The influence of illness‐related variables,personal resources and context‐related factors on real‐life functioning of people with schizophrenia

In people suffering from schizophrenia, major areas of everyday life are impaired, including independent living, productive activities and social relationships. Enhanced understanding of factors that hinder real‐life functioning is vital for treatments to translate into more positive outcomes. The goal of the present study was to identify predictors of real‐life functioning in people with schizophrenia, and to assess their relative contribution. Based on previous literature and clinical experience, several factors were selected and grouped into three categories: illness‐related variables, personal resources and context‐related factors. Some of these variables were never investigated before in relationship with real‐life functioning. In 921 patients with schizophrenia living in the community, we found that variables relevant to the disease, personal resources and social context explain 53.8% of real‐life functioning variance in a structural equation model. Neurocognition exhibited the strongest, though indirect, association with real‐life functioning. Positive symptoms and disorganization, as well as avolition, proved to have significant direct and indirect effects, while depression had no significant association and poor emotional expression was only indirectly and weakly related to real‐life functioning. Availability of a disability pension and access to social and family incentives also showed a significant direct association with functioning. Social cognition, functional capacity, resilience, internalized stigma and engagement with mental health services served as mediators. The observed complex associations among investigated predictors, mediators and real‐life functioning strongly suggest that integrated and personalized programs should be provided as standard treatment to people with schizophrenia.     

Breast Cancer “Tailored Follow-up” in Italian Oncology Units: A Web-Based Survey

Purpose

Breast cancer follow-up procedures after primary treatment are still a controversial issue. Aim of this study was to investigate, through a web-based survey, surveillance methodologies selected by Italian oncologists in everyday clinical practice.

Methods

Referents of Italian medical oncology units were invited to participate to the study via e-mail through the SurveyMonkey website. Participants were asked how, in their institution, exams of disease staging and follow-up are planned in asymptomatic women and if surveillance continues beyond the 5^th year.

Results

Between February and May 2013, 125 out of 233 (53.6%) invited referents of Italian medical oncology units agreed to participate in the survey. Ninety-seven (77.6%) referents state that modalities of breast cancer follow-up are planned according to the risk of disease progression at diagnosis and only 12 (9.6%) oncology units apply the minimal follow-up procedures according to international guidelines. Minimal follow-up is never applied in high risk asymptomatic women. Ninety-eight (78.4%) oncology units continue follow-up in all patients beyond 5 years.

Conclusions

Our survey shows that 90.4% of participating Italian oncology units declare they do not apply the minimal breast cancer follow-up procedures after primary treatment in asymptomatic women, as suggested by national and international guidelines. Interestingly, about 80.0% of interviewed referents performs the so called “tailored follow-up”, high intensity for high risk, low intensity for low risk patients. There is an urgent need of randomized clinical trials able to determine the effectiveness of risk-based follow-up modalities, their ideal frequency and persistence in time.     

Tobacco Smoke and Risk of Childhood Acute Non-Lymphocytic Leukemia: Findings from the SETIL Study

Background

Parental smoking and exposure of the mother or the child to environmental tobacco smoke (ETS) as risk factors for Acute non-Lymphocytic Leukemia (AnLL) were investigated.

Methods

Incident cases of childhood AnLL were enrolled in 14 Italian Regions during 1998–2001. We estimated odds ratios (OR) and 95% confidence intervals (95%CI) conducting logistic regression models including 82 cases of AnLL and 1,044 controls. Inverse probability weighting was applied adjusting for: age; sex; provenience; birth order; birth weight; breastfeeding; parental educational level age, birth year, and occupational exposure to benzene.

Results

Paternal smoke in the conception period was associated with AnLL (OR for ≥11 cigarettes/day  = 1.79, 95% CI 1.01–3.15; P trend 0.05). An apparent effect modification by maternal age was identified: only children of mothers aged below 30 presented increased risks. We found weak statistical evidence of an association of AnLL with maternal exposure to ETS (OR for exposure>3 hours/day  = 1.85, 95%CI 0.97–3.52; P trend 0.07). No association was observed between AnLL and either maternal smoking during pregnancy or child exposure to ETS.

Conclusions

This study is consistent with the hypothesis that paternal smoke is associated with AnLL. We observed statistical evidence of an association between maternal exposure to ETS and AnLL, but believe bias might have inflated our estimates.     

Annelated pyrrolo-pyrimidines from amino-cyanopyrroles and BMMAs as leads for new DNA-interactive ring systems

The efficient one-pot synthesis of several new tricyclic systems of type 1 and 2, obtained from the reaction of substituted 2-amino-3-cyanopyrroles and 3-amino-4-cyanopyrroles with BMMAs, is reported. The duration and yields of the reaction strongly depend on the reactivity of the starting pyrrole and on the size of the ring to be formed. Mechanist features of the reaction were investigated and proposed by studying also the reactivity of a 3-aminopyrrole-2,4-dicyano substituted. The method reported represents the first example of the use of BMMA reagents in combination with pyrrole derivatives and allows an easy and versatile entry to a large number of hitherto unknown pyrrolo-pyrimidines further annelated with nitrogen heterocycles of different sizes. These new polycondensed heterocycles possess the requisite to interact with DNA.     

