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O Cohen

Publications and source records attributed to O Cohen.

At least 19 recordsLinked to original sources
PubMed1999

Structure-function analysis of an evolutionary conserved protein, DAP3, which mediates TNF-alpha- and Fas-induced cell death.

A novel approach to the isolation of positive mediators of programmed cell death, based on random inactivation of genes by expression of anti sense RNAs, was employed to identify mediators of interferon-gamma-induced apoptosis. One of the several genes identified is DAP3, which codes for a 46 kDa protein with a potential nucleotide-binding motif. Structure-function studies of the protein indicate that the intact full-length protein is required for its ability to induce apoptosis when overexpressed. The N-terminal 230 amino acids, on the other hand, act in a dominant-negative fashion. Both of these functions are dependent on the integrity of the nucleotide binding motif. Expression of anti-sense DAP3 RNA and of the dominant interfering form of DAP3 both protected cells from apoptosis induced by activation of Fas and tumor necrosis factor alpha (TNF-alpha) receptors. Thus, DAP3 is implicated as a positive mediator of these death-inducing stimuli. It functions downstream of the receptor signaling complex and its death promoting effects depend on caspase activity. In the nematode Caenorhabditis elegans, a potential homolog of DAP3 showing 35% identity and 64% similarity to the human protein was isolated. Overexpression of the nematode DAP3 cDNA in mammalian cells induced cell death, indicating that the protein is conserved at the functional level as well as the structural level.

Amino Acid Sequence↗
PubMed1998

Complication-free duration and the risk of development of retinopathy in elderly diabetic patients.

BACKGROUND: Determining which diabetic patients are at risk for complications and targeting these patients for intensive therapy may avoid the unwanted consequences of hypoglycemia in low-risk patients. Since aging is associated with a decrease in the incidence of diabetic retinopathy, we assessed whether long complication-free duration can define elderly patients at lower risk for future development of diabetic retinopathy. METHODS: In a 10-year clinic-based study, we studied 833 type 2 diabetic patients who were free of diabetic retinopathy and older than 50 years, followed up for more than 4 years. Data included demographic and clinical information on arrival, updated every 3 to 6 months, and yearly direct ophthalmoscopic examination after pupillary dilation by experienced ophthalmologists. All the data were prospectively compiled on relational databases. End points studied were presence of retinopathy, nephropathy, peripheral neuropathy, peripheral vascular disease, hyperlipidemia, and hypertension. RESULTS: Of the patients without retinopathy at the age of 50 years, 10% developed retinopathy during 4 years of follow-up. These patients had longer duration and younger onset of diabetes than the group without retinopathy at the 4-year follow-up. Clustering of microvascular and macrovascular complications was noted. Discriminant analysis showed the following factors to be significant and independent predictors of the development of retinopathy in the elderly: duration of diabetes, body mass index, age, and glucose control. CONCLUSIONS: A long complication-free period does not define elderly patients with type 2 diabetes who are at lower risk for future development of retinopathy. On the contrary, the increase in disease duration is significantly associated with the development of retinopathy in this age group, as described in younger patients.

Aged↗
PubMed1998

Cerebrospinal fluid and plasma concentrations of dipyrone metabolites after a single oral dose of dipyrone.

OBJECTIVE: Dipyrone is a veteran analgesic and antipyretic drug. After oral administration it is rapidly converted by hydrolysis to 4-methylaminoantipyrine (MAA), which is further metabolized to 4-formylaminoantipyrine (FAA), 4-aminoantipyrine (AA) and 4-acetylaminoantipyrine (AAA). It is still debated whether the site of dipyrone action is in the central nervous system or in the periphery. The purpose of this study was to assess whether dipyrone metabolites cross the blood-brain barrier (BBB) when administered systemically. METHODS: Twenty-eight patients undergoing diagnostic lumbar puncture (LP) were randomly assigned to receive two 0.5-g dipyrone tablets either 30 min, 1, 1.5, 2, 4, 6, 8 h or 12 h before the lumbar tap. A 5-ml blood sample was drawn concomitantly. RESULTS: All four metabolites were found in the cerebrospinal fluid (CSF). Their appearance in the CSF lagged but followed that found in the plasma. Mean CSF/plasma ratios were 0.40 (for samples taken between 0.5-2 h) and 0.83 (for samples taken between 4-12 h) for MAA, 0.62 for AA, 0.55 for FAA and 0.40 for AAA (for all samples). Significant correlation was found between plasma and CSF concentrations for MAA, AA, FAA and AAA. CONCLUSION: The concentration-time course of dipyrone metabolite CSF concentrations are in agreement with that of their plasma concentrations and the analgesic effect of dipyrone.

