On the various manifestations of spontaneous autoimmune diabetes in rodent models

Autoimmune (type 1) diabetes mellitus in mouse, rat, and humans shares several features, including T lymphocyte infiltration into pancreatic islets and a dependence on permissive class II major histocompatibility complex (MHC) alleles. We report here on an experimental model involving mice that express influenza hemagglutinin (HA) under the control of the insulin promoter and, at the same time, a transgenic class II MHC-restricted T cell receptor (TcR) specific for an HA peptide. These mice spontaneously develop islet infiltrates resembling those found in NOD mice and most animals become diabetic within 8 weeks of age. Because of the availability of a clonotypic TcR antibody, we can be confident that the Ins-HA transgene does not induce any measurable alterations in the vast majority of T cells with the transgenic TcR in primary and secondary lymphoid organs. Continuous export of large numbers of HA-specific lymphocytes from the thymus was not required for the manifestation of the disease since mice thymectomized at 3 days after birth still developed the disease albeit with smaller infiltrates.     

Novel TAP1 polymorphisms in indigenous Zimbabweans: their potential implications on TAP function and in human diseases

Because of the essential role of transporter associated with antigen processing (TAP1 or TAP2) molecule in antigen processing, the implication of its polymorphism as a factor involved in human diseases and the possible genetic variation at this locus among ethnically diverse populations, we underwent a study to analyze the full extent of TAP1 polymorphism in an indigenous Zimbabwean population (Shona ethnic group). Using single-stranded conformation polymorphism and DNA direct sequencing procedures, we detected the presence of 11 nucleotide sequence variations in the entire coding region of TAP1. Of these variants, eight are nonconservative substitutions with respect to amino acid composition and are located in a critical part of the protein that could modulate its function. Five new polymorphic sites were identified in exon 1 (codons 7 Pro --> Ser, 17 Gly --> Arg, 141 Val --> Val), exon 6 (codon 419 Gly --> Cys), and exon 7 (codon 487 Arg --> Arg). Significant differences were seen in the distribution of TAP1*0201 and TAP1*0401 alleles, and codon 333 (Ile --> Val) polymorphism among African and non-African populations. Thus, TAP1 polymorphism has evolved differently among populations presumably because of the evolutionary pressures generated by prevalent pathogens in these geographically distinct regions.     

Genotypic differences in larval olfactory discrimination in twoDrosophila melanogaster strains

Wild-type (+B) and compound chromosome mutant(bB) Drosophila melanogaster larvae were tested in a U-maze. FreshDrosophila food or food and larvae were placed in each of the two goals (+B only in goal 1,bB in goal 2) and served as stimulus. Separate trials were conducted using +B andbB larvae to test for preference in the maze. Significantly more test larvae went to the arm of the maze containing their own strain as stimulus when (1) both goals contained larvae, (2) one goal contained homogenetic larvae and the other fresh food only, and (3) the goals contained biotic residues of stimulus larvae. The strength of the stimulus necessary to elicit the response differed for the two strains, the +B strain apparently being more sensitive. As the density of the stimulus larvae was increased, the choices of the test larvae became statistically nonsignificant and the number of larvae remaining in the starting arm of the maze increased. The data suggested that the strains of larvae utilized here have the capacity for olfactory discrimination.Part of this investigation was supported by National Institutes of Health Award 1 F 32 NS05155-01 CMS from the Institute of Neurological and Communicative Disorders and Stroke to A. P.     

Is the Parkland formula still the best method for determining the fluid resuscitation volume in adults for the first 24 hours after injury? — A retrospective analysis of burn patients in Germany

BackgroundR Rapid fluid resuscitation is a crucial therapy during the treatment of patients with extensive burns. In 1968, the Parkland Formula was introduced for the calculation of the estimated volume of the resuscitation fluid. Since then, different methods for the calculation of fluid resuscitation volume have been developed. We aimed to evaluate if the Parkland formula is still the most effective method for fluid resuscitation volume calculation in burn patients.MethodsIn the period between January 2015 and January 2019, data from 569 patients over 16 years old with burns of more than 20% total body surface area (TBSA) and at least 15% TBSA full thickness burns were entered in the German burn registry. The patients were divided into 5 groups (0, +1, ?1, +2, ?2) according to the volume of the resuscitation fluid they received. Group 0 patients received the amount of fluid calculated according to the Parkland formula (n = 83). The 4 other groups received reduced (-1, -2) or increased (+1, +2) fluid volumes in comparison to the value obtained by the Parkland formula.ResultsPatients in Group 0 presented a significantly lower mortality in the first week (4.5%) compared to groups –2 (16.7%) and group +2 (19.5%) (p = 0.021). Furthermore, the mean number of operations in group +2 (5.81) was higher than in group ?2 (3.81). Surviving patients from group +2 presented a longer hospital stay (68.1 days) compared to the other groups. Additionally, the logistic regression analysis showed a higher survival of patients in groups ?2 and ?1 (regression coefficients ?0.11 and ?0.086; Odds Ratio 0.896 and 0.918; 95% Confidence Interval (CI) 0,411–1.951 and 0.42–2.004).ConclusionIn this retrospective study, register based analysis a restrictive fluid regime was associated with a higher survival compared to the liberal Parkland guided fluid regime.     

