Biomedical subjects

D Stein

Publications and source records attributed to D Stein.

At least 73 records · Page 4Linked to original sources

PubMed1998

Spatially restricted expression of pipe in the Drosophila egg chamber defines embryonic dorsal-ventral polarity.

Expression of pipe in the somatic tissue of the Drosophila ovary is required for the formation of embryonic dorsal-ventral polarity. pipe, which encodes an enzyme similar to the glycosaminoglycan-modifying enzyme heparan sulfate 2-O-sulfotransferase, is expressed in a spatially restricted domain of follicle cells on the ventral side of the egg chamber. Mutations that affect follicular polarity correspondingly alter the spatial pattern of pipe expression. Directed expression of pipe in otherwise pipe mutant females restores embryonic lateral and ventral pattern elements and can orient the dorsal-ventral axis of the embryo. Thus, the localized expression of pipe and the spatially restricted modification of carbohydrate chains play pivotal roles in the mechanisms that establish embryonic pattern and integrate follicular and embryonic polarity.

5' Untranslated Regions↗

PubMed1998

Occupation of the cytochrome P450 substrate pocket by diverse compounds at general anesthesia concentrations.

Each of a diverse array of compounds, at concentrations reported to effect general anesthesia, when added to liver microsomes, forms a complex with cytochromes P450 to generate, with reference to a cuvette containing microsomes only, a characteristic absorbance-difference spectrum. This spectrum results from a change in the electron-spin state of the heme iron atom induced upon entry by the anesthetic molecule into the enzyme catalytic pocket. The difference spectrum, representing the anesthetic-P450 complex, is characteristic of substances that are substrates for the enzyme. For the group of compounds as a whole, the magnitudes of the absorbance-difference spectra vary only about twofold, although the anesthetic potencies vary by several orders of magnitude. The dissociation constants (Ks), calculated from absorbance data and representing affinities of the anesthetics for P450, agree closely with the respective EC50 (concentration that effects anesthesia in 50% of individuals) values, and with the respective Ki (concentration that inhibits P450 catalytic activities half-maximally) values reported by us previously. The absorbance complex resulting from the occupation of the catalytic pocket by endogenous substrates, androstenedione and arachidonic acid, is inhibited, competitively, by anesthetics. Occupation of and perturbation of the heme catalytic pocket by anesthetic, as monitored by the absorbance-difference spectrum, is rapidly reversible. The presumed in vivo consequences of perturbation by general anesthetics of heme proteins is suppression of the generation of chemical signals that determine cell sensitivity and response.

Anesthetics, General↗

PubMed1998

The cAMP-dependent protein kinase site (Ser312) enhances dorsal nuclear import through facilitating nuclear localization sequence/importin interaction.

Control over the nuclear import of transcription factors (TFs) represents a level of gene regulation integral to cellular processes such as differentiation and transformation. The Drosophila TF Dorsal shares with other rel TF family members the fact that it contains a phosphorylation site for the cAMP-dependent protein kinase (PKA) 22 amino acids N-terminal to the nuclear localization signal (NLS) at amino acids 335-340. This study examines for the first time the nuclear import kinetics of Dorsal fusion proteins in rat hepatoma cells in vivo and in vitro. Nuclear uptake was found to be not only NLS-dependent, but also strongly dependent on the PKA site, whereby substitution of Ser312 by either Ala or Glu using site-directed mutagenesis severely reduced nuclear accumulation. Exogenous cAMP or PKA catalytic subunit significantly enhanced the nuclear import of wild-type proteins both in vivo and in vitro. Using a direct binding assay, the molecular basis of PKA site enhancement of Dorsal fusion protein nuclear import was determined to be PKA site-mediated modulation of NLS recognition by the importin 58/97 complex. The physiological relevance of these results is supported by the observation that Drosophila embryos expressing PKA site Dorsal mutant variants were impaired in development. We conclude that the Dorsal NLS and PKA site constitute a phosphorylation-regulated NLS essential to Dorsal function and able to function in heterologous mammalian cell systems, where phosphorylation modulates the affinity of NLS recognition by importin.

