DNA damage signalling from the placenta to foetal blood as a potential mechanism for childhood leukaemia initiation

Abstract For many diseases with a foetal origin, the cause for the disease initiation remains unknown. Common childhood acute leukaemia is thought to be caused by two hits, the first in utero and the second in childhood in response to infection. The mechanism for the initial DNA damaging event are unknown. Here we have used in vitro, ex vivo and in vivo models to show that a placental barrier will respond to agents that are suspected of initiating childhood leukaemia by releasing factors that cause DNA damage in cord blood and bone marrow cells, including stem cells. We show that DNA damage caused by in utero exposure can reappear postnatally after an immune challenge. Furthermore, both foetal and postnatal DNA damage are prevented by prenatal exposure of the placenta to a mitochondrially-targeted antioxidant. We conclude that the placenta might contribute to the first hit towards leukaemia initiation by bystander-like signalling to foetal haematopoietic cells

The Impact of the Financial Crisis and Natural Catastrophes on CAT Bonds

CAT bonds are important instruments for the insurance of catastrophe risk. Due to a low degree of deal standardization, there is uncertainty about the determination of the CAT bond premium. In addition, it is not apparent how CAT bonds react after the financial crisis or a natural catastrophe. We empirically verify which factors determine the CAT bond premium and what effects arise if a catastrophe occurs. On a broad data set using secondary market premiums we find strong evidence that the recent financial crisis has a significant impact on CAT bond premiums. Furthermore, we find that after hurricane Katrina an increased risk perception for hurricanes can be observed

Low energy atmospheric muon neutrinos in MACRO

We present the measurement of two event samples induced by atmospheric $\nu_\mu$ of average energy $\bar {E}_\nu \sim 4 GeV$. In the first sample, the neutrino interacts inside the MACRO detector producing an upward-going muon leaving the apparatus. The ratio of the number of observed to expected events is $0.57 \pm0.05_{stat} \pm0.06_{syst} \pm0.14_{theor}$ with an angular distribution similar to that expected from the Bartol atmospheric neutrino flux. The second is a mixed sample of internally produced downward-going muons and externally produced upward-going muons stopping inside the detector. These two subsamples are selected by topological criteria; the lack of timing information makes it impossible to distinguish stopping from downgoing muons. The ratio of the number of observed to expected events is $0.71 \pm 0.05_{stat} \pm0.07_{syst} \pm0.18_{theor}$ . Using the ratio of the two subsamples (for which most theoretical uncertainties cancel) we can test the pathlength dependence of the oscillation hypothesis. The probability of agreement with the no-oscillation hypothesis is 5% . The deviations of our observations from the expectations has a preferred interpretation in terms of $\nu_\mu$ oscillations with maximal mixing and $\Delta m^2 \sim 10^{-3} \div 10^{-2} eV^2$. These parameters are in agreement with our results from upward throughgoing muons, induced by $\nu_\mu$ of much higher energies.Comment: 7 pages, 6 figures. Submitted to Phys. Lett.

Evolutionary explanations in medical and health profession courses: are you answering your students' "why" questions?

BACKGROUND: Medical and pre-professional health students ask questions about human health that can be answered in two ways, by giving proximate and evolutionary explanations. Proximate explanations, most common in textbooks and classes, describe the immediate scientifically known biological mechanisms of anatomical characteristics or physiological processes. These explanations are necessary but insufficient. They can be complemented with evolutionary explanations that describe the evolutionary processes and principles that have resulted in human biology we study today. The main goal of the science of Darwinian Medicine is to investigate human disease, disorders, and medical complications from an evolutionary perspective. DISCUSSION: This paper contrasts the differences between these two types of explanations by describing principles of natural selection that underlie medical questions. Thus, why is human birth complicated? Why does sickle cell anemia exist? Why do we show symptoms like fever, diarrhea, and coughing when we have infection? Why do we suffer from ubiquitous age-related diseases like arteriosclerosis, Alzheimer's and others? Why are chronic diseases like type II diabetes and obesity so prevalent in modern society? Why hasn't natural selection eliminated the genes that cause common genetic diseases like hemochromatosis, cystic fibrosis, Tay sachs, PKU and others? SUMMARY: In giving students evolutionary explanations professors should underscore principles of natural selection, since these can be generalized for the analysis of many medical questions. From a research perspective, natural selection seems central to leading hypotheses of obesity and type II diabetes and might very well explain the occurrence of certain common genetic diseases like cystic fibrosis, hemochromatosis, Tay sachs, Fragile X syndrome, G6PD and others because of their compensating advantages. Furthermore, armed with evolutionary explanations, health care professionals can bring practical benefits to patients by treating their symptoms of infection more specifically and judiciously. They might also help curtail the evolutionary arms race between pathogens and antibiotic defenses

Acute weight gain, gender, and therapeutic response to antipsychotics in the treatment of patients with schizophrenia

BACKGROUND: Previous research indicated that women are more vulnerable than men to adverse psychological consequences of weight gain. Other research has suggested that weight gain experienced during antipsychotic therapy may also psychologically impact women more negatively. This study assessed the impact of acute treatment-emergent weight gain on clinical and functional outcomes of patients with schizophrenia by patient gender and antipsychotic treatment (olanzapine or haloperidol). METHODS: Data were drawn from the acute phase (first 6-weeks) of a double-blind randomized clinical trial of olanzapine versus haloperidol in the treatment of 1296 men and 700 women with schizophrenia-spectrum disorders. The associations between weight change and change in core schizophrenia symptoms, depressive symptoms, and functional status were examined post-hoc for men and women and for each medication group. Core schizophrenia symptoms (positive and negative) were measured with the Brief Psychiatric Rating Scale (BPRS), depressive symptoms with the BPRS Anxiety/Depression Scale and the Montgomery-Asberg Depression Rating Scale, and functional status with the mental and physical component scores on the Medical Outcome Survey-Short Form 36. Statistical analysis included methods that controlled for treatment duration. RESULTS: Weight gain during 6-week treatment with olanzapine and haloperidol was significantly associated with improvements in core schizophrenia symptoms, depressive symptoms, mental functioning, and physical functioning for men and women alike. The conditional probability of clinical response (20% reduction in core schizophrenia symptom), given a clinically significant weight gain (at least 7% of baseline weight), showed that about half of the patients who lost weight responded to treatment, whereas three-quarters of the patients who had a clinically significant weight gain responded to treatment. The positive associations between therapeutic response and weight gain were similar for the olanzapine and haloperidol treatment groups. Improved outcomes were, however, more pronounced for the olanzapine-treated patients, and more olanzapine-treated patients gained weight. CONCLUSIONS: The findings of significant relationships between treatment-emergent weight gain and improvements in clinical and functional status at 6-weeks suggest that patients who have greater treatment-emergent weight gain are more likely to benefit from treatment with olanzapine or haloperidol regardless of gender

Non-pharmacological interventions for weight gain in patients with schizophrenia taking antipsychotics

