Identification of the putative ancestral allele of bovine single-nucleotide polymorphisms.

Identifying the action of natural selection from patterns of standing genetic variation has long been of interest to the population genetic community. Thanks to the availability of large single-nucleotide polymorphism (SNP) data sets for many species and of high-throughput SNP genotyping methods, whole-genomic surveys to detect selective sweeps are now possible. Knowing the ancestral allele increases the power to detect selection. We present here a comparative genomic approach to determine the putative ancestral allele of bovine SNPs deposited in public databases. We analysed 19,551,488 SNPs and identified the putative ancestral allele for 14,339,107 SNPs. Our predicted ancestral alleles were in agreement with ancestral alleles detected by genotyping outgroup species for 97% SNPs from the BovineSNP50 BeadChip. This comparison indicates that our comparative genomic-based approach to identify putative ancestral alleles is reliable.

Variants of renal angiomyolipoma closely simulating renal cell carcinoma: difficulties in the histological diagnosis.

Renal angiomyolipoma is considered to be a benign renal tumor composed of atypical blood vessels, smooth muscles and fat cells. We report 2 cases of unilateral renal angiomyolipoma. In both cases, our preoperative diagnosis was renal cell carcinoma, because no low density area compatible with fat tissue was noted in the tumors on radiographic evaluation. Through histological examination, both tumors proved to be angiomyolipomas mainly composed of epithelioid cells in 1 case, and spindle-shaped smooth muscle cells mimicking a leiomyoma in the other case. Both patients are well showing no evidence of metastases 16 and 14 months after nephrectomy, respectively.

Influence of cigarette smoking on P53 gene mutations in bladder carcinomas.

BACKGROUND: The aim of this study was to analyse the influence of cigarette smoking on bladder carcinomas. PATIENTS AND METHODS: 98 cases of bladder cancers were examined by single strand conformation polymorphism analysis of exons 5 to 9, followed by DNA direct sequencing. RESULTS: The incidence of p53 gene mutations was not significantly influenced by habitual smoking. However, the p53 mutation spectrum of current smokers differed significantly from the pattern for non-smokers and ex-smokers. Differences between the two populations included multiple mutations in the current-smokers and an absence in non- and ex-smokers (p<0.01), with the predominance of G:C to A:T transitions at CpG sites in non-smokers (60.0%) in comparison with current smokers (7.6%) (p<0.02). Moreover, G:C to T:A and G:C to C:G transversions were found solely in current smokers. CONCLUSION: It would appear that, in current-smokers, the spectrum of p53 gene mutations is related to tobacco-smoke carcinogens and that the habit of smoking increases the extent of DNA damage.

Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors.

We recently identified activating mutations of fibroblast growth factor receptor 3 (FGFR3) in bladder carcinoma. In this study we assessed the incidence of FGFR3 mutations in a series of 132 bladder carcinomas: 20 carcinoma in situ (CIS), 50 pTa, 19 pT1, and 43 pT2-4. All 48 mutations identified were identical to the germinal activating mutations that cause thanatophoric dysplasia, a lethal form of dwarfism. The S249C mutation, found in 33 of the 48 mutated tumors, was the most common. The frequency of mutations was higher in pTa tumors (37 of 50, 74%) than in CIS (0 of 20, 0%; P < 0.0001), pT1 (4 of 19, 21%; P < 0.0001) and pT2-4 tumors (7 of 43, 16%; P < 0.0001). FGFR3 mutations were detected in 27 of 32 (84%) G1, 16 of 29 (55%) G2, and 5 of 71 (7%) G3 tumors. This association between FGFR3 mutations and low grade was highly significant (P < 0.0001). FGFR3 is the first gene found to be mutated at a high frequency in pTa tumors. The absence of FGFR3 mutations in CIS and the low frequency of FGFR3 mutations in pT1 and pT2-4 tumors are consistent with the model of bladder tumor progression in which the most common precursor of pT1 and pT2-4 tumors is CIS.

[Uretero-vesical implantation after failure of endoscopic treatment of reflux: anatomical and histological study of 61 resection specimens from 40 children]. / Réimplantation urétéro-vésicale après échec du traitement endoscopique d'un reflux: étude anatomique et histologique de 61 pièces de résection chez 40 enfants.

