Contemporary management of drug-packers

Experience with management of drug-packers (mules) is variable among different centres. However, despite a recorded increase in drug trafficking in general, as yet, no unified, clear guidelines exist to guide the medical management of those who only occasionally encounter these individuals. We describe our recent experience with this growing problem and discuss the most salient points concerning the contemporary management of body packers. Our recent experience demonstrates that type IV packages may now be managed conservatively for the most part

T cells reactive to an inducible heat shock protein induce disease in toxin-induced interstitial nephritis.

T cells reactive against immunodominant regions of inducible heat shock proteins (HSPs) have been identified in the chronic inflammatory lesions of several experimental autoimmune diseases. Since HSPs are known to be induced by a number of renal tubular epithelial cell toxins associated with chronic interstitial nephritis, we investigated the relevance of HSP expression and T cell reactivity to HSP70 in a model of progressive inflammatory interstitial nephritis. Chronic administration of cadmium chloride (CdCl2) to SJL/J mice induces HSP70 expression in renal tubular cells 4-5 wk before the development of interstitial mononuclear cell infiltrates. CdCl2 also induces HSP70 expression in cultured tubular epithelial cells from SJL/J mice. CD4+, TCR-alpha/beta+ T cell lines specific for an immunodominant HSP peptide are cytotoxic to heat stressed or CdCl2-treated renal tubular cells. Such HSP-reactive T cells mediate an inflammatory interstitial nephritis after adoptive transfer to CdCl2-treated mice at a time when immunoreactive HSP70 is detectable in the kidneys, but before the development of interstitial mononuclear cell infiltrates. T cells isolated from the nephritic kidneys of mice treated with CdCl2 for 13 wk are also cytotoxic to heat shocked or cadmium-treated tubular cells. These kidney-derived T cells additionally induced interstitial nephritis after passive transfer, indicating their pathogenic significance. Our studies strongly support a role for HSP-reactive T cells in CdCl2-induced interstitial nephritis and suggest that the induction of HSPs in the kidney by a multitude of "non-immune" events may initiate or facilitate inflammatory damage by HSP-reactive lymphocytes

Mass Drug Administration and beyond: how can we strengthen health systems to deliver complex interventions to eliminate neglected tropical diseases?

Achieving the 2020 goals for Neglected Tropical Diseases (NTDs) requires scale-up of Mass Drug Administration (MDA) which will require long-term commitment of national and global financing partners, strengthening national capacity and, at the community level, systems to monitor and evaluate activities and impact. For some settings and diseases, MDA is not appropriate and alternative interventions are required. Operational research is necessary to identify how existing MDA networks can deliver this more complex range of interventions equitably. The final stages of the different global programmes to eliminate NTDs require eliminating foci of transmission which are likely to persist in complex and remote rural settings. Operational research is required to identify how current tools and practices might be adapted to locate and eliminate these hard-to-reach foci. Chronic disabilities caused by NTDs will persist after transmission of pathogens ceases. Development and delivery of sustainable services to reduce the NTD-related disability is an urgent public health priority. LSTM and its partners are world leaders in developing and delivering interventions to control vector-borne NTDs and malaria, particularly in hard-to-reach settings in Africa. Our experience, partnerships and research capacity allows us to serve as a hub for developing, supporting, monitoring and evaluating global programmes to eliminate NTDs

Biochemical Thermodynamic Modelling of Cellular Bioenergetics: A Quantitative Systems Pharmacology Approach

In this thesis, thermodynamic-based mathematical modelling is combined with experimental in vitro extracellular flux analysis in order to assess drug redox cycling and cellular bioenergetics. It is widely accepted that pharmacological activity of certain classes of drugs (e.g. anticancer, antimalarial) is related to their ability to accept one or two electrons. However, pharmacological activity via redox cycling is an understated mechanism of toxicity associated with many classes of drugs. In particular, oxidative stress as a result of redox cycling plays a pivotal role in the cause of cardiac toxicity. For example, doxorubicin is an anti-neoplastic drug used to treat cancer. It has strong links to redox cycling-induced cardiac toxicity associated directly with elevated levels of reactive oxygen species (ROS) and oxidative stress within the mitochondria. The underlying mechanisms of redox cycling is very difficult to elucidate, due to the fleeting existence of the radical species. However, assessment of such cellular bioenergetics can be ameliorated with the aid of computational assistance. In chapter 2 the development of a novel thermodynamic-based in silico model of doxorubicin redox cycling is described, which is parameterized using data from in vitro extracellular flux analysis. The model is used to simulate mitochondrial-specific ROS, with its outputs confirmed against in vitro data. Chapter 3 describes construction of a pH-dependent thermodynamic model of hepatic glycolytic flux, used to determine the role of the monocarboxylate transporter 1 flux during extracellular acidification. Finally, chapter 4 describes a thermodynamic-based in silico model of mitochondrial bioenergetics, capable of simulating oxygen consumption rates of a cohort of in vitro human primary hepatocyte data. The model is finally used to simulate perturbations in key bioenergetic variables and reaction fluxes, illustrating the resulting changes on mitochondrial pH, membrane potential and subsequent oxygen consumption rates

Neonatal desensitisation for the study of regenerative medicine

Cell replacement is a therapeutic option for numerous diseases of the CNS. Current research has identified a number of potential human donor cell types, for which preclinical testing through xenotransplantation in animal models is imperative. Immune modulation is necessary to promote donor cell survival for sufficient time to assess safety and efficacy. Neonatal desensitization can promote survival of human donor cells in adult rat hosts with little impact on the health of the host and for substantially longer than conventional methods, and has subsequently been applied in a range of studies with variable outcomes. Reviewing these findings may provide insight into the method and its potential for use in preclinical studies in regenerative medicine

The Seroepidemiology of Haemophilus influenzae Type B Prior to Introduction of an Immunization Programme in Kathmandu, Nepal.

Haemophilus influenzae type b (Hib) is now recognized as an important pathogen in Asia. To evaluate disease susceptibility, and as a marker of Hib transmission before routine immunization was introduced in Kathmandu, 71 participants aged 7 months-77 years were recruited and 15 cord blood samples were collected for analysis of anti-polyribosylribitol phosphate antibody levels by enzyme-linked immunosorbent assay. Only 20% of children under 5 years old had levels considered protective (>0.15 µg/ml), rising to 83% of 15-54 year-olds. Prior to introduction of Hib vaccine in Kathmandu, the majority of young children were susceptible to disease

Incidence of Lead System Malfunction Detected During Implantable Defibrillator Generator Replacement

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71565/1/j.1540-8159.1996.tb04183.x.pd

Blind Biological Sequence Denoising with Self-Supervised Set Learning

Biological sequence analysis relies on the ability to denoise the imprecise output of sequencing platforms. We consider a common setting where a short sequence is read out repeatedly using a high-throughput long-read platform to generate multiple subreads, or noisy observations of the same sequence. Denoising these subreads with alignment-based approaches often fails when too few subreads are available or error rates are too high. In this paper, we propose a novel method for blindly denoising sets of sequences without directly observing clean source sequence labels. Our method, Self-Supervised Set Learning (SSSL), gathers subreads together in an embedding space and estimates a single set embedding as the midpoint of the subreads in both the latent and sequence spaces. This set embedding represents the "average" of the subreads and can be decoded into a prediction of the clean sequence. In experiments on simulated long-read DNA data, SSSL methods denoise small reads of $\leq 6$ subreads with 17% fewer errors and large reads of $>6$ subreads with 8% fewer errors compared to the best baseline. On a real dataset of antibody sequences, SSSL improves over baselines on two self-supervised metrics, with a significant improvement on difficult small reads that comprise over 60% of the test set. By accurately denoising these reads, SSSL promises to better realize the potential of high-throughput DNA sequencing data for downstream scientific applications

Measuring Potential Dermal Transfer of a Pesticide to Children in a Child Care Center

Currently, the major determinants of children’s exposure to pesticides are not fully understood, and approaches for measuring and assessing dermal exposure in a residential setting have not been sufficiently evaluated. In one approach, dermal exposure is estimated using empirically derived transfer coefficients. To assess the feasibility of using this approach for assessing children’s exposure to pesticides, we conducted a study was conducted in a child care center that had a preexisting contract with a pest control service for regular monthly pesticide applications. Children in the selected child care center were monitored using full-body cotton garments to measure dermal loading. Pesticide residues on classroom surfaces were measured in the areas where the children spent time. Measured surface-wipe loadings ranged from 0.47 to 120 ng/cm(2), and total garment loadings ranged from 0.5 to 660 pg/cm(2). The garment and surface loading measurements were used to calculate dermal-transfer coefficients for use in assessing children’s residential exposure to pesticides. Dermal-transfer coefficients calculated using these data range from approximately 10 to 6,000 cm(2)/hr. The wide range in these values demonstrates the importance of developing standard surface-measurement protocols if this approach is to be used to assess dermal exposure in a residential environment. The upper-range values resulting from this study were found to be similar to the default value used by the U.S. Environmental Protection Agency to assess children’s dermal exposures resulting from contact with indoor surfaces

Predicting physiologically-relevant oxygen concentrations in precision-cut liver slices using mathematical modelling

Precision cut liver slices represent an encouraging ex vivo method to understand the pathogenesis of liver disease alongside drug induced liver injury. Despite being more physiologically relevant compared to in vitro models, precision cut liver slices are limited by the availability of healthy human tissue and experimental variability. Internal oxygen concentration and media composition govern the longevity and viability of the slices during the culture period and as such, a variety of approaches have been taken to maximise the appropriateness of the internal oxygen concentrations across the slice. The aim of this study was to predict whether it is possible to generate a physiologically relevant oxygen gradient of 35-65mmHg across a precision cut liver slice using mathematical modelling. Simulations explore how the internal oxygen concentration changes as a function of the diameter of the slice, the position inside the well and the external incubator oxygen concentration. The model predicts that the desired oxygen gradient may be achieved using a 5mm diameter slice at atmospheric oxygen concentrations, provided that the slice is positioned at a certain height within the well of a 12-well plate