Mutation analyses of Uroplakin II in children with renal tract malformations.

BACKGROUND: Uroplakin (UP) proteins cover urothelial apical surfaces. Mice lacking UPIIIa have elevated urothelial permeability and congenital renal tract anomalies, and UPIIIa mutations have been reported in children with kidney and ureter malformations. Mice with null mutation of another UP family member, UPII, are often born with congenital hydronephrosis. We hypothesized that UPII mutations may be present in humans with renal tract malformations. METHODS: Mutations were sought, using direct sequencing of the five UPII exons, in 42 children with diverse renal tract anomalies. RESULTS: No UPII abnormalities were detected in 41 patients, whereas one index case had a heterozygous frameshift change which, if expressed, would generate a truncated protein. This Caucasian child presented with vesicoureteric reflux (VUR), bilateral nephropathy and renal failure. The genetic change was also found in the index case's mother who had normal renal ultrasonography, but it was absent in 150 healthy Caucasian control individuals (96 assessed by direct sequencing and another 54 assessed by restriction digests). UPII was immunolocalized in urothelium of the normal human embryonic renal pelvis in a pattern similar to UPIIIa. CONCLUSION: This study offers no definitive support for UPII mutations causing human renal tract malformations. In rare patients, UPII variants might be implicated in pathogenesis when acting in conjunction with other yet-to-be-defined, genetic or environmental modifying factors.     

Anxiety in medical students: is preparation for full‐time clinical attachments more dependent upon differences in maturity or on educational programmes for undergraduate and graduate entry students?

INTRODUCTION: The transition to full-time clinical studies holds anxieties for most medical students. While graduate entry medical education has only recently begun in the UK, the parallel undergraduate and graduate entry MBBS courses taught at our school allowed us to study how 2 differently prepared groups perceived this vital time at a comparable stage in their training. METHOD: An anonymous questionnaire collected demographic data and graded anxiety in 13 statements relating to starting full-time clinical attachments. Two open questions allowed free text comment on the most positive and negative influences perceived during this time. Both a statistical analysis and a qualitative assessment were performed to compare the 2 groups of students. RESULTS: The 2 groups were similar with respect to gender but the graduate entry students were significantly older. The graduate entry students were significantly less anxious about most aspects of the transition period compared to the undergraduates. These course differences remained after adjusting for age and sex. When adjusted for course and age, male students expressed less anxiety. The main positive qualitative statements related to continual clinical and communication skills training in the graduate entry group. The main qualitative concerns in both groups related to 'fitting in' and perceived lack of factual knowledge. DISCUSSION: These data support the early introduction of clinical skills teaching, backed up by a fully integrated clinically relevant curriculum with continued assessment, in preparing students and reducing levels of anxiety before they start full-time clinical attachments. These course design differences appear to be more important than any differences in maturity between the 2 groups.     

Whole-Genome Linkage and Association Scan in Primary,Nonsyndromic Vesicoureteric Reflux

