[A severely disturbed lipid profile]. / Un bilan lipidique très perturbé

We report here the case of a 30-year-old woman presenting a disturbed lipid profile since her childhood. The rarity of this pathology (Anderson' disease or chylomicron retention disease) and its recent recognition explain its late detection in this case. The description of the biochemical profile is interesting especially the low level of vitamin A and E which explains the severity of the disease. A vitamin enriched-diet may be useful.

Molecular screening of the CFTR gene in men with anomalies of the vas deferens: identification of three novel mutations.

Many studies have shown that congenital absence of the vas deferens (CAVD) is a genital cystic fibrosis transmembrane conductance regulator (CFTR)-mediated phenotype, with a broad spectrum of abnormalities causing male infertility. The genotype of these patients includes mutations in the CFTR gene, e.g. DeltaDeltaF508, R117H and the T5 allele; all of which are commonly found in CAVD. In this study we have screened the entirety of CFTR gene in 47 males with anomalies of the vas deferens: 37 cases of congenital bilateral absence of the vas deferens, three cases of congenital unilateral absence of the vas deferens and seven cases of obstructive azoospermia with hypoplastic vas deferens. Among the 94 chromosomes studied, 65 mutations, of which three are novel (2789+2insA, L1227S, 4428insGA), were identified. The majority of patients (63.8%) had two detectable CFTR gene mutations. Furthermore, high frequencies of the DeltaDeltaF508 mutation (44.7%), the T5 allele (36.2%) and R117H mutation (19.1%) were observed.

Eukaryotic translation termination factor gene (ETF1/eRF1) maps at D5S500 in a commonly deleted region of chromosome 5q31 in malignant myeloid diseases.

The human genome contains four ETF1 (eukaryotic translation termination factor 1) homologous sequences, localized on chromosomes 5, 6, 7 and X, and corresponding to a functional gene on chromosome 5 and three processed pseudogenes on the other chromosomes. ETF1 genomic or cDNA probes were mapped by fluorescence in situ hybridization to 5q31, 6p21, 7q11 and Xp11.4-->p11.1. A microsatellite marker (D5S500) was identified in intron 7 of the functional ETF1 gene providing its exact position in the 5q31 band. Thus, the ETF1 gene is located in a 5q region which contains unidentified genes responsible for genetic or malignant disorders, and it might be considered as a candidate gene involved in the pathogenesis of these diseases.

Human release factor eRF1: structural organisation of the unique functional gene on chromosome 5 and of the three processed pseudogenes.

In lower and higher eukaryotes, a family of tightly related proteins designated eRF1 (for eukaryotic release factor 1) catalyses termination of protein synthesis at all three stop codons. The human genome contains four eRF1 homologous sequences localised on chromosomes 5, 6, 7 and X. We report here the cloning and the structural analysis of the human eRF1 gene family. It appears that the gene located on chromosome 5 alone is potentially functional, whereas the other three sequences resemble processed pseudogenes. This is the first description of the structural organisation of the human eRF1 gene, which has been remarkably conserved during evolution and which is essential in the translation termination process.

In patients with cirrhosis, serum albumin determination should be carried out by immunonephelometry rather than by protein electrophoresis.

OBJECTIVE: Serum albumin is a key parameter for prognosis in cirrhosis. We compared levels of serum albumin determined by both protein electrophoresis and immunonephelometry, with special reference to the Child-Pugh classification. DESIGN AND METHODS: One hundred and thirty-one patients, including 39 with cirrhosis, were included prospectively during 2 months. The aetiology of cirrhosis was mainly alcoholism (67%) and hepatitis C virus (HCV) (18%). Serum albumin was determined simultaneously by electrophoresis (Hydrasys SEBIA following protein determination by the biuret reaction) and by immunonephelometry (BECKMAN Nephelometer). Values were compared by non-parametric tests. RESULTS: For the whole population, electrophoretic and immunonephelometric values correlated (p = 0.85; P < 0.0001), but electrophoresis significantly overestimated serum albumin by a median 1.6 g/l (P < 0.0001) with a large spread in values (range, -3.9 to 12.7). Median overestimation in cirrhosis was 2.6 g/l (P < 0.0001; range, -2.0 to 10.2) and 1.0 g/l (P < 0.0001; range, -3.9 to 12.7) in patients without cirrhosis (difference, P < 0.02). For 6/39 (15.4%) patients with cirrhosis, this overestimation led to an underestimation in the Child-Pugh classification. CONCLUSION: In our experience, electrophoresis can lead to serum albumin values which are significantly different compared to those obtained by immunonephelometry. This discrepancy may lead to an incorrect Child-Pugh classification. Therefore, in the follow-up of cirrhotic patients, serum albumin should be determined by immunonephelometry.

Magnetic resonance imaging in the treatment planning of radiation therapy in carcinoma of the cervix treated with the four-field pelvic technique.

