Fibro-Adipogenic Progenitors: Versatile keepers of skeletal muscle homeostasis, beyond the response to myotrauma.

While Fibro-Adipogenic Progenitors (FAPs) have been originally identified as muscle-interstitial mesenchymal cells activated in response to muscle injury and endowed with inducible fibrogenic and adipogenic potential, subsequent studies have expanded their phenotypic and functional repertoire and revealed their contribution to skeletal muscle response to a vast range of perturbations. Here we review the emerging contribution of FAPs to skeletal muscle responses to motor neuron injuries and to systemic physiological (e.g., exercise) or pathological metabolic (e.g., diabetes) perturbations. We also provide an initial blueprint of discrete sub-clusters of FAPs that are activated by specific perturbations and discuss their role in muscle adaptation to these conditions.

The impact of reclassification of C3 predominant glomerulopathies on diagnostic accuracy, outcome and prognosis in patients with C3 glomerulonephritis.

BACKGROUND: C3 glomerulonephritis is a recently described entity with heterogeneous histopathological features. This study was conducted to assess the effect of reclassification of C3 glomerulopathies on renal outcomes, mortality, and response to therapy. METHODS: We undertook a retrospective analysis of 857 renal biopsies collected at The Canberra Hospital. Samples with predominant C3 staining were reviewed by a renal histopathologist. Of 31 biopsies with predominant C3 staining, 10 fulfilled histological criteria for C3 glomerulonephritis, while the remaining 21 cases were used as C3 Controls. RESULTS: Aside from a higher incidence of C3 glomerulonephritis in Torres Strait islanders (40% vs 5% C3 Controls, p = 0.04), presentation demographics were similar between the two groups. Median creatinine at diagnosis was higher in patients with C3 glomerulonephritis (253 umol/L IQR 103-333 vs 127 umol/L C3 Controls, IQR 105-182, p = 0.01). Prior to reclassification, a majority of C3 glomerulonephritis cases were diagnosed as membranoproliferative glomerulonephritis (60% vs 5% (C3 Controls) p < 0.01). Electron microscopy demonstrated all C3 glomerulonephritis patients had C3 deposition (100% vs 38% p = 0.02), these deposits were amorphous in nature (50% vs 5% respectively p = 0.007). C3 glomerulonephritis patients had shorter median follow-up (405 days IQR 203-1197 vs 1822 days respectively, IQR 1243-3948, p = 0.02). Mortality was higher in C3 glomerulonephritis patients (30% vs 14% in C3 Controls (log rank p = 0.02)). CONCLUSION: We have devised a diagnostic and treatment algorithm based on the results of literature review and our current study. Further prospective assessment is required to review diagnostic and treatment outcomes for this disease in Australian centres.

Inflammatory bowel disease in patients with Hirschsprung's disease: a systematic review and meta-analysis.

AIM AND OBJECTIVES: Hirschsprung-associated enterocolitis (HAEC) continues to be an important cause of morbidity in patients with Hirschsprung's disease (HSCR). HAEC can occur at any time during the course of the disease. The reported incidence of HAEC before surgery ranges from 6 to 50%, and after surgery, it ranges from 2 to 35%. HAEC and inflammatory bowel disease (IBD) have similar clinical presentation including diarrhea, hematochezia, and abdominal pain. In recent years, isolated cases of IBD have been reported in patients who had surgical treatment for HSCR. The exact pathogenesis of HAEC or IBD is not known. However, both conditions are characterized by an abnormal intestinal mucosal barrier function, which may be a common pathway. The purpose of this meta-analysis was to determine the clinical presentation and outcome in patients with HSCR who developed IBD after pull-through operation. MATERIALS AND METHODS: A systematic literature search for relevant articles was performed in four databases using the combinations of the following terms "inflammatory bowel disease", "Crohn/Crohn's disease", "ulcerative colitis", and "Hirschsprung disease/Hirschsprung's disease" for studies published between 1990 and 2017. The relevant cohorts of HSCR associated with IBD were systematically searched for clinical presentation and outcomes. RESULTS: 14 studies met defined inclusion criteria, reporting a total of 66 patients who had HSCR associated with IBD. Mean age at first operation for HSCR was 5.8 months, mean age at diagnosis of IBD was 7.7 years, and the majority of patients were male (73%). The extent of aganglionosis was total colonic aganglionosis in 41% of patients, long segment in 45%, and rectosigmoid in 14%. The majority of patients underwent a Duhamel procedure (84%) for HSCR. The distribution of IBD was Crohn's disease in 72.3% of patients, ulcerative colitis in 16.9%, and others in 10.8%. Eight articles (47 patients) reported about HAEC, and 22 patients (47%) had experienced HAEC after surgery for HSCR. CONCLUSION: Male patients with extensive colonic aganglionosis who continue to suffer from postoperative HAEC after a Duhamel procedure are more susceptible to develop IBD. Recognition of IBD may be important in the long-term follow-up of HSCR patients who have had postoperative HAEC.