OBJECTIVE: To evaluate the anatomy and histology of the ureterovesical junction resected during secondary surgical reimplantation for persistent reflux after failure of initial endoscopic treatment by polytetrafluoroethylene (Teflon) in 27 cases and polydimethylsiloxane (Macroplastique) in 13 cases. MATERIAL AND METHOD: 61 ureterovesical junctions from 40 children were studied histologically. The mean age of the patients at the time of the operation was 4.1 years (range: 1 to 15 years). The mean interval between endoscopic injection and surgical reimplantation was 15.3 months (range: 2 to 54 months). RESULTS: Persistent reflux was not correlated with the anatomical situation of the implant, which was found to be in a satisfactory position in 52.4% of cases. Both of the substances used induced a giant-cell macrophage reaction which colonized the implant and triggered new vessel formation. Macroplastique appeared to be associated with a more intense inflammatory reaction than Teflon. Despite the difference in particle size, the two substances induced a macrophage phenomenon characterized by microfragmentation into 6 micron particles. No conclusions can be drawn concerning distant migration, but this study showed rarefaction of particles which were replaced by fibrosis, the density of which was correlated with the age of the implant. CONCLUSION: Extinction of the local reaction induced by the products used in this study appears to be long and the end of this process is unknown, which justifies prolonged surveillance of children treated for reflux by endoscopic submeatal injection.

The predictive value of muscularis mucosae invasion and p53 over expression on progression of stage T1 bladder carcinoma.

PURPOSE: We determine the significance of muscularis mucosae invasion and nuclear p53 over expression on the progression of stage T1 transitional cell bladder cancer. MATERIALS AND METHODS: The pathological findings in 149 cases of T1 tumors diagnosed between 1973 and 1996 were reviewed. Diagnosis was stage T1 in 94 tumors in which the muscular layer was clearly identifiable and disease-free. Mean followup was 64.9 months (range 5 to 288). T1 bladder cancers were subclassified into 2 groups, with (T1b) or without (T1a) muscularis mucosae invasion. The p53 nuclear antibody immunoreactivity was determined with antibody D07 and a cutoff point at 15%. RESULTS: T1 subclassification was possible in all 94 patients. Of all tumors 37.2% expressed p53 nuclear over expression. Univariate statistical analysis showed that p53 expression (p <0.05) and tumor invasion depth (p <0.001) significantly correlated with progression. However, on multivariate analysis only invasion depth (p <0.0001) and associated carcinoma in situ (p <0.03) remained independently significant as predictors of progression. CONCLUSIONS: In our study the depth of tumor invasion was a significant independent predictor of progression in patients with T1 bladder cancer. This result suggests that the depth of invasion in stage T1 should be included in the histopathological report.

[Erdheim-Chester disease. Apropos of a case with autopsy findings]. / La maladie d'Erdheim-Chester. A propos d'un cas avec étude autopsique.

Erdheim-Chester's Disease is a very uncommon variety of non-Langerhans histiocytosis of unknown etiology, which characteristically affects long bones bilaterally and symmetrically in adults. It may be accompanied by visceral foci of variable localization and extension determining prognosis. Bone scintigraphy is characteristic enough to evoke the disease but histologic examination of a peripheral specimen is required to confirm the diagnosis: spumous histiocytes CD68+, PS100+/-, CD1a-. We describe a case revealed by a severe lung disease with detailed autopsy.

[Unusual variety of bladder urothelial carcinoma: "nest type" microlobular carcinoma: report of an anatomoclinical case and review of the literature]. / Une variété rare de carcinome urothélial de la vessie: le carcinome microlobulaire "à type de nids": à propos d'un cas anatomo-clinique avec revue de la littérature.

We report a case of nested cell carcinoma, an uncommon transitional tumor. These tumors are composed of regular cuboidal transitional cells forming small nests with minimal cytologic atypia. Despite the benign course, this tumor resembling proliferation of Brunn's nests or inverted papilloma, must be considered as an aggressive transitional tumor. Thus, morphologic criteria are needed to make the diagnosis. Because of its aggressive behaviour, the surgical therapy depends on the tumor's infiltration.

