Amyloid β inhibits retinoic acid synthesis exacerbating Alzheimer disease pathology which can be attenuated by an retinoic acid receptor α agonist

The retinoic acid receptor (RAR) α system plays a key role in the adult brain, participating in the homeostatic control of synaptic plasticity, essential for memory function. Here we show that RARα signalling is down‐regulated by amyloid beta (Aβ), which inhibits the synthesis of the endogenous ligand, retinoic acid (RA). This results in the counteraction of a variety of RARα‐activated pathways that are key in the aetiopathology of Alzheimer's disease (AD) but which can be reversed by an RARα agonist. RARα signalling improves cognition in the Tg2576 mice, it has an anti‐inflammatory effect and promotes Aβ clearance by increasing insulin degrading enzyme and neprilysin activity in both microglia and neurons. In addition, RARα signalling prevents tau phosphorylation. Therefore, stimulation of the RARα signalling pathway using a synthetic agonist, by both clearing Aβ and counteracting some of its toxic effects, offers therapeutic potential for the treatment of AD.     

Hepatitis E in post‐liver transplantation: is it time to routinely consider it?

Hepatitis E, although commonly recognized in the Eastern Hemisphere, is less well recognized in the West. Particularly owing to this disease's grave impact on outcomes after liver transplantation, greater consideration of hepatitis E is necessary in the context of abnormal liver tests. Here, we review the most recent data on detecting and managing hepatitis E, both pre‐ and post‐liver transplantation, discuss major detection assay limitations, consider future directions, and propose an algorithm for the diagnosis and management of pre‐and post‐transplantation hepatitis E.     

Arteriolar rarefaction in the conjunctiva of human essential hypertensives

Hypertension has been shown to have a component of increased vascular resistance. In general, the terms increased resistance and vasoconstriction have been used interchangeably. This study demonstrates that in the bulbar conjunctiva of human essential hypertensives, the decrease in number of arterioles may be just as significant as the arteriolar constriction. When compared to 12 age and sex matched normotensive controls, 12 untreated essential hypertensives had a 20% reduction in arteriolar density and a 5% decrease in arteriolar diameter. Both of these findings were significant at the 5% level. In a calculated “Poiseuille resistance,” the vessel rarefaction and the vessel constriction would contribute approximately equally to the increased resistance. These findings support the contention that microcirculatory density and caliber should be considered in discussions of alterations of vascular resistance.     

The promotion of functional urinary bladder regeneration using anti-inflammatory nanofibers

Current attempts at tissue regeneration utilizing synthetic and decellularized biologic-based materials have typically been met in part by innate immune responses in the form of a robust inflammatory reaction at the site of implantation or grafting. This can ultimately lead to tissue fibrosis with direct negative impact on tissue growth, development, and function. In order to temper the innate inflammatory response, anti-inflammatory signals were incorporated through display on self-assembling peptide nanofibers to promote tissue healing and subsequent graft compliance throughout the regenerative process. Utilizing an established urinary bladder augmentation model, the highly pro-inflammatory biologic scaffold (decellularized small intestinal submucosa) was treated with anti-inflammatory peptide amphiphiles (AIF-PAs) or control peptide amphiphiles and used for augmentation. Significant regenerative advantages of the AIF-PAs were observed including potent angiogenic responses, limited tissue collagen accumulation, and the modulation of macrophage and neutrophil responses in regenerated bladder tissue. Upon further characterization, a reduction in the levels of M2 macrophages was observed, but not in M1 macrophages in control groups, while treatment groups exhibited decreased levels of M1 macrophages and stabilized levels of M2 macrophages. Pro-inflammatory cytokine production was decreased while anti-inflammatory cytokines were up-regulated in treatment groups. This resulted in far fewer incidences of tissue granuloma and bladder stone formation. Finally, functional urinary bladder testing revealed greater bladder compliance and similar capacities in groups treated with AIF-PAs. Data demonstrate that AIF-PAs can alleviate galvanic innate immune responses and provide a highly conducive regenerative milieu that may be applicable in a variety of clinical settings.     

