Mutant WD-repeat protein in triple-A syndrome.

Triple-A syndrome (MIM 231550; also known as Allgrove syndrome) is an autosomal recessive disorder characterized by adrenocorticotropin hormone (ACTH)-resistant adrenal insufficiency, achalasia of the oesophageal cardia and alacrima. Whereas several lines of evidence indicate that triple-A syndrome results from the abnormal development of the autonomic nervous system, late-onset progressive neurological symptoms (including cerebellar ataxia, peripheral neuropathy and mild dementia) suggest that the central nervous system may be involved in the disease as well. Using fine-mapping based on linkage disequilibrium in North African inbred families, we identified a short ancestral haplotype on chromosome 12q13 (<1 cM), sequenced a BAC contig encompassing the triple-A minimal region and identified a novel gene (AAAS) encoding a protein of 547 amino acids that is mutant in affected individuals. We found five homozygous truncating mutations in unrelated patients and ascribed the founder effect in North African families to a single splice-donor site mutation that occurred more than 2,400 years ago. The predicted product of AAAS, ALADIN (for alacrima-achalasia-adrenal insufficiency neurologic disorder), belongs to the WD-repeat family of regulatory proteins, indicating a new disease mechanism involved in triple-A syndrome. The expression of the gene in both neuroendocrine and cerebral structures points to a role in the normal development of the peripheral and central nervous systems.

Identification of human cancer-related genes by naturally occurring Hepatitis B Virus DNA tagging.

Proviral tagging has been used in animals as a powerful tool for cancer genetics. We show that a similar approach is possible in patients with hepatocellular carcinoma (HCC) infected by Hepatitis B Virus (HBV), a human pararetrovirus which may act by insertional mutagenesis. In this work, the HBV genome is used as a probe to identify cancer-related genes. By using HBV-Alu-PCR, we obtained 21 HBV/cellular DNA junctions from 18 different patients. In six of 21, we found the HBV DNA integrated into a cellular gene: (1) Sarco/Endoplasmic Reticulum Calcium ATPase1 Gene; (2) Thyroid Hormone Receptor Associated Protein 150 alpha Gene; (3) Human Telomerase Reverse Transcriptase Gene; (4) Minichromosome Maintenance Protein (MCM)-Related Gene; (5) FR7, a new gene expressed in human liver and cancer tissues; and (6) Nuclear Matrix Protein p84 Gene. Seven junctions contained unique cellular sequences. In the remaining eight, the HBV DNA was next to repetitive sequences, five of them of LINE1 type. The cellular genes targeted by HBV are key regulators of cell proliferation and viability. Our results show that studies on HBV-related HCCs allow to identify cellular genes involved in cancer. We therefore propose this approach as a valuable tool for functional cancer genomic studies in humans.

Recurrent de novo mitochondrial DNA mutations in respiratory chain deficiency.

Starting from a cohort of 50 NADH-oxidoreductase (complex I) deficient patients, we carried out the systematic sequence analysis of all mitochondrially encoded complex I subunits (ND1 to ND6 and ND4L) in affected tissues. This approach yielded the unexpectedly high rate of 20% mutation identification in our series. Recurrent heteroplasmic mutations included two hitherto unreported (T10158C and T14487C) and three previously reported mutations (T10191C, T12706C and A13514G) in children with Leigh or Leigh-like encephalopathy. The recurrent mutations consistently involved T-->C transitions (p<10(-4)). This study supports the view that an efficient molecular screening should be based on an accurate identification of respiratory chain enzyme deficiency.

[Laparoscopic promontofixation technique]. / Technique de promontofixation laparoscopique Laparoscopic promontofixation technique.

Laparoscopic promontofixation often remains possible whatever the previous history of pelvic surgery, including the placing of prosthetic material. Preoperative care is standardized and is accompanied by antibiotic prophylaxis, preventive antithrombotic treatment and in the event of a history of pelvic surgery, a digestive preparation. Positioning of the patient must plan a 30 degrees Trendelenbourg position. After the introduction of trocars, initial surgery comprises interrectovaginal dissection to free the whole posterior surface of the vagina. This is followed by the installation of a posterior mesh pre-cut in an arch. The anterior face of the promontory is then freed after incision of the posterior peritoneum with the patient placed beforehand in a Trendelenbourg position. After intervesical vaginal dissection, the anterior prosthesis comprising a precut polyester mesh is fixed avoiding excess traction. The end of the surgery involves careful reperitonization of all the prosthetic parts. Possible specific surgical complications are vascular and visceral wounds. Postoperative secondary haemorrhage and gastrointestinal occlusion may occur. Occurrence of an inflammatory syndrome and low back pain suggests spondylodicitis and MRI should be performed. Vaginal erosion on the prosthesis (1.6 to 10% depending on the series) may occur after several months and seems relatively independent of the prosthetic material used.