INTRODUCTION: Schizophrenic patients have a higher prevalence of obesity than the general population. There are several factors implicated in weight gain, including poor dietary conditions, sedentary lifestyle and antipsychotic drugs use. Obesity is also associated with metabolic disturbances such as diabetes mellitus. Weight gain interventions are necessary in this population, especially non-pharmacological interventions. OBJECTIVE: To review the non-pharmacological interventions for weight gain management in patients with schizophrenia. METHODS: Eight clinical trials and four open-label studies using these interventions were found. The methodology, strength and limitations of the studies were reviewed. CONCLUSIONS: Non-pharmacological interventions seem to have an important effect on weight gain prevention and control, and should be encouraged and adapted to patients and in mental health institution's reality.INTRODUÇÃO: Pacientes com esquizofrenia têm maior prevalência de obesidade em comparação à população geral. Esse fato está relacionado a uma alimentação inadequada, ao sedentarismo e ao uso de antipsicóticos. O aumento da obesidade associa-se a diversos distúrbios metabólicos, como o diabetes melito. As intervenções para prevenção e controle do ganho de peso são necessárias nessa população, em especial as intervenções não farmacológicas. OBJETIVO: Revisar os estudos sobre intervenções não farmacológicas para prevenção e controle do ganho de peso em pacientes com esquizofrenia. MÉTODOS: Foram encontrados oito estudos controlados e quatro não controlados sobre intervenções não farmacológicas. Foi feita uma revisãosobre a metodologia e os fatores positivos e limitações dos estudos. CONCLUSÕES: As intervenções não farmacológicas parecem ter um efeito importante em termos de prevenção e controle do ganho de peso e, portanto, devem ser incentivadas e adaptadas à realidade dos pacientes e serviços de saúde., Universidade Federal de São Paulo (UNIFESP) Departamento de PsiquiatriaUNIFESP Disciplina de Endocrinologia Departamento de MedicinaUNIFESP, Depto. de PsiquiatriaUNIFESP, Disciplina de Endocrinologia Depto. de MedicinaSciEL

Passive and Motivated Perception of Emotional Faces: Qualitative and Quantitative Changes in the Face Processing Network

Emotionally expressive faces are processed by a distributed network of interacting sub-cortical and cortical brain regions. The components of this network have been identified and described in large part by the stimulus properties to which they are sensitive, but as face processing research matures interest has broadened to also probe dynamic interactions between these regions and top-down influences such as task demand and context. While some research has tested the robustness of affective face processing by restricting available attentional resources, it is not known whether face network processing can be augmented by increased motivation to attend to affective face stimuli. Short videos of people expressing emotions were presented to healthy participants during functional magnetic resonance imaging. Motivation to attend to the videos was manipulated by providing an incentive for improved recall performance. During the motivated condition, there was greater coherence among nodes of the face processing network, more widespread correlation between signal intensity and performance, and selective signal increases in a task-relevant subset of face processing regions, including the posterior superior temporal sulcus and right amygdala. In addition, an unexpected task-related laterality effect was seen in the amygdala. These findings provide strong evidence that motivation augmentsco-activity among nodes of the face processing network and the impact of neural activity on performance. These within-subject effects highlight the necessity to consider motivation when interpreting neural function in special populations, and to further explore the effect of task demands on face processing in healthy brains

Olanzapine-Induced Hyperphagia and Weight Gain Associate with Orexigenic Hypothalamic Neuropeptide Signaling without Concomitant AMPK Phosphorylation

The success of antipsychotic drug treatment in patients with schizophrenia is limited by the propensity of these drugs to induce hyperphagia, weight gain and other metabolic disturbances, particularly evident for olanzapine and clozapine. However, the molecular mechanisms involved in antipsychotic-induced hyperphagia remain unclear. Here, we investigate the effect of olanzapine administration on the regulation of hypothalamic mechanisms controlling food intake, namely neuropeptide expression and AMP-activated protein kinase (AMPK) phosphorylation in rats. Our results show that subchronic exposure to olanzapine upregulates neuropeptide Y (NPY) and agouti related protein (AgRP) and downregulates proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC). This effect was evident both in rats fed ad libitum and in pair-fed rats. Of note, despite weight gain and increased expression of orexigenic neuropeptides, subchronic administration of olanzapine decreased AMPK phosphorylation levels. This reduction in AMPK was not observed after acute administration of either olanzapine or clozapine. Overall, our data suggest that olanzapine-induced hyperphagia is mediated through appropriate changes in hypothalamic neuropeptides, and that this effect does not require concomitant AMPK activation. Our data shed new light on the hypothalamic mechanism underlying antipsychotic-induced hyperphagia and weight gain, and provide the basis for alternative targets to control energy balance

Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000–3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons—Leu844, Cys845, Ala846, Leu847, and Gly848—located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844–848 exists and will be valuable in the management and genetic counseling of a significant number of individuals