Animals↗

PubMed1998

Identification, sequence and developmental expression of invertebrate flotillins from Drosophila melanogaster.

Caveolae are vesicular organelles that represent a sub-compartment of the plasma membrane. Caveolins (Cav-1, -2 and -3) and flotillins (FLO-1 and FLO-2 [also known as epidermal surface antigens (ESAs)] are two families of mammalian caveolae-associated integral membrane proteins. Although a caveolin gene family has recently been described in the invertebrate Caenorhabditis elegans, it remains unknown as to whether flotillin homologues exist in invertebrates. Here, we report the identification, cDNA sequence and embryonic expression pattern of the first invertebrate flotillin, i.e. flotillin from Drosophila melanogaster (FLODm). FLODm is most closely related to mammalian flotillin-1. Remarkably, the invertebrate FLODm protein behaves like mammalian flotillins and is targeted to the caveolae-enriched membrane fraction after transient expression in mammalian cells. Localization of the FLODm message in D. melanogaster embryos reveals that expression of FLODm is confined primarily to the developing nervous system. This is consistent with our previous observation that mammalian flotillin-1 mRNA and protein is expressed abundantly in brain tissue. Interestingly, the FLODm gene is localized to chromosomal region 52 B1-B2. In addition, we find that at least two flotillin-related genes are expressed in D. melanogaster. Our current results provide a starting point and systematic basis for dissecting the role of flotillin in caveolae and neuronal development using Drosophila as a genetic system.

Amino Acid Sequence↗

PubMed1998

Basic fibroblast growth factor downregulates Bcl-2 and promotes apoptosis in MCF-7 human breast cancer cells.

Basic fibroblast growth factor (bFGF) is a mitogen and a survival factor in fibroblasts and endothelial cells. It acts as an angiogenesis factor in breast cancer, but paradoxically inhibits proliferation in several breast cancer cell lines. In this study, we investigated the effects of bFGF on the survival of MCF-7 human breast cancer cells in order to determine if these effects were also opposite to those in fibroblasts. Incubation of NIH 3T3 cells with bFGF for 24 h caused an approximately 30% increase in day 12 +/- 2 adherent colonies while causing an approximately 50% decrease in MCF-7 colony formation. Incubation of NIH 3T3 cells with bFGF prior to etoposide or 5-fluorouracil treatment caused a proportionally smaller decrease in colony forming efficiency as a result of drug treatment, while preincubation of MCF-7 cells with bFGF caused a similar but opposite additive increase in drug-induced diminution of colony forming efficiency. These effects on MCF-7 cells were observed at variable times of incubation and doses of etoposide to 1 microM and 5-fluorouracil to 200 microM and at variable times of incubation and concentrations of bFGF to 1 ng/ml. Incubating with bFGF after drug exposure had similar effects on the reduction of cloning efficiency. The effects of bFGF were similar on programmed cell death, as determined by morphologic characteristics of apoptosis on 400 cell counts and FITC-dUTP 3'-OH DNA end labeling. Basic FGF promoted apoptosis and increased the rate of drug-induced cell death with both etoposide and 5-fluorouracil. While recombinant bFGF affected Bcl-2 protein and mRNA levels in NIH 3T3 cells only marginally and variably and had no discernible effects on Bax protein levels, it markedly downregulated Bcl-2 mRNA and protein levels in MCF-7 cells and caused an increase in Bax protein levels. These changes resulted in a decreased association of Bcl-2 with immunoprecipitable Bax and an increased association of Bax with immunoprecipitable Bcl-2 in MCF-7 cells treated with bFGF. These data suggest that bFGF may cause different phenotypic responses in breast cancer cells from those in surrounding cells and offer one possible mechanism through opposite regulation of Bcl-2 and Bax. Inhibition of colony formation by bFGF was observed in several breast cancer cells lines, demonstrating that this effect demonstrated in MCF-7 cells was more universal.

3T3 Cells↗

PubMed1998

Frequency of delayed sleep phase syndrome among hospitalized adolescent psychiatric patients.