Probiotics for the prevention of Hirschsprung-associated enterocolitis: a systematic review and meta-analysis.

BACKGROUND/PURPOSE: Hirschsprung-associated enterocolitis (HAEC) is a life-threatening complication of Hirschsprung's disease. HAEC is reported to occur in 6-50% of patients preoperatively and in 2-35% postoperatively. The exact cause of HAEC is not fully understood, but disturbances of intestinal microbiota have recently been reported in patients with HAEC. In recent years, the administration of probiotics has been proposed to reduce the incidence of HAEC. We conducted a systematic review and meta-analysis to determine the effect of probiotics on postoperative HAEC. METHODS: A systematic literature search for relevant articles was performed in four databases using the combinations of following terms "probiotics", "microbiota", "enterocolitis", "Lactobacillus", "Bifidobacterium", "Saccharomyces", "Streptococcus", and "Hirschsprung disease/Hirschsprung's disease" for studies published between 2002 and 2017. The relevant cohorts of the effect of probiotics in postoperative patients were systematically searched for clinical outcomes. Odds ratio (OR) or standard mean difference (SMD) with 95% confidence intervals (CI) were calculated using standardized statistical methodology. RESULTS: The search strategy identified 1274 reports. Overall, five studies met defined inclusion criteria, reporting a total of 198 patients. Two studies were prospective multicenter randomized control trials. Lactobacillus, Bifidobacterium, Streptococcus, and Enterococcus were used as probiotics. The incidence of HAEC with/without probiotics was 22.6 and 30.5%, respectively, but this was not statistically different (OR 0.72; 95% CI 0.37-1.39; P = 0.33). CONCLUSION: This study shows that the administration of probiotics was not associated with a significant reduction in the risk of HAEC. Additional studies are required to understand more fully the role of microbiota and complex interactions that cause HAEC. With increasing knowledge of the role of microbiota in HAEC, we are likely to understand better the potential benefits of probiotics in this disease.

Laparoscopic-assisted pull-through operation for Hirschsprung's disease: a systematic review and meta-analysis.

PURPOSE: In the last two decades, laparoscopic-assisted pull-through (LAPT) has gained much popularity in the treatment of Hirschsprung's disease. The aim of this meta-analysis was to determine the long-term outcome of patients treated laparoscopically. METHODS: A systematic literature-based search for relevant cohorts was performed using the terms "Hirschsprung's disease and Laparoscopy", "Laparoscopic-assisted pull-through outcome", "Laparoscopic-assisted Soave pull-through" "Laparoscopic-assisted Swenson pull-through" and Laparoscopic-assisted Duhamel pull-through. The relevant cohorts of laparoscopic operated HD were systematically searched for outcome regarding continence, constipation, secondary surgery related to the laparoscopic approach and enterocolitis. Pooled incidence rates and odds ratios (ORs) with 95 % confidence intervals (CI) were calculated using standardized statistical methodology. RESULTS: Sixteen studies met defined inclusion criteria, reporting a total of 820 patients. All studies were retrospective case series, with variability in outcome assessment quality and length of follow-up. The median cohort size consisted of 28 patients (range 15-218). In the long-term follow-up, 97 patients (11.14 %) experienced constipation (OR 0.06, 95 % CI 0.05-0.08, p < 0.00001), 53 (6.46 %) incontinence/soiling (OR 0.01 95 % CI 0.01-0.01, p < 0.00001), 75 (9.14 %) recurrent enterocolitis (OR 0.02 95 % CI 0.01-0.02, p < 0.00001) and 69 (8.4 %) developed complications requiring secondary surgery (OR 0.01 95 % CI 0.01-0.02, p < 0.00001). Overall events in long-term follow-up occurred in 225 (27.5 %) patients (OR 0.24 95 % CI 0.20-0.30, p < 0.00001). CONCLUSIONS: This meta-analysis shows that nearly one-third of the patients continue to have long-term bowel problems, such as constipation, soiling and recurrent enterocolitis following LAPT. Many patients treated by LAPT require secondary surgery. Large randomized studies with long-term follow-up are necessary to determine the difference in outcome between LAPT and completely transanal pull-through operation.

