Sex-specific hypnotic effects of the neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile are mediated by peripheral metabolism into an active hypnotic steroid

BACKGROUND: The novel synthetic neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH) blocks T-type calcium channels but does not directly modulate neuronal γ-aminobutyric acid type A (GABA METHODS: We used a combination of behavioural loss of righting reflex, neuroendocrine, pharmacokinetic, in vitro patch-clamp electrophysiology, and in vivo electrophysiological approaches in wild-type mice and in genetic knockouts of the Ca RESULTS: Adult male mice were less sensitive to the hypnotic effects of 3β-OH compared with female mice, and these differences appeared during development. Adult males had higher 3β-OH brain concentrations despite being less sensitive to its hypnotic effects. Females metabolised 3β-OH into the active GABA CONCLUSIONS: The sex-specific differences in the hypnotic effect of 3β-OH in mice are attributable to differences in its peripheral metabolism into the more potent hypnotic metabolite 3α-OH

Hemorragia intracraneal en el recién nacido a término. Intracranial hemorrhage in a term infant

Los accidentes vasculares hemorrágicos cerebrales en el recién nacido a término constituyen un aspecto importante  de la morbimortalidad en la etapa neonatal. Se presenta el caso de un recién nacido a término, normopeso, varón, nacido de parto distócico en presentación pelviana (distocia de cabeza última), con una asfixia severa al nacer, que requirió de medidas de reanimación y de asistencia ventilatoria mecánica, constatando las manifestaciones clínicas de un accidente vascular hemorrágico, que se corroboró con los estudios imagenológicos realizados. Es egresado al mes de edad, sin compromiso de sus funciones vitales,  y seguido por una consulta multidisciplinaria. A los tres meses de edad muestra evidencias de secuelas determinadas por retraso en su desarrollo psico-motor y trastornos  neurosensoriales. La rehabilitación se está realizando con el objetivo de  mejorar su actividad motora y su proyección psicosocial. Palabras clave: HEMORRAGIA INTRACRANEAL/Recién nacido a término. ABSTRACT Cerebrovascular haemorrhagic accidents in term infant constitute an important feature of mortality in neonatal stage. A case of a male normoweight term infant who was born from a dystocic delivery in pelvis presentation (late-head dystocia) with a severe asphyxia at birth was analyzed. The infant required resuscitation techniques and mechanical ventilation, noting the clinical manifestations of haemorrhagic vascular accident, which could be proved through imaging studies carried out. At the age of one month the patient was discharged from the hospital with no compromise of vital functions and multidisciplinary follow-up. At the age of 3 months he showed specific sequels of retardation in psychomotor development and neurosensory disorders. Rehabilitation is been carried out with the objective of improving motor activity and psychosocial projection. Key words: INTRACRANIAL HAEMORRHAGE/term infant

Hemorragia intracraneal en el recién nacido a término. Intracranial hemorrhage in a term infant

Los accidentes vasculares hemorrágicos cerebrales en el recién nacido a término constituyen un aspecto importante  de la morbimortalidad en la etapa neonatal. Se presenta el caso de un recién nacido a término, normopeso, varón, nacido de parto distócico en presentación pelviana (distocia de cabeza última), con una asfixia severa al nacer, que requirió de medidas de reanimación y de asistencia ventilatoria mecánica, constatando las manifestaciones clínicas de un accidente vascular hemorrágico, que se corroboró con los estudios imagenológicos realizados. Es egresado al mes de edad, sin compromiso de sus funciones vitales,  y seguido por una consulta multidisciplinaria. A los tres meses de edad muestra evidencias de secuelas determinadas por retraso en su desarrollo psico-motor y trastornos  neurosensoriales. La rehabilitación se está realizando con el objetivo de  mejorar su actividad motora y su proyección psicosocial. Palabras clave: HEMORRAGIA INTRACRANEAL/Recién nacido a término. ABSTRACT Cerebrovascular haemorrhagic accidents in term infant constitute an important feature of mortality in neonatal stage. A case of a male normoweight term infant who was born from a dystocic delivery in pelvis presentation (late-head dystocia) with a severe asphyxia at birth was analyzed. The infant required resuscitation techniques and mechanical ventilation, noting the clinical manifestations of haemorrhagic vascular accident, which could be proved through imaging studies carried out. At the age of one month the patient was discharged from the hospital with no compromise of vital functions and multidisciplinary follow-up. At the age of 3 months he showed specific sequels of retardation in psychomotor development and neurosensory disorders. Rehabilitation is been carried out with the objective of improving motor activity and psychosocial projection. Key words: INTRACRANIAL HAEMORRHAGE/term infant

Autoimmune/inflammatory syndrome induced by adjuvants: a review

The autoimmune/inflammatory syndrome induced by adjuvants (ASIA) includes several autoimmune conditions and phenomena that occur after exposure to substances with adjuvant activity. The spectrum of the disease is heterogeneous with respect to the clinical presentation as well as the severity of the clinical manifestations. Different substances and medical devices with adjuvant activity are currently known, such as vaccines, oils, silicones, mineral salts, lipopolysaccharides, peptidoglycans, among others. These adjuvants are immunological molecules that function through potentiation of antigen-specific immune responses. Thus, the etiopathogenesis of ASIA syndrome involves a multifactorial interaction between environmental factors and genetic predisposition, and secondary activation of the adaptive and innate arms of the immune system through various mechanisms. Although in some reported cases the ASIA syndrome improves considerably when removing the implants, there are no conclusive results for the clinical benefit of removing the implants, so it is necessary to carry out further basic, clinical and surgical investigations in order to determine the best therapeutic decision

