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Biomedical subjects

Z Cohen

Publications and source records attributed to Z Cohen.

At least 55 records · Page 3Linked to original sources

Salicylhydroxamic acid inhibits delta6 desaturation in the microalga Porphyridium cruentum.

Treatment of the microalga Porphyridium cruentum with salicylhydroxamic acid (SHAM) inhibited growth and affected fatty acid composition. At a relatively low concentration (40 microM) SHAM predominantly inhibits Delta6 desaturation. The effect of the inhibitor was most intense in phosphatidylcholine (PC) and phosphatidylethanolamine, in which the proportions of the downstream products of the Delta6 desaturase were reduced, whereas that of the substrate, 18:2, increased. As a result of the availability of 18:2, 18:3omega3, which under normal conditions is not observed, appeared predominantly in chloroplastic lipids. Pulse labeling with linoleic acid has shown that SHAM inhibits Delta6 desaturation almost immediately, suggesting an apparent inhibition of the activity of the desaturase, rather than its synthesis or that of its cofactors. Furthermore, the addition of gamma-linolenic acid to SHAM-inhibited cultures relieved the inhibition. Following exposure to the inhibitor, 18:3omega3 appeared first in chloroplastic glycolipids and only later in PC, indicating that the former are the substrates for the first dedicated step of the proposed omega3 pathway in this alga.

Carbon Radioisotopes↗

[Laparoscopic spermatic vein ligation: first experience in the treatment for varicocele in adolescents].

We report our initial experience with laparoscopic ligation of spermatic veins in the treatment of varicocele in adolescence. 19 boys, 13 to 18 years old, underwent this treatment between I 1997 and III 98. The varicocele was always on the left side. 12 complained of scrotal discomfort and pain, but in 7 it was found incidentally during routine medical examination by the family or school physician. The diagnosis was based only on physical examination. There has been no morbidity related to the laparoscopic procedure and all returned to normal activity within a few days. Follow-up 2-12 months after surgery showed no varicocele in any. We conclude that laparoscopy is useful in the treatment of varicocele in adolescents.

Adolescent↗

[Diagnostic and therapeutic laparoscopy for non-palpable testis--3.5 years of experience at Soroko Medical Center].

From January 1994 to July 1997, 20 boys 1.5-13 years of age underwent laparoscopic examination and treatment for non-palpable testis. In 1 there was bilateral nonpalpable testis. Only 3 had intra-abdominal testes viable for orchiopexy. In 8 atrophic testicles were removed and in 9 laparoscopic examination revealed intra-abdominal blind ending of the spermatic cord and no testicular tissue. We conclude that laparoscopy is a useful and safe technique for accurate diagnosis and may avoid additional intervention in treating non-palpable testes. Furthermore, intra-abdominal testes may be managed laparoscopically under the same anesthetic.

Adolescent↗

Negative genetic test result in familial adenomatous polyposis: clinical screening implications.

PURPOSE: The goal of genetic testing is to define individual risk, which in turn may guide clinical management. METHODS: Thirty-two international familial adenomatous polyposis registries were surveyed regarding their approach to a specific clinical management question. There were 30 respondents. Respondents declared their clinical policy for an at-risk, first-degree relative who undergoes direct mutation analysis and does not have an APC gene mutation known to be present in his or her family. RESULTS: Nineteen of 30 (63.3 percent) registries would discharge this negative APC mutation case from clinical screening. Eleven of 30 (37 percent) registries would maintain clinical screening. Reasons offered for maintaining surveillance included the need for additional confirmation of the APC mutation in two affected relatives, the possibility of sampling error or two different mutations in an affected family, limited prospective data, and patient anxiety. CONCLUSIONS: The discrepancy in response to the survey suggests that some clinicians are as yet reluctant to accept fully that predictive genetic analysis is a definitive guide to clinical management in familial adenomatous polyposis. Nevertheless, we believe that use of a predictive gene test for familial adenomatous polyposis should alter management, decrease cost, and reduce psychological trauma for the tested individual. Although the benefit of APC analysis is accepted for the positive gene carrier, the challenge remains to reclassify the negative gene carriers who are no longer at risk for familial adenomatous polyposis.

Adenomatous Polyposis Coli↗

Comparison of ileal pouch-anal anastomosis and ileorectal anastomosis in patients with familial adenomatous polyposis.