[Protocol for the pathologic examination of cystectomy and cystoprostatectomy specimens. Proposal for a standardized form]. / Protocole d'étude anatomopathologique des pièces de cystectomie et de cystoprostatectomie.

We present practice guidelines for the examination of bladder specimens removed for bladder cancer and propose an example of standardized form for their reporting. This approach takes place in looking for better quality and facilitates use of the morphologic data.

Immunohistochemical detection of p53 protein overexpression versus gene sequencing in urinary bladder carcinomas.

PURPOSE: Mutations of p53 tumor suppressor gene and nuclear accumulation of p53 protein are common in bladder tumors. The prognostic significance of p53 alterations in bladder tumors has not been established. The aim of the present study was to evaluate an immunohistochemical (IHC) method for the routine determination of p53 protein overexpression in human bladder tumors and to determine the relation between nuclear accumulation of p53 with the traditional prognostic indicators and patient survival. MATERIALS AND METHODS: 104 transitional cell carcinomas of the bladder were analyzed simultaneously by immunohistochemistry for p53 protein overexpression and direct DNA sequencing for p53 gene mutations. RESULTS: The overexpression of p53 protein was reported in 30.8% of the cases and mutations of p53 gene in 23.0%. A significant association was observed between p53 alterations established either by IHC or direct DNA sequencing and stage (p<0.0001), grade (p<0.001), vascular invasion (p = 0.0005), DNA ploidy (p = 0.0002) and carcinoma in situ (p<0.0001). The correlation between the p53 gene mutations and p53 nuclear reactivity as detected by IHC was highly significant (p<0.0001). Univariate statistical analysis showed that the expression of p53 was significantly correlated to poor prognosis (p<0.0001). However, in multivariate analysis, only stage was significantly correlated to prognosis (p<0.0001). CONCLUSIONS: The IHC method was highly sensitive and specific and simple to apply for the routine examination of p53 overexpression in bladder tumors. However, overexpression of p53 as determined immunohistochemically, does not appear to have a better predictive prognostic value than stage in bladder tumors.

[Epididymal cysts in adolescents]. / Les kystes de l'épididyme chez l'adolescent.

Epididymal tumours are uncommon in children and adolescents and are usually benign. Epididymal cyst is exceptionally reported in the literature, although it is certainly underdiagnosed. The authors report 3 cases of epididymal cyst in 3 children, 12, 14 and 16 years of age. These children presented with an uncomfortable scrotal mass and were treated by excision of the cyst in every case. The aetiology of epididymal cysts is unclear. It is probably a congenital abnormality related to hormonal disorders during embryonic life. Physical examination is very important, but not sufficient for the diagnosis and must be completed by scrotal ultrasonography, which shows an echo-free cystic epididymal structure. Despite ultrasonography, the differential diagnosis of other scrotal cystic masses and even some solid epididymal tumours, which may present all of the sonographic characteristics of a cyst, must be considered. The treatment of symptomatic epididymal cyst in children must be surgical. For asymptomatic cysts diagnosed by sonography, clinical follow-up to document stability of the mass is justified.

Mycophenolate mofetil in renal transplant recipients with cyclosporine-associated nephrotoxicity: a preliminary report.

BACKGROUND: There is a great concern over cyclosporine (CsA) nephrotoxicity in renal transplant recipients, and the effects of conversion from CsA to azathioprine (AZA) remain controversial. Large studies have demonstrated that mycophenolate mofetil (MMF), the morpholinoethyl ester of mycophenolic acid, is superior to AZA as a posttransplant immunosuppressant. METHODS: Six patients with isolated biopsy-proven CsA nephrotoxicity were converted from CsA-AZA to MMF. RESULTS: Mean follow-up was 12+/-2 months. No patient experienced acute rejection. The mean serum creatinine concentration decreased from 225+/-58 to 159+/-66 micromol/L (P<0.0005). Hyperlipidemia and blood pressure improved after CsA withdrawal. CONCLUSION: In a selected transplant population with biopsy-proven CsA nephrotoxicity, CsA withdrawal with a concomitant switch from AZA to MMF seems to be safe and allows a significant improvement of renal function.

