Glycerol contributes to tuberculosis susceptibility in male mice with type 2 diabetes.

Diabetes mellitus increases risk for tuberculosis disease and adverse outcomes. Most people with both conditions have type 2 diabetes, but it is unknown if type 1 and type 2 diabetes have identical effects on tuberculosis susceptibility. Here we show that male mice receiving a high-fat diet and streptozotocin to model type 2 diabetes, have higher mortality, more lung pathology, and higher bacterial burden following Mycobacterium tuberculosis infection compared to mice treated with streptozotocin or high-fat diet alone.

Short-term and 1-year outcome of patients' with borderline personality admitted to a short-term recovery-oriented residential service.

Objectives: Given the paucity of literature, this study investigated whether a prevention and recovery care (PARC) service supported recovery in patients with borderline personality disorder (BPD).

Method: This retrospective study included patients with BPD who had their first (index) admission to North West PARC between 2011 and 2016. Patient medical records and the state-wide database were the sources of information.

Impact of Diabetes and Low Body Mass Index on Tuberculosis Treatment Outcomes.

Background: Diabetes was identified as a tuberculosis (TB) risk factor mostly in retrospective studies with limited assessments of metabolic variables. The prospective Effects of Diabetes on Tuberculosis Severity study compared adults with pulmonary TB in Chennai, India, who were classified as having either diabetes or a normal glucose tolerance at enrollment.

Methods: Baseline TB severity, sputum conversion, and treatment outcomes (cure, failure, death, or loss to follow-up) were compared between groups with respect to glycemic status and body mass index (BMI).

Maternal health after Ebola: unmet needs and barriers to healthcare in rural Sierra Leone.

Sierra Leone has the world's highest estimated maternal mortality. Following the 2014-16 Ebola outbreak, we described health outcomes and health-seeking behaviour amongst pregnant women to inform health policy. In October 2016-January 2017, we conducted a sequential mixed-methods study in urban and rural areas of Tonkolili District comprising: household survey targeting women who had given birth since onset of the Ebola outbreak; structured interviews at rural sites investigating maternal deaths and reporting; and in-depth interviews (IDIs) targeting mothers, community leaders and health workers.

mTORC2/Akt activation in adipocytes is required for adipose tissue inflammation in tuberculosis.

Background: Mycobacterium tuberculosis has co-evolved with the human host, adapting to exploit the immune system for persistence and transmission. While immunity to tuberculosis (TB) has been intensively studied in the lung and lymphoid system, little is known about the participation of adipose tissues and non-immune cells in the host-pathogen interaction during this systemic disease.

Methods: C57BL/6J mice were aerosol infected with M.

Cellular versus acellular matrix devices in the treatment of diabetic foot ulcers: Interim results of a comparative efficacy randomized controlled trial.

Healing of diabetic foot ulcers is a major challenge. Despite adhering to optimal standard of care (SOC), less than 30% of wounds heal after 20 weeks. Advanced cellular tissue-based products have shown better healing over SOC, albeit with great cost and modest improvement.

Reclaiming Autologous Amputated Tissue for Limb Salvage of a Diabetic Foot Burn with Underlying Critical Limb Ischemia.

Background: Diabetes mellitus is a worldwide pandemic that impacts more than 387 million people, with 29 million individuals affected in the United States alone. Diabetic patients have a 25% lifetime risk of developing a diabetic foot ulcer (DFU). Having a DFU is associated with a risk of recurrence approaching 70%.

Systems Immunology of Diabetes-Tuberculosis Comorbidity Reveals Signatures of Disease Complications.

Comorbid diabetes mellitus (DM) increases tuberculosis (TB) risk and adverse outcomes but the pathological interactions between DM and TB remain incompletely understood. We performed an integrative analysis of whole blood gene expression and plasma analytes, comparing South Indian TB patients with and without DM to diabetic and non-diabetic controls without TB. Luminex assay of plasma cytokines and growth factors delineated a distinct biosignature in comorbid TBDM in this cohort.