Finishers and nonfinishers in the 'Swiss Cycling Marathon ' to qualify for the 'Race Across America '

Knechtle, B, Knechtle, P, Rüst, CA, Rosemann, T, and Lepers, R. Finishers and nonfinishers in the 'Swiss Cycling Marathon' to qualify for the 'Race across America.' J Strength Cond Res 25(12): 3257-3263, 2011-We compared the characteristics of prerace anthropometry, previous experience, and training and support during the race in 39 finishers and 37 nonfinishers in the 'Swiss Cycling Marathon,' over 720 km. In this race, the cyclists intended to qualify for the 'Race across America,' the longest nonstop cycling race in the World from the West to the East of the USA. Finishers in the 'Swiss Cycling Marathon' had a lower body mass, a lower body mass index, lower circumferences of upper arm and thigh, a lower percent body fat, completed more weekly training units, covered more kilometers in the longest training ride, rode at a faster speed during training, rode more kilometers per week and for more hours, had more previous finishes in the 'Swiss Cycling Marathon' and a lighter race bike compared to the nonfinishers. In the bivariate analysis, the cycling distance per training unit (r = 0.37), the duration per training unit (r = 0.44), the speed per training unit (r = -0.59), using nutrition provided by the organizer (r = 0.50), and using own nutrition (r = 0.49) during the race were significantly and positively associated with race time. For practical applications, anthropometric characteristics such as a low body mass or low body fat were not related to race time, whereas training characteristics and nutrition during the race were associated with race time. The key to a successful finish in an ultraendurance cycling race such as the 'Swiss Cycling Marathon' seems a high speed in training and an appropriate nutrition during the race.     

Leveraging the contribution of thermodynamics in drug discovery with the help of fluorescence-based thermal shift assays

The development of new drugs with better pharmacological and safety properties mandates the optimization of several parameters. Today, potency is often used as the sole biochemical parameter to identify and select new molecules. Surprisingly, thermodynamics, which is at the core of any interaction, is rarely used in drug discovery, even though it has been suggested that the selection of scaffolds according to thermodynamic criteria may be a valuable strategy. This poor integration of thermodynamics in drug discovery might be due to difficulties in implementing calorimetry experiments despite recent technological progress in this area. In this report, the authors show that fluorescence-based thermal shift assays could be used as prescreening methods to identify compounds with different thermodynamic profiles. This approach allows a reduction in the number of compounds to be tested in calorimetry experiments, thus favoring greater integration of thermodynamics in drug discovery.     

Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase

Anti-apoptotic Bcl2 family proteins such as Bcl-x(L) protect cells from death by sequestering apoptotic molecules, but also contribute to normal neuronal function. We find in hippocampal neurons that Bcl-x(L) enhances the efficiency of energy metabolism. Our evidence indicates that Bcl-x(L)interacts directly with the β-subunit of the F(1)F(O)?ATP synthase, decreasing an ion leak within the F(1)F(O) ATPase complex and thereby increasing net transport of H(+) by F(1)F(O) during F(1)F(O) ATPase activity. By patch clamping submitochondrial vesicles enriched in F(1)F(O) ATP synthase complexes, we find that, in the presence of ATP, pharmacological or genetic inhibition of Bcl-x(L) activity increases the membrane leak conductance. In addition, recombinant Bcl-x(L) protein directly increases the level of ATPase activity of purified synthase complexes, and inhibition of endogenous Bcl-x(L) decreases the level of F(1)F(O) enzymatic activity. Our findings indicate that increased mitochondrial efficiency contributes to the enhanced synaptic efficacy found in Bcl-x(L)-expressing?neurons.     

Characterization of Pdgfrb-Cre transgenic mice reveals reduction of ROSA26 reporter activity in remodeling arteries

With the intention to modulate gene expression in vascular mural cells of remodeling vessels, we generated and characterized transgenic mouse lines with Cre recombinase under the control of the platelet-derived growth factor receptor-β promoter, referred to as Tg(Pdgfrb-Cre)(35Vli) . Transgenic mice were crossed with the Gt(ROSA)26Sor(tm1Sor) strain and examined for Cre activation by β-galactosidase activity, which was compared with endogenous Pdgfrb expression. In addition, Pdgfrb-Cre mice were used to drive expression of a conditional myc-tagged Cthrc1 transgene. There was good overlap of β-galactosidase activity with endogenous Pdgfrb immunoreactivity. However, dedifferentiation of vascular mural cells induced by carotid artery ligation revealed a dramatic discrepancy between ROSA26 reporter activity and Pdgfrb promoter driven Cre dependent myc-tagged Cthrc1 transgene expression. Our studies demonstrate the capability of the Pdgfrb-Cre mouse to drive conditional transgene expression as a result of prior Cre-mediated recombination in tissues known to express endogenous Pdgfrb. In addition, the study shows that ROSA26 promoter driven reporter mice are not suitable for lineage marking of smooth muscle in remodeling blood vessels.     

A retinal proteomics-based study identifies αA-crystallin as a sex steroid-regulated protein

Sex steroids influence the structural and functional organization of ocular tissues, promote survival in several pathological conditions including retinal neurodegeneration and have a prominent role in age-related eye diseases as well as neurodegenerative diseases. However, their underlying mechanisms are still elusive. We explored proteomic profiling of rat retinas following intravitreal injection of the bioactive 17β-estradiol or androgen dihydrotestosterone. Using narrow range 2-DE gels and MALDI-TOF-MS analysis, we identified three sex steroid-regulated proteins: the galectin-related-inter-fiber (GRIFIN) which is a galectin family member protein of unknown function, the fatty acid-binding protein epidermal-5 (FABP5) protein responsible for the fatty acid uptake and transport and the small heat shock αA-crystallin (CRYAA) protein involved in preventing aggregation of denatured or unfolded proteins. Changes in the expression of these proteins revealed a predominant estrogenic effect and the multiple CRYAA protein species reflected posttranslational modifications. Sex steroid-mediated modifications of CRYAA were confirmed by Western blotting analysis. This study provides new target proteins for sex steroids with a potential link to age-related diseases associated with proteotoxic stress.