Further evidence against a direct genotoxic mode of action for arsenic-induced cancer

Arsenic in drinking water, a mixture of arsenite and arsenate, is associated with increased skin and other cancers in Asia and Latin America, but not the United States. Arsenite alone in drinking water does not cause skin cancers in experimental animals; therefore, it is not a complete carcinogen in skin. We recently showed that low concentrations of arsenite enhanced the tumorigenicity of solar UV irradiation in hairless mice, suggesting arsenic cocarcinogenesis with sunlight in skin cancer and perhaps with different carcinogenic partners for lung and bladder tumors. Cocarcinogenic mechanisms could include blocking DNA repair, stimulating angiogenesis, altering DNA methylation patterns, dysregulating cell cycle control, induction of aneuploidy and blocking apoptosis. Arsenicals are documented clastogens but not strong mutagens, with weak mutagenic activity reported at highly toxic concentrations of inorganic arsenic. Previously, we showed that arsenite, but not monomethylarsonous acid (MMA[III]), induced delayed mutagenesis in HOS cells. Here, we report new data on the mutagenicity of the trivalent methylated arsenic metabolites MMA(III) and dimethylarsinous acid [DMA(III)] at the gpt locus in Chinese hamster G12 cells. Both methylated arsenicals seemed mutagenic with apparent sublinear dose responses. However, significant mutagenesis occurred only at highly toxic concentrations of MMA(III). Most mutants induced by MMA(III) and DMA(III) exhibited transgene deletions. Some non-deletion mutants exhibited altered DNA methylation. A critical discussion of cell survival leads us to conclude that clastogenesis occurs primarily at highly cytotoxic arsenic concentrations, casting further doubt as to whether a genotoxic mode of action (MOA) for arsenicals is supportable.     

Sex is a defining feature of neuroimaging phenotypes in major brain disorders

Sex is a biological variable that contributes to individual variability in brain structure and behavior. Neuroimaging studies of population-based samples have identified normative differences in brain structure between males and females, many of which are exacerbated in psychiatric and neurological conditions. Still, sex differences in MRI outcomes are understudied, particularly in clinical samples with known sex differences in disease risk, prevalence, and expression of clinical symptoms. Here we review the existing literature on sex differences in adult brain structure in normative samples and in 14 distinct psychiatric and neurological disorders. We discuss commonalities and sources of variance in study designs, analysis procedures, disease subtype effects, and the impact of these factors on MRI interpretation. Lastly, we identify key problems in the neuroimaging literature on sex differences and offer potential recommendations to address current barriers and optimize rigor and reproducibility. In particular, we emphasize the importance of large-scale neuroimaging initiatives such as the Enhancing NeuroImaging Genetics through Meta-Analyses consortium, the UK Biobank, Human Connectome Project, and others to provide unprecedented power to evaluate sex-specific phenotypes in major brain diseases.     

Alteplase and ischaemic stroke: have new reviews of old data helped?

BACKGROUND: Thrombolysis for stroke is still not widely used as current recommendations restrict treatment to selected patients. In general, these are patients who can be assessed quickly by specialised stroke teams, have intracranial haemorrhage excluded by appropriate brain imaging, and are treated with alteplase (recombinant tissue plasminogen activator; rt-PA) within 3 h of symptom onset. There is, however, still much debate regarding the scope of treatment and the reorganisation of services required to support an effective service. RECENT DEVELOPMENTS: Two recent publications have helped clarify some issues. The first was an individual-patient data meta-analysis of the alteplase trials. These analyses suggest treatment effects beyond the usual 3 h time window, but other than time to treatment no other factors influenced the effects of treatment. The second publication was a reanalysis of the original National Institute of Neurological Disorders and Stroke (NINDS) alteplase trial, done after criticism of the original study. The reanalysis confirmed that there was significant baseline imbalance of stroke severity between treatment and control groups in the NINDS trial, but established that this did not materially affect the positive results of the trial. However, the recording of blood pressure in the study was found to be inconsistent and therefore unsuitable for reanalysis. The previously published data on recommendations for blood-pressure control, arising from the NINDS trial, needs to be reconsidered in this light. Both studies included too few patients to provide reliable data on which clinical and radiological features influence the response to alteplase. WHERE NEXT?: The individual-patient data meta-analysis and reanalysis of the NINDS trial have probably exhausted the potential of previous trials to answer questions on the effects of thrombolysis. Further randomised trials comparing thrombolysis with control will be required to determine whether elderly people benefit from treatment or whether there are worthwhile benefits from alteplase beyond 3 h (and in such patients, whether advanced magnetic resonance imaging is an effective way to select those most likely to benefit). Various new approaches to reperfusion also require assessment in large-scale trials: new thrombolytic drugs, the combination of intravenous and intra-arterial thrombolytic drugs, combinations of thrombolytics with new antiplatelet agents, and augmentation of thrombolysis either with mechanical devices or with transcranial ultrasound.     

Social validation data on three methods of physical restraint: views of consumers,staff and students

The use and evaluation of restraint methods with people with mental retardation is a continuing area of concern. Twenty-four undergraduate students, 21 residential care staff and 18 service-users from community settings rated videotapes of three physical restraint procedures. Two of the methods involved restraining an individual on the floor and a third method involved restraining an individual in a chair. Participants answered two open-ended questions to rate the methods of restraint and rated the methods on a 5-point scale of satisfaction [J. Ment. Defic. Res. 30 (1986) 369]. Participants also rated the three restraint methods by a forced-choice comparison. Restraint was rated negatively by all participants. However, both the satisfaction ratings and the forced-choice methods rated the chair method of restraint as most acceptable all three groups of participants. Consumers rated restraint more negatively than other groups. Restraint was evaluated negatively by all three groups, but the chair method was rated the least worst.     

Identification and understanding of pre-term birth at Kintampo Municipal Hospital: a qualitative cross-sectional study

Up to 42% of nearly 10 million under five deaths occur in neonates with prematurity being a principal cause. This paper presents the outcome of a cross sectional qualitative study conducted among 14 hospital staff engaged in infant care in Kintampo, Ghana. Confidential interviews were used to evaluate their knowledge and practice of preterm care. Critical steps in caring for normal and preterm infants were ranked as adequate, satisfactory or inadequate if 75% or more, 50% to 74%, or less than 50% of the health workers completed them respectively. For term infants, adequate care was provided in terms of cleaning and wrapping, weighing, and initiating early feeds. Knowledge and practice were inadequate in relation to preterm care. Educational interventions emphasizing preterm care are recommended as an essential package for rural health workers. A newborn assessment tool was designed to address the gap in data collection identified during the study.