Long-term results of transanal pull-through for Hirschsprung's disease: a meta-analysis.

INTRODUCTION: Several operative techniques have been developed for the treatment of Hirschsprung's disease (HD) in the past decades. Since one-stage transanal pull-through (TAPT) was first performed in 1998, multiple studies have shown favourable short-and midterm results compared to other techniques with shorter operation length, shorter hospital stay and lower complication rates. The aim of this meta-analysis was to determine the longterm results following TAPT for HD. METHODS: A systematic literature search for relevant articles was performed in four databases using the following terms "Hirschsprung/Hirschsprung's disease", "aganglionosis", "transanal", "pullthrough/pull-through", "longterm/long-term" "results", "follow-up" and "outcome". A meta-analysis was conducted for relevant articles for one-stage transanal pull-through for HD with a minimal follow-up of median 36 months regarding constipation, incontinence/soiling, enterocolitis and secondary operations. Odds ratio (OR) with 95 % confidence intervals (CI) were calculated. RESULTS: Six studies with 316 patients matched the set criteria and were included in this analysis. Overall 45 (14.2 %) patients had disturbances of bowel function (OR 0.05, 95 % CI 0.03-0.07, p < 0.00001). Of these, 24 (53.3 %) patients experienced constipation, 8 (17.8 %) incontinence/soiling and 13 (28.9 %) enterocolitis. 10 (3.2 %) patients developed complications requiring secondary surgery. Most patients had a daily defecation frequency of 1-3 bowel movements 3 years postoperatively, resembling the stooling patterns of healthy controls. CONCLUSION: Nearly 15 % of all patients operated with TAPT for HD continue to experience persistent bowel symptoms with constipation as the main problem. Further studies on the long-term outcome of children operated with this technique for HD are necessary to evaluate stooling patterns, urinary and sexual function as well as general quality of life during adolescence and adulthood.

RET gene is a major risk factor for Hirschsprung's disease: a meta-analysis.

PURPOSE: During the past two decades several genes have been identified that control morphogenesis and differentiation of the enteric neuron system (ENS). These genes, when mutated or deleted, interfere with ENS development. RET gene is the major gene causing Hirschsprung's disease (HD). Mutations in RET gene are responsible for 50% of familial HD cases and 15-20% of sporadic cases. The aim of this meta-analysis was to determine the incidence of RET gene mutations in patients with HD and to correlate RET mutations with the extent of aganglionosis. METHODS: A systematic literature-based search for relevant cohorts was performed using the terms "Hirschsprung's disease AND RET Proto-oncogene", "Hirschsprung's disease AND genetic polymorphism" and "RET Gene". The relevant cohorts of HD were systematically searched for reported mutations in the RET gene (RET+). Data on mutation site, phenotype, and familial or sporadic cases were extracted. Combined odds ratio (OR) with 95% CI was calculated to estimate the strength of the different associations. RESULTS: In total, 23 studies concerning RET with 1270 individuals affected with HD were included in this study. 228 (18%) of these HDs were RET+. Of these 228, 96 (42%) presented as rectosigmoid, 81 (36%) long segment, 18 (8%) as TCA, 16 (7%) as total intestinal aganglionosis and 17 (7%) individuals were RET+ but no extent of aganglionosis was not reported. In the rectosigmoid group, no significant association between phenotype and RET mutation could be shown (P = 0.006), whereas a clear association could be shown between long-segment disease, total colonic- and total intestinal aganglionosis and RET mutations (P = 0.0002). Mutations most often occurred in Exon 13 (24) and showed significant association with rectosigmoid disease (P = 0.004). No significance could be shown between RET+ and sporadic cases (P = 0.53), albeit a trend towards RET+ and Familial cases could be observed (P = 0.38). CONCLUSIONS: The association with the RET gene and HD is well recognized. This study showed a clear association between RET+ mutations and the long-segment, total colonic- and total intestinal aganglionosis. Exon 13 appears to be a mutational "hot spot" in rectosigmoid disease.

Knockout mouse models of Hirschsprung's disease.

