TcsL is an essential virulence factor in Clostridium sordellii ATCC 9714

Clostridium sordellii is an important pathogen of humans and animals, causing a range of diseases, including myonecrosis, sepsis, and shock. Although relatively rare in humans, the incidence of disease is increasing, and it is associated with high mortality rates, approaching 70%. Currently, very little is known about the pathogenesis of C. sordellii infections or disease. Previous work suggested that the lethal large clostridial glucosylating toxin TcsL is the major virulence factor, but a lack of genetic tools has hindered our ability to conclusively assign a role for TcsL or, indeed, any of the other putative virulence factors produced by this organism. In this study, we have developed methods for the introduction of plasmids into C. sordellii using RP4-mediated conjugation from Escherichia coli and have successfully used these techniques to insertionally inactivate the tcsL gene in the reference strain ATCC 9714, using targetron technology. Virulence testing revealed that the production of TcsL is essential for the development of lethal infections by C. sordellii ATCC 9714 and also contributes significantly to edema seen during uterine infection. This study represents the first definitive identification of a virulence factor in C. sordellii and opens the way for in-depth studies of this important human pathogen at the molecular level.     

Developmental Trajectories in Siblings of Children with Autism: Cognition and Language from 4 Months to 7 Years

We compared the cognitive and language development at 4, 14, 24, 36, 54 months, and 7 years of siblings of children with autism (SIBS-A) to that of siblings of children with typical development (SIBS-TD) using growth curve analyses. At 7 years, 40% of the SIBS-A, compared to 16% of SIBS-TD, were identified with cognitive, language and/or academic difficulties, identified using direct tests and/or parental reports. This sub-group was identified as SIBS-A-broad phenotype (BP). Results indicated that early language scores (14–54 months), but not cognitive scores of SIBS-A-BP and SIBS-A-nonBP were significantly lower compared to the language scores of SIBS-TD, and that the rate of development was also significantly different, thus pinpointing language as a major area of difficulty for SIBS-A during the preschool years.     

Essential role for MFG-E8 as ligand for alphavbeta5 integrin in diurnal retinal phagocytosis

The integrin receptor alphavbeta5 controls two independent forms of interactions of the retinal pigment epithelium (RPE) with adjacent photoreceptor outer segments that are essential for vision. Alphavbeta5 localizes specifically to apical microvilli of the RPE and contributes to retinal adhesion that maintains RPE contacts with intact outer segments at all times. Additionally, alphavbeta5 synchronizes diurnal bursts of RPE phagocytosis that clear photoreceptor outer segment fragments (POS) shed in a circadian rhythm. Dependence of retinal phagocytosis and adhesion on alphavbeta5 receptors suggests that the extracellular matrix ensheathing RPE microvilli contains ligands for this integrin. Here we studied mice lacking expression of functional MFG-E8 to test the contribution of this integrin ligand to alphavbeta5 functions in the retina. Lack of MFG-E8 only minimally reduced retinal adhesion. In contrast, lack of MFG-E8, like lack of alphavbeta5 receptor, eliminated alphavbeta5 downstream signaling involving the engulfment receptor MerTK and peak POS phagocytosis, both of which follow light onset in wild-type retina. MFG-E8-deficient RPE in primary culture retained normal epithelial morphology and levels of apical alphavbeta5 receptors, but showed impaired binding and engulfment of isolated POS. Soluble or POS-bound recombinant MFG-E8 was sufficient to fully restore phagocytosis by MFG-E8-deficient RPE. Furthermore, MFG-E8 supplementation strongly increased POS binding by wild-type and MerTK-deficient RPE, but did not affect POS binding by RPE lacking alphavbeta5. Thus, MFG-E8 stimulates rhythmic POS phagocytosis by ligating apical alphavbeta5 receptors of the RPE. These results identify MFG-E8 as the first extracellular ligand in the retina that is essential for diurnal POS phagocytosis.     