Variable effects of obesity on access to total hip and knee arthroplasty

BackgroundObesity is an important comorbidity affecting outcomes after total joint arthroplasty. Consequently, surgeons may delay care of obese patients to first address obesity through different care pathways. The effect of obesity on patient wait times for total joint arthroplasty has not been explored. The purpose of this study was to evaluate the effect of obesity on access to total hip (THA) and knee (TKA) arthroplasty.MethodsThe study data set was constructed from the Nova Scotia Health Authority’s Horizon Patient Folder system and the Patient Access Registry Nova Scotia. Wait time was measured as days between the decision to treat and date of surgery. Body mass index (BMI) was calculated from a preoperative assessment, and patients were grouped into BMI categories. Multivariate log-linear regression was used to test for statistical differences, controlling for confounding factors.ResultsWe observed longer wait times for TKA with increasing BMI weight class. Patients with BMIs greater than 50 had 34% longer waits than reference weight patients. However, THA recipients showed no statistical difference in wait times across weight categories. Furthermore, there was variability among surgeons in the wait times experienced by patients.ConclusionThe finding of longer wait times for TKAs, but not THAs, among patients who were obese was unexpected. This shows the variable wait times for THA and TKA that patients who are obese can experience with different surgeons. It is important to understand the variability in wait times so that efforts to standardize the patient experience can be accomplished.     

A phase 3, randomized,double-blind,parallel-group study to evaluate tezacaftor/ivacaftor in people with cystic fibrosis heterozygous for F508del-CFTR and a gating mutation

BackgroundTezacaftor (TEZ)/ivacaftor (IVA) is an approved CFTR modulator shown to be efficacious and generally safe and well tolerated in people ≥12 years of age with cystic fibrosis (CF) homozygous for the F508del-CFTR mutation or heterozygous for the F508del-CFTR mutation and a residual function mutation. Although previous studies with IVA alone showed clinical benefits in people with CFTR gating mutations, TEZ/IVA has not yet been evaluated in a Phase 3 study of participants heterozygous for F508del-CFTR and a gating mutation (F/gating genotypes). Here, we present results from a randomized, double-blind, IVA-controlled, parallel-group, Phase 3 study assessing the efficacy, safety, and pharmacokinetics (PK) of TEZ/IVA in participants ≥12 years of age with F/gating genotypes.MethodsEnrolled participants entered a 4-week IVA run-in period to create a stable IVA baseline. Participants were then randomized to receive IVA or TEZ/IVA for 8 weeks in an active comparator treatment period (ACTP). The primary endpoint was absolute change in percent predicted forced expiratory volume in 1 second (ppFEV₁). Key secondary endpoints were relative change in ppFEV₁ and absolute change in CF Questionnaire–Revised respiratory domain score. Secondary endpoints included absolute change in sweat chloride (SwCl) concentration, PK parameters, and safety. All endpoints except PK parameters and safety were assessed from baseline through Week 8.ResultsSixty-nine participants (92.0%) in the IVA group and 75 participants (98.7%) in the TEZ/IVA group completed treatment. No improvements were seen in efficacy endpoints from baseline at the end of the IVA run-in period through the end of the ACTP in the IVA group. No significant differences in ppFEV₁ or any key secondary endpoint were observed between the IVA and TEZ/IVA groups. SwCl concentrations decreased more in the TEZ/IVA versus IVA group during the ACTP. The safety profile and PK parameters of TEZ/IVA were consistent with those of previous studies in participants ≥12 years of age with CF.ConclusionsThis Phase 3 study showed that the dual-combination regimen of TEZ/IVA demonstrated clinical efficacy but did not have significantly greater clinical efficacy than IVA alone in participants ≥12 years of age with F/gating genotypes. However, as reported in other studies, TEZ/IVA was generally safe and well tolerated (NCT02412111).