PURPOSE: To evaluate magnetic resonance imaging (MRI) in the planning of radiation therapy for patients with carcinoma of the cervix treated with a four-field technique. METHODS AND MATERIALS: Between May 1994 and February 1995, 18 patients with carcinoma of the cervix were entered in the study (1 T1 N-; 2 T2a N-; 1 T2b NO; 10 T2b N-; 2 T2b N+; 2 T3b N+). Node status was assessed by a laparoscopic pelvic lymphadenectomy. During the first step, all the patients were simulated with an isocentric four-field pelvic technique. In one group (11 patients) simulation was done based on clinical examination, computed tomography (CT), and standard guidelines. In the second group (seven patients) simulation was based on clinical examination, CT, and with the help of diagnostic MRI, which was available at that time. During the second step, MRI in treatment position with skin markings of the isocenter of the radiation fields was then performed in every patient. During the third step, in each patient, the simulated radiation fields were correlated with the MRI defined target volume by superimposing them on midsagittal and midcoronal MR images. The adequacy of the margins was arbitrarly defined as 1 cm around the MRI defined target volume (tumor of the cervix and its extension, and uterus). RESULTS: In the first group (11 patients), MRI in treatment position led to a change in 7 patients: six inadequate margins in the lateral fields and one in the anterior and lateral field. In almost all the cases, the adjustments were of an increase of 10 mm, equally matched between the anterior and posterior borders of the lateral fields. In the second group (seven patients), MRI in treatment position has led to a change in lateral fields in five patients. The mean adjustment was 10 mm: four increases (two anterior border, one posterior border, one anterior and posterior border), and one decrease of the posterior border. In the two groups, modifications of the anterior border of the lateral fields have allowed adequate margins around the uterine fundus and modifications of the posterior border have allowed adequate coverage of the cervical tumor. CONCLUSION: When treating carcinoma of the cervix with a four-field radiation technique, standard portals do not exist. The design of lateral fields has to be based on individual morbid anatomy, which is given accurately by diagnostic MRI. Magnetic resonance imaging in treatment position assesses the design of simulated lateral fields.

Linkage disequilibrium and extended haplotypes in the HLA-A to D6S105 region: implications for mapping the hemochromatosis gene (HFE).

The hemochromatosis gene (HFE) maps to 6p21.3, in close linkage with the HLA Class I genes. Linkage disequilibrium (LD) studies were designed to narrow down the most likely candidate region for HFE, as an alternative to traditional linkage analysis. However, both the HLA-A and D6S105 subregions, which are situated 2-3 cM and approximately 3 Mb apart, have been suggested to contain HFE. The present report extends our previous study based upon the analysis of a large number of HFE and normal chromosomes from 66 families of Breton ancestry. In addition to the previously used RFLP markers spanning the 400-kb surrounding HLA-A, we examined three microsatellites: D6S510, HLA-F, and D6S105. Our combined data not only confirm a peak of LD at D6S105, but also reveal a complex pattern of LD over the i82 to D6S105 interval. Within our ethnically well-defined population of Brittany, the association of HFE with D6S105 is as great as that with HLA-A, while the internal markers display a lower LD. Fine haplotype analysis enabled us to identify two categories of haplotypes segregating with HFE. In contrast to the vast majority of normal haplotypes, 50% of HFE haplotypes are completely conserved over the HLA-A to D6S105 interval. These haplotypes could have been conserved through recombination suppression, selective forces and/or other evolutionary factors. This particular haplotypic configuration might account for the apparent inconsistencies between genetic linkage and LD data, and additionally greatly complicates positional cloning of HFE through disequilibrium mapping.

Structural analysis of CFTR gene in congenital bilateral absence of vas deferens.

Congenital bilateral absence of the vas deferens (CBAVD) is found in most males with cystic fibrosis (CF), but this malformation can be observed without any pulmonary or digestive features. We have analyzed 13 exons of the CF gene in a cohort of 25 CBAVD patients. Among the 50 chromosomes studied, 24 mutations were identified: delta F508 (14 cases), R117H (7 cases), R1070W (2 cases), 621 + 1 G --> T (1 case), and A1067V (1 case). Except for delta F508, the most frequent mutations (R117H, R1070W) were not observed in the CF group (109 patients) studied in our laboratory. We discuss the significance of these results.

Proteases.

Proteases are enzymes which are widely distributed in cells and play a key role in protein metabolism. The aim of this paper is to review the classification and nomenclature of proteases, their catalytic mechanisms, the regulation of proteolytic activity and finally the major biological functions of proteases.

Anonymous marker loci within 400 kb of HLA-A generate haplotypes in linkage disequilibrium with the hemochromatosis gene (HFE)

The hemochromatosis gene (HFE) maps to 6p21.3 and is less than 1 cM from the HLA class I genes; however, the precise physical location of the gene has remained elusive and controversial. The unambiguous identification of a crossover event within hemochromatosis families is very difficult; it is particularly hampered by the variability of the phenotypic expression as well as by the sex- and age-related penetrance of the disease. For these practical considerations, traditional linkage analysis could prove of limited value in further refining the extrapolated physical position of HFE. We therefore embarked upon a linkage-disequilibrium analysis of HFE and normal chromosomes from the Brittany population. In the present report, 66 hemochromatosis families yielding 151 hemochromatosis chromosomes and 182 normal chromosomes were RFLP-typed with a battery of probes, including two newly derived polymorphic markers from the 6.7 and HLA-F loci located 150 and 250 kb telomeric to HLA-A, respectively. The results suggest a strong peak of existing linkage disequilibrium focused within the i82-to-6.7 interval (approximately 250 kb). The zone of linkage disequilibrium is flanked by the i97 locus, positioned 30 kb proximal to i82, and the HLA-F gene, found 250 kb distal to HLA-A, markers of which display no significant association with HFE. These data support the possibility that HFE resides within the 400-kb expanse of DNA between i97 and HLA-F. Alternatively, the very tight association of HLA-A3 and allele 1 of the 6.7 locus, both of which are comprised by the major ancestral or founder HFE haplotype in Brittany, supports the possibility that the disease gene may reside immediately telomeric to the 6.7 locus within the linkage-disequilibrium zone. Additionally, hemochromatosis haplotypes possessing HLA-A11 and the low-frequency HLA-F polymorphism (allele 2) are supportive of a separate founder chromosome containing a second, independently arising mutant allele. Overall, the establishment of a likely "hemochromatosis critical region" centromeric boundary and the identification of a linkage-disequilibrium zone both significantly contribute to a reduction in the amount of DNA required to be searched for novel coding sequences constituting the HFE defect.

[Breast microcalcifications]. / Les microcalcifications mammaires.

Microcalcifications of the breast are better recognized as the quality of mammographs is improving. The clinical examination and complementary modalities are often essential to evaluate their significance and point out to an indication for surgery. However, especially when the microcalcifications are detected during a systematic examination, a strict analysis of mammographs is essential. The number of useless punctures must be reduced, as their psychological impact and socioeconomic weight are already demonstrated. Although there is no consensus, most recent publications contain ideas converging on the selection of the indications for a histological control on the basis of an accurate semiological study.

Anonymous markers located on chromosome 6 in the HLA-A class I region: allelic distribution in genetic haemochromatosis.

Two yeast artificial chromosomes of the HLA class I region were subcloned. Four of the subclones studied displayed restriction polymorphisms that corresponded to six bi-allelic series. Allelic distribution of the anonymous markers was then studied by comparing a control population with a group of patients with familial haemochromatosis. Only one marker presents an unequivocal association with the haemochromatosis gene and is 100 kb centromeric to HLA-A. This association however is not as strong as with HLA-A3. The results suggest two possible locations for the haemochromatosis gene: less than 100 kb centromeric to the HLA-A locus, or on the telomeric side.

[Extramammary carcinoid tumor metastatic to the breast. Apropos of a case]. / Les carcinoïdes d'origine extramammaire métastasiant au sein. A propos d'une observation.

We report the case of a 42-year-woman treated for an appendicular carcinoid tumor with bilateral ovary metastases and mesenteric node involvement. After a systematic mammography, an infraclinical lesion of the breast was detected. Mammographic and echographic images revealed nodular mass with possibly malignant features. Fine-needle aspiration biopsy indicated malignancy. The definitive diagnosis of breast metastasis of a carcinoid tumor was made by biopsy. This case is related to 14 previously published cases. The authors emphasize the importance of making a precise histological diagnosis to avoid overtreatment of a metastatic lesion.

Metastases to the breast: differential diagnosis from primary breast carcinoma.

Eight patients with breast metastases from primary tumors other than breast carcinoma were studied: 3 malignant melanomas, 2 rhabdomyosarcomas, 1 malignant mesothelioma, 1 appendiceal carcinoid, and 1 epidermoid cervical carcinoma. All had mammographic, histopathologic, and immunohistochemical examinations. The main problem was differential diagnosis from primary breast carcinoma. History of extramammary primary tumor was helpful but breast metastasis was the first clinical feature in 2 cases. Patients had noticed palpable, round, rapid growth masses which were mammographically benign. Pathologic diagnosis was difficult and immunohistochemical studies necessary, whenever the proliferation had histologic features of primary breast carcinoma or when no primary tumor was known. However, some histologic features were of value for diagnosis of metastasis: atypical histologic features for a primary breast carcinoma, a well-circumscribed tumor with multiple satellite foci, the absence of an intraductal component, and the presence of many lymphatic emboli. In adults, the most frequent types of tumors metastasizing in the breast are malignant melanoma and neuroendocrine-like tumors, especially small cell carcinoma and carcinoid. In children, rhabdomyosarcoma is the most common. Accurate diagnosis of breast metastasis is important to avoid unnecessary mastectomy and to implement an appropriate systemic therapy.