly one-third of patients had findings consistent with chronic pancreatitis at the time of index ERCP. It is unclear whether this may be a feature of the natural history of annular pancreas

Investment in sensory structures, testis size, and wing coloration in males of a diurnal moth species: trade-offs or correlated growth?

For dioecious animals, reproductive success typically involves an exchange between the sexes of signals that provide information about mate location and quality. Typically, the elaborate, secondary sexual ornaments of males signal their quality, while females may signal their location and receptivity. In theory, the receptor structures that receive the latter signals may also become elaborate or enlarged in a way that ultimately functions to enhance mating success through improved mate location. The large, elaborate antennae of many male moths are one such sensory structure, and eye size may also be important in diurnal moths. Investment in these traits may be costly, resulting in trade-offs among different traits associated with mate location. For polyandrous species, such trade-offs may also include traits associated with paternity success, such as larger testes. Conversely, we would not expect this to be the case for monandrous species, where sperm competition is unlikely. We investigated these ideas by evaluating the relationship between investment in sensory structures (antennae, eye), testis, and a putative warning signal (orange hindwing patch) in field-caught males of the monandrous diurnal painted apple moth Teia anartoides (Lepidoptera: Lymantriidae) in southeastern Australia. As predicted for a monandrous species, we found no evidence that male moths with larger sensory structures had reduced investment in testis size. However, contrary to expectation, investment in sensory structures was correlated: males with relatively larger antennae also had relatively larger eyes. Intriguingly, also, the size of male orange hindwing patches was positively correlated with testis size

HIV-1 Vpr Enhances Viral Burden by Facilitating Infection of Tissue Macrophages but Not Nondividing CD4+ T Cells

Prior experiments in explants of human lymphoid tissue have demonstrated that human immunodeficiency virus type 1 (HIV-1) productively infects diverse cellular targets including T cells and tissue macrophages. We sought to determine the specific contribution of macrophages and T cells to the overall viral burden within lymphoid tissue. To block infection of macrophages selectively while preserving infection of T cells, we used viruses deficient for viral protein R (Vpr) that exhibit profound replication defects in nondividing cells in vitro. We inoculated tonsil histocultures with matched pairs of congenic viruses that differed only by the presence of a wild-type or truncated vpr gene. Although these viruses exhibited no reduction in the infection or depletion of T cells, the ability of the Vpr-deficient R5 virus to infect tissue macrophages was severely impaired compared with matched wild-type R5 virus. Interestingly, the Vpr-deficient R5 virus also exhibited a 50% reduction in overall virus replication compared with its wild-type counterpart despite the fact that macrophages represent a small fraction of the potential targets of HIV-1 infection in these tissues. Collectively, these data highlight the importance of tissue macrophages in local viral burden and further implicate roles for CC chemokine receptor 5, macrophages, and Vpr in the life cycle and pathogenesis of HIV-1

Low prevalence of valvular heart disease in 226 phentermine-fenfluramine protocol subjects prospectively followed for up to 30 months

AbstractOBJECTIVESThis investigation sought to determine the effect of phentermine-fenfluramine (phen-fen) on the prevalence of valvular heart disease in 226 obese subjects enrolled in a prospective, strict weight loss, research protocol.BACKGROUNDEarly reports have suggested that the use of phen-fen for weight loss may be associated with increased valvular heart disease. Such reports were based on small numbers of patients, limited data on dose and duration of phen-fen therapy, and no correlation with matched controls.METHODSAll subjects underwent transthoracic echocardiography for significant valvular lesions within a mean of 97 days from the manufacturer’s announcement of the voluntary withdrawal of fenfluramine and dexfenfluramine. All echocardiograms were interpreted by two independent readers.RESULTSThe study population included 183 women and 43 men with a mean age of 46.9 ± 8.9 years and mean starting body mass index of 39.8 ± 7.7 kg/m2. Using the Food and Drug Administration criteria, significant aortic regurgitation was detected in 15 subjects (6.6%) and mitral regurgitation in 3 subjects (1.3%). Only one patient had significant regurgitation of both aortic and mitral valves. No valves had severe regurgitation. Significant valvular disease did not correlate with the dose or duration of phen-fen therapy. Furthermore, the prevalence of valvular regurgitation is comparable to the normal offspring in the Framingham Heart Study, who are similar in age, gender, and geographical location.CONCLUSIONSPhen-fen therapy is associated with a low prevalence of significant valvular regurgitation. Valvular regurgitation in our subjects may reflect age-related degenerative changes

