Morphological and Mechanistic Aspects of Thiourea-Induced Acute Lung Injury and Tolerance in the Rat.

Thiourea-based molecules cause pulmonary edema when administered to rats at relatively low doses. However, rats survive normally lethal doses after prior exposure to a lower, nonlethal dose; this phenomenon is known as tolerance. The present study investigated the morphological and functional aspects of acute lung injury (ALI) induced by methylphenylthiourea (MPTU) in the Wistar rat and the pulmonary response involved in prevention of the injury.

Identification of Flucloxacillin-Haptenated HLA-B*57:01 Ligands: Evidence of Antigen Processing and Presentation.

Flucloxacillin is a β-lactam antibiotic associated with a high incidence of drug-induced liver reactions. Although expression of human leukocyte antigen (HLA)-B*57:01 increases susceptibility, little is known of the pathological mechanisms involved in the induction of the clinical phenotype. Irreversible protein modification is suspected to drive the reaction through the modification of peptides that are presented by the risk allele.

Development of an Improved T-cell Assay to Assess the Intrinsic Immunogenicity of Haptenic Compounds.

The prediction of drug hypersensitivity is difficult due to the lack of appropriate models and known risk factors. In vitro naïve T-cell priming assays that assess immunogenicity have been developed. However, their application is limited due requirements for 2 batches of autologous dendritic cells (DC) and inconsistent results; a consequence of single well readouts when exploring reactions where compound-specific T-cell frequency is undefined.

Quantitative Systems Toxicology Modeling To Address Key Safety Questions in Drug Development: A Focus of the TransQST Consortium.

Omics data have been increasingly generated with limited demonstrated value in drug safety assessment. The TransQST consortium was launched to use omics and other data in mechanistic-based quantitative systems toxicology (QST) models to evaluate their potential use in species translation.

Non-invasive imaging reveals conditions that impact distribution and persistence of cells after in vivo administration.

Background: Cell-based regenerative medicine therapies are now frequently tested in clinical trials. In many conditions, cell therapies are administered systemically, but there is little understanding of their fate, and adverse events are often under-reported. Currently, it is only possible to assess safety and fate of cell therapies in preclinical studies, specifically by monitoring animals longitudinally using multi-modal imaging approaches.

Vancomycin Povidone-Iodine Protocol Improves Survivorship of Periprosthetic Joint Infection Treated With Irrigation and Debridement.

Background: Irrigation and debridement with modular component and liner exchange (IDLE) is a low morbidity procedure for treatment of periprosthetic joint infection (PJI) with reported failure rates exceeding 50%. Dilute povidone-iodine lavage has been shown to be safe and effective in decreasing acute PJI in primary total joint arthroplasty. Vancomycin powder has also shown to be effective in preventing infection in spine surgery.

Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy.

Approximately 30% of epilepsy patients do not respond to antiepileptic drugs, representing an unmet medical need. There is evidence that neuroinflammation plays a pathogenic role in drug-resistant epilepsy. The high-mobility group box 1 (HMGB1)/TLR4 axis is a key initiator of neuroinflammation following epileptogenic injuries, and its activation contributes to seizure generation in animal models.

Characterization of Drug-Specific Signaling Between Primary Human Hepatocytes and Immune Cells.

It is now apparent that antigen-specific T-cells are activated in certain patients with drug-induced liver injury (DILI). Since cross-talk between hepatocytes and immune cells is likely to be critical in determining the outcome of drug exposure, the aim of this study was to profile the signals released by drug-treated hepatocytes and to characterize the impact of these molecules on dendritic cells. Human hepatocytes were exposed to 3 drugs (flucloxacillin, amoxicillin, and isoniazid) associated with DILI potentially mediated by the adaptive immune system as drug-specific T-cells have been isolated from DILI patients, and the metabolite nitroso-sulfamethoxazole (SMX-NO).

Reduction of anterior glenohumeral dislocations: a new closed reduction technique.

Objective: A new closed reduction technique for anterior glenohumeral dislocations and tuberosity fracture dislocations is introduced.

Methods: Forty-one consecutive patients with an acute anterior glenohumeral dislocation or tuberosity fracture dislocation underwent closed reduction by an orthopaedic surgeon employing this new method.

Results: Closed reduction was successful in 88% of patients using the reduction maneuver.

Imaging technologies for monitoring the safety, efficacy and mechanisms of action of cell-based regenerative medicine therapies in models of kidney disease.

The incidence of end stage kidney disease is rising annually and it is now a global public health problem. Current treatment options are dialysis or renal transplantation, which apart from their significant drawbacks in terms of increased morbidity and mortality, are placing an increasing economic burden on society. Cell-based Regenerative Medicine Therapies (RMTs) have shown great promise in rodent models of kidney disease, but clinical translation is hampered due to the lack of adequate safety and efficacy data.

Preventing Plasmon Coupling between Gold Nanorods Improves the Sensitivity of Photoacoustic Detection of Labeled Stem Cells in Vivo.

Gold nanorods are excellent contrast agents for imaging technologies which rely on near-infrared absorption such as photoacoustic imaging. For cell tracking applications, the cells of interest are labeled with the contrast agent prior to injection. However, after uptake into cells by endocytosis, the confinement and high concentration in endosomes leads to plasmon band broadening and reduced absorbance.