PURPOSE: Hirschsprung's disease (HSCR) is a developmental disorder of the enteric nervous system, which occurs due to the failure of neural crest cell migration. Rodent animal models of aganglionosis have contributed greatly to our understanding of the genetic basis of HSCR. Several natural or target mutations in specific genes have been reported to produce developmental defects in neural crest migration, differentiation or survival. The aim of this study was to review the currently available knockout models of HSCR to better understand the molecular basis of HSCR. METHODS: A review of the literature using the keywords "Hirschsprung's disease", "aganglionosis", "megacolon" and "knockout mice model" was performed. Resulting publications were reviewed for relevant mouse models of human aganglionosis. Reference lists were screened for additional relevant studies. RESULTS: 16 gene knockout mouse models were identified as relevant rodent models of human HSCR. Due to the deletion of a specific gene, the phenotypes of these knockout models are diverse and range from small bowel dilatation and muscular hypertrophy to total intestinal aganglionosis. CONCLUSIONS: Mouse models of aganglionosis have been instrumental in the discovery of the causative genes of HSCR. Although important advances have been made in understanding the genetic basis of HSCR, animal models of aganglionosis in future should further help to identify the unknown susceptibility genes in HSCR.

The impact of Clostridium difficile on paediatric surgical practice: a systematic review.

PURPOSE: The pathogenic potential of Clostridium difficile in children remains a controversial subject as healthy infants can be colonised by this organism. However recent analyses have clarified that C. difficile is an important enteropath in paediatric populations, particularly in antibiotic-associated diarrhoea. Paediatric surgical patients including those with Hirschsprung's disease (HD) may be especially vulnerable to C. difficile infection (CDI) and complicated C. difficile enterocolitis such as pseudomembranous colitis may require surgical management if refractory to medical therapy. Reports of increasing prevalence and emergence of hyper-virulent strains of C. difficile worldwide prompted an examination of the literature to assess the impact of CDI on current paediatric surgical practise. METHODS: The literature was searched using a combination of the MESH terms "hirschsprung's disease", "enterocolitis", "clostridium difficile", and "children". Cases of Hirschsprung's associated enterocolitis (HAEC) investigated for C. difficile and complicated CDI in non HD patients were identified and analysed for clinical parameters, diagnostic evaluations, surgical interventions and outcome. RESULTS: Pathogen isolation in HAEC was infrequently described. Only 98 children have been reported with C. difficile during an episode of HAEC over the last 40 years and aetiology remains unclear as asymptomatic carriage of C. difficile in HD occurs. Nonetheless 34 confirmed cases of pseudomembranous colitis complicating HD are reported in the literature with an associated 50 % mortality rate. Over 20 % of non Hirschsprung's patients with reported severe or complicated CDI required operative intervention. The need for surgery was associated with the presence of co-morbidity and high mortality occurred in this group. CONCLUSION: Severe or complicated CDI in both HD and non HD paediatric patients is associated with high mortality and often requires surgical intervention. Although these patient cohorts represent a small number of cases, CDI should be suspected in children presenting with enterocolitis to enable early diagnosis and timely surgical intervention, particularly in patients with co-morbid conditions or preceding antibiotic use.

Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitors.

Pharmacological interventions that increase myofiber size counter the functional decline of dystrophic muscles. We show that deacetylase inhibitors increase the size of myofibers in dystrophin-deficient (MDX) and alpha-sarcoglycan (alpha-SG)-deficient mice by inducing the expression of the myostatin antagonist follistatin in satellite cells. Deacetylase inhibitor treatment conferred on dystrophic muscles resistance to contraction-coupled degeneration and alleviated both morphological and functional consequences of the primary genetic defect. These results provide a rationale for using deacetylase inhibitors in the pharmacological therapy of muscular dystrophies.

Micro-/bio-/nano-/syn-encapsulations and co-treatments of bioactive microbial feed supplementation in augmenting finfish health and aquaculture nutrition: a review.

Finfish and fish products are globally the most acknowledged health-promoting foods. The rising incidence of pathogenic and disease outbreaks have had a sizeable impact on aquaculture. Microbial supplementation of food in the form of probiotics, prebiotics, and their controlled release combinations (=co-encapsulations) as 'synbiotics' is noted for its significant biotherapeutic and health benefits. Supplementation of probiotic microbial feed additives in the fish diet claims to improve fish health by modulation of resident intestinal microbiota and by introducing healthy microbiota procured from an exogenous source, capable of combating pathogens, improving nutrient uptake, assimilation, growth as well as survival. Prebiotics are selectively digestible substrates beneficially used by host gut microbes to enhance probiotic effects. Formulating a fish diet with augmented probiotics and prebiotic microbial bio-supplements can ensure a sustainable alternative for establishing fish health in a naturally susceptible aquaculture scenario. Micro-encapsulation, co-encapsulation, and nano-encapsulation are novel strategies of biotechnical interventions in functional feeds for finfish. These aim to improve probiotic persistence, survivability, and efficacy in commercial formulations during probiotic transit through the host-gut environment. This review discusses the importance of co-treatment and encapsulation strategies for improving probiotic and prebiotic potential in aquafeed formulations, reliably improving finfish health and nutritional returns from aquaculture, and, consequently, for consumers.

