A cytogenetic deletion, del(17)(q11.22q21.1), in a patient with sporadic neurofibromatosis type 1 (NF1) associated with dysmorphism and developmental delay.

We report the first visible cytogenetic deletion involving the NF1 gene in a patient with sporadic neurofibromatosis, dysmorphic features, and marked developmental delay. The combined evidence of molecular and cytogenetic techniques based on dosage reduction, hemizygosity for microsatellite markers, high resolution G banding, and FISH analysis, predicts this deletion to be approximately 7 Mb in size. Our findings highlight the importance of conducting a detailed cytogenetic and FISH analysis in patients with NF1 who have additional dysmorphic features or particularly severe learning difficulties.     

Is Irregular Regression of Corpora Lutea in Climacteric Women Caused by Age-Induced Alterations in the “Tissue Control System”?

PROBLEM: We have recently observed that the regression of corpora lutea (CL) in women during the reproductive period of life is accompanied by a diminution of Thy-1 differentiation protein release from vascular pericytes and an accumulation of T lymphocytes and activated macrophages among both degenerating granulosa lutein cells (GLC) and theca lutein cells. These data suggest that the immune system and other stromal factors, representing components of the “tissue control system,” may play a role in regression of the CL. We investigated degenerating CL from climacteric women to address the possibility that the decline of immune functions with advancing age may result in incomplete regression of luteal tissue. This could contribute to the altered hormonal profiles and abnormal uterine bleeding that frequently occur during the climacteric. METHOD: Immunoperoxidase staining and image analysis were used to localize Thy-1 differentiation protein of vascular pericytes, cytokeratin staining of GLC, neural cell adhesion molecule expression by theca lutein cells, CD15 of neutrophils, CD4, CD14, CD68, and leukocyte common antigens of macrophages, and CD3 and CD8 determinants of T lymphocytes. We also investigated the expression of luteinizing hormone receptor (LH receptor) and mitogen activated protein kinases (MAP kinases) in luteal cells. Samples of regressing luteal tissue were obtained during the follicular phase from perimenopausal women (age 45–50) who exhibited prolonged or irregular cycles. For comparison, luteal tissues from women with regular cycles (age 29–45) and CL of pregnancy were also investigated. RESULTS: Corpora lutea of the climacteric women exhibited irregular regression of luteal tissue characterized by a lack of cytoplasmic vacuolization and nuclear pyknosis in GLC, and by a persistence of theca lutein cells exhibiting hyperplasia and adjacent theca externa layers. This was accompanied by a continuing release of Thy-1 differentiation protein from vascular pericytes. Persisting GLC lacked surface expression of macrophage markers (CD4, CD14, CD68 and leukocyte common antigen) as well as nuclear granules exhibiting CD15 of neutrophils, detected in regularly regressing GLC. In addition, such persisting GLC showed weak or no LH receptor expression, and retained the expression of cytokeratin. They also exhibited enhanced staining for MAP kinases. Strong cytoplasmic MAP kinase expression with occasional nuclear translocation was also detected in persisting theca lutein cells, indicating high metabolic activity of these cells. T lymphocytes, although occasionally present in luteal stroma within luteal convolutions, did not invade among persisting GLC and were virtually absent from layers of theca externa and theca lutein cells. CONCLUSIONS: These data indicate that the regressing CL in climacteric women may exhibit persistence of luteal cells, perhaps because of age-induced alterations of the immune system and other local stromal homeostatic mechanisms involved in the elimination of luteal cells. Persisting GLC and/or theca lutein cells may exhibit abnormal hormonal secretion that contributes to the alteration of target tissues, such as the endometrium, resulting in abnormal uterine bleeding, hyperplasia, and neoplasia.     

A closely linked DNA marker for facioscapulohumeral disease on chromosome 4q.

Close linkage of a hypervariable DNA probe on chromosome 4q (pH30, locus D4S139) has been found with the locus for facioscapulohumeral disease. Three recombinants were identified in a total of 140 meioses, giving a maximum lod score of 36.77 at a recombination fraction of 0.02. All but two of the families studied proved informative with this probe; all informative families showed evidence of linkage (except one family with a single scorable meiosis), making genetic heterogeneity unlikely from our data. The close linkage and highly informative nature of the probe will make it suitable for clinical application in presymptomatic and prenatal diagnosis. We have also confirmed loose linkage with the marker (Mfd22, locus D4S171) used to establish the initial assignment of the disorder to chromosome 4.     

Neurofibromatous neuropathy in neurofibromatosis 1 (NF1)

Background: Neurofibromatosis 1 (NF1) is a common, autosomal dominant, neurocutaneous disease that is clinically and genetically distinct from the rare condition neurofibromatosis 2 (NF2). Neurofibromatous neuropathy has been regarded as a common feature of NF2, but is an unusual and unexplained complication of NF1. The clinical and histological features of the NF1 neuropathy are distinct from those encountered in NF2. We describe eight patients with a symmetrical polyneuropathy, which has been called neurofibromatous neuropathy

Methods: Clinical assessments, laboratory investigations, neuroimaging, and neurophysiology were undertaken in eight individuals with neurofibromatous neuropathy. None were referred because of neuropathic symptoms. Two subjects underwent sural nerve biopsy and three agreed to mutational analysis.