Previous research seems to indicate that a substantial percentage of patients with delayed sleep phase syndrome (DSPS) also suffer from personality disorders. In the present study, we attempted to ascertain whether, in a population of hospitalized psychiatric patients, we would find a greater frequency of DSPS among patients suffering from personality disorders than among patients suffering from any of the other psychiatric disorders. Sixty-three hospitalized adolescents took part in the study. None of them had any diagnosed medical disorders, and all were being treated with psychiatric drugs. Ten subjects were diagnosed as suffering from DSPS according to a sleep-wake schedule structured interview. As hypothesized, subjects diagnosed as suffering from personality disorders had a significantly higher probability of also suffering from DSPS. Additional findings were that patients with DSPS were more likely to have received an Axis II diagnosis only, and were more likely to be diagnosed as suffering from a distinct group of disorders characterized by affective lability. The latter finding may be due to the sleepiness that accompanies DSPS. The findings of the present study suggest that there may be an interrelationship between DSPS and personality disorders, and may lend some support to the hypothesis that inborn peculiarities in the sleep-wake rhythm lead to the social and functional difficulties characteristic of personality disorders.

Adolescent↗

PubMed1998

The correlation of telomerase and IL-10 with leukemia transformation in a mouse model of chronic lymphocytic leukemia (CLL).

Telomerase activity is upregulated in activated and malignant lymphocytes. We studied the correlation of telomerase and IL-10 to leukemia transformation in the NZB mouse model of human chronic lymphocytic leukemia (CLL). Telomerase levels increased from early to late leukemic stages, likewise IL-10 gene expression levels increased with the leukemic progression. The inverse relationship of telomerase and IL-10 levels to the survival of NZB mice was also established. Our data suggested that telomerase and IL-10 were involved in transformation in the murine model of CLL and the detection of telomerase activities might be of value in the prediction of CLL progression.

Age Factors↗

PubMed1998

Cubic approximation neural network for multivariate functions.

This paper introduces a novel neural network architecture-cubic approximation neural network (CANN), capable of local approximation of multivariate functions. It is particularly simple in concept and in structure. Its simplicity enables a quantitative evaluation of its approximation capabilities, namely, for a desired error bound the size of the needed network can be calculated. In addition, if a training session is used, a thorough analysis of the learning process performance is performed. The trade-off between the rate of learning and the steady-state performance is clearly demonstrated. On the other hand, this approach suffers from the problem common to all local approximation networks-the number of neurons grows exponentially with the dimension of the input vector.

Journal Article↗

PubMed1998

Vitamin E (alpha-tocopherol) in the treatment of tardive dyskinesia: a statistical meta-analysis.

Tardive dyskinesia is an involuntary movement disorder developing following treatment with neuroleptics. As many as 50% of chronic psychotic patients develop this disabling condition. No treatment has been found effective for tardive dyskinesia. This study was undertaken to meta-analyze the effects of vitamin E (alpha-tocopherol) reported in the last decade. All studies published since 1987, focusing on vitamin E and tardive dyskinesia are reviewed. Double-blind studies are analyzed using measures of effect and variance as described by secondary analysis of magnitude of effects in pooled data. A total of 223 patients received vitamin E treatment (400-1600 IU/day) for tardive dyskinesia, in 12 studies. A significant subgroup (28.3%) showed a modest improvement. Vitamin E was well tolerated, and only rarely did side effects occur-of no clinical significance. Vitamin E is a safe, well-tolerated compound that may provide some beneficial effects in patients suffering from neuroleptic-induced tardive dyskinesia.

Adult↗

PubMed1998

Preimplantation diagnosis by FISH: the Rambam experience.

PURPOSE: Our purpose was to summarize our experience gained using fluorescence in situ hybridization for preimplantation diagnosis at the Rambam Medical Center. METHODS: Seventy-three embryos (29 cycles) were analyzed for preimplantation diagnosis for the following indications: advanced maternal age (> 39 years), X-linked diseases, poor-quality embryos, repeated failure in vitro fertilization cycles and fast-dividing embryos. An additional 38 embryos with unequal pronuclei size were examined for ploidy. Biopsy of embryonic blastomeres was performed at the six- to eight-cell stage. Five fluorescence probes, for chromosomes X, Y, 13, 18, and 