PURPOSE: The aim of this study was to evaluate the surgical complications and long-term outcome and assess the functional results and quality of life after ileorectal anastomosis and ileal pouch-anal anastomosis in patients with familial adenomatous polyposis. METHODS: From 1980 to 1997, 131 patients with familial adenomatous polyposis were operated on or were followed up or both at the Familial Gastrointestinal Cancer Registry at Mount Sinai Hospital. Demographic and operative data were prospectively collected in the ileal pouch-anal anastomosis group, and retrospectively in the ileorectal anastomosis group. A questionnaire or telephone interview or both were undertaken to evaluate functional outcome and quality of life. RESULTS: The ileorectal anastomosis group consisted of 60 patients (mean age, 31 years; mean follow-up, 7.7 years). In the ileal pouch-anal anastomosis group there were 50 patients (mean age, 35 years; mean follow-up, 6 years). There were no statistically significant differences with respect to anastomotic leak rate in ileal pouch-anal anastomosis vs. ileorectal anastomosis (12 vs. 3 percent; P = 0.21), risk of small-bowel obstruction (24 vs. 15 percent; P = 0.58), and risk of intra-abdominal sepsis (3 vs. 2 percent; P = 0.86). Reoperation rate was similar in the two groups (14 vs. 16 percent; P = 0.94). Twenty-one patients (37 percent) with ileorectal anastomosis were converted to ileal pouch-anal anastomosis (12 patients) or proctocolectomy (9 patients), because of rectal cancer (5 patients), dysplasia (1 patient), or uncontrollable rectal polyps (15 patients). Two pelvic pouches were excised, and another one was defunctioned. Information regarding functional results and quality of life was obtained in 40 patients (66.6 percent) in the ileorectal anastomosis group and in 43 patients (86 percent) in the ileal pouch-anal anastomosis group. Patients with ileorectal anastomosis had a significantly better functional outcome with regard to nighttime continence and perineal skin irritation. But otherwise, functional results and quality of life were similar. CONCLUSIONS: Although ileorectal anastomosis has a better functional outcome, ileal pouch-anal anastomosis may be preferable because of the lower long-term failure rate. Ileorectal anastomosis is still an option in patients with familial adenomatous polyposis with rectal polyp sparing and good compliance for follow-up.

Adenomatous Polyposis Coli↗

Functional outcome of conversion of ileorectal anastomosis to ileal pouch-anal anastomosis in patients with familial adenomatous polyposis and ulcerative colitis.

PURPOSE: The aim of this study was to review the functional outcome in 20 patients with familial adenomatous polyposis and ulcerative colitis who were converted from ileorectal anastomosis to ileal pouch-anal anastomosis. METHODS: From 1985 to 1997, 12 patients with familial adenomatous polyposis (5 males; mean age, 39.1 years) and 8 patients with ulcerative colitis (5 males; mean age, 36.7 years) underwent conversion from ileorectal anastomosis to ileal pouch-anal anastomosis. Clinical and operative data were analyzed retrospectively. Functional results were obtained by telephone interview in 16 patients (94 percent) after pouch construction. Four patients were not interviewed (2 were deceased, 1 was lost to follow-up, and 1 was not reachable). RESULTS: Indications for conversion were uncontrollable rectal polyps (10 patients) and colonic cancer found in the pathology specimen after ileorectal anastomosis in patients with familial adenomatous polyposis (2 patients), intractable proctitis (5 patients), colonic cancer found in the pathology specimen of patients with ulcerative colitis after ileorectal anastomosis (2 patients), and rectal dysplasia (1 patients). Mean follow-up time was 5 (range, 1-11) years. Ileal pouch-anal anastomosis was handsewn in 14 patients, and the remaining cases were double-stapled in 4 patients with ulcerative colitis. No intraoperative difficulties were reported in 13 cases; technical problems were related to adhesions (3 cases), difficult rectal dissection (2 cases), and stapler-related difficulties (2 cases). Postoperative complications after ileal pouch-anal anastomosis included small-bowel obstruction (4 patients) and ileal pouch-anal anastomosis leak (1 patient). Patients with ileorectal anastomosis vs. those with ileal pouch-anal anastomosis had a better functional outcome with regard to nighttime continence (14 (88 percent) vs. 6 (38 percent) patients) and average bowel movements (<6/day; 12 (75 percent) vs. 4 (25 percent) patients). Complete daytime continence, 15 (94 percent) vs. 10 (62 percent) patients, was similar in the two groups. Physical and emotional well-being were similarly rated as very good to excellent. CONCLUSIONS: In patients with familial adenomatous polyposis and ulcerative colitis with ileorectal anastomosis, conversion to ileal pouch-anal anastomosis may be required. In view of the risk of rectal cancer or intractable proctitis, patients seem to accept the conversion in spite of poorer bowel function.

