Clinical, genetic, and cellular analysis of 49 osteopetrotic patients: implications for diagnosis and treatment.

BACKGROUND: Osteopetrosis, a genetic disease characterised by osteoclast failure, is classified into three forms: infantile malignant autosomal recessive osteopetrosis (ARO), intermediate autosomal recessive osteopetrosis (IRO), and autosomal dominant osteopetrosis (ADO). METHODS: We studied 49 patients, 21 with ARO, one with IRO, and 27 with type II ADO (ADO II). RESULTS: Most ARO patients bore known or novel (one case) ATP6i (TCIRG1) gene mutations. Six ADO II patients had no mutations in ClCN7, the only so far recognised gene implicated, suggesting involvement of yet unknown genes. Identical ClCN7 mutations produced differing phenotypes with variable degrees of severity. In ADO II, serum tartrate resistant acid phosphatase was always elevated. Bone alkaline phosphatase (BALP) was generally low, but osteocalcin was high, suggesting perturbed osteoblast differentiation or function. In contrast, BALP was high in ARO patients. Elevated osteoclast surface/bone surface was noted in biopsies from most ARO patients. Cases with high osteoclasts also showed increased osteoblast surface/bone surface. ARO osteoclasts were morphologically normal, with unaltered formation rates, intracellular pH handling, and response to acidification. Their resorption activity was greatly reduced, but not abolished. In control osteoclasts, all resorption activity was abolished by combined inhibition of proton pumping and sodium/proton antiport. CONCLUSIONS: These findings provide a rationale for novel therapies targeting pH handling mechanisms in osteoclasts and their microenvironment.

Fixed and unstable I-related transposable elements in heterochromatin of Drosophila melanogaster.

Transposable elements are disproportionately abundant in the heterochromatin of Drosophila melanogaster. Among the forces contributing to this bias in genomic distribution, fixation due to positive selection has been put forward. We have studied I-related elements which are located in pericentromeric heterochromatin and are believed to have a role in the control of active I elements. Flies straight from the wild have been studied where fixed elements are expected to emerge clearly over the highly polymorphic background in the genomic distribution of transposable elements. The results show that some restriction fragments due to I-related elements are conserved in size and are present in all individuals tested, consistent with a selective pressure for a role. Other fragments are polymorphic in presence/absence and intensity in individuals from the wild but appear homogeneous in laboratory stocks. Although the significance of this type of instability is unclear, the finding that these polymorphic bands are recurrent in populations from distant geographical locations is also suggestive of a selective pressure for a role.

[Steroid receptors in brain tumors]. / I recettori steroidei nei tumori cerebrali.

Recently the presence of steroid hormone receptors (SHR) have been reported in a series of nervous system human tumors, mainly in meningiomas. The possibility of characterizing brain tumors deserves attention because of the poor knowledge of endocrine-related behaviour of such tumors. The reliability of biochemical characterization of various receptor types should allow for better understanding of biological profile of primary and metastatic brain tumor, together with new avenues for combined modality treatment. In the future the highest priority might be assigned to the definition of the cut-off value of positivity for single receptors and to the receptor-endocrine modulation complex relationship for individual patients. A clear definition of the role of SHR in human brain tumors might improve our therapeutic potentials.

Evidence for genomic regulation of the telomeric activity in Drosophila melanogaster.

The structural integrity of TART elements has been used as reporter of instability at chromosomal ends in numerous Drosophila stocks and over time in an unstable stock. The results show that telomeric activity is a regulated process that may differ between the stocks as well as over time within a stock.

Tetracyclines, doxycycline and calcified tissues.

The use of radioactive isotope techniques has led to a thorough re-assessment of our knowledge of bone histology. It is known that tetracyclines faithfully follow the pattern of calcium metabolism in the body. Fluorescence microscopy, after double labeling with tetracyclines and alizarin red S, is very useful for collection of qualitative and quantitative data on compact and spongy bone remodeling. Two illustrations are presented which demonstrate how oxytetracycline and doxycycline administered in therapeutic doses to growing dogs, become deposited in the dentine. The significance of these findings is discussed.

The dramatic reality of biliary tract injury during laparoscopic cholecystectomy. An anonymous multicenter Belgian survey of 65 patients.

BACKGROUND: Most reports concerning the outcome of patients with biliary tract injury during laparoscopic cholecystectomy come from tertiary referral centers, and results could be very different in the everyday practice of community surgeons. OBJECTIVE: The objective is to define the presentation, mechanisms, results of treatment, and long-term outcome of biliary tract injuries during laparoscopic cholecystectomy in the setting of a community surgeon's practice. METHODS: An anonymous retrospective multicenter survey of 9,959 patients who underwent laparoscopic cholecystectomy was conducted by the Belgian Group for Endoscopic Surgery, composed mainly of community general surgeons. RESULTS: Sixty-five patients with bile duct injury were reported on; the incidence was 0.5%, varying from 0. 35 to 1.3% according to the experience of the surgeon. Thirty-four percent of ductal injuries occurred with experienced surgeons, often in association with local predisposing risk factors. Injury occurred in 87% of cases during dissection of the Calot triangle, with severe injury occurring in 46% of patients. Intraoperative cholangiography was performed in 34% of patients and was associated with a significantly improved operative detection rate of injury (68% vs 32%, p = 0.007). Operative detection of injury occurred in 45% of patients; diffuse bile ascitis was encountered postoperatively in 29%. The overall mortality was 9%, the postoperative biliary complication rate 31%, and the reintervention rate 14%. During a median follow-up of 49 months (range, 3-78 months), 20 of the 61 surviving patients (33%) had recurrent biliary strictures. Multivariate analysis demonstrated that the age of the patient (odds ratio: 0.893) and the presence of biliary peritonitis (odds ratio: 0.061) were independent predictive factors for mortality and that the age of the patient (odds ratio: 1.049) and the occurrence of postoperative biliary complications (odds ratio: 0.161) after the initial biliary repair were independent predictive factors for late biliary stricture. CONCLUSIONS: Biliary tract injury is associated with significant mortality and complications in the practice of Belgian community surgeons. Intraoperative detection of ductal injury by the routine use and a correct interpretation of intraoperative cholangiography improved outcome. The impact of the primary biliary repair on long-term outcome is an argument to refer these patients to specialized multidisciplinary experts. The results highlight the importance of surgical experience, proper selection of patients for laparoscopic cholecystectomy, and conversion to laparotomy in difficult cases.