Administration, Oral↗
PubMed1998

Cerebrospinal fluid prostaglandins after systemic dipyrone intake.

OBJECTIVE: The object of this study was to evaluate the time course of thromboxane B2 and prostaglandin E2 concentrations in cerebrospinal fluid after oral administration of dipyrone (INN, metamizole). METHODS: A single 1.0 gm oral dose of dipyrone was given to consenting patients undergoing elective diagnostic lumbar puncture 0.5, 1, 1.5, 2, 4, 6, 8, or 12 hours before the tap. RESULTS: For thromboxane B2 a time decrease in cerebrospinal fluid concentration was apparent. In contrast, for prostaglandin E2 cerebrospinal fluid levels no consistent trend was observed. CONCLUSIONS: A time-related decrease in cerebrospinal fluid thromboxane B2 level was noted in patients receiving dipyrone. Thirty minutes after dipyrone intake cerebrospinal fluid thromboxane B2 levels already tended to be lower than those seen in patients with neurologic diseases who were not receiving dipyrone. These results are consistent with the hypothesis that dipyrone acts in the central nervous system by inhibition of particular prostanoids.

Administration, Oral↗
PubMed1998

Self-representation of suicidal adolescents.

This study focused on the self-representations of suicidal adolescent. Twenty-six Israeli suicidal inpatients, 24 nonsuicidal inpatients, and 24 control participants completed scales on suicidal tendencies, the hedonic value of self-representations, the complexity (differentiation, integration) of these self-representations, and the discrepancies among self domains (actual, ideal, ought). Suicidal adolescents showed more negative self-representations, a less differentiated and less integrated organization of self-attributes, and more discrepancies between the 3 assessed domains of the self than did control participants. In addition, compared with psychiatric nonsuicidal participants, suicidal adolescents showed a less complex organization of self-attributes and a higher discrepancy between ideal self and ought self. Results were discussed in terms of the vulnerable self of suicidal adolescents, characterized by uneven processing of positive and negative information, confusion, and simplicity.

Adolescent↗
PubMed1998

Lithium carbonate therapy is not a risk factor for osteoporosis.

Lithium carbonate is a widely used drug for affective disorders. It may effect calcium metabolism and alter parathyroid physiology by causing hypersecretion of parathyroid hormone. Patients treated with this medication might therefore be predisposed to osteoporosis. The purpose of this study was to evaluate the effect of either short- or long-term lithium carbonate therapy on parameters of bone metabolism. Parathyroid function and indices of bone metabolism were assessed in 23 patients treated for affective disorders. 10 patients were treated for 0.4-1.0 year (Group 1), and 13 patients were treated for more than 3 years (Group 2). In all subjects, bone mineral density measurements in the hip and lumbar spine regions were performed using dual energy X-ray absorptiometry. Serum thyroid hormone, PTH, LH, testosterone and urine OH-proline, free cortisol, calcium and phosphate excretion were measured. The two groups were well matched for sex, weight, calcium intake, lithium levels and smoking habits, although Group 2 was slightly older. No differences between the two groups were noted in either bone mineral density or other parameters that were assessed. Urinary OH-proline was elevated similarly in both groups. Our results did not detect any effect on bone density after short- or long-term lithium carbonate therapy, although the data does suggest an increase in bone turnover associated with this treatment. Thus, short- or long-term treatment with lithium is not associated with increased risk for osteoporosis.

Absorptiometry, Photon↗
PubMed1998

Uterine leiomyomata--a feature of acromegaly.

In order to assess the prevalence of leiomyomata in patients diagnosed with acromegaly, files of all women so diagnosed were obtained (n = 25). Eight of these patients had undergone hysterectomy. In eight of the remaining patients, assessment of the uterus was performed by gynaecological examination and transvaginal ultrasound. The prevalence of leiomyomata was 81% (13/16) in patients who had undergone hysterectomy (8/8) or who underwent gynaecological examination (5/8). In conclusion, the very high prevalence of leiomyomata in patients diagnosed with acromegaly warrants the inclusion of growth hormone excess as a cause of leiomyomata. Leiomyomata are a feature of the organomegalic syndrome associated with acromegaly.

Acromegaly↗
PubMed1998

Herpes simplex virus type 1 latency-associated transcripts suppress viral replication and reduce immediate-early gene mRNA levels in a neuronal cell line.

