Mutations in protocadherin 15 and cadherin 23 affect tip links and mechanotransduction in mammalian sensory hair cells

Immunocytochemical studies have shown that protocadherin-15 (PCDH15) and cadherin-23 (CDH23) are associated with tip links, structures thought to gate the mechanotransducer channels of hair cells in the sensory epithelia of the inner ear. The present report describes functional and structural analyses of hair cells from Pcdh15av3J (av3J), Pcdh15av6J (av6J) and Cdh23v2J (v2J) mice. The av3J and v2J mice carry point mutations that are predicted to introduce premature stop codons in the transcripts for Pcdh15 and Cdh23, respectively, and av6J mice have an in-frame deletion predicted to remove most of the 9th cadherin ectodomain from PCDH15. Severe disruption of hair-bundle morphology is observed throughout the early-postnatal cochlea in av3J/av3J and v2J/v2J mice. In contrast, only mild-to-moderate bundle disruption is evident in the av6J/av6J mice. Hair cells from av3J/av3J mice are unaffected by aminoglycosides and fail to load with [3H]-gentamicin or FM1-43, compounds that permeate the hair cell's mechanotransducer channels. In contrast, hair cells from av6J/av6J mice load with both FM1-43 and [3H]-gentamicin, and are aminoglycoside sensitive. Transducer currents can be recorded from hair cells of all three mutants but are reduced in amplitude in all mutants and have abnormal directional sensitivity in the av3J/av3J and v2J/v2J mutants. Scanning electron microscopy of early postnatal cochlear hair cells reveals tip-link like links in av6J/av6J mice, substantially reduced numbers of links in the av3J/av3J mice and virtually none in the v2J/v2J mice. Analysis of mature vestibular hair bundles reveals an absence of tip links in the av3J/av3J and v2J/v2J mice and a reduction in av6J/av6J mice. These results therefore provide genetic evidence consistent with PCDH15 and CDH23 being part of the tip-link complex and necessary for normal mechanotransduction

Toxocariasis: a silent threat with a progressive public health impact

Background: Toxocariasis is a neglected parasitic zoonosis that afflicts millions of the pediatric and adolescent populations worldwide, especially in impoverished communities. This disease is caused by infection with the larvae of Toxocara canis and T. cati, the most ubiquitous intestinal nematode parasite in dogs and cats, respectively. In this article, recent advances in the epidemiology, clinical presentation, diagnosis and pharmacotherapies that have been used in the treatment of toxocariasis are reviewed. Main text: Over the past two decades, we have come far in our understanding of the biology and epidemiology of toxocariasis. However, lack of laboratory infrastructure in some countries, lack of uniform case definitions and limited surveillance infrastructure are some of the challenges that hindered the estimation of global disease burden. Toxocariasis encompasses four clinical forms: visceral, ocular, covert and neural. Incorrect or misdiagnosis of any of these disabling conditions can result in severe health consequences and considerable medical care spending. Fortunately, multiple diagnostic modalities are available, which if effectively used together with the administration of appropriate pharmacologic therapies, can minimize any unnecessary patient morbidity. Conclusions: Although progress has been made in the management of toxocariasis patients, there remains much work to be done. Implementation of new technologies and better understanding of the pathogenesis of toxocariasis can identify new diagnostic biomarkers, which may help in increasing diagnostic accuracy. Also, further clinical research breakthroughs are needed to develop better ways to effectively control and prevent this serious disease

QCD and strongly coupled gauge theories : challenges and perspectives

We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.Peer reviewe

The personalisation of the fetus or, 'He looks just like his father!'

OBJETIVO: Avaliar a magnitude, a distribuição espacial e a tendência temporal da anemia em pré-escolares no Estado da Paraíba, Brasil. MÉTODOS: Corte transversal com amostra aleatória, do tipo multietapas, em oito cidades da zona urbana, de três mesorregiões do Estado da Paraíba, no ano de 1992, pela qual foram selecionados aleatoriamente 1.287 pré-escolares de ambos os sexos. A hemoglobina foi dosada pelo método da cianometa-hemoglobina em sangue venoso, empregando <11,0 g/dl como ponto de corte para anemia. A análise estatística de proporções incluiu o teste do qui-quadrado e a de médias, os de Mann-Whitney e Kruskal-Wallis, com intervalo de confiança de 95%. RESULTADOS: A prevalência da anemia no Estado da Paraíba foi de 36,4% (IC 33,7-39,1), maior (p= 0,00) do que a de 1982, que foi de 19,3% (IC 17,3-21,5). Apenas 1,0% (IC 0,6-1,8) e 6,8% (IC 5,5-8,3) dos casos de anemia foram categorizados nas formas grave e moderada, respectivamente. Crianças do sexo masculino apresentaram concentrações médias de hemoglobina mais baixas (p=0,00), e crianças menores de três anos constituíram o grupo biológico de maior suscetibilidade ao desenvolvimento do quadro carencial (p=0,00). O segundo ano de vida mostrou-se como o período vital mais crítico à exacerbação da deficiência nutricional (p=0,00). A mesorregião do Agreste configurou-se como o espaço geográfico de maior risco (p=0,00), desenhando uma outra dinâmica epidemiológica do problema, comparada àquela de 1982, em que a mesorregião do Sertão representava a área geográfica de maior risco para a deficiência. CONCLUSÕES: Os resultados mostraram que a anemia é um problema de saúde pública do tipo moderado, segundo os critérios internacionais para caracterizar a endemia em escala epidemiológica. Admitindo-se a comparabilidade entre os dois cortes transversais em análise, concluiu-se pelo caráter evolutivo ascendente na prevalência da anemia nutricional (+88,5%) em todas as três mesorregiões, no período de 10 anos, entre 1982-1992