Adenomatous Polyposis Coli↗

Operative and environmental risk factors for recurrence of Crohn's disease.

This retrospective study determined whether a hand-sewn or stapled anastomosis leads to a greater recurrence rate in patients undergoing ileocecal resection for terminal ileal Crohn's disease. The effects of oral contraceptive use, smoking, and age at onset of disease were also examined. Ninety-two patients with Crohn's disease of the terminal ileum whose first operation was an ileocecal resection (terminal ileum and right colon up to but not including the hepatic flexure) were studied for symptomatic and operative recurrence. The symptomatic recurrence rates were 15% at 1 year, 31% at 2 years, and 45% at 3 years. The operative recurrence rates were 6% at 1 year, 14% at 2 years, and 22% at 3 years. The type of anastomosis, whether hand-sewn or stapled, did not affect the rates of symptomatic (P = 0.3) or operative (P = 0.6) recurrence. After the initial resection smoking affected both symptomatic (P = 0.03, risk ratio = 2.380) and operative (P = 0.041, risk ratio = 3.13) recurrence, but there was no effect of age at onset of disease or use of the birth control pill.

Age Factors↗

Family history characteristics, tumor microsatellite instability and germline MSH2 and MLH1 mutations in hereditary colorectal cancer.

Recent characterization of the molecular genetic basis of hereditary nonpolyposis colorectal cancer provides an important opportunity for identification of individuals and their families with germline mutations in mismatch repair genes. Cancer family history criteria that accurately define hereditary colorectal cancer are necessary for cost-effective testing for germline mutations in mismatch repair genes. The present report describes the results of analysis of 33 colorectal cancer cases/families that satisfy our modified family history criteria (Mount Sinai criteria) for colorectal cancer. Fourteen of these families met the more stringent Amsterdam criteria. Germline MSH2 and MLH1 mutations were identified by the reverse transcription-polymerase chain reaction and the protein truncation test, and confirmed by sequencing. Microsatellite instability analysis was performed on available tumors from affected patients. MSH2 or MLH1 mutations were detected in 8 of 14 Amsterdam criteria families and in 5 of the remaining 19 cases/families that only satisfied the Mount Sinai criteria. Three of the latter families had features of the Muir-Torre syndrome. A high level of microsatellite instability (MSI-H) was detected in almost all (16/18) colorectal cancers from individuals with MSH2 and MLH1 mutations, and infrequently (1/21) in colorectal cancer specimens from cases without detectable mutations. Families with germline MSH2 and MLH1 mutations tended to have individuals affected at younger ages and with multiple tumors. The Amsterdam criteria are useful, but not sufficient, for detecting hereditary colorectal cancer families with germline MSH2 and MLH1 mutations, since a proportion of cases and families with mutations in mismatch repair genes will be missed. Further development of cancer family history criteria are needed, using unbiased prospectively collected cases, to define more accurately those who will benefit from MSH2 and MLH1 mutation analysis.

Adaptor Proteins, Signal Transducing↗

Familial adenomatous polyposis-associated thyroid cancer: a clinical, pathological, and molecular genetics study.