During herpes simplex virus type 1 (HSV-1) latent infection in human dorsal root ganglia, limited viral transcription, which has been linked to HSV-1 reactivation ability, takes place. To study the involvement of this transcription in HSV-1 replication in neuronal cells and consequently in viral latency, we constructed stably transfected neuronal cell lines containing (i) the entire HSV-1 latency transcriptionally active DNA fragment, (ii) the same DNA sequence with deletions of the latency-associated transcript (LAT) promoters, or (iii) the DNA coding sequence of the LAT domain. Replication of HSV-1 or a LAT-negative mutant was markedly repressed in the LAT-expressing cells, a phenomenon mediated by the LATs. To study the mechanism responsible for this effect, we examined LAT influence upon expression of HSV-1 immediate-early (IE) genes ICP0, ICP4, and ICP27, by Northern blot analysis. Following infection of a LAT-expressing neuronal cell line with a LAT-negative mutant, the steady-state levels of all three IE mRNAs were reduced compared to those for control cells. Transient transfections into a neuronal cell line indicated that the LAT suppressive effect upon ICP0 mRNA was mediated directly and was not due to the LAT effect upon the ICP0 promoter. We therefore propose that the LATs may repress viral replication in neuronal cells by reducing IE gene mRNA levels and thus facilitate the establishment of HSV-1 latency in nervous tissue.

Animals↗
PubMed1998

Immunohistochemical analysis of p27/kip1 expression in thyroid carcinoma.

Cyclin-dependent kinase inhibitors, including the protein product of the p27/kip1 gene, play an important role in cell-cycle regulation. Loss of p27 expression was reported in a number of neoplasms and shown to be an independent prognostic factor in colorectal, lung, and breast carcinoma By immunohistochemical analysis, we investigated p27/kip1 expression, using a polyclonal antibody, in a series of 87 benign and malignant thyroid neoplasms. We correlated its expression with the Ki-67 labeling index and other prognostic factors. All of the thyroid neoplasms examined exhibited significantly lower p27 expression than did normal thyroid tissue (P < .001). Poorly differentiated carcinomas had the lowest p27 staining frequency of all carcinomas examined. p27 staining frequency of the papillary carcinomas was significantly lower than that of the follicular carcinomas (P < .001). This difference could not be attributed solely to the inverse correlation between the staining patterns of p27 and Ki-67, which was reported for other neoplasms, because there was no significant difference between the Ki-67 labeling indices of these two groups. The follicular variant of papillary carcinoma had a significantly higher p27 staining frequency (P = .05) than did classical papillary carcinoma. We saw no significant difference in the p27 staining frequencies between minimally and widely invasive follicular carcinomas nor between localized and nonlocalized papillary carcinoma. In summary, the p27 immunostaining pattern of thyroid neoplasms is related to neoplastic transformation and varies according to tumor phenotype. It seems, however, to have limited routine diagnostic or prognostic significance in thyroid neoplasia.

Adenocarcinoma, Follicular↗
PubMed1997

DAP kinase links the control of apoptosis to metastasis.

DAP kinase is a new type of calcium/calmodulin-dependent enzyme that phosphorylates serine/threonine residues on proteins. Its structure contains ankyrin repeats and the 'death' domain, and it is associated with the cell cytoskeleton. The gene encoding DAP kinase was initially isolated as a positive mediator of apoptosis induced by interferon-gamma, by using a strategy of functional cloning. We have now tested whether this gene has tumour-suppressive activity. We found that lung carcinoma clones, characterized by their highly aggressive metastatic behaviour and originating from two independent murine lung tumours, did not express DAP kinase, in contrast to their low-metastatic counterparts. Restoration of DAP kinase to physiological levels in high-metastatic Lewis carcinoma cells suppressed their ability to form lung metastases after intravenous injection into syngeneic mice, and delayed local tumour growth in a foreign 'microenvironment' Conversely, in vivo selection of rare lung lesions following injection into syngeneic mice of low-metastatic Lewis carcinoma cells or of DAP kinase transfectants, was associated with loss of DAP kinase expression. In situ TUNEL staining of tumour sections revealed that DAP kinase expression from the transgene raised the incidence of apoptosis in vivo. DAP-kinase transfectants also showed increased sensitivity in vitro to apoptotic stimuli, of the sort encountered by metastasizing cells at different stages of malignancy. We propose that loss of DAP kinase expression provides a unique mechanism that links suppression of apoptosis to metastasis.

Animals↗
PubMed1997

DAP-kinase loss of expression in various carcinoma and B-cell lymphoma cell lines: possible implications for role as tumor suppressor gene.