Metanephric adenoma of the kidney. A clinicopathologic, immunohistochemical and electron microscopic study of two cases. / L'adénome métanéphrique du rein. Une étude anatomoclinique, immunohistochimique et ultrastructurale de deux cas.

We report two cases of metanephric adenoma in 40 and 48 year-old women. These rare kidney tumors were composed of cuboidal epithelial cells forming tubules, glomeruloid structures and sheets. Ultrastructural and immunohistochemical studies revealed that the tumor cells are similar to epithelial cells of developing nephrons. These features differentiate the metanephric adenoma from tubulo-papillary renal carcinoma, nephroblastoma, and cortical adenoma. According to its invariably benign course, the metanephric adenoma treatment could be restricted to a simple tumorectomy.

Fibrinogen A alpha chain mutation (Arg554 Leu) associated with hereditary renal amyloidosis in a French family.

A French family with hereditary renal amyloidosis (HRA) was studied. The disease presented in 7 of the 8 affected individuals with proteinuria or the nephrotic syndrome. The age of onset was in the fifth decade of life. There is currently no sign of extrarenal involvement in any affected individual. However, the nephropathy in this family is progressive and led to terminal renal failure in 4 patients. Immunohistochemistry studies of glomerular amyloid deposits suggested that the amyloid protein was the fibrinogen A alpha chain. Direct DNA sequencing revealed a G 4993 T transversion and subsequently Arg 554 Leu mutation in the fibrinogen A alpha chain. This is the first description of this fibrinogen A alpha chain mutation in Europe. This family is of French descent and cannot be related to the previously reported Peruvian/Mexican and African-American kindreds.

A genotype study of the c-Ha-ras-1 locus in human bladder tumors.

PURPOSE: To clarify the role of the c-Ha-ras-1 gene in bladder cancer predisposition and prognosis. MATERIALS AND METHODS: The c-Ha-ras-1 locus was studied by Southern blotting in white blood cells and tumor samples obtained from 126 patients with bladder cancer (74 Ta-T1 and 52 T2-T4). A comparison with 84 unaffected patients and a survival analysis were performed. RESULTS: The patients with bladder cancer presented 7 different c-Ha-ras-1 alleles, 12 different genotypes, heterozygosity in 49% of cases and a loss of heterozygosity (in the tumor) in 13 cases. The most frequent allele (a1, 6.6 kb) was present in 83% of patients. Heterozygosity correlated with vascular invasion in the tumor (p < 0.0001). In the small subgroup of 11 patients with rare alleles and genotypes, these alleles and genotypes occurred more often in patients with T2-T4 tumors (p < 0.01 for alleles and genotypes), aneuploid tumors (p < 0.001, p < 0.005) and tumors with vascular invasion (p < 0.01, p < 0.005). However, in this study, the majority of patients with high risk tumors possessed common alleles and genotypes. Survival analysis showed that neither the c-Ha-ras-1 genotype nor allelomorphism was an independent prognostic factor. Elsewhere, no rare allele occurred more frequently in bladder cancer affected patients than in unaffected patients. CONCLUSION: This study confirms c-Ha-ras-1 gene polymorphism in a bladder cancer affected population and, in some cases, a loss of genetic material in the vicinity of this locus. No specific genotype can be implicated in the predisposition to bladder carcinoma, and c-Ha-ras-1 genotyping appears of limited value in the clinical management of these patients.

Glomerular lesions in juvenile cystinosis: report of 2 cases.

We report glomerular lesions in 2 siblings presenting a juvenile cystinosis. Kidney biopsy in one of them showed focal, segmental, mesangial proliferative and hyalinosis lesions, and the second showed segmental juxtahilar hyalinosis in one third of glomeruli. Neither of the 2 patients displayed a Toni-Debre-Fanconi syndrome. In one of the patients, cystine crystals were found by means of electronic microscopy. The first patient developed chronic renal failure and a kidney transplantation was performed. No recurrence of the cystine deposits was observed in the graft. Pedigree of the described family seems to be in accordance with an autosomal dominant pattern of inheritance.