We report two familial adenomatous polyposis (FAP) kindreds with thyroid cancer, harboring two apparently novel germlineAPC mutations. The clinical phenotype in the first kindred was typical of classical adenomatous polyposis, whereas the second kindred exhibited an attenuated adenomatous polyposis phenotype. There was a female predominance with a mean age of 34 years (range, 23-49) at cancer diagnosis. Multiple sections of four thyroid tumors from three FAP patients were analyzed in detail. Histological examination of thyroid tumors showed a range of morphological features. Some tumors exhibited typical papillary architecture and were associated with multifocal carcinoma; in others, there were unusual areas of cribriform morphology, and spindle-cell components with whorled architecture. Immunoreactivity for thyroglobulin and high molecular weight keratins was strong. Somatic APC mutation analysis revealed an insertion of a novel long interspersed nuclear element-1-like sequence in one tumor sample, suggesting disruption of APC. In three FAP patients, ret/PTC-1 and ret/PTC-3 were expressed in thyroid cancers. No positivity was observed for ret/ PTC-2. p53 immunohistochemistry was positive in only one section of a recurrent thyroid tumor sample. Our data suggest that genetic alterations in FAP-associated thyroid cancer involve loss of function of APC along with the gain of function of ret/PTC, while alterations of p53 do not appear to be an early event in thyroid tumorigenesis.

Adenomatous Polyps↗

STK11/LKB1 germline mutations are not identified in most Peutz-Jeghers syndrome patients.

Germline mutations of the STK11 gene mapped to chromosome 19p13.3 are responsible for Peutz Jeghers syndrome (PJS), a dominant disorder associated with characteristic gastrointestinal hamartomatous polyps and a predisposition to various cancers. We conducted a detailed investigation of germline STK11 alterations by protein truncation test and genomic DNA sequence analysis in ten unrelated PJS families. We identified a novel truncating deletion spanning STK11 exons 2-7 in a single patient and several known polymorphisms. Loss of heterozygosity studies in PJS polyps of four of these patients identified an allelic deletion of D19S886 in another patient. Our results suggest that STK11 mutations account for only a proportion of PJS cases.

AMP-Activated Protein Kinase Kinases↗

Near total intestinal aganglionosis with extreme short-bowel syndrome--a difficult surgical dilemma.

Forty cases of total or near-total intestinal agangliosis (NTIA) were described to date in the English literature. Most cases had a lethal outcome. We describe the 41st case--a Beduin male neonate--who had only 30 cm of proximal hypoganglionic jejunum. He is presently almost one-year-old and thriving on home TPN, receiving one quarter of his caloric requirements orally using pregestamil, an MCT formula. The initial intricate course, diagnosis and several operative procedures, are elaborated. A review of the scant literature is discussed. The elusiveness of the correct diagnosis is pointed out and means to overcome these errors are described. Various surgical procedures have been suggested, none of which offer the perfect solution to the severe basic problem of short bowel. Long-term parenteral hyperalimentation is still the main modality of treatment. Based on our modest experience, we suggest saving every possible length of jejunum, even if hypoganglionic, since this bowel, following a few weeks of adaptation, starts to function fairly well, suggesting perhaps some neuro-muscular maturation. The best surgical approach is still pending. We present a report of a child with this disease and discuss the therapeutic dilemma.

Hirschsprung Disease↗

Nissen fundoplication and Boix-Ochoa antireflux procedure: comparison between two surgical techniques in the treatment of gastroesophageal reflux in children.

Over a period of 19 years an antireflux procedure was performed for gastroesophageal reflux in 59 children. Thirty-two patients underwent Nissen fundoplication and 27 children underwent the Boix-Ochoa antireflux procedure. Six patients died between two and 15 months post surgery of unrelated causes. Follow-up period from six months to 18 years was available in 45 (85%) of the surviving patients. This report summarizes the complications and long-term results with the two surgical procedures and their comparisons. The follow-up evaluation included parental interview and physical examination. Upper GI series and pH monitoring were performed only in children with signs and symptoms of recurrent GER or other post-operative complications. At follow-up with a mean period of 8.7 years following Nissen fundoplication, 87.5% showed good results without any residual symptoms. However, the overall complication rate was as high as 50%. Following the Boix-Ochoa antireflux procedure, 17 (81%) children showed excellent results while four children had recurrent GER. This occurred in two neurologically impaired children and two patients following esophageal atresia repair. No other post-operative complications were encountered with the Boix-Ochoa antireflux procedure. In our experience, the Boix-Ochoa antireflux procedure should be the procedure of choice in the surgical treatment of GER in otherwise normal children while the Nissen fundoplication is preferable in neurologically impaired children and in patients with GER following esophageal atresia repair.

Female↗

Expression of neuropeptide Y receptors mRNA and protein in human brain vessels and cerebromicrovascular cells in culture.