DAP-kinase is a novel calmodulin dependent serine/threonine kinase that carries ankyrin repeats and the death domain. It was recently isolated, by a functional selection approach of gene cloning, as a positive mediator of programmed cell death. In this study the expression of DAP-kinase was examined in the cell lines derived from various human neoplasms. DAP-kinase mRNA and protein expression were below the limit of detection in eight out of ten neoplastic derived B-cell lines. In six out of 14 examined bladder carcinoma, in three out of five renal cell carcinoma, and in four out of ten tested breast carcinoma cell lines, the DAP-kinase protein levels were below detection limits or lower than 1% compared to the positive cell lines. Interestingly, DAP-kinase expression could be restored in some of the negative bladder carcinoma and B-cell lines by treatment of cells with 5'-azadeoxycytidine that causes DNA demethylation. The high frequency of loss of DAP-kinase expression in human tumor cell lines, and the occasional involvement of methylation in this process raise the possibility that this novel mediator of cell death may function as a tumor suppressor gene.

Apoptosis Regulatory Proteins↗
PubMed1997

DAP-kinase is a Ca2+/calmodulin-dependent, cytoskeletal-associated protein kinase, with cell death-inducing functions that depend on its catalytic activity.

DAP-kinase was initially identified as a gene whose anti-sense-mediated reduced expression protected HeLa cells from interferon-gamma-induced programmed cell death. It was cloned in our laboratory by a functional gene selection approach. According to its amino acid sequence, this 160 kDa protein was predicted to be a novel type of calmodulin-regulated serine/threonine kinase which carries ankyrin repeats and the death domain. In this work we have shown that the kinase was autophosphorylated and capable of phosphorylating an exogenous substrate in a Ca2+/calmodulin-dependent manner. We proved that calmodulin binds directly to the recombinant kinase, and generated a constitutively active kinase mutant by the deletion of the calmodulin-regulatory domain. By immunostaining and biochemical fractionations we demonstrated that the kinase is localized to the cytoskeleton, in association with the microfilament system, and mapped a region within the protein which is responsible for binding to the cytoskeleton. Several assays attributed a cell death function to the gene. Ectopic expression of wild-type DAP-kinase induced the death of target cells, and the killing property depended strictly on the status of the intrinsic kinase activity. Conversely, a catalytically inactive mutant that carried a lysine to alanine substitution within the kinase domain, displayed dominant-negative features and protected cells from interferon-gamma-induced cell death. DAP-kinase is therefore a novel cytoskeletal-associated cell death serine/threonine kinase whose activation by Ca2+/calmodulin may be linked to the biochemical mechanism underlying the cytoskeletal alterations that occur during cell death.

Actin Cytoskeleton↗
PubMed1997

Intrafamilial heterogeneity of movement disorders: report of three cases in one family.

We report three members of a single family with an apparently autosomal dominant, nonparoxysmal, hyperkinetic movement disorder with onset in adolescence. The proband, a 56-year-old woman, manifested dystonia, tremor and myoclonus; one of her daughters exhibited myoclonus with tremor, and the other demonstrated myoclonus with chorea later accompanied by tremor and dystonia. The slowly progressive but not debilitating symptoms were restricted to the head, arms and hands and were only moderately affected by alcohol. Laboratory investigations failed to identify any abnormality, and linkage analysis excluded the region containing the DYT1 locus, indicating that the gene responsible for idiopathic torsion dystonia was not implicated in this family. While this disorder shares manifestations with myoclonic dystonia, essential myoclonus and benign chorea, the marked intrafamilial heterogeneity and the sex-limited phenotype expressed only in females of two generations appear to be unique.

Adolescent↗
PubMed1997

The dominant developmental mutants of tomato, Mouse-ear and Curl, are associated with distinct modes of abnormal transcriptional regulation of a Knotted gene.

The Curl (Cu) and Mouse-ear (Me) mutations of tomato cause two seemingly unrelated developmental syndromes with a wide range of pleiotropic phenotypes. Yet, the distinct morphogenic alterations in shoots, leaves, and inflorescences conferred by the two mutations appear to be caused by unchecked meristematic activity that characterizes dominant mutations in Knotted1 (Kn1)-like genes of monocot plants. We have been unable to separate the two closely linked Cu and Me mutations, and they may lie in the same gene. A homeobox-containing class I Kn1-like gene, TKn2, also maps to the same location. Significantly, the dominant mutations are associated with two aberrant modes of TKn2 transcription. Overexpression of the two in-frame wild-type transcripts of TKn2 is associated with the Cu mutation, whereas misexpression of an abundant and oversized fusion mRNA is associated with the Me mutation. Available molecular evidence strongly suggests that the defective Me-TKn2 transcript is generated via a novel splicing event that merges transcripts of two closely linked genes. The translated fusion product is comprised of most of the 5' end of the adjacent PPi-dependent fructose 6-phosphate phosphotransferase (PFP) transcript spliced in-frame to coding position 64 of the TKn2 transcript, leaving the TKn2 homeobox intact. We suggest that class I Kn1-like genes were selected early during evolution to regulate basic programs of aerial meristems and that subtle alterations in their function may be the basis for the wide diversity in growth parameters of shoot systems, leaves, and inflorescences among plant species.

