Aggression in male mice lacking functional estrogen receptor alpha

Estrogen receptor alpha knockout (ERaKO) male mice fail to display sexual behavior. The authors hypothesized that ERalphaKOs require higher testosterone (T) concentrations than wild-type (WT) males to exhibit copulatory behavior. Increasing T stimulated sexual behavior and preference for females in WT males but failed to do so in ERalphaKOs. However, T did induce female-directed aggression in ERaKOs. In aggression tests, WT residents selectively attacked T-treated male intruders. ERaKO residents attacked female, T-treated male, and estrogen-treated male intruders equally. Increased access to olfactory cues prior to direct contact reduced overall aggression in ERalphaKO versus WT males but did not cause ERalphaKOs to differentially attack male and female opponents. Results suggest that ERalpha is essential for normal social behavior, perhaps via processing of chemoinvestigatory cues, which are required to discriminate males from females.     

Conquering the complex world of human septins: implications for health and disease

Peterson EA and Petty EM. Conquering the complex world of human septins: implications for health and disease. Septins are highly conserved filamentous proteins first characterized in budding yeast and subsequently identified in must eukaryotes. Septins can bind and hydrolyze GTP, which is intrinsically related to their formation of septin hexamers and functional protein interactions. The human septin family is composed of 14 loci, SEPT1‐SEPT14, which encode dozens of different septin proteins. Their central GTPase and polybasic domain regions are highly conserved but they diverge in their N‐terminus and/or C‐terminus. The mechanism by which the different isoforms are generated is not yet well understood, but one can hypothesize that the use of different promoters and/or alternative splicing could give rise to these variants. Septins perform diverse cellular functions according to tissue expression and their interacting partners. Functions identified to date include cell division, chromosome segregation, protein scaffolding, cellular polarity, motility, membrane dynamics, vesicle trafficking, exocytosis, apoptosis, and DNA damage response. Their expression is tightly regulated to maintain proper filament assembly and normal cellular functions. Alterations of these proteins, by mutation or expression changes, have been associated with a variety of cancers and neurological diseases. The association of septins with cancer results from alterations of expression in solid tumors or translocations in leukemias [mixed lineage leukemia (MLL)]. Expression changes in septins have also been associated with neurological conditions such as Alzheimer's and Parkinson's disease, as well as retinopathies, hepatitis C, spermatogenesis and Listeria infection. Pathogenic mutations of SEPT9 were identified in the autosomal dominant neurological disorder hereditary neuralgic amyotrophy (HNA). Human septin research over the past decade has established their importance in cell biology and human disease. Further functional characterization of septins is crucial to our understanding of their possible diagnostic, prognostic, and therapeutic applications.     

Developmental screening in South Africa: comparing the national developmental checklist to a standardized tool

BackgroundWorldwide, more than 200 million children in low- and middle-income countries have developmental delays and/or disabilities. In South Africa the only nationally implemented developmental ‘screening’ tool is integrated as part of ''The Road to Health Booklet (RTHB).MethodThe study employed a comparative cross-sectional within-subject design to evaluate the accuracy of the RTHB developmental checklist against a standardized international tool i.e. the PEDS tools, consisting of the PEDS and PEDS:DM. A total of 201 participants were included through convenience sampling at primary health care facilities in Tshwane, South Africa.ResultsSensitivity of the RTHB developmental checklist is low, but specificity is high. The RTHB developmental checklist failed to identify more than half the infants at risk of delays or disorders. The nationally implemented developmental checklist is ineffective to identify at-risk infants. It should be adapted and validated or replaced in order to improve identification of at-risk infants.     

Insights into reasons for discontinuation according to year of starting first regimen of highly active antiretroviral therapy in a cohort of antiretroviral‐naïve patients

Objectives

The aim of the study was to determine whether the incidence of first‐line treatment discontinuations and their causes changed according to the time of starting highly active antiretroviral therapy (HAART) in an Italian cohort.

Methods

We included in the study patients from the Italian COhort Naïve Antiretrovirals (ICoNA) who initiated HAART when naïve to antiretroviral therapy (ART). The endpoints were discontinuation within the first year of ≥1 drug in the first HAART regimen for any reason, intolerance/toxicity, poor adherence, immunovirological/clinical failure and simplification. We investigated whether the time of starting HAART (stratified as ‘early’, 1997–1999; ‘intermediate’, 2000–2002; ‘recent’, 2003–2007) was associated with the probability of reaching the endpoints by a survival analysis.

Results

Overall, the 1‐year probability of discontinuation of ≥1 drug in the first regimen was 36.1%. The main causes of discontinuation were intolerance/toxicity (696 of 1189 patients; 58.5%) and poor adherence (285 of 1189 patients; 24%). The hazards for all‐reason change were comparable according to calendar period [2000–2002, adjusted relative hazard (ARH) 0.82, 95% confidence interval (CI) 0.69–0.98; 2003–2007, ARH 0.94, 95% CI 0.76–1.16, vs. 1997–1999; global P‐value=0.08]. Patients who started HAART during the ‘recent’ period were less likely to change their initial regimen because of intolerance/toxicity (ARH 0.67, 95% CI 0.51–0.89 vs. ‘early’ period). Patients who started in the ‘intermediate’ and ‘recent’ periods had a higher risk of discontinuation because of simplification (ARH 15.26, 95% CI 3.21–72.45, and ARH 37.97, 95% CI 7.56–190.64, vs. ‘early’ period, respectively).

Conclusions

It seems important to evaluate reason‐specific trends in the incidence of discontinuation in order to better understand the determinants of changes over time. The incidence of discontinuation because of intolerance/toxicity has declined over time while simplification strategies have become more frequent in recent years. Intolerance/toxicity remains the major cause of drug discontinuation.     

Tissue and blood superoxide dismutase activity and malondialdehyde level in leprosy

Background Oxidative stress (OS) results from an imbalance between free radical generating and scavenging systems. The end product of lipid peroxidation, malondialdehyde (MDA) serves as a marker of cellular damage. Superoxide dismutase (SOD) traps free radicals and acts as a free radical scavenging system. Objective To study OS indices in paucibacillary (PB) and multibacillary (MB) leprosy in tissues and blood. Materials and methods The study group comprised untreated PB patients (n = 14), untreated MB patients (n = 18) and normal human volunteers (n = 20). SOD activity, MDA level and MDA/SOD ratio were estimated in both blood and tissue. Results Compared with controls, SOD activity in tissues decreased significantly in both PB and MB patients, while SOD activity in erythrocytes decreased significantly only in MB. In addition, MDA levels increased significantly in tissues of both PB and MB patients. Moreover, the mean level of MDA in plasma of MB patients was significantly higher, whereas there was no significant difference in that of PB patients. This study showed significant increase in OS index (MDA/SOD ratio) in tissue of PB and MB patients and in blood of MB patients only, whereas there was no significant difference in OS index in blood of PB patients compared with that in the controls. Conclusion Oxidative stress was observed in both tissues and blood of MB patients and in tissues of PB patients, denoting its crucial involvement in the pathogenesis of leprosy. This can constitute an important tool in prognosis, treatment and control of leprosy.