Impaired Recognition of Mycobacterium tuberculosis by Alveolar Macrophages From Diabetic Mice.

Background:  Diabetes mellitus is associated with increased tuberculosis risk and severity. We previously reported that tuberculosis susceptibility in diabetic mice results from a delay in innate immune response to inhaled Mycobacterium tuberculosis, leading to delayed adaptive immune priming and, consequently, a higher plateau lung bacterial burden and greater immune pathology.

Methods:  We tested the capacity of alveolar macrophages from diabetic mice to phagocytose M.

Defects in early cell recruitment contribute to the increased susceptibility to respiratory Klebsiella pneumoniae infection in diabetic mice.

Diabetes is associated with increased susceptibility to Klebsiella pneumoniae and poor prognosis with infection. We demonstrate accelerated mortality in mice with streptozotocin-induced diabetes following tracheal instillation of K. pneumoniae.

High Prevalence and Heterogeneity of Diabetes in Patients With TB in South India: A Report from the Effects of Diabetes on Tuberculosis Severity (EDOTS) Study.

Background: Previous studies reported an association of diabetes mellitus (DM) with TB susceptibility. Many studies were retrospective, had weak diagnostic criteria for DM, and did not assess other comorbidities. The Effects of Diabetes on Tuberculosis Severity (EDOTS) study is addressing these limitations with a longitudinal comparison of patients with TB who are classified as diabetic or normoglycemic according to World Health Organization criteria.

A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling.

Humans that are heterozygous for the common S180L polymorphism in the Toll-like receptor (TLR) adaptor Mal (encoded by TIRAP) are protected from a number of infectious diseases, including tuberculosis (TB), whereas those homozygous for the allele are at increased risk. The reason for this difference in susceptibility is not clear. We report that Mal has a TLR-independent role in interferon-gamma (IFN-γ) receptor signaling.

Identification of QS-21 as an Inflammasome-activating Molecular Component of Saponin Adjuvants.

Many immunostimulants act as vaccine adjuvants via activation of the innate immune system, although in many cases it is unclear which specific molecules contribute to the stimulatory activity. QS-21 is a defined, highly purified, and soluble saponin adjuvant currently used in licensed and exploratory vaccines, including vaccines against malaria, cancer, and HIV-1. However, little is known about the mechanisms of cellular activation induced by QS-21.

Differential adjuvant activities of TLR7 and TLR9 agonists inversely correlate with nitric oxide and PGE2 production.

Activation of different pattern recognition receptors causes distinct profiles of innate immune responses, which in turn dictate the adaptive immune response. We found that mice had higher CD4+ T cell expansion to an immunogen, ovalbumin, when coadministered with CpG than with CL097 in vivo. To account for this differential adjuvanticity, we assessed the activities of CpG and CL097 on antigen-specific CD4+ T cell expansion in vitro using an OT-II CD4+ T cell/bone marrow-derived dendritic cell (DC) co-culture system.

Bacillary replication and macrophage necrosis are determinants of neutrophil recruitment in tuberculosis.

We previously determined that burst size necrosis is the chief mode of mononuclear cell death in the lungs of mice with tuberculosis. The present study explored the link between infection-induced necrosis of mononuclear phagocytes and neutrophil accumulation in the lungs of mice challenged with one of four Mycobacterium tuberculosis strains of increasing virulence (RvΔphoPR mutant, H37Ra, H37Rv and Erdman). At all time points studied, Erdman produced the highest bacterial load and the highest proportion and number of M.

Chromatin decondensation and T cell hyperresponsiveness in diabetes-associated hyperglycemia.

Diabetes is linked to increased inflammation and susceptibility to certain infectious diseases including tuberculosis (TB). We previously reported that aerosol TB in mice with chronic (≥ 12 wk) hyperglycemia features increased bacterial load, overproduction of several cytokines, and increased immune pathology compared with normoglycemic controls. A similar phenotype exists in human patients with diabetes with TB.

Contribution of TLR4 and MyD88 for adjuvant monophosphoryl lipid A (MPLA) activity in a DNA prime-protein boost HIV-1 vaccine.