Amino Acid Sequence↗
PubMed1997

"Broken Glass": the divorced woman in Moslem Arab society in Israel.

This article presents the findings of a preliminary, qualitative, exploratory study of divorce in Israeli-Arab society from the perspectives of divorced women living in Jaffa, Israel, and of Arab professionals engaged in therapeutic work. It explores the causes of divorce, the women's coping with the divorce process, and what constitutes post-divorce adjustment, based on the experiences of nine divorced Moslem Arab women and the input of six Arab professionals. The women attributed their divorces to extreme external factors: their husband's substance abuse, mental illness, and/or severe physical violence against them, as well as to interference by their husband's family of origin. They told of coping by relying on their inner resources and the strength their children gave them, while their own families of origin were almost uniformly critical and rejecting. They defined post-divorce adjustment as passing the test of female honor posed by their community, which they did by downplaying their femininity and immersing themselves in housework and childcare. The findings were compared with the research and clinical knowledge that has accumulated on divorce in Western society.

Adaptation, Psychological↗
PubMed1997

Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5: studies in populations with contrasting clinical phenotypes, defined racial background, and quantified risk.

BACKGROUND: CC chemokine receptor 5 (CCR5) is a cell entry cofactor for macrophage-tropic isolates of human immunodeficiency virus-1 (HIV-1). Recently, an inactive CCR5 allele (designated here as CCR5-2) was identified that confers resistance to HIV-1 infection in homozygotes and slows the rate of progression to AIDS in heterozygotes. The reports conflict on the effect of heterozygous CCR5-2 on HIV-1 susceptibility, and race and risk levels have not yet been fully analyzed. Here we report our independent identification of CCR5-2 and test its effects on HIV-1 pathogenesis in individuals with contrasting clinical outcomes, defined race, and quantified risk. MATERIALS AND METHODS: Mutant CCR5 alleles were sought by directed heteroduplex analysis of genomic DNA from random blood donors. Genotypic frequencies were then determined in (1) random blood donors from North America, Asia, and Africa; (2) HIV-1+ individuals; and (3) highly exposed-seronegative homosexuals with quantified risk. RESULTS: CCR5-2 was the only mutant allele found. It was common in Caucasians, less common in other North American racial groups, and not detected in West Africans or Tamil Indians. Homozygous CCR5-2 frequencies differed reciprocally in highly exposed-seronegative (4.5%, n = 111) and HIV-1-seropositive (0%, n = 614) Caucasians relative to Caucasian random blood donors (0.8%, n = 387). This difference was highly significant (p < 0.0001). By contrast, heterozygous CCR5-2 frequencies did not differ significantly in the same three groups (21.6, 22.6, and 21.7%, respectively). A 55% increase in the frequency of heterozygous CCR5-2 was observed in both of two cohorts of Caucasian homosexual male, long-term nonprogressors compared with other HIV-1+ Caucasian homosexuals (p = 0.006) and compared with Caucasian random blood donors. Moreover, Kaplan-Meier estimates indicated that CCR5-2 heterozygous seroconvertors had a 52.6% lower risk of developing AIDS than homozygous wild-type seroconvertors. CONCLUSIONS: The data suggest that homozygous CCR5-2 is an HIV-1 resistance factor in Caucasians with complete penetrance, and that heterozygous CCR5-2 slows the rate of disease progression in infected Caucasian homosexuals. Since the majority (approximately 96%) of highly exposed-seronegative individuals tested are not homozygous for CCR5-2, other resistance factors must exist. Since CCR5-2 homozygotes have no obvious clinical problems, CCR5 may be a good target for the development of novel antiretroviral therapy.

Adult↗
PubMed1997

Intussusception in adults.

Adult intussusception is a rare condition, chronic and recurring in nature, and presenting as intermittent intestinal obstruction. Surgeons generally have limited experience with it. We present 13 cases that have been treated in our department over a period of 19 years. In most of the cases there is an identifiable cause and it is often a malignancy. Awareness, plain abdominal films, barium enema and CT are valuable tools for diagnosis. Resection without reduction is the treatment of choice in most cases. In instances where resection would necessitate a permanent stoma, attempts at manual reduction are justified. Timely treatment, properly carried out, should result in a good prognosis.

Adult↗