Hepatotoxicity of 6-mercaptopurine in childhood acute lymphocytic leukemia: Pharmacokinetic characteristics

Treatment with 6-mercaptopurine (6MP) is associated with adverse gastrointestinal (GI) and hepatic effects. Four patients, ages 6.9 ± 2.6 (mean ± S.D.) years, with acute lymphocytic leukemia (ALL) on maintenance chemotherapy including 6MP, developed nausea, vomiting, abdominal pain, elevated liver enzymes, and hyperbilirubinemia after 1.4 ± 1.0 (range 0.5–2) years. Liver biopsy in 1 patient was suggestive of drug-induced intrahepatic cholestatis. Symptoms resolved and liver function returned to normal after discontinuation of 6MP. Pharmacokinetic data of the symptomatic patients were compared with those of 25 ALL patients on the same protocol but without GI symptoms or hepatotoxicity. Levels of 6-thioguanine nucleotides (6-TGN) and the methylated metabolites of 6MP in red blood cells of the patients with hepatotoxicity, were not significantly different when compared to patients without hepatotoxicity, suggesting similar absorption of 6MP in both groups. Time to achieve peak 6MP levels was significantly longer in the symptomatic patients compared to the asymptomatic patients (P = 0.005). Peak levels and standardized concentration versus time curve (AUC) per 1 mg of 6MP per m² of body surface area were significantly lower in the patients with hepatotoxicity (P = 0.016; P = 0.037, respectively). A significant correlation between peak 6MP levels and standardized AUC (r = 0.729, P < 0.0001) was found. These results suggest accumulation of 6MP and its metabolites in the liver of the patients with GI symptoms, leading to hepatotoxicity. © 1996 Wiley-Liss, Inc.     

A phase I trial to assess the value of recombinant human granulocyte colony stimulating factor (r-MetHuG-CSF,filgrastim) in accelerating the dose rate of chemotherapy for intermediate and high-grade non-Hodgkin's lymphoma (NHL)

In a multi-centre phase I study we investigated the possibility of reducing the interval between courses of standard CHOP (cyclophosphamide 750 mg/mdoxorubicin 50 mg/mvincristine 2 mgs day 1, and prednisolone 40 mg/m² days 1–8) from 21 days to 15 days and then 10 days using granulocyte colony stimulating factor (r-MetHuG-CSF (Amgen)-filgrastim) to accelerate neutrophil recovery. Patients received CHOP followed by G-CSF 5 μg/kg s.c. from day 2 to the day before the next course (e.g. days 2–14 for the 15-day interval). A total of 28 patients with newly diagnosed intermediate grade or high grade NHL were studied. Four patients were studied at a 21-day interval, six patients were treated at a 15-day interval and subsequently six patients at a 10-day interval. Following analysis of this initial cohort, a further 12 patients were evaluated; four at the 15-day interval, and eight at the 10-day interval. No dose-limiting toxicity was seen in the four patients receiving 21-day CHOP. Dose-limiting toxicity was seen in 4/10 patients treated at the 15-day interval (M:F 7:3, median age 55·5, range 39–67 years). This consisted of infection in two patients, recurrent infection and debility in a third, and mucositis in a fourth. Seven patients experienced one or more infectious episodes requiring antibiotics (median number of episodes: 2, range 1–4). Fourteen patients (M:F 4:3, median age 47·5, range 25–63 years) were treated at the 10-day interval. Dose-limiting toxicity was seen in six patients. This consisted of severe mucositis in three patients, neutropenia and thrombocytopenia on two separate occasions in one patient, and steroid-induced gastritis in two patients. Nine patients had one or more documented infections (median: 2, range 1–3) requiring antibiotics, of which six were severe (WHO grade 3 or 4). One patient died of Pneumocystis carinii (PCP) pneumonia. In summary, G-CSF (filgrastim) will facilitate the shortening of the dosage interval between cycles of CHOP chemotherapy due to accelerated hematological recovery. However, non-hematological toxicity due to the shorter dosage interval is increased and infective episodes are frequent. © 1996 John Wiley & Sons, Ltd.