Primary vesicoureteric reflux accounts for approximately 10% of kidney failure requiring dialysis or transplantation, and sibling studies suggest a large genetic component. Here, we report a whole-genome linkage and association scan in primary, nonsyndromic vesicoureteric reflux and reflux nephropathy. We used linkage and family-based association approaches to analyze 320 white families (661 affected individuals, generally from families with two affected siblings) from two populations (United Kingdom and Slovenian). We found modest evidence of linkage but no clear overlap with previous studies. We tested for but did not detect association with six candidate genes (AGTR2, HNF1B, PAX2, RET, ROBO2, and UPK3A). Family-based analysis detected associations with one single-nucleotide polymorphism (SNP) in the UK families, with three SNPs in the Slovenian families, and with three SNPs in the combined families. A case-control analysis detected associations with three additional SNPs. The results of this study, which is the largest to date investigating the genetics of reflux, suggest that major loci may not exist for this common renal tract malformation within European populations.Vesicoureteric reflux (VUR) is abnormal movement of urine from the bladder retrogradely through the vesicoureteric junctions into the upper urinary tract. This is a study of primary VUR, i.e., VUR that is not secondary to bladder outflow obstruction caused by neurogenic damage or urethral valves or part of a multiorgan syndrome. VUR is usually a benign condition but can be associated with transient kidney damage, acute inflammation from ascending pyelonephritis, or permanent damage as a consequence of scarring after infection and/or congenital kidney defects histologically comprising renal hypoplasia (too few nephrons) and/or renal dysplasia (incomplete differentiation).^1–3 These renal defects are grouped under the term reflux nephropathy (RN). In the United Kingdom, RN accounts for 12% of the approximately 40,000 adults and 7% of the 768 children who require renal transplantation and/or life-long dialysis.⁴Traditionally, the diagnosis of VUR has been based on cystography with radiodense or radioisotopic materials to visualize retrograde passage of urine. Williams et al.³ reviewed 15 cystography studies in well children: The largest study reported no VUR in 722 children, whereas some of the smaller studies reported much higher percentages of affected individuals. The true prevalence of (primary) VUR in children remains uncertain: 1% is probably conservative, and 10 to 20% is possible.³ Screening studies of first-degree relatives of individuals with VUR identifies reflux in one third to one half of siblings^5,6 and 65% of offspring.⁷ Futhermore, there is a high concordance of primary VUR in identical twins,⁸ and families have been identified with multiple generations affected by primary VUR and RN.⁹ Collectively, these studies suggest that there is a substantial genetic component to VUR.The first genome-wide linkage analysis for VUR, based on seven kindreds,⁹ provided preliminary evidence for a locus on chromosome 1 and also for genetic heterogeneity. In this study, multipoint parametric and nonparametric linkage analysis was undertaken; however, one of the markers defining the interval on chromosome 1, GATA176C01, was subsequently found to be on chromosome 2 (Ensembl release 55, July 2009), so this localization should be treated with caution. Subsequent studies using similar kindreds^10–12 have supported the notion that the condition is genetically heterogeneous. In the largest linkage study of VUR before this report, Kelly et al.¹³ performed a linkage genome scan of 609 individuals (283 affected individuals in 129 families) and detected six to seven regions with suggestive evidence of linkage,¹⁴ one of which at chromosome 2q37 attained genome-wide significance when analyzed in a phenotypically derived subset of the data. The high incidence in offspring of affected individuals and the large number of pedigrees consistent with autosomal dominant inheritance, albeit with reduced penetrance, is in keeping with a dominant model; however, recently, a locus was identified on 12p11-q13 using a recessive model.¹⁵Here we report on linkage and association analysis in affected sibling pairs from two populations. We used the Affymetrix NspI array to generate genome-wide data, adding in haplotype-tagging single-nucleotide polymorphisms (SNPs) to obtain full coverage for six candidate genes: AGTR2, HNF1B, PAX2, RET, ROBO2, and UPK3A.¹⁶     

Effects of Feeding on Respiratory Mechanics of Healthy Newborn Infants

Methods for the study of respiratory mechanics of the newborn infant are described. In 20 healthy neonates, small feeds had no adverse effect on respiratory mechanics.     

EYE SYMPTOMS IN BRAIN TUMORS*

“An education isn't how much you have committed to memory, or even how much you know; it's being able to differentiate between what you know and what you don't.”     

Interleukin 4 is localized to and released by human mast cells

Recent attention has focused on the T helper type 2 (Th2) lymphocyte as a source of interleukin 4 (IL-4) in allergic disease. However, Th2 cells themselves require a pulse of IL-4 to initiate this synthesis. Here we provide immunohistochemical evidence of IL-4 localization to human mast cells of the skin and respiratory tract, and demonstrate that immunoglobulin E-dependent stimulation of purified human lung mast cells leads to the rapid release of IL-4 into the extracellular environment. We propose that mast cell activation in an allergic response provides a rapid and local pulse of IL-4 into the local environment essential for the triggering of T lymphocytes into sustained IL-4 production and to initiate inflammatory cell accumulation and activation.