Neuropeptide Y (NPY) has been suggested as an important regulator of CBF. However, except for the presence of Y1 receptors in large cerebral arteries, little is known about its possible sites of action on brain vessels. In this study, we sought to identify the NPY receptors present in the human cerebrovascular bed. Specific Y1 receptor binding sites, localized on the smooth muscle of human pial vessels and potently competed by NPY, polypeptide YY (PYY), and the selective Y1 receptor antagonist BIBP 3226, were identified by quantitative radioautography of the Y1 radioligand [125I]-[Leu31, Pro34]-PYY. In contrast, no specific binding of the Y2-([125I]-PYY3-36) and Y4/Y5-(125I-human pancreatic polypeptide [hPP]) radioligands could be detected. By in situ hybridization, expression of Y1 receptor mRNA was restricted to the smooth muscle layer of pial vessels, whereas no specific signals were detected for either Y2, Y4, or Y5 receptors. Similarly, using reverse transcriptase-polymerase chain reaction (RT-PCR), mRNA for Y1 but not Y2, Y4, or Y5 receptors was consistently detected in isolated human pial vessels, intracortical microvessels, and capillaries. In human brain microvascular cells in culture, PCR products for the Y1 receptors were exclusively found in the smooth muscle cells. In cultures of human brain astrocytes, a cell type that associates intimately with brain microvessels, PCR products for Y1, Y2, and Y4 but not Y5 receptors were identified. Finally, NPY significantly inhibited the forskolin-induced cAMP production in smooth muscle but not in endothelial cell cultures. We conclude that smooth muscle Y1 receptors are the primary if not exclusive NPY receptors associated with human brain extraparenchymal and intraparenchymal blood vessels, where they most likely mediate cerebral vasoconstriction.

Astrocytes↗

Functional acetylcholine muscarinic receptor subtypes in human brain microcirculation: identification and cellular localization.

Acetylcholine is an important regulator of local cerebral blood flow. There is, however, limited information available on the possible sites of action of this neurotransmitter on brain intraparenchymal microvessels. In this study, a combination of molecular and functional approaches was used to identify which of the five muscarinic acetylcholine receptors (mAChR) are present in human brain microvessels and their intimately associated astroglial cells. Microvessel and capillary fractions isolated from human cerebral cortex were found by reverse transcriptase-polymerase chain reaction to express m2, m3, and, occasionally, m1 and m5 receptor subtypes. To localize these receptors to a specific cellular compartment of the vessel wall, cultures of human brain microvascular endothelial and smooth muscle cells were used, together with cultured human brain astrocytes. Endothelial cells invariably expressed m2 and m5 receptors, and occasionally the m1 receptor; smooth muscle cells exhibited messages for all except the m4 mAChR subtypes, whereas messages for all five muscarinic receptors were identified in astrocytes. In all three cell types studied, acetylcholine induced a pirenzepine-sensitive increase (62% to 176%, P<0.05 to 0.01) in inositol trisphosphate, suggesting functional coupling of m1, m3, or m5 mAChR to a phospholipase C signaling cascade. Similarly, coupling of m2 or m4 mAChR to adenylate cyclase inhibition in endothelial cells and astrocytes, but not in smooth muscle cells, was demonstrated by the ability of carbachol to significantly reduce (44% to 50%, P<0.05 to 0.01) the forskolin-stimulated increase in cAMP levels. This effect was reversed by the mAChR antagonist AFDX 384. The results indicate that microvessels are able to respond to neurally released acetylcholine and that mAChR, distributed in different vascular and astroglial compartments, could regulate cortical perfusion and, possibly, blood-brain barrier permeability, functions that could become jeopardized in neurodegenerative disorders such as Alzheimer's disease.

Astrocytes↗

Multiple microvascular and astroglial 5-hydroxytryptamine receptor subtypes in human brain: molecular and pharmacologic characterization.

