Investigations into the absorption of insulin and insulin derivatives from the small intestine of the anaesthetised rat

Experiments have been undertaken to determine the extent to which cholic acid conjugates of insulin were absorbed from the small intestine of anaesthetised rats by means of the bile salt transporters of the ileum. The measure used to assess the absorption of the cholyl-insulins was the amount of hypoglycaemia following infusion into the small intestine. Control experiments involving infusion of natural insulin into the ileum showed either nil absorption or absorption of a small amount of insulin as indicated by transient dip in the blood glucose concentration. However, when insulin was co-infused with the bile salt taurocholate, this was followed by a marked hypoglycaemic response which was specific to the ileum and did not occur on infusion into the jejunum. When the two cholyl conjugates of insulin were tested viz. B 29-Lys-cholyl-insulin and B 1-Phe-cholyl-insulin, both were biologically active as indicated by hypoglycaemic responses on systemic injection, though their potency was about 40% of that of natural insulin. While there was no evidence for the absorption of B 29-Lys-cholyl-insulin when infused into the ileum, B 1-Phe-cholyl-insulin did cause a long lasting hypoglycaemic response, indicating that absorption had occurred. Since the hypoglycaemic response was blocked on co-infusion with taurocholate and was absent for infusion of the conjugate into the jejunum, these results were taken as evidence that B 1-Phe-cholyl-insulin had been taken up by the ileal bile salt transporters. This would indicate that B 1-Phe-cholyl-insulin is worthy of further investigation for use in an oral insulin formulation

ISMB/ECCB 2009 Stockholm

The International Society for Computational Biology (ISCB; http://www.iscb.org) presents the Seventeenth Annual International Conference on Intelligent Systems for Molecular Biology (ISMB), organized jointly with the Eighth Annual European Conference on Computational Biology (ECCB; http://bioinf.mpi-inf.mpg.de/conferences/eccb/eccb.htm), in Stockholm, Sweden, 27 June to 2 July 2009. The organizers are putting the finishing touches on the year's premier computational biology conference, with an expected attendance of 1400 computer scientists, mathematicians, statisticians, biologists and scientists from other disciplines related to and reliant on this multi-disciplinary science. ISMB/ECCB 2009 (http://www.iscb.org/ismbeccb2009/) follows the framework introduced at the ISMB/ECCB 2007 (http://www.iscb.org/ismbeccb2007/) in Vienna, and further refined at the ISMB 2008 (http://www.iscb.org/ismb2008/) in Toronto; a framework developed to specifically encourage increased participation from often under-represented disciplines at conferences on computational biology. During the main ISMB conference dates of 29 June to 2 July, keynote talks from highly regarded scientists, including ISCB Award winners, are the featured presentations that bring all attendees together twice a day. The remainder of each day offers a carefully balanced selection of parallel sessions to choose from: proceedings papers, special sessions on emerging topics, highlights of the past year's published research, special interest group meetings, technology demonstrations, workshops and several unique sessions of value to the broad audience of students, faculty and industry researchers. Several hundred posters displayed for the duration of the conference has become a standard of the ISMB and ECCB conference series, and an extensive commercial exhibition showcases the latest bioinformatics publications, software, hardware and services available on the market today. The main conference is preceded by 2 days of Special Interest Group (SIG) and Satellite meetings running in parallel to the fifth Student Council Symposium on 27 June, and in parallel to Tutorials on 28 June. All scientific sessions take place at the Stockholmsmässan/Stockholm International Fairs conference and exposition facility

The Spectrum of Bogomol'nyi Solitons in Gauged Linear Sigma Models

Gauged linear sigma models with C^m-valued scalar fields and gauge group U(1)^d, d \leq m, have soliton solutions of Bogomol'nyi type if a suitably chosen potential for the scalar fields is also included in the Lagrangian. Here such models are studied on (2+1)-dimensional Minkowski space. If the dynamics of the gauge fields is governed by a Maxwell term the appropriate potential is a sum of generalised Higgs potentials known as Fayet-Iliopoulos D-terms. Many interesting topological solitons of Bogomol'nyi type arise in models of this kind, including various types of vortices (e.g. Nielsen-Olesen, semilocal and superconducting vortices) as well as, in certain limits, textures (e.g. CP^(m-1) textures and gauged CP^(m-1) textures). This is explained and general results about the spectrum of topological defects both for broken and partially broken gauge symmetry are proven. When the dynamics of the gauge fields is governed by a Chern-Simons term instead of a Maxwell term a different scalar potential is required for the theory to be of Bogomol'nyi type. The general form of that potential is given and a particular example is discussed.Comment: 32 pages, harvmac, no figure