The spatio-temporal patterning of Hoxa9 and Hoxa13 in the developing zebrafish enteric nervous system.

BACKGROUND: Hirschsprung's disease is characterised by the absence of ganglion cells in the distal bowel, a process which is controlled by complex genetic pathways. Homeobox genes have a major role in gut development and this is depicted by the enteric Hox code which describes the different spatial and temporal expression of Hox genes. Hoxa9 and Hoxa13 mutations have been discovered in patients with Hirschsprung's disease (HD). The aim of this study was to determine the spatio-temporal pattern of Hoxa9 and Hoxa13 in enteric nervous system (ENS) development using the zebrafish model. METHODS: Purified plasmids that contained the gene of interest were obtained and inoculated into culture medium to exponentially increase the number of bacteria containing the plasmid. Cells were then harvested by centrifugation and plasmid DNA was extracted, which was then linearised and precipitated. RNA digoxigenin-labelled probes were made by in vitro transcription reaction. In situ hybridisation was carried out using these probes on zebrafish embryos which were collected from 24 to 120 h post fertilisation (hpf), by which time the zebrafish intestine is fully developed. Embryos were then mounted in glycerol and imaged using an Olympus B40 microscope and images were taken using an Olympus Super F1.8 digital camera. RESULTS: At 24 hpf, Hoxa9 expression is seen in the forebrain and hindbrain and also in the very distal myotome whereas Hoxa13 expression, however, is seen only at the forebrain and hindbrain. At 48 hpf, Hoxa9- and Hoxa13-labelled cells are seen migrating distally from the forebrain into the notochord and spinal cord. At 72 hpf, Hoxa9-labelled cells can be seen throughout the spinal cord whereas Hoxa13 positive cells are seen migrating down from the spinal cord and in the proximal gut. By 96 hpf, Hoxa9- and Hoxa13-labelled cells have migrated down the full length of the spinal cord and along the proximal and mid intestine. By 120 hpf, Hoxa9 and Hoxa13 positive cells can be seen along the entire length of the zebrafish intestine. CONCLUSIONS: These results show further evidence that Hoxa9 and Hoxa13 are involved in the early and organised patterning of ENS development in the zebrafish model.

Melasma in men: a clinical, aetiological and histological study.

BACKGROUND: Melasma, a facial hypermelanosis, is more common in women. In Indians, men seem to be frequently involved. There are hardly any studies delineating the clinical, aetiological and histological features of melasma in men and the present study was taken up to fill this lacuna. MATERIALS AND METHODS: A total of 200 patients with melasma were screened for only men having melasma. Data including duration, illnesses, sunlight exposure, use of cosmetics, oil or medication, familial pigmentation, nutritional, parasitic infestations, infections, hepatic disorders, occupation were taken followed by general physical, cutaneous and Woods light examination. Laboratory investigations including skin biopsy were performed. RESULTS: Of 200 patients screened, 41 (20.5%) were men. Their ages ranged from 19 to 53 years. Twenty-four (58.5%) of the patients were outdoor workers. Twelve (29.3%) originally belonged to hilly regions. Clinical patterns were malar in 61%, centrofacial in 29.3% and mandibular in 9.7%. The aetiological factors identified were: sun-exposure in 20 (48.8%), mustard oil usage in 18 (43.9%), family history in 16 (37%), chronic illnesses in five (12.2%) and phenytoin in three (7.3%); of these sun-exposure and family history were statistically significant when compared with those for women. Laboratory investigations revealed anaemia in five (12.2%), giardiasis in two (4.9%), increased leuteinizing hormone (LH) and low testosterone in four (9.7%) men. Skin biopsies in 20 (48.8%) patients revealed features of epidermal melasma in 10 (50%) and a mixed type in nine (45%) patients. CONCLUSIONS: Melasma is frequently observed in Indian men. The main causative factors among the male patients appeared to be sun-exposure and family history. Melasma in men is definitely less common than in women, but shares the same clinicohistopathological characteristics as in women.