Physiologic and anatomic evidence suggest that 5-hydroxytryptamine (5-HT) neurons regulate local cerebral blood flow and blood-brain barrier permeability. To evaluate the possibility that some of these effects occur directly on the blood vessels, molecular and/or pharmacologic approaches were used to assess the presence of 5-HT receptors in human brain microvascular fractions, endothelial and smooth muscle cell cultures, as well as in astroglial cells which intimately associate with intraparenchymal blood vessels. Isolated microvessels and capillaries consistently expressed messages for the h5-HT1B, h5-HT1D, 5-HT1F, 5-HT2A but not 5-HT7 receptors. When their distribution within the vessel wall was studied in more detail, it was found that capillary endothelial cells exhibited mRNA for the h5-HT1D and for the 5-HT7 receptors whereas microvascular smooth muscle cells, in addition to h5-HT1D and 5-HT7, also showed polymerase chain reaction products for h5-HT1B receptors. Expression of 5-HT1F and 5-HT2A receptor mRNAs was never detected in any of the microvascular cell cultures. In contrast, messages for all 5-HT receptors tested were detected in human brain astrocytes with a predominance of the 5-HT2A and 5-HT7 subtypes. In all cultures, sumatriptan inhibited (35-58%, P < .05) the forskolin-stimulated production of cyclic AMP, an effect blocked by the 5-HT1B/1D receptor antagonists GR127935 and GR55562. In contrast, 5-carboxamidotryptamine induced strong increases (> or = 400%, P < .005) in basal cyclic AMP levels that were abolished by mesulergine, a nonselective 5-HT7 receptor antagonist. Only astroglial cells showed a ketanserin-sensitive increase (177%, P < .05) in IP3 formation when exposed to 5-HT. These results show that specific populations of functional 5-HT receptors are differentially distributed within the various cellular compartments of the human cortical microvascular bed, and that human brain astroglial cells are endowed with multiple 5-HT receptors. These findings emphasize the complex interactions between brain serotonergic pathways and non-neuronal cells within the CNS and, further, they raise the possibility that some of these receptors may be activated by antimigraine compounds such as brain penetrant triptan derivatives.

Astrocytes↗

Functional calcitonin gene-related peptide type 1 and adrenomedullin receptors in human trigeminal ganglia, brain vessels, and cerebromicrovascular or astroglial cells in culture.

Calcitonin gene-related peptide (CGRP) and adrenomedullin (ADM) are potent dilators of human brain arteries, and they have been implicated in the neurogenic inflammation underlying migraine headache and in the evolution of stroke, respectively. However, little is known about the presynaptic and postsynaptic distribution of their respective receptors in the human cerebrovascular bed and trigeminovascular system. In the current study, the expression of mRNA for ADM and the two cloned human CGRP1 receptors (identified here as A-CGRP1 receptors [Aiyar et al., 1996] and K-CGRP1 receptors) [Kapas and Clark, 1995] were evaluated in human brain vessels and trigeminal ganglia. Further, the ability of CGRP and ADM to activate adenylate cyclase in cerebromicrovascular and astroglial cell cultures was determined, and the receptors involved were characterized pharmacologically. Isolated human pial vessels, intracortical microvessels, and capillaries, as well as cultures of brain endothelial (EC), smooth muscle (SMC), and astroglial (AST) cells, all expressed mRNA for the two cloned CGRP1 receptors; however, message for the K-CGRP1 receptor was barely detectable in microvascular tissues and cells. In contrast, only isolated capillaries and cultured AST exhibited message for the ADM receptor. In human trigeminal ganglia, mRNA for ADM and the two CGRP1 receptors was systematically present. The CGRP dose-dependently increased (up to 50-fold) cAMP formation in cell cultures, an effect significantly blocked by 0.1 to 10 micromol/L of the CGRP1 receptor antagonist CGRP8-37. The ADM receptor agonist, ADM13-52 (1 micromol/L), similarly increased cAMP production in all cell types, and this response was virtually abolished by 1 micromol/L CGRP8-37. Low concentrations (1 to 10 micromol/L) of the ADM receptor antagonist ADM22-52 blocked the ADM13-52-induced cAMP formation in AST (26% at 10 micromol/L, P < 0.05), whereas they potentiated this response in brain EC and SMC (40% and 100%, P < 0.001, respectively). Even at a higher dose (50 micromol/L), ADM22-52 inhibited the ADM13-52 effect in vascular cells (45%) much less effectively than in AST (95%). These results indicate that both CGRP and ADM can affect human brain vessels through a CGRP1 receptor, and they further suggest the presence of functional ADM receptors in human astroglial cells.

Astrocytes↗