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Both 2-dimensional and 3-dimensional endoanal ultrasounds have been shown to be accurate in the definition of the anatomy of complex fistulae-in-ano in patients with perianal Crohn's disease. Recently, a Crohn's Ultrasound Fistula Sign (CUFS) has been suggested as a discriminating feature of perianal Crohn's disease as has the presence of fistulous debris and fistular bifurcation. We blindly assessed 197 patients (39 Crohn's fistulae and 158 cryptogenic fistulae) to determine if these signs differentiated fistula types. The incidence of CUFS in Crohn's cases was 17/39 (43.6%) and in cryptogenic cases was 4/158 (2.5%) (P < 0.0001). The sensitivity, specificity, positive and negative predictive values and accuracy for CUFS were 43.6%, 97.5%, 80.9%, 87.5% and 86.8%, respectively. The presence of debris and fistula bifurcation in evaluable cases had a high specificity (87.2% and 81.8%, respectively) but poor sensitivity. The kappa values for or against CUFS, debris and bifurcation in Crohn's cases between 2 observers blinded to the diagnosis were 0.85, 0.72 and 0.93, respectively and in cryptogenic fistulae were 0.89, 0.85 and 0.80, respectively. The kappa values of an agreed consensus for CUFS in Crohn's disease, cryptogenic fistulae and overall with a third observer with no ultrasound experience were 0.62, 0.85 and 0.77, respectively. The presence of CUFS differentiates Crohn's-related from cryptogenic fistulae-in-ano with a high level of agreement for this sign between experienced and inexperienced observers blinded to the underlying diagnosis.

Objectives The aetiology of RA is unknown; however, bacterial exposure, particularly to Escherichia coli, Proteus mirabilis and Klebsiella pneumoniae, has been linked to disease pathogenesis. The strongest association was observed for RF(+) RA. We compare colonization patterns of these bacteria, and the anti-bacterial antibody levels in early onset RF(+) and RF(-) inflammatory arthritis. Methods Bacteria isolated from stool and urine of early-stage RF(+) and RF(-) patients recruited to the Early Arthritis Registry were biochemically identified and genotyped. IgM and IgA anti-bacterial and RF antibodies were assessed by ELISA. Results Differences in the types of colonizing pathogenic E. coli were identified. RF(+) patients were more commonly colonized with phylogenetic Group D E. coli, whereas RF(-) patients were more commonly colonized with phylogenetic Group B2 E. coli and these individuals also had lower joint scores and inflammatory markers yet higher IgA anti-E. coli antibody responses. Conclusions These studies link the type of colonizing bacteria in the gut and urine with the immune response (anti-bacterial and RF) in early-onset inflammatory arthritis and provide evidence for a role of the host-pathogen response in the aetiology of RF.

The Birt-Hogg-Dubé (BHD) syndrome is an inherited genodermatosis characterized by a predisposition to hamartomatous skin lesions, pulmonary cysts, and renal carcinoma. Seventy-seven renal tumors from 12 patients with germline BHD mutations were examined by DNA sequencing to identify somatic mutations in the second copy of BHD. Sequence alterations were detected in the majority of renal tumors (41 of 77, 53%), with loss of heterozygosity at the BHD locus in a minority of additional tumors (14 of 77, 17%). The somatic mutations were distributed across the entire gene, and the majority resulted in frameshifts that are predicted to truncate the BHD protein. These results support a role for BHD as a tumor suppressor gene that predisposes to the development of renal tumors when both copies are inactivated.

Background A small percentage of patients presenting with perirectal sepsis will have complicated or recurrent disease. In these cases, clinical examination may be difficult or unreliable and accurate preoperative imaging may be of value Methods A prospective study using a specially designed internal coil for magnetic resonance imaging (MRI) was carried out in ten patients with simple cryptogenic perirectal sepsis and in 11 patients with complex recurrent disease. Fistulas and abscesses were classified independently by a colorectal surgeon unaware of the results of MRI and a radiologist unaware of the operative findings. Results In patients with simple perirectal infection, endoanal MRI accurately detected all abscesses and four of five fistulas. In complicated cases (multiple recurrences, sepsis secondary to inflammatory bowel disease or where the fistula track(s) traversed the main sphincter complex), endoanal MRI identified six of seven abscesses with confirmation of abscess site and horseshoe configuration when present in all cases. Surgical and radiological concordance was present in 12 of 14 fistulas with identification by MRI of the internal opening in nine of 12 cases. Conclusion Endoanal MRI provides high-resolution images of the relationship of collections and tracks to the levator plate and is recommended in the evaluation of complex or recurrent perirectal sepsis.

