Variations in PROKR2, but not PROK2, are associated with hypopituitarism and septo-optic dysplasia.

Context: Loss-of-function mutations in PROK2 and PROKR2 have been implicated in Kallmann syndrome (KS), characterized by hypogonadotropic hypogonadism and anosmia. Recent data suggest overlapping phenotypes/genotypes between KS and congenital hypopituitarism (CH), including septo-optic dysplasia (SOD).

Objective: We screened a cohort of patients with complex forms of CH (n = 422) for mutations in PROK2 and PROKR2.

Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder caused by cilia and sperm dysmotility. About 12% of cases show perturbed 9+2 microtubule cilia structure and inner dynein arm (IDA) loss, historically termed "radial spoke defect." We sequenced CCDC39 and CCDC40 in 54 "radial spoke defect" families, as these are the two genes identified so far to cause this defect.

Variation in recorded child maltreatment concerns in UK primary care records: a cohort study using The Health Improvement Network (THIN) database.

Objectives: To determine variation over time and between practices in recording of concerns related to abuse and neglect (maltreatment) in children's primary care records.

Design: Retrospective cohort study using a United Kingdom representative primary care database.

Setting: 448 General Practices.

Childhood psychosocial adversity and adult cortisol patterns.

Background: Cortisol levels may be altered in childhood in association with maltreatment (neglect, abuse and witnessing abuse) and other adversities, yet little is known about whether effects on cortisol persist into later life.

Aims: To establish whether childhood psychosocial adversities predict cortisol levels in mid-adulthood.

Method: Childhood psychosocial adversities were ascertained in the 1958 British birth cohort and cortisol was measured in two saliva samples, one 45 min after awaking (T(1)) and the other 3 h later the same day (T(2)), from 6524 participants aged 45 years.

Analysis of LIN28A in early human ovary development and as a candidate gene for primary ovarian insufficiency.

Lin28 proteins are emerging as important regulators of microRNAs in endocrine systems. Lin28a regulates primordial germ cell development and puberty timing in mice, whereas the related protein LIN28B is associated with age at menarche in genome-wide association studies in humans. Here, we studied expression of LIN28A and LIN28B in early human gonad development.

Acclimatization of skeletal muscle mitochondria to high-altitude hypoxia during an ascent of Everest.

Ascent to high altitude is associated with a fall in the partial pressure of inspired oxygen (hypobaric hypoxia). For oxidative tissues such as skeletal muscle, resultant cellular hypoxia necessitates acclimatization to optimize energy metabolism and restrict oxidative stress, with changes in gene and protein expression that alter mitochondrial function. It is known that lowlanders returning from high altitude have decreased muscle mitochondrial densities, yet the underlying transcriptional mechanisms and time course are poorly understood.

Cytoskeletal remodeling mediated by WASp in dendritic cells is necessary for normal immune synapse formation and T-cell priming.

Rearrangement of the cytoskeleton in T cells plays a critical role in the organization of a complex signaling interface referred to as immunologic synapse (IS). Surprisingly, the contribution of antigen presenting cells, in particular dendritic cells (DCs), to the structure and function of the IS has not been investigated in as much detail. We have used a natural model of cytoskeletal dysfunction caused by deficiency of the Wiskott-Aldrich syndrome protein (WASp) to explore the contribution of the DC cytoskeleton to IS formation and to T-cell priming.

Rest-activity disturbances in children with septo-optic dysplasia characterized by actigraphy and 24-hour plasma melatonin profiles.

Introduction: A trial of melatonin treatment in children with septo-optic dysplasia (SOD) and sleep disruption is accepted clinical practice in many centers. However, no objective measurements of sleep/activity patterns with 24-h melatonin profiles have been published for these individuals, and the pathophysiological basis underlying sleep disorders in SOD remains largely unknown.

Methods: We studied six children with rest-activity disturbances and SOD.

IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy.

Jeune asphyxiating thoracic dystrophy, an autosomal recessive chondrodysplasia, often leads to death in infancy because of a severely constricted thoracic cage and respiratory insufficiency; retinal degeneration, cystic renal disease and polydactyly may be complicating features. We show that IFT80 mutations underlie a subset of Jeune asphyxiating thoracic dystrophy cases, establishing the first association of a defective intraflagellar transport (IFT) protein with human disease. Knockdown of ift80 in zebrafish resulted in cystic kidneys, and knockdown in Tetrahymena thermophila produced shortened or absent cilia.