Voluntary access to a warm plate reduces hyperactivity in activity-based anorexia

Activity-based anorexia (ABA) is considered an animal model of anorexia nervosa. In ABA, scheduled feeding in combination with voluntary wheel running leads to hyperactivity, reduced food intake, severe body weight loss and hypothermia. In this study it was investigated whether hyperactivity in ABA could be reduced by introducing a warm plate (which was voluntary accessible and did not influence ambient temperature) into a part of the cage. In ad libitum fed rats, the presence of the warm plate did not influence body temperature, running wheel activity (RWA), body weight or food intake. During ABA, however, rats preferred the warm plate and hypothermia was prevented, while hyperactivity and body weight loss were significantly reduced when compared to ABA rats without a plate. Correlation analysis revealed a significant association between basal body temperature and RWA during the light phase in ABA rats. However, there was no evidence that initiation of light phase RWA was a result of hypothermia. These data suggest that ABA rats prefer to prevent hypothermia passively by choosing a warm plate rather than actively regulating body temperature by hyperactivity.     

Homeostasis of T cell numbers: from thymus production to peripheral compartmentalization and the indexation of regulatory T cells

A system under homeostatic control tends to maintain its structure and functions by establishing dynamic equilibriums controlled by multiple regulatory mechanisms. We have shown that this is the case for immune system. Several different mechanisms seem to participate in the homeostatic control of T cell numbers and population distribution. In other words, besides a quantitative dimension, there is also a qualitative dimension in T cell homeostasis. This is achieved through competition by driving the specialization of sub-populations of lymphocytes to occupy specific niches in the peripheral pool and by developing independent homeostatic mechanisms for each particular cell sub-set. Thus, the sizes of the na?ve and memory T cell compartments are governed by independent homeostatic mechanisms, which preserve the capacity to deal with any novel infection (conferred by the presence of na?ve T cells) whilst ensuring the efficacy of memory responses when dealing with recurring antigens. Peripheral T cell homeostasis also depends on the integrity of sub-population structure and the presence of regulatory CD4+ CD25+ T cells. The indexation of regulatory CD4+ CD25+ T cell numbers to the numbers of peripheral activated CD4+ T cells is another mechanism of homeostasis that has major advantages in the control of immune responses. It ensures continuous regulation of T cell numbers throughout immune responses, allowing for increases in cell numbers as long as the proportion of CD4+ CD25+ regulatory T cells is kept.     

Consistent variation in yolk androgens in the Australian Brush-turkey, a species without sibling competition or parental care

Maternal hormones are an excellent pathway for the mother to influence offspring development, and birds provide exceptional opportunities to study these hormone-mediated maternal effects. Two dominant hypotheses about the function of yolk androgens in avian eggs concern maternal manipulation of sibling competition and post hatching paternal care. In megapodes, however, neither sibling competition nor post hatching parental care exists. Eggs are incubated by external heat sources, and chicks dig themselves out of their underground nest and live independently of their parents and their siblings. In this first study on egg androgens of such a megapode, the Australian Brush-turkey Alectura lathami, we found nevertheless substantial amounts of maternal androgens. Since size of the incubation mound, incubation temperature, egg size and laying date greatly vary in this species, we analysed variation in testosterone (T), androstenedione (A4) and dihydrotestosterone (DHT) in relation to these factors. T concentrations were significantly higher in eggs from bigger mounds and laid at greater depth, which may compensate via anabolic effects for the longer duration and higher energetic requirements of chicks when digging themselves out. T concentrations were higher in smaller eggs, and both yolk A4 and T concentrations increased with laying date, perhaps as a compensatory measure, while DHT concentrations only varied across different mounds. These results indicate that maternal androgens may influence offspring development outside the contexts of sibling competition or parental care.     