Neuronal SIRT1 regulates endocrine and behavioral responses to calorie restriction

Mammalian life span can be extended by both calorie restriction (CR) and mutations that diminish somatotropic signaling. Sirt1 is a mediator of many effects of CR in mammals, but any role in controlling somatotropic signaling has not been shown. Since the somatotropic axis is controlled by the brain, we created mice lacking Sirt1 specifically in the brain and examined the impacts of this manipulation on somatotropic signaling and the CR response. These mutant mice displayed defects in somatotropic signaling when fed ad libitum, and defects in the endocrine and behavioral responses to CR. We conclude that Sirt1 in the brain is a link between somatotropic signaling and CR in mammals.     

The use of motivational interviewing techniques to enhance the efficacy of guided self-help behavioral weight loss treatment

This study assessed whether motivational interviewing (MI), applied as part of a standard guided self-help (GSH) behavioral weight loss treatment, reduced attrition rate and improved participant weight loss and other eating-related and general psychological measures, relative to a standard GSH treatment alone. Thirty-nine overweight patients (7 males, 32 females) were randomized to receive either 6 sessions of traditional guided self-help and 2 traditional motivation-focused sessions (GSH treatment); or 6 guided self-help sessions and 2 sessions utilizing an MI approach to motivation (GSH/MI treatment). In intention-to-treat analyses, significant differences were found in the areas of eating concern and control over eating, favoring GSH/MI. Between-group effect size estimates indicated a small advantage for GSH/MI over GSH in weight loss, as well as on a number of secondary eating-related measures. Implications and future directions are discussed.     

Parity-related mortality: shape of association among middle-aged and elderly men and women

Parity is associated with mortality among middle-aged women, while substantially less is known about this relationship for men and the elderly. Using the census-based Israel Longitudinal Mortality Study (ILMS) II (1995–2004) we sought to examine the parity–mortality relationship among men and women, middle-aged and elderly. In our study cohort of 71,733 married men and 62,822 married women ages 45–89 years at baseline, 19,437 deaths were reported. Mortality differentials by parity were assessed using Cox proportional hazard regression models adjusted stepwise for age, origin, education and number of rooms. Analyzes were carried out for middle-aged (45–64 years) and elderly (65–89 years) men and women separately. We observed a non-linear relationship between parity and mortality for all individuals even after adjustment for demographic and socio-economic variables. In fully adjusted models, for example, nulliparous middle-aged women experienced the highest mortality risks (hazard ratios [HR] = 1.57, 95% confidence intervals [CI] 1.24, 1.98) followed by those with one child (HR = 1.29, 95% CI 1.10, 1.51). These results were attenuated somewhat for nulliparous older women (HR = 1.25, 95% CI 1.11, 1.41). The detrimental effects of low and high parity on mortality among both men and women suggest a non pregnancy-related pathway that is likely mediated by biological and psychosocial factors and other lifestyle characteristics that have long-term consequences into older ages. Further research is warranted to examine the effects of parity by specific cause of death.     

The multiple dimensions of sustained attention

Sustained counting (or temporal numerosity judgements) has been one of the key means of investigating anterior attentional processes. Forty-three patients with localised lesions to the frontal lobes were assessed on two tests of the ability to count the number (8-22) of stimuli presented at either a slow (roughly one per 3 sec) or fast (roughly three per sec) rate. Patients with lesions to the Superior Medial (SM) region (particularly Brodmann areas 24, 32, and 9) were impaired both in the Slow condition and also in the Fast condition, where they underestimated the number of stimuli. Patients with Right Lateral (RL) lesions (8, 45, and 46) also had difficulties in the Fast condition, especially when the number of targets was greater than 15. The results are considered from the perspectives of alternative positions on anterior attentional processes developed by Posner and Petersen (1990) and by Stuss et al. (1995). The most plausible interpretation is in terms of energising processes which involve the SM frontal cortex and monitoring processes which involve the RL frontal cortex.