Results: The patients had an indolent symmetrical predominantly sensory axonal neuropathy and unusually early development of large numbers of neurofibromas. The biopsied nerves showed diffuse neurofibromatous change and disruption of the perineurium. Two patients developed a high grade malignant peripheral nerve sheath tumour. Disease causing mutations were detected in two individuals and molecular studies did not reveal any whole gene deletions.

Conclusions: Neurofibromatous neuropathy occurred in 1.3% of 600 patients with NF1. Its cause may be a diffuse neuropathic process arising from inappropriate signalling between Schwann cells, fibroblasts, and perineurial cells.

     

Rectal atresia: transanal, end-to-end, rectorectal anastomosis: a simplified, rational approach to management

Transanal, end-to-end, rectorectal anastomosis (TERA) is a new technique for the surgical correction of rectal atresia. Hitherto performed abdominoperineal or sacroperineal procedures entailed major traumatizing surgery with an inherent risk of complications. The rationale of TERA is based on three factors: (1) the anorectal canal distal to the atresia is normally developed, as are the sphincteric muscles surrounding it; (2) the anorectum can be preoperatively dilated to allow a transanal anastomosis of good size; and (3) the atretic segment can be effectively "intussuscepted" into the anal canal, almost up to the anal verge, by an oversized metal bougie passed through the sigmoid colostomy. A midline sagittal incision over the metal bougie exposes the rectal pouch, which is mobilized from the surrounding muscle fibers, and a direct, end-to-end anastomosis is performed. This technique has been successfully used in two cases of rectal atresia having a gap between the two pouches.     

Structure-activity relationships among the ortho-, meta- and para-isomers of phenylenebis (methylene)seleno cyanate (XSC) as inhibitors of 7,12-dimethylbenz(a)anthracene-DNA binding in mammary glands of female CD rats

As shown earlier p-XSC inhibits DMBA-induced mammary cancer in female CD rats. This inhibition is due, in part, to inhibition of DMBA-DNA adduct formation in the target organ. We have now utilized the DMBA-DNA binding assay to evaluate the chemopreventive potential of positional isomers of XSC (o-, m- and p-XSC) applied at selenium doses of 5 and 15 ppm; p-XTC, the sulfur analog of p-XSC, was used at an equimolar dose to determine whether selenium is required for the observed inhibitory effect. Selenium and sulfur compounds were administered in a semipurified high-fat diet (23.5% corn oil). Rats were fed for 1 week prior to oral administration of a single dose of [H-3]DMBA (5 mg/rat); animals were sacrificed 24 h later, DNA was isolated from mammary fat pads and levels of total binding were determined. All agents produced a dose-dependent inhibition of DMBA-DNA binding in the mammary tissues. The inhibition at 5, respectively 15 ppm Se in the form of XSC isomers and at 30 mu M, respectively 90 mu M in the form of p-XTC was: o-XSC (27%, 42%); m-XSC (32%, 47%); p-XSC (22%, 29%); and p-XTC (10%, 20%); only inhibition by dietary o-XSC and m-XSC at 15 ppm Se reached statistical significance (p<0.05). Thus, o-XSC and m-XSC equally inhibit DMBA-DNA binding and both are better inhibitors than p-XSC; the latter appears to be slightly more effective than its sulfur analog p-XTC. Clearly, the structure of the selenium-containing compound is a critical factor in determining the extent of inhibition of DMBA-DNA binding. The described short-term in vivo assay may constitute the basis for future selection of chemopreventive agents in the rat mammary tumor model system.     

A comparison of anaesthesia using remifentanil combined with either isoflurane, enflurane or propofol in patients undergoing gynaecological laparoscopy, varicose vein or arthroscopic surgery

BACKGROUND: Anaesthesia comprising remifentanil plus isoflurane, enflurane or propofol was randomly evaluated in 285, 285 and 284 patients, respectively, undergoing short-procedure surgery. METHODS: Anaesthesia was induced with propofol (0.5 mg x kg(-1) and 10 mg x 10 s(-1)), and a remifentanil bolus (1 microg x kg(-1)) and infusion at 0.5 microg x g(-1) x min(-1). Five minutes after intubation, remifentanil infusion was halved and 0.5 MAC of isoflurane or enflurane, or propofol at 100 microg x kg(-1) x min(-1) were started and titrated for maintenance. RESULTS: Patient demography and anaesthesia duration were similar between the groups. Surgery was performed as daycases (52%) or inpatients (48%). The median times (5-7 min) to extubation and postoperative recovery were similar between the groups. Responses to tracheal intubation (15% vs 8%) and skin incision (13% vs 7%) were significantly greater in the total intravenous anaesthesia (TIVA) group (P<0.05). Fewer patients given remifentanil and isoflurane (21%) or enflurane (19%) experienced > or =1 intraoperative stress response compared to the TIVA group (28%) (P<0.05). Median times to qualification for and actual recovery room discharge were 0.5-0.6 h and 1.1-1.2 h, respectively. The most common remifentanil-related symptoms were muscle rigidity (6-7%) at induction, hypotension (3-5%) and bradycardia (1-4%) intraoperatively and, shivering (6-7%), nausea and vomiting postoperatively. Nausea (7%) and vomiting (3%) were significantly lower with TIVA compared with inhaled anaesthetic groups (14-15% and 6-8%, respectively; P<0.05). CONCLUSION: Anaesthesia combining remifentanil with volatile hypnotics or TIVA with propofol was effective and well tolerated. Times of extubation, postanaesthesia recovery and recovery room discharge were rapid, consistent and similar for all three regimens.