Lattice Study of the Decay B^0-bar -> rho^+ l^- nu_l-bar: Model-Independent Determination of |V_{ub}|

We present results of a lattice computation of the vector and axial-vector current matrix elements relevant for the semileptonic decay B^0-bar -> rho^+ l^- nu_l-bar. The computations are performed in the quenched approximation of lattice QCD on a 24^3 x 48 lattice at beta = 6.2, using an O(a) improved fermionic action. Our principal result is for the differential decay rate, dGamma/dq^2, for the decay B^0-bar -> rho^+ l^- nu_l-bar in a region beyond the charm threshold, allowing a model-independent extraction of |V_{ub}| from experimental measurements. Heavy quark symmetry relations between radiative and semileptonic decays of B-bar mesons into light vector mesons are also discussed.Comment: 22 pages LaTeX-209 (dependent on settings in a4.sty), 23 PostScript figures included with epsf.sty. Complete PostScript file including figures available at http://wwwhep.phys.soton.ac.uk/hepwww/papers/shep9518

Endemic fungal infections in solid organ and hematopoietic cell transplant recipients enrolled in the Transplant‐Associated Infection Surveillance Network ( TRANSNET )

Background Invasive fungal infections are a major cause of morbidity and mortality among solid organ transplant ( SOT ) and hematopoietic cell transplant ( HCT ) recipients, but few data have been reported on the epidemiology of endemic fungal infections in these populations. Methods Fifteen institutions belonging to the Transplant‐Associated Infection Surveillance Network prospectively enrolled SOT and HCT recipients with histoplasmosis, blastomycosis, or coccidioidomycosis occurring between March 2001 and March 2006. Results A total of 70 patients (64 SOT recipients and 6 HCT recipients) had infection with an endemic mycosis, including 52 with histoplasmosis, 9 with blastomycosis, and 9 with coccidioidomycosis. The 12‐month cumulative incidence rate among SOT recipients for histoplasmosis was 0.102%. Occurrence of infection was bimodal; 28 (40%) infections occurred in the first 6 months post transplantation, and 24 (34%) occurred between 2 and 11 years post transplantation. Three patients were documented to have acquired infection from the donor organ. Seven SOT recipients with histoplasmosis and 3 with coccidioidomycosis died (16%); no HCT recipient died. Conclusions This 5‐year multicenter prospective surveillance study found that endemic mycoses occur uncommonly in SOT and HCT recipients, and that the period at risk extends for years after transplantation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106980/1/tid12186.pd

Effects of space allocation within a deep-bedded finishing system on pig growth performance, fatty acid composition and pork quality

The objectives of the current study were to determine the degree to which space allocation in a deep-bedded system influences swine performance and pork quality. The deep-bedded method employed was hoop structures, which are large, tent-like shelters with cornstalks or straw for bedding. One hundred gilts ranging in weight from 59 to 71 kg were randomly assigned to treatments of low (0.70 m2 per pig, n = 50) or high (1.13 m2 per pig, n = 50) space allocation. During the 45-day experimental period, gilts were ad libitum fed a two-phase diet. Six gilts per treatment were used for carcass composition and pork quality evaluation for each replication. Five replications were conducted over a period of 4 months. Pigs finished with greater space allocation had smaller longissimusmuscle area and produced pork that appeared to be darker. Variations in fatty acid composition and lipid percentage of subcutaneous adipose and longissimus dorsi muscle were observed when space allocation was changed within hoop structures. Less space resulted in greater proportion of lipid present as polyunsaturated fatty acids. Greater space allocation resulted in lower total lipid in subcutaneous pork adipose tissue. Space allocation did not affect fat firmness. Replications spanned the months of August to November, with temperatures ranging from 32°C to −2°C within the hoop structure. As environmental temperature declined, the proportion of monounsaturated fatty acids increased. Providing more space during finishing in these systems had only a small affect on pig growth and pork quality. Variations observed from replication to replication at fluctuating temperatures provide insight to seasonal differences in growth and adipose tissue composition and firmness. Therefore, finishing pigs in these systems may lead to seasonal variation in lipid composition

Relationship between human leukocyte antigen alleles and risk of Kaposi’s sarcoma in Cameroon