A serious drug interaction leading to spontaneous total hyphema.

A 70 year-old diabetic man receiving anti-coagulant therapy (Warfarin) for pulmonary embolism secondary to factor V Leiden deficiency, presented to the hospital for chest pain. After initial evaluation, he was started on aspirin (300 mg) and clopidogrel (300 mg). Three days after he was discharged, he presented with preseptal cellulitis complicating left upper eyelid chalazion. Initially, he was treated with several anti-microbial agents used sequentially. Although, the cellulitis resolved, he developed total hyphema of the left eye. The complication seems to have resulted from a complex interaction amongst anti-microbial agents, Warfarin and anti-platelet agents.

Prevalence of Celiac Disease in Children with Unexplained Failure to Thrive.

BACKGROUND: Gluten sensitive enteropathy or celiac disease (CD) is a disorder of small bowel that occurs upon exposure to gluten. A total of 67 children of either sex in the age group of 1-12 years with unexplained failure to thrive were studied for the prevalence of CD. METHODS: This was a cross-sectional study. It included detailed history, clinical assessment, estimation of anti gliadin (AGA), tissue transglutaminase antibodies (tTGA) and duodenal biopsy. Treatment with gluten free diet and follow-up of diagnosed cases was done for one year. RESULT: Sixteen cases (23.88%) had villous atrophy and positive serology, essential criteria for the diagnosis of CD. Forty six (69%) children were between 4-12 years of age. Male to female ratio was 2.3:1. Main symptoms were irritability (63%), diarrhea (56%) and weight loss (56%). Thirty seven (56%) children had weight less than 3(rd) percentile. tTGA was 100% sensitive and 90.2% specific. Duodenal biopsy showed decreased villious-crypt ratio in 81.25% and intra epithelial lymphocytosis in 81% children (p<0.000001). All the confirmed cases were advised strict gluten free diet for one year. On follow-up at six months, all children showed improvement in their symptoms and weight gain. CONCLUSION: CD is an important cause of unexplained failure to thrive in children.

Neurons in the rat dentate gyrus granular layer substantially increase during juvenile and adult life.

Volumetric estimates of the total number of granule cells in rats 30, 120, 200, and 365 days old increase linearly by approximately 35 to 43 percent between 1 month and 1 year. Total volume of the granular layer also grows linearly during that time. These results demonstrate a numerical increase in a neuronal population during adulthood in the mammalian brain.

Genomic alterations driving psoriasis pathogenesis.

Psoriasis is an immune mediated inflammatory skin disease with complex etiology involving interplay between environmental and genetic risk factors as disease initiating event. Enhanced understanding on genetic risk factors, differentially expressed genes, deregulated proteins and pathway-targeted therapeutics have established multiple axis of psoriasis pathogenesis. So far, loci in 424 genes are reported to be associated with psoriasis alongside copy number variations and epigenetic alterations. From clinical perspective, presence of specific genetic trigger(s) in individual psoriasis patient could aid in devising a personalized therapeutic strategy. Therefore, the review presents an updates on reported genomic alterations and their subsequent course of cutaneous inflammations that potentially drive to psoriasis.

A genome-wide scan for genes involved in primary vesicoureteric reflux.

BACKGROUND: Vesicoureteric reflux (VUR) is the retrograde flow of urine from the bladder into the ureters. It is the most common urological anomaly in children, and a major cause of end-stage renal failure and hypertension in both children and adults. VUR is seen in approximately 1-2% of Caucasian newborns and is frequently familial. OBJECTIVE AND METHODS: In order to search for genetic loci involved in VUR, we performed a genome-wide linkage scan using 4710 single-nucleotide polymorphisms (SNPs) in 609 individuals from 129 Irish families with >1 affected member. RESULTS: Nonparametric linkage (NPL) analysis of the dataset yielded moderately suggestive linkage at chromosome 2q37 (NPL(max) = 2.67, p<0.001). Analysis of a subset without any additional features, such as duplex kidneys, yielded a maximum NPL score of 4.1 (p = 0.001), reaching levels of genome-wide statistical significance. Suggestive linkage was also seen at 10q26 and 6q27, and there were several smaller peaks. CONCLUSION: Our results confirm the previous conclusion that VUR is genetically heterogeneous, and support the identification of several disease-associated regions indicated by smaller studies, as well as indicating new regions of interest for investigation.