Influence of polymorphisms of drug metabolizing enzymes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) on the pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide

PURPOSE: The anticancer agent, cyclophosphamide, is metabolized by cytochrome P450 (CYP), glutathione S-transferase (GST) and aldehyde dehydrogenase (ALDH) enzymes. Polymorphisms of these enzymes may affect the pharmacokinetics of cyclophosphamide and thereby its toxicity and efficacy. The purpose of this study was to evaluate the effects of known allelic variants in the CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1 genes on the pharmacokinetics of the anticancer agent, cyclophosphamide, and its active metabolite 4-hydroxycyclophosphamide. EXPERIMENTAL DESIGN: A cohort of 124 Caucasian patients received a high-dose chemotherapy combination consisting of cyclophosphamide (4-6 g/m2), thiotepa (320-480 mg/m2) and carboplatin (area under the curve 13-20 mg x min/ml) as intravenous infusions over 4 consecutive days. Genomic DNA was analysed using PCR and sequencing. Liquid chromatography-tandem mass spectrometry was used to measure plasma concentrations of cyclophosphamide and 4-hydroxycyclophosphamide. The relationship between allelic variants and the elimination pharmacokinetic parameters noninducible cyclophosphamide clearance (CL(nonind)), inducible cyclophosphamide clearance (CL(ind)) and elimination rate constant of 4-hydroxycyclophosphamide (k(4OHCP)) were evaluated using nonlinear mixed effects modelling. RESULTS: The interindividual variability in the noninducible cyclophosphamide clearance, inducible cyclophosphamide clearance and 4-hydroxycyclophosphamide clearance was 23, 27 and 31%, respectively. No effect of the allelic variants investigated on the clearance of cyclophosphamide or 4-hydroxycyclophosphamide could be demonstrated. CONCLUSION: This study indicates that the presently evaluated variant alleles in the CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1 genes do not explain the interindividual variability in cyclophosphamide and 4-hydroxycyclophosphamide pharmacokinetics and are, probably, not the cause of the observed variability in toxicity.     

Relations between polymorphisms in drug-metabolising enzymes and toxicity of chemotherapy with cyclophosphamide, thiotepa and carboplatin

PURPOSE: High-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin (CTC) has been developed as a possible curative treatment modality in several solid tumours. However, a large interindividual variability in toxicity is encountered in high-dose chemotherapy. A priori identification of patients at risk for toxicity could be an attractive prospect. Genotyping of genes encoding drug-metabolising enzymes might provide such a tool. EXPERIMENTAL DESIGN: We assessed 16 selected polymorphisms in nine genes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) of putative relevance in CTC metabolism using polymerase chain reaction and DNA sequencing in 113 patients who were treated with high-dose chemotherapy regimens based on CTC. RESULTS: Patients heterozygous for the ALDH3A1*2 allele (allelic frequency 21.2%) had an increased risk of haemorrhagic cystitis when compared with patients with wild-type alleles [5/38 vs. 1/70; odds ratio (OR): 11.95, 95% confidence interval (CI): 1.18-120.56; P=0.04]. Furthermore, patients heterozygous for the ALDH1A1*2 allele (allelic frequency 5.8%) had an increased risk of liver toxicity when compared with patients with wild-type alleles (6/13 vs. 19/99; OR: 5.13, 95% CI: 1.30-20.30; P=0.02). No other relations reached significance. CONCLUSION: Patients heterozygous for the ALDH3A1*2 and ALDH1A1*2 allele have an increased risk of haemorrhagic cystitis and liver toxicity, respectively, compared with patients with wild-type alleles when treated with a high-dose chemotherapy combination of CTC. Pharmacogenetic approaches can identify patients who are at risk of experiencing toxic side effects in high-dose chemotherapy.     

Effects of repetitive transcranial magnetic stimulation on improvement of cognition in elderly patients with cognitive impairment: a systematic review and meta‐analysis

Objective

This systematic review and meta‐analysis aimed to examine the effects of repetitive transcranial magnetic stimulation (rTMS) on cognitive function in older patients with cognitive impairment.

Methods

A literature search was performed for articles published in English using the 10 databases (MEDLINE, EMBASE, PsycINFO, INSPEC, the Cumulative Index to Nursing and Allied Health Literature Plus, AMED, Biological Sciences, ClinicalTrials.gov , the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews) from their inception to May 2016. The primary outcome was cognitive function as measured by the Mini‐Mental State Examination or the Alzheimer's Disease Assessment Scale‐cognitive subscale.

Results

Seven RCTs were included in the meta‐analysis, with a sample of 107 active and 87 sham rTMS. Active rTMS was found to be more effective in improving cognition (Hedges' g = 0.48; 95% confidence interval 0.12 to 0.84).

Conclusions

High‐frequency rTMS showed a benefit on cognition amongst older patients with mild to moderate Alzheimer's disease. rTMS was shown to have great potential as a safe and well‐tolerated alternative intervention for cognition. Copyright © 2017 John Wiley & Sons, Ltd.