Expansion of Umbilical Cord Blood Aldehyde Dehydrogenase Expressing Cells Generates Myeloid Progenitor Cells that Stimulate Limb Revascularization

Uncompromised by chronic disease-related comorbidities, human umbilical cord blood (UCB) progenitor cells with high aldehyde dehydrogenase activity (ALDHhi cells) stimulate blood vessel regeneration after intra-muscular transplantation. However, implementation of cellular therapies using UCB ALDHhi cells for critical limb ischemia, the most severe form of severe peripheral artery disease, is limited by the rarity (\u3c0.5%) of these cells. Our goal was to generate a clinically-translatable, allogeneic cell population for vessel regenerative therapies, via ex vivo expansion of UCB ALDHhi cells without loss of pro-angiogenic potency. Purified UCB ALDHhi cells were expanded \u3e18-fold over 6-days under serum-free conditions. Consistent with the concept that ALDH-activity is decreased as progenitor cells differentiate, only 15.1% ± 1.3% of progeny maintained high ALDH-activity after culture. However, compared to fresh UCB cells, expansion increased the total number of ALDHhi cells (2.7-fold), CD34+/CD133+ cells (2.8-fold), and hematopoietic colony forming cells (7.7-fold). Remarkably, injection of expanded progeny accelerated recovery of perfusion and improved limb usage in immunodeficient mice with femoral artery ligation-induced limb ischemia. At 7 or 28 days post-transplantation, mice transplanted with expanded ALDHhi cells showed augmented endothelial cell proliferation and increased capillary density compared to controls. Expanded cells maintained pro-angiogenic mRNA expression and secreted angiogenesis-associated growth factors, chemokines, and matrix modifying proteins. Coculture with expanded cells augmented human microvascular endothelial cell survival and tubule formation under serum-starved, growth factor-reduced conditions. Expanded UCB-derived ALDHhi cells represent an alternative to autologous bone marrow as an accessible source of pro-angiogenic hematopoietic progenitor cells for the refinement of vascular regeneration-inductive therapies. Stem Cells Translational Medicine 2017;6:1607–1619

Cost‐effectiveness of real‐world administration of tobacco pharmacotherapy in the United States Veterans Health Administration

Background and aimsCost‐effectiveness studies in randomized clinical trials have shown that tobacco cessation pharmacotherapy is among the most cost‐effective of health‐care interventions. Clinical trial eligibility criteria and treatment protocols may not be followed in actual practice. This study aimed to determine whether tobacco cessation pharmacotherapy is cost‐effective in real‐world settings.DesignA retrospective analysis of costs and outcomes.SettingHospitals and clinics of the US Veterans Health Administration, USA.ParticipantsA total of 589 862 US veterans who screened positive for tobacco use in 2011.Intervention and comparatorTobacco users who initiated smoking cessation pharmacotherapy in the 6 months after screening were compared with those who did not use pharmacotherapy in this period. Pharmacotherapy included nicotine replacement therapy, bupropion (if prescribed at 300 mg per day or specifically for tobacco cessation) or varenicline.MeasuresEffectiveness was determined from responses to a subsequent tobacco screening conducted between 7 and 18 months after the treatment observation period. Cost of medications and prescribing health‐care encounters was determined for the period between initial and follow‐up tobacco use screening. Multivariate fixed‐effects regression was used to assess the effect of initial treatment status on cost and outcome while controlling for differences in case‐mix with propensity weighting to adjust for confounding by indication.FindingsThirteen per cent of participants received tobacco cessation pharmacotherapy within 6 months of initial screening. After an average of an additional 218.1 days’ follow‐up, those who initially received pharmacotherapy incurred $143.79 in additional treatment cost and had a 3.1$4705 per quit. The upper limit of the 99.9% confidence region was $5600 per quit. Without propensity adjustment, the cost‐effectiveness ratio was$7144 per quit, with the upper limit of the 99.9% confidence region $9500/quit.ConclusionsTobacco cessation pharmacotherapy provided by the US Veterans Health Administration in 2011/12 was cost‐effective in this real‐world setting, with an incremental cost‐effectiveness ratio of$4705 per quit.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150598/1/add14621_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150598/2/add14621.pd