Several studies published to date report associations between human leukocyte antigen (HLA) alleles and different types of Kaposi’s Sarcoma (KS). However, there is little concordance between the HLA alleles identified and the populations studied. To test whether HLA alleles associate with KS in a Cameroonian case–control study, we performed high-resolution HLA typing in KSHV seropositive individuals. Among HIV-positive individuals, carriers of HLA-B*14:01 were at a significantly higher risk of AIDS-KS (p = 0.033). For HIV-negative patients, a gene-wise comparison of allele frequencies identified the HLA-B (p = 0.008) and -DQA1 (p = 0.002) loci as possible risk factors for endemic KS. Our study provides additional understanding of genetic determinants of KS and their implications in disease pathogenesis. Further validation of these findings is needed to define the functional relevance of these associations

Translational characterization of the temporal dynamics of metabolic dysfunctions in liver, adipose tissue and the gut during diet-induced NASH development in Ldlr-/-.Leiden mice

BackgroundNAFLD progression, from steatosis to inflammation and fibrosis, results from an interplay of intra- and extrahepatic mechanisms. Disease drivers likely include signals from white adipose tissue (WAT) and gut. However, the temporal dynamics of disease development remain poorly understood.MethodsHigh-fat-diet (HFD)-fed Ldlr−/−.Leiden mice were compared to chow-fed controls. At t = 0, 8, 16, 28 and 38w mice were euthanized, and liver, WAT depots and gut were analyzed biochemically, histologically and by lipidomics and transcriptomics together with circulating factors to investigate the sequence of pathogenic events and organ cross-talk during NAFLD development.ResultsHFD-induced obesity was associated with an increase in visceral fat, plasma lipids and hyperinsulinemia at t = 8w, along with increased liver steatosis and circulating liver damage biomarkers. In parallel, upstream regulator analysis predicted that lipid catabolism regulators were deactivated and lipid synthesis regulators were activated. Subsequently, hepatocyte hypertrophy, oxidative stress and hepatic inflammation developed. Hepatic collagen accumulated from t = 16 w and became pronounced at t = 28–38 w. Epididymal WAT was maximally hypertrophic from t = 8 w, which coincided with inflammation development. Mesenteric and subcutaneous WAT hypertrophy developed slower and did not appear to reach a maximum, with minimal inflammation. In gut, HFD significantly increased permeability, induced a shift in microbiota composition from t = 8 w and changed circulating gut-derived metabolites.ConclusionHFD-fed Ldlr−/−.Leiden mice develop obesity, dyslipidemia and insulin resistance, essentially as observed in obese NAFLD patients, underlining their translational value. We demonstrate that marked epididymal-WAT inflammation, and gut permeability and dysbiosis precede the development of NAFLD stressing the importance of a multiple-organ approach in the prevention and treatment of NAFLD.Proteomic

Anti-CD30 CAR-T Cell Therapy in Relapsed and Refractory Hodgkin Lymphoma

PURPOSE Chimeric antigen receptor (CAR) T-cell therapy of B-cell malignancies has proved to be effective. We show how the same approach of CAR T cells specific for CD30 (CD30.CAR-Ts) can be used to treat Hodgkin lymphoma (HL). METHODS We conducted 2 parallel phase I/II studies (ClinicalTrials.gov identifiers: NCT02690545 and NCT02917083) at 2 independent centers involving patients with relapsed or refractory HL and administered CD30.CAR-Ts after lymphodepletion with either bendamustine alone, bendamustine and fludarabine, or cyclophosphamide and fludarabine. The primary end point was safety. RESULTS Forty-one patients received CD30.CAR-Ts. Treated patients had a median of 7 prior lines of therapy (range, 2-23), including brentuximab vedotin, checkpoint inhibitors, and autologous or allogeneic stem cell transplantation. The most common toxicities were grade 3 or higher hematologic adverse events. Cytokine release syndrome was observed in 10 patients, all of which were grade 1. No neurologic toxicity was observed. The overall response rate in the 32 patients with active disease who received fludarabine-based lymphodepletion was 72%, including 19 patients (59%) with complete response. With a median follow-up of 533 days, the 1-year progression-free survival and overall survival for all evaluable patients were 36% (95% CI, 21% to 51%) and 94% (95% CI, 79% to 99%), respectively. CAR-T cell expansion in vivo was cell dose dependent. CONCLUSION Heavily pretreated patients with relapsed or refractory HL who received fludarabine-based lymphodepletion followed by CD30.CAR-Ts had a high rate of durable responses with an excellent safety profile, highlighting the feasibility of extending CAR-T cell therapies beyond canonical B-cell malignancies