The Y chromosome provides a unique opportunity to study mutational processes within the human genome, decoupled from the confounding eVects of interchromosomal recombination. It has been suggested that the increased density of certain dispersed repeats on the Y could account for the high frequency of causative microdeletions relative to single nucleotide mutations in infertile males. Previously we localised breakpoints of an AZFa microdeletion close to two highly homologous complete human endogenous retroviral sequences (HERV), separated by 700 kb. Here we show, by sequencing across the breakpoint, that the microdeletion occurs in register within a highly homologous segment between the HERVs. Furthermore, we show that recurrent double crossovers have occurred between the HERVs, resulting in the loss of a 1.5 kb insertion from one HERV, an event underlying the first ever Y chromosomal polymorphism described, the 12f2 deletion. This event produces a substantially longer segment of absolute homology and as such may result in increased predisposition to further intrachromosomal recombination. Intrachromosomal crosstalk between these two HERV sequences can thus result in either homogenising sequence conversion or a microdeletion causing male infertility. This represents a major subclass of AZFa deletions. (J Med Genet 2000;37:752-758)

Protocadherins are members of the cadherin superfamily involved in cell-cell interactions critical in the development of the central nervous system. This paper describes the isolation, sequence, and expression analysis of two novel protocadherin genes from the hominid specific Yp11.2/Xq21.3 block of homology between the sex chromosomes. The X-(PCDHX) and Y-linked (PCDHY) genes share 98.1% nucleotide and 98.3% amino acid identity and have an identical gene structure of six exons. The open reading frames of PCDHX and PCDHY encode proteins of 1025 and 1037 amino acids respectively and specify seven extracellular cadherin domains. Small differences in amino acid sequence affect regions that potentially have a large impact on function: thus, the X and Y genes may be differentiated in this respect. Sequence analysis of cDNA clones shows that both the X and Y loci are transcribed. RT-PCR expression analysis of mRNA from a variety of tissues and cell lines has demonstrated that both transcripts are expressed predominantly in the brain, with differential regional expression. From studies in the NTERA pluripotential cell line (which differentiates along neuronal and spermatogenic pathways in response to retinoic acid), it emerges that the X and Y-linked genes are regulated differently. This indicates that PCDHX and PCDHY possess different promoter regions. These findings suggest a role for PCDHX and PCDHY in the brain, consistent with the involvement of protocadherins in segmental brain morphogenesis and function. The implications of Y-linked genes expressed predominantly in tissues and organs other than the testis are considered within the context of the concept of sexual selection.

BackgroundLong-term inhaled corticosteroids (ICS) may reduce growth velocity and final height of children with asthma. We aimed to evaluate the association between ICS use of >12 months and growth.MethodsWe initially searched MEDLINE and EMBASE in July 2013, followed by a PubMed search updated to December 2014. We selected RCTs and controlled observational studies of ICS use in patients with asthma. We conducted random effects meta-analysis of mean differences in growth velocity (cm/year) or final height (cm) between groups. Heterogeneity was assessed using the I2 statistic.ResultsWe found 23 relevant studies (twenty RCTs and three observational studies) after screening 1882 hits. Meta-analysis of 16 RCTs showed that ICS use significantly reduced growth velocity at one year follow-up (mean difference -0.48 cm/year (95% CI -0.66 to -0.29)). There was evidence of a dose-response effect in three RCTs. Final adult height showed a mean reduction of -1.20 cm (95% CI -1.90 cm to -0.50 cm) with budesonide versus placebo in a high quality RCT. Meta-analysis of two lower quality observational studies revealed uncertainty in the association between ICS use and final adult height, pooled mean difference -0.85 cm (95% CI -3.35 to 1.65).ConclusionUse of ICS for >12 months in children with asthma has a limited impact on annual growth velocity. In ICS users, there is a slight reduction of about a centimeter in final adult height, which when interpreted in the context of average adult height in England (175 cm for men and 161 cm for women), represents a 0.7% reduction compared to non-ICS users.

Background Despite modern antimicrobials and supportive therapy, bacterial and fungal infections are still major complications in people with prolonged disease-related or therapy-related neutropenia. Since the late 1990s there has been increasing demand for donated granulocyte transfusions to treat or prevent severe infections in people who lack their own functional granulocytes. This is an update of a Cochrane review first published in 2009. Objectives To determine the effectiveness and safety of prophylactic granulocyte transfusions compared with a control population not receiving this intervention for preventing all-cause mortality, mortality due to infection, and evidence of infection due to infection or due to any other cause in people with neutropenia or disorders of neutrophil function. Search methods We searched for randomised controlled trials (RCTs) and quasi-RCTs in the Cochrane Central Register of Controlled Trials (Cochrane Library 2015, Issue 3), MEDLINE (from 1946), EMBASE (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1980) and ongoing trial databases to April 20 2015. Selection criteria Randomised controlled trials (RCTs) and quasi-RCTs comparing people receiving granulocyte transfusions to prevent the development of infection with a control group receiving no granulocyte transfusions. Neonates are the subject of another Cochrane review and were excluded from this review. There was no restriction by outcomes examined, but this review focuses on mortality, mortality due to infection and adverse events. Data collection and analysis We used standard methodological procedures expected by The Cochrane Collaboration. Main results Twelve trials met the inclusion criteria. One trial is still ongoing, leaving a total of 11 trials eligible involving 653 participants. These trials were conducted between 1978 and 2006 and enrolled participants from fairly comparable patient populations. None of the studies included people with neutrophil dysfunction. Ten studies included only adults, and two studies included children and adults. Ten of these studies contained separate data for each arm and were able to be critically appraised. One study re-randomised people and therefore quantitative analysis was unable to be performed. Overall, the quality of the evidence was very low to low across different outcomes according to GRADE methodology. This was due to many of the studies being at high risk of bias, and many of the outcome estimates being imprecise. All-cause mortality was reported for nine studies (609 participants). There was no difference in all-cause mortality over 30 days between people receiving prophylactic granulocyte transfusions and those that did not (seven studies; 437 participants; RR 0.92, 95% CI 0.63 to 1.36, very low-quality evidence). Mortality due to infection was reported for seven studies (398 participants). There was no difference in mortality due to infection over 30 days between people receiving prophylactic granulocyte transfusions and those that did no...