The Red Sea, Coastal Landscapes, and Hominin Dispersals

This chapter provides a critical assessment of environment, landscape and resources in the Red Sea region over the past five million years in relation to archaeological evidence of hominin settlement, and of current hypotheses about the role of the region as a pathway or obstacle to population dispersals between Africa and Asia and the possible significance of coastal colonization. The discussion assesses the impact of factors such as topography and the distribution of resources on land and on the seacoast, taking account of geographical variation and changes in geology, sea levels and palaeoclimate. The merits of northern and southern routes of movement at either end of the Red Sea are compared. All the evidence indicates that there has been no land connection at the southern end since the beginning of the Pliocene period, but that short sea crossings would have been possible at lowest sea-level stands with little or no technical aids. More important than the possibilities of crossing the southern channel is the nature of the resources available in the adjacent coastal zones. There were many climatic episodes wetter than today, and during these periods water draining from the Arabian escarpment provided productive conditions for large mammals and human populations in coastal regions and eastwards into the desert. During drier episodes the coastal region would have provided important refugia both in upland areas and on the emerged shelves exposed by lowered sea level, especially in the southern sector and on both sides of the Red Sea. Marine resources may have offered an added advantage in coastal areas, but evidence for their exploitation is very limited, and their role has been over-exaggerated in hypotheses of coastal colonization

Advancing the Role of Proton Therapy for Spine Metastases Through Diagnostic Scan–Based Planning

Purpose: Many patients with metastatic cancer live years beyond diagnosis, and there remains a need to improve the therapeutic ratio of metastasis-directed radiation for these patients. This study aimed to assess a process for delivering cost-effective palliative proton therapy to the spine using diagnostic scan–based planning (DSBP) and prefabricated treatment delivery devices. Materials and Methods: We designed and characterized a reusable proton aperture system that adjusts to multiple lengths for spine treatment. Next, we retrospectively identified 10 patients scan treated with thoracic proton therapy who also had a diagnostic computed tomography within 4 months of simulation. We contoured a T6-T9 target volume on both the diagnostic scans (DS) and simulation scans (SS). Using the aperture system, we generated proton plans on the DS using a posterior–anterior beam with no custom range compensator to treat T6-T9 to 8 Gy × 1. Plans were transferred to the SS to compare coverage and normal tissue doses, followed by robustness analysis. Finally, we compared normal tissue doses and costs between proton and photon plans. Results were compared using the Wilcoxon signed-rank test. Results: Median D95% on the DS plans was 101% (range, 100%–102%) of the prescription dose. Median Dmax was 107% (range, 105%–108%). When transferred to SS, coverage and hot spots remained acceptable for all cases. Heart and esophagus doses did not vary between the DS and SS proton plans (P >.2). Robustness analysis with 5 mm X/Y/Z shifts showed acceptable coverage (D95% > 98%) for all cases. Compared with the proton plans, the mean heart dose was higher for both anterior–posterior/posterior–anterior and volumetric modulated arc therapy plans (P < .01). Cost for proton DSBP was comparable to more commonly used photon regimens. Conclusion: Proton DSBP is technically feasible and robust, with superior sparing of the heart compared with photons. Eliminating simulation and custom devices increases the value of this approach in carefully selected patients

Developing risk prediction models for type 2 diabetes: a systematic review of methodology and reporting

<p>Abstract</p> <p>Background</p> <p>The World Health Organisation estimates that by 2030 there will be approximately 350 million people with type 2 diabetes. Associated with renal complications, heart disease, stroke and peripheral vascular disease, early identification of patients with undiagnosed type 2 diabetes or those at an increased risk of developing type 2 diabetes is an important challenge. We sought to systematically review and critically assess the conduct and reporting of methods used to develop risk prediction models for predicting the risk of having undiagnosed (prevalent) or future risk of developing (incident) type 2 diabetes in adults.</p> <p>Methods</p> <p>We conducted a systematic search of PubMed and EMBASE databases to identify studies published before May 2011 that describe the development of models combining two or more variables to predict the risk of prevalent or incident type 2 diabetes. We extracted key information that describes aspects of developing a prediction model including study design, sample size and number of events, outcome definition, risk predictor selection and coding, missing data, model-building strategies and aspects of performance.</p> <p>Results</p> <p>Thirty-nine studies comprising 43 risk prediction models were included. Seventeen studies (44%) reported the development of models to predict incident type 2 diabetes, whilst 15 studies (38%) described the derivation of models to predict prevalent type 2 diabetes. In nine studies (23%), the number of events per variable was less than ten, whilst in fourteen studies there was insufficient information reported for this measure to be calculated. The number of candidate risk predictors ranged from four to sixty-four, and in seven studies it was unclear how many risk predictors were considered. A method, not recommended to select risk predictors for inclusion in the multivariate model, using statistical significance from univariate screening was carried out in eight studies (21%), whilst the selection procedure was unclear in ten studies (26%). Twenty-one risk prediction models (49%) were developed by categorising all continuous risk predictors. The treatment and handling of missing data were not reported in 16 studies (41%).</p> <p>Conclusions</p> <p>We found widespread use of poor methods that could jeopardise model development, including univariate pre-screening of variables, categorisation of continuous risk predictors and poor handling of missing data. The use of poor methods affects the reliability of the prediction model and ultimately compromises the accuracy of the probability estimates of having undiagnosed type 2 diabetes or the predicted risk of developing type 2 diabetes. In addition, many studies were characterised by a generally poor level of reporting, with many key details to objectively judge the usefulness of the models often omitted.</p

Global economic burden of unmet surgical need for appendicitis

Background: There is a substantial gap in provision of adequate surgical care in many low-and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods: Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results: Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion: For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially