We're in this Together: Sensation of the Host Cell Environment by Endosymbiotic Bacteria

Bacteria inhabit diverse environments, including the inside of eukaryotic cells. While a bacterial invader may initially act as a parasite or pathogen, a subsequent mutualistic relationship can emerge in which the endosymbiotic bacteria and their host share metabolites. While the environment of the host cell provides improved stability when compared to an extracellular environment, the endosymbiont population must still cope with changing conditions, including variable nutrient concentrations, the host cell cycle, host developmental programs, and host genetic variation. Furthermore, the eukaryotic host can deploy mechanisms actively preventing a bacterial return to a pathogenic state. Many endosymbionts are likely to use two-component systems (TCSs) to sense their surroundings, and expanded genomic studies of endosymbionts should reveal how TCSs may promote bacterial integration with a host cell. We suggest that studying TCS maintenance or loss may be informative about the evolutionary pathway taken toward endosymbiosis, or even toward endosymbiont-to-organelle conversion.Peer reviewe

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8–13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05–6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50–75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life. Funding Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron

Funcionalidade e incapacidade humana: explorando o escopo da classificação internacional da Organização Mundial da Saúde Human functioning and disability: exploring the scope of the World Health Organization's international classification

A produção teórica sobre incapacidade se apresenta dicotomizada nas perspectivas médica e social. O modelo biomédico foca a deficiência, doença ou anormalidade corporal e como esses fatores produzem incapacidade. A abordagem social sugere que o significado de deficiência e incapacidade emerge de contextos sociais e culturais específicos. A OMS criou a Classificação Internacional de Funcionalidade, Incapacidade e Saúde (CIF), que traz um sistema de classificação e modelo teórico baseados na junção dos modelos médico e social e usa uma abordagem biopsicossocial para integrar as dimensões da saúde. Apesar da importância e atualidade da CIF, alguns conceitos foram pouco detalhados e justificados, podendo ocasionar interpretações distintas. Propõe-se com este ensaio descrever o modelo da CIF e analisar o alcance da teoria biopsicossocial para explorar a natureza relacional das categorias deficiência e incapacidade, bem como o caráter universal da proposta da OMS. Um dos aspectos mais positivos da CIF é trazer à baila a natureza interativa da incapacidade e a divisão do fenômeno em três dimensões, mostrando o grau de complexidade do processo de funcionalidade e incapacidade humana.<br>The theoretical discussion on disability is dichotomized according to the medical and social perspectives. The biomedical model focuses on impairment, disease, or physical abnormality and how these factors produce disability. The social approach suggests that the meaning of disability and impairment emerges from specific social and cultural contexts. The WHO created the International Classification of Functioning, Disability and Health (ICF), with a classification system and theoretical model based on the combination of the medical and social models and using a biopsychosocial approach to integrate the health dimensions. Despite the importance and immediacy of the ICF, some concepts were insufficiently detailed and justified and could lead to distinct interpretations. This essay proposes to describe the ICF model and analyze the scope of the biopsychosocial theory for exploring the relational nature of the "disability" and "impairment" categories, as well as the universal nature of the WHO proposal. One of the most positive aspects of the ICF is to highlight the interactive nature of disability and the division of the phenomenon into three dimensions, thus demonstrating the degree of complexity in the process of human functioning and disability

PDCD10 Gene Mutations in Multiple Cerebral Cavernous Malformations

Abstract Cerebral cavernous malformations (CCMs) are vascular abnormalities that may cause seizures, intracerebral haemorrhages, and focal neurological deficits. Familial form shows an autosomal dominant pattern of inheritance with incomplete penetrance and variable clinical expression. Three genes have been identified causing familial CCM: KRIT1/CCM1, MGC4607/ CCM2, and PDCD10/CCM3. Aim of this study is to report additional PDCD10/CCM3 families poorly described so far which account for 10-15% of hereditary cerebral cavernous malformations. Our group investigated 87 consecutive Italian affected individuals (i.e. positive Magnetic Resonance Imaging) with multiple/familial CCM through direct sequencing and Multiplex Ligation-Dependent Probe Amplification (MLPA) analysis. We identified mutations in over 97.7% of cases, and PDCD10/ CCM3 accounts for 13.1%. PDCD10/CCM3 molecular screening revealed four already known mutations and four novel ones. The mutated patients show an earlier onset of clinical manifestations as compared to CCM1/CCM2 mutated patients. The study of further families carrying mutations in PDCD10/CCM3 may help define a possible correlation between genotype and phenotype; an accurate clinical follow up of the subjects would help define more precisely whether mutations in PDCD10/ CCM3 lead to a characteristic phenotype

Bases conceituais para uma estratégia de gestão: o caso da Rede Nacional de Bancos de Leite Humano The management strategy of the Brazilian National Network of Human Milk Banks

A Rede Nacional de Bancos de Leite Humano (REDEBLH), com sede na Fundação Oswaldo Cruz, experimenta rápido desenvolvimento. O trabalho desenvolvido foi reconhecido pela Organização Mundial de Saúde e distinguido, com o prêmio Sasakawa de Saúde - 2001, como o melhor projeto de saúde pública dentre os apresentados. Um dos grandes desafios atuais é dar continuidade ao desenvolvimento de competências que respondam aos desafios decorrentes de seu crescimento. Na realidade, busca-se uma nova estratégia de pensar as questões relacionadas a sua gestão. Este artigo tem como objetivos desenvolver um marco conceitual que possa contribuir para elaboração de um quadro teórico para novas estratégias de gestão da REDEBLH. Através da utilização de conceitos, busca-se, à luz da tipologia de redes descrita na literatura especializada, identificar o perfil institucional da REDEBLH. A partir do entendimento de que é necessário identificar e compreender os processos que ocorrem no âmbito das redes para então pensar as questões relacionadas a sua gestão, foi utilizada como instrumento de análise proposta desenvolvida para formação de redes de inovação.<br>The Brazilian National Network of Human Milk Banks (REDEBLH), with its headquarters in the Oswaldo Cruz Foundation in Rio de Janeiro, is experiencing rapid growth. The Network's activity has been acknowledged by the World Health Organization and received the Sasakawa Health Award in 2001 for best public health project. One of the main challenges is to ensure continuing development of competencies to respond to the needs arising from such growth. A new strategy is being pursued to deal with the Network's management issues. This article aims to develop a conceptual framework to contribute to the elaboration of a theoretical framework for new management strategies in the REDEBLH. Using such concepts, the aim is to draw on the typology of networks described in the specialized literature to identify the institutional profile of the REDEBLH. Based on the understanding that it is necessary to identify and understand the processes occurring within networks, and after which to consider management-related issues, the study used a proposal developed for the formation of innovation networks as its analytical tool

Frequency and risk factors of mitoxantrone-induced amenorrhea in multiple sclerosis: the FEMIMS study

Improved prognosis in women with multiple sclerosis (MS) undergoing immunosuppressive treatment with mitoxantrone (MITO) has led to an increased interest in the effect of such treatments on fertility. FErtility and Mitoxantrone In MS (FEMIMS) is a collaborative retrospective study aimed at evaluating the impact of MITO treatment on fertility in women with MS