Type 1 diabetic mice are protected from acetaminophen hepatotoxicity.

Streptozotocin (STZ)-induced diabetic (DB) mice challenged with single ordinarily lethal doses of acetaminophen (APAP), carbon tetrachloride (CCl4), or bromobenzene (BB) were resistant to all three hepatotoxicants. Mechanisms of protection against APAP hepatotoxicity were investigated. Plasma alanine aminotransferase, aspartate aminotransferase, and liver histopathology revealed significantly lower hepatic injury in DB mice after APAP administration. HPLC analysis of plasma and urine revealed lower plasma t1/2, increased volume of distribution (Vd), and increased plasma clearance (CLp) of APAP in the DB mice and no difference in APAP-glucuronide, a major metabolite in mice. Interestingly, covalent binding of 14C-labeled APAP to liver target proteins; arylation of APAP to 58, 56, and 44 kDa acetaminophen binding proteins (ABPs); and glutathione (GSH) depletion in the liver did not differ between nondiabetic (non-DB) and DB mice in spite of downregulated hepatic microsomal CYP2E1 and 1A2 proteins in the DB mice, known to be involved in bioactivation of APAP. Compensatory cell division measured via 3H-thymidine pulse labeling and immunohistochemical staining for proliferating cell nuclear antigen (PCNA) indicated earlier onset of S-phase in the DB mice after exposure to APAP. Antimitotic intervention of liver cell division by colchicine (CLC) after administration of APAP led to significantly higher mortality in the DB mice suggesting a pivotal role of liver cell division and tissue repair in the protection afforded by diabetes. In conclusion, the resistance of DB mice against hepatotoxic and lethal effects of APAP appears to be mediated by a combination of enhanced APAP clearance and robust compensatory tissue repair.     

Violent Crime in the Lives of Homeless Female Ex-Offenders

The cyclical pattern of violence in the lives of homeless female ex-offenders may precipitate ongoing substance use and recidivism; all of which have shown to be mounting public health issues affecting successful reentry. This paper, which analyzed baseline data from a longitudinal study of 126 female ex-offenders in Los Angeles and Pomona, California, highlighted the factors found to be associated with violent crime among homeless female ex-offenders. A multiple logistic regression model for whether or not the last conviction was for a violent offense indicated that poor housing (p = .011) and self-reported anger or hostility (p < .001) were significant correlates. An ordinal regression model for the number of violent offenses also indicated that affectionate support was associated with committing fewer number of violent crimes (p = .001), while positive social interactions (p = .007), and anger/hostility (p = .015) were associated with greater number of violent crimes. Implications for developing a comprehensive array of strategies that can mitigate the pattern of violence often seen in the lives of homeless female who have recently exited jails and prisons is discussed.     

Fossilized Venom: The Unusually Conserved Venom Profiles of Heloderma Species (Beaded Lizards and Gila Monsters)

Research into snake venoms has revealed extensive variation at all taxonomic levels. Lizard venoms, however, have received scant research attention in general, and no studies of intraclade variation in lizard venom composition have been attempted to date. Despite their iconic status and proven usefulness in drug design and discovery, highly venomous helodermatid lizards (gila monsters and beaded lizards) have remained neglected by toxinological research. Proteomic comparisons of venoms of three helodermatid lizards in this study has unravelled an unusual similarity in venom-composition, despite the long evolutionary time (~30 million years) separating H. suspectum from the other two species included in this study (H. exasperatum and H. horridum). Moreover, several genes encoding the major helodermatid toxins appeared to be extremely well-conserved under the influence of negative selection (but with these results regarded as preliminary due to the scarcity of available sequences). While the feeding ecologies of all species of helodermatid lizard are broadly similar, there are significant morphological differences between species, which impact upon relative niche occupation.     

Clinical approach to hip pain

Hip joint pain occurs not uncommonly in clinical practice. Arthritis of the hip joint, ligament strain and bursitis are some of the common causes of hip joint pain encountered by physicians. This article dwells on relevant clinical anatomy of the hip and the diagnostic approach to hip pain in rheumatology clinic.     

Targeting the mutant p53 secretome

While p53 is the most highly mutated and perhaps best studied tumor suppressor protein related to cancer, it remains refractory to targeted therapeutic strategies. In this issue of the JCI, Tan and colleagues investigated the mechanistic basis of the mutant p53 secretome in preclinical models of lung adenocarcinoma. The authors uncovered miR-34a as a regulator of a conventional protein secretion axis, which is mediated by three proteins: the Golgi reassembly and stacking protein 55 kDa (GRASP55), basic leucine zipper nuclear factor 1, and myosin IIA. Inhibition of GRASP55 in TP53-deficient lung adenocarcinoma suppressed protumorigenic secretion of osteopontin/secreted phosphoprotein 1 and insulin-like growth factor binding protein 2 and reduced tumor growth and metastases in mice as well as in patient-derived xenografts. These results provide a therapeutic opportunity to target downstream effects of p53 loss.     

HIV transmission transcends three generations: can we prevent secondary transmission in India?

This case history documents four instances of HIV secondary transmission within a single family, which could have been stopped at multiple points by timely prevention. These cases of HIV secondary transmission that have occurred since the scale-up of HIV testing, prevention and clinical services in India raises the question whether the current HIV prevention infrastructure is sufficient and comprehensive in resource-limited settings.