Follow-up study of the use of antihypertensive drug treatment and of the population treated.

We carried out a study describing the extent and patterns of use of antihypertensive drugs and identifying common diseases in a cohort of workers. The population was monitored on a yearly basis by a questionnaire to assess the use of antihypertensive drugs. The extent and causes of absenteeism for medical reasons and diagnoses of cancer were taken from systematic records from the company. Four cross-sectional analyses covering a period of 5 years are presented. For the 17,244 respondents in 1990--12,731 men aged 41 to 51 years and 4,513 women aged 36 to 51 years--the prevalence of antihypertensive drug use was 6.5%, and 5 years later, antihypertensive drug use had doubled. This increase involved calcium channel inhibitors in particular. In all analyses, excess absenteeism for all health-related disorders was observed among those treated with antihypertensive drugs compared with the remainder of the population, who were almost all nonhypertensive: 44% v 34% (P < .000) in 1990, 42% v 34% (P < .000) in 1991, 41% v 34% (P < .000) in 1993, and 37% v 29% (P < .000) in 1994. Psychiatric disorders and fatigue were among the most frequent causes of absenteeism and were more frequent in individuals treated with antihypertensive drugs.

[Rehabilitation of the knee movement after ligamentoplasty using Mac Intosh's procedure augmented by Kennedy-Lad: a comparison between recent and old rupture of the anterior cruciate ligament]. / La récupération de la mobilité du genou après ligamentoplastie type Mac Intosh renforcé par Kennedy-Lad: étude comparative entre rupture récente et rupture ancienne du ligament croisé antérieur.

About 60 ligamentoplasties of the A.C.L. using the Mac Intosh procedure with augmentation by the Kennedy-Lad, the authors compare the rehabilitation of knee motion between fresh tears (30 cases) and old tears (30 cases) of the A.C.L. operated on by the same procedure. All the operations were performed by the same surgeon. The rehabilitation program was the same for everybody; no plaster cast, total weight-bearing after the 15th day, no more crutches-stick after the 21th day and beginning of flexion on the 12th day, 88 per cent of the knees were rehabilitated by the same physiotherapists. The plaster cast is usually incriminated to be the main reason of post-operative knee stiffness. But no plaster cast for fresh A.C.L. tear also give such a stiffness (16.5 per cent). The authors think that the initial injury increased by the surgical trauma, for a non conditioned patient are the main factors of post-operative stiffnesses. This study justifies the late reconstruction of "isolated" A.C.L. tears (between the 2nd and 3rd month), after "cooling down" of the lesions.

[Laparoscopic promontofixation]. / Promontofijación laparoscópica. Nuestra técnica.

OBJECTIVES: The pathology of the pelvic floor, including the urinary incontinence, the anal incontinence and the genital prolapse, is very dominant, concerning approximately a third of the adult women. It is fundamental that this musculature supports a good function, because of the weakness of the pelvic floor produces urinary incontinence, cysto and rectocele, genital prolapses and sexual dysfunctions. The above mentioned pathology can be corrected by laparoscopic promontofixation, whatever the previous history of pelvic surgery, including the placing of prosthetic material. In this article we describe the above mentioned intervention. MATERIAL AND METHODS: Preoperative care is standardized and is accompanied by antibiotic prophylaxis, preventive antithrombotic treatment and in the event of a history of pelvic surgery, a digestive preparation. Positioning of the patient must plan a 30° Trendelenbourg position. After the introduction the trocars, initial surgery comprises anterior dissection of promontory after incision of the posterior peritoneum with the patient placed beforehand in a Trendelembourg position. After that, we make interrectovaginal dissection to free the whole posterior surface of the vagina. This is followed by the installation of a posterior mesh pre-cut in an arc. After intervesical vaginal dissection, the anterior prosthesis comprising a precut polyester mesh is fixed avoiding excess traction. The end of the surgery involves careful reperitonization of all the prosthetic parts. Possible specific surgical complications are vascular and visceral wounds. RESULTS Y CONCLUSIONS: The technique allows the correction of the dysfunction of the pelvic floor and incontinence with good anatomical and functional results. Postoperative secondary haemorrhage and gastrointestinal occlusion may occur. Occurrence of an inflammatory syndrome and low back pain suggests spondylodicitis and MRI should be performed. Vaginal erosion on the prosthesis may occur after several months and seems relatively independent of the prosthetic material used.