UHRF1 regulation of the Keap1-Nrf2 pathway in pancreatic cancer contributes to oncogenesis.

The cellular defence protein Nrf2 is a mediator of oncogenesis in pancreatic ductal adenocarcinoma (PDAC) and other cancers. However, the control of Nrf2 expression and activity in cancer is not fully understood. We previously reported the absence of Keap1, a pivotal regulator of Nrf2, in ∼70% of PDAC cases.

Revision of Failed Hip Resurfacing and Large Metal-on-Metal Total Hip Arthroplasty Using Dual-Mobility Components.

Revision of metal-on-metal (MoM) total hip arthroplasty (THA) or hip resurfacing is associated with high complication rates. The authors propose dual-mobility components as a surgical option and present short- to mid-term results of MoM hips revised with dual-mobility components. Eighteen consecutive hips that underwent revision of MoM THA or hip resurfacing using dual-mobility components were identified.

Anatomic variant of the inferior lateral cutaneous branch of the radial nerve during the posterior approach to the humerus: a case report.

Iatrogenic injury during the posterior approach to the humerus during operative fixation is not an uncommon occurrence. A comprehensive understanding of the normal anatomy and its variants is of paramount importance in order to avoid such injury. Typically, the inferior lateral cutaneous branch of the radial nerve originates towards the distal end of the humerus at the inferior portion of the spiral groove.

Are drug metabolites able to cause T-cell-mediated hypersensitivity reactions?

Introduction: Adverse drug reactions with an immune pathogenesis are a problem in the clinic and an impediment to drug development. T lymphocytes are believed to play a role in the pathogenesis; however, the nature of the drug interaction with immune receptors remains an area of debate.

Areas Covered: This article reviews recent advances in our understanding of drug hypersensitivity focusing specifically on the way in which drugs are displayed in MHC molecules.

Acute management of shoulder dislocations.

The shoulder joint has the greatest range of motion of any joint in the body. However, it relies on soft-tissue restraints, including the capsule, ligaments, and musculature, for stability. Therefore, this joint is at the highest risk for dislocation.

Arthroscopic treatment of labral tears and concurrent avascular necrosis of the femoral head in young adults.

Avascular necrosis (AVN) of the femoral head is a progressive disease affecting young adults that results in collapse of the femoral head and subsequent degenerative joint disease. Although precollapse stages of AVN can be successfully treated with core decompression, making the diagnosis is often difficult given alternative sources of hip pain in this age group. We propose that arthroscopic-assisted core decompression of the femoral head offers an effective method of addressing AVN of the femoral head as well as coexistent hip disorders in the same operation.

Genetic and environmental factors determining clinical outcomes and cost of warfarin therapy: a prospective study.

Background: In this prospective cohort study, we have undertaken a comprehensive evaluation of clinical parameters along with variation in 29 genes (including CYP2C9 and VKORC1) to identify factors determining interindividual variability in warfarin response.

Methods: Consecutive patients (n=311) were followed up prospectively for 26 weeks. Several outcomes chosen to capture both warfarin efficacy and toxicity were assessed.

Effects of CYP4F2 genetic polymorphisms and haplotypes on clinical outcomes in patients initiated on warfarin therapy.

Background: A variant in the CYP4F2 gene, rs2108622, has been recently shown to determine stable warfarin dose requirements. CYP4F2 has also been shown recently to metabolize vitamin K.

Methods: Three hundred and eleven patients were recruited prospectively from two UK hospitals and followed-up for 6 months.

The roles of drug metabolism in the pathogenesis of T-cell-mediated drug hypersensitivity.

Purpose Of Review: The purpose of this review is to highlight recent studies on drug metabolism in T-cell-mediated reactions. Although the hapten theory and the danger hypothesis imply an important role of reactive metabolites in the pathogenesis of drug hypersensitivity, the more recent pi concept gives the central role to the parent drug. It is therefore important to have a broad vision on data supporting each theory to understand the potential role(s) of drug metabolism in T-cell-mediated hypersensitivity.

Comparative preclinical drug metabolism and pharmacokinetic evaluation of novel 4-aminoquinoline anti-malarials.

The disposition of three 4-aminoquinoline leads, namely isoquine (ISO), des-ethyl isoquine (DEI) and N-tert-butyl isoquine (NTBI), were studied in a range of in vivo and in vitro assays to assist in selecting an appropriate candidate for further development. Analogous to amodiaquine (ADQ), ISO undergoes oxidative N-dealkylation to form DEI in vivo. Blood clearance of DEI was as much as 10-fold lower than that of ISO in animals and after oral administration, metabolite exposure exceeded that of parent by as much as 14-fold.

Activation of T-cells from allergic patients and volunteers by p-phenylenediamine and Bandrowski's base.

Allergic contact dermatitis is commonly associated with exposure to p-phenylenediamine. The aim of this study was to determine whether p-phenylenediamine (PPD) and/or Bandrowski's base (BB) stimulate T cells from allergic patients and volunteers, and to explore the relationship between T-cell immunogenicity and allergy. Lymphocytes from allergic patients proliferated with PPD and BB (n=8).