Germline H255Y and K508R missense mutations in the folliculin (FLCN) gene have been identified in patients with bilateral multifocal (BMF) kidney tumours and clinical manifestations of Birt-Hogg-Dubé (BHD) syndrome, or with BMF kidney tumours as the only manifestation; however, their impact on FLCN function remains to be determined. In order to determine if FLCN H255Y and K508R missense mutations promote aberrant kidney cell proliferation leading to pathogenicity, we generated mouse models expressing these mutants using BAC recombineering technology and investigated their ability to rescue the multi-cystic phenotype of Flcn-deficient mouse kidneys. Flcn H255Y mutant transgene expression in kidney-targeted Flcn knockout mice did not rescue the multi-cystic kidney phenotype. However, expression of the Flcn K508R mutant transgene partially, but not completely, abrogated the phenotype. Notably, expression of the Flcn K508R mutant transgene in heterozygous Flcn knockout mice resulted in development of multi-cystic kidneys and cardiac hypertrophy in some mice. These results demonstrate that both FLCN H255Y and K508R missense mutations promote aberrant kidney cell proliferation, but to different degrees. Based on the phenotypes of our preclinical models, the FLCN H255Y mutant protein has lost it tumour suppressive function leading to the clinical manifestations of BHD, whereas the FLCN K508R mutant protein may have a dominant negative effect on the function of wild-type FLCN in regulating kidney cell proliferation and, therefore, act as an oncoprotein. These findings may provide mechanistic insight into the role of FLCN in regulating kidney cell proliferation and facilitate the development of novel therapeutics for FLCN-deficient kidney cancer.

A locus for recessive neurosensory nonsyndromic hearing impairment maps to chromosome 9q13-q21 in two regionally separate consanguineous families from India. Each family demonstrates a LOD score greater than 4.5 to this region. D9S15, tightly linked to the Friedreich's ataxia locus, a region that has been defined with over 1 Mb of YAC contig information and several expressed sequences, is one of the flanking markers. In mice, the deafness (dn) locus maps to mouse chromosome 19 and flanking loci are syntenic to human chromosome 9q11-q21. The dn mouse is a potential model for the hearing impairment found in both these families.

Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome characterised by the development of retinal and central nervous system haemangioblastomas, renal cell carcinoma and phaeochromocytoma. The gene for VHL disease has been mapped to chromosome 3p25-p26 and presymptomatic diagnosis using linked DNA markers is available. We have previously mapped the VHL disease gene to a 4 cM interval between D3S1250 and D3S18. To increase access to presymptomatic diagnosis and to accelerate progress towards isolating the VHL disease gene we attempted to identify microsatellite DNA markers linked to the disease gene by genetic linkage analysis in 29 families. We found significant linkage between the VHL disease gene and dinucleotide (CA) repeat polymorphisms at D3S1038 (Zmax = 22.24 at theta = 0.01, CI 0.0001-0.06), D3S1110 (Zmax = 11.32 at theta = 0.07, CI 0.03-0.14) and D3S651 (Zmax = 7.73 at theta = 0.04, CI 0.008-0.13). We localised D3S1038 between D3S1250 and D3S601, and mapped D3S1110 and D3S651 centromeric to D3S1250. Multipoint linkage analysis mapped the VHL disease locus between D3S1038 and D3S18 with the maximum likelihood at D3S601. There was no evidence of locus heterogeneity. This study has (i) identified three microsatellite DNA markers in chromosome 3p25 linked to the VHL disease gene and (ii) narrowed the target region for the isolation of the VHL disease gene by positional cloning techniques. These findings will improve the management of families with VHL disease by improving the accuracy and availability of presymptomatic diagnosis using linked DNA markers, and will accelerate progress towards isolating the VHL disease gene.

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Background Patients with von Hippel-Lindau disease (VHL) are at risk of developing pancreatic cysts, microcystic adenomas and neuroendocrine tumours. Pancreatic neuroendocrine tumours (PNETs) are found in 19 per cent of families with VHL. These tumours can behave in a malignant fashion, with up to 17 per cent of patients developing distant disease. The authors' initial experience with the diagnosis and management of these lesions, with resection based on size greater than 3 cm in imaging studies, has been reported previously. This is a report on their prospective experience using these criteria as well as on the role of genotype/phenotype analysis of germline VHL gene mutations in predicting clinical course. Methods Some 389 patients with VHL were screened between December 1998 and December 1999. The diagnosis of PNET was made by either pathological analysis of tissues or by characteristic radiographic appearance on computed tomography and magnetic resonance imaging. VHL gene germline mutations were determined by quantitative Southern blotting to detect deletions of the gene, Southern blotting to detect gene rearrangements, fluorescence in situ hybridization to confirm deletions and complete gene sequencing. Results Forty-four patients with PNET have been identified. Of these, 25 have undergone definitive surgical resection, five were found to have metastatic disease and 14 are being followed prospectively. No patient who has undergone resection based on the aforementioned tumour size criteria has developed metastatic disease. These patients represent 36 families (19 per cent) of a total of 188 VHL families who have had germline mutation analysis. Compared with all 188 VHL families, those with PNETs are more likely to have missense mutations (58 per cent) and more likely to have intragenic mutations. Four of five patients with metastatic disease have mutations in exon 3 compared with 18 of 39 patients without metastatic disease. Conclusion An aggressive approach to imaging for detection and surgical resection based on established size criteria has resulted in the successful management of patients with VHL and PNETs. Analysis of germline mutations may help predict those patients with VHL who are at risk of developing a PNET and which patients with a PNET may benefit from earlier surgical intervention to prevent spread of disease.