Recombinant protein vaccines are commonly formulated with an immune-stimulatory compound, or adjuvant, to boost immune responses to a particular antigen. Recent studies have shown that, through recognition of molecular motifs, receptors of the innate immune system are involved in the functions of adjuvants to generate and direct adaptive immune responses. However, it is not clear to which degree those receptors are also important when the adjuvant is used as part of a novel heterologous prime-boost immunization process in which the priming and boosting components are not the same type of vaccines.

Reduced MyD88 dependency of ISCOMATRIX™ adjuvant in a DNA prime-protein boost HIV vaccine.

ISCOMATRIX™ adjuvant is an integrated adjuvant system due to its ability to both facilitate antigen delivery and immunomodulate the innate and adaptive immune responses to vaccination. ISCOMATRIX™ adjuvant strongly induces both humoral and cell-mediated immunity in formulation with a range of antigens in pre-clinical and clinical evaluations. In this study, we describe the adaptive and innate immune responses associated with ISCOMATRIX™ adjuvant in the context of a previously described HIV-1 vaccine, DP6-001.

Serum cytokine profiles associated with specific adjuvants used in a DNA prime-protein boost vaccination strategy.

In recent years, heterologous prime-boost vaccines have been demonstrated to be an effective strategy for generating protective immunity, consisting of both humoral and cell-mediated immune responses against a variety of pathogens including HIV-1. Previous reports of preclinical and clinical studies have shown the enhanced immunogenicity of viral vector or DNA vaccination followed by heterologous protein boost, compared to using either prime or boost components alone. With such approaches, the selection of an adjuvant for inclusion in the protein boost component is expected to impact the immunogenicity and safety of a vaccine.

Trait stacking via targeted genome editing.

Modern agriculture demands crops carrying multiple traits. The current paradigm of randomly integrating and sorting independently segregating transgenes creates severe downstream breeding challenges. A versatile, generally applicable solution is hereby provided: the combination of high-efficiency targeted genome editing driven by engineered zinc finger nucleases (ZFNs) with modular 'trait landing pads' (TLPs) that allow 'mix-and-match', on-demand transgene integration and trait stacking in crop plants.

Post-translational intracellular trafficking determines the type of immune response elicited by DNA vaccines expressing Gag antigen of Human Immunodeficiency Virus Type 1 (HIV-1).

In the current study, immune responses induced by Gag DNA vaccines with different designs were evaluated in Balb/C mice. The results demonstrated that the DNA vaccine with the full length wild type gag gene (Wt-Gag) mainly produced Gag antigens intracellularly and induced a higher level of cell-mediated immune (CMI) responses, as measured by IFN-gamma ELISPOT, intracellular cytokine staining (ICS), and cytotoxic T lymphocytes (CTL) assays against a dominant CD8(+) T cell epitope (AMQMLKETI). In contrast, the addition of a tissue plasminogen activator (tPA) leader sequence significantly improved overall Gag protein expression/secretion and Gag-specific antibody responses; however, Gag-specific CMI responses were decreased.

Application of automated pathology reporting concepts to radiology reports.

Objective: This study was designed to extend the concept of automated pathology reporting to radiology reports to find central nervous system (CNS) neoplasms that may currently go undetected.

Methods: Existing E-Path software was modified to account for the structure and language of radiology reports. Logic was added to allow registries to configure whether they want only new reports or if they also want history, metastatic, and/or previously known reports.

Analysis of human monoclonal antibodies generated by dengue virus-specific memory B cells.

Dengue, caused by the four serotypes of dengue virus (DENV), represents an expanding global health challenge. The potential for serotype-cross-reactive antibodies to exacerbate disease during a secondary infection with a heterologous DENV serotype has driven efforts to study human DENV-specific antibodies. Most DENV-specific antibodies generated in humans are serotype-cross-reactive, weakly neutralizing, and directed against the immature pre-membrane (prM), envelope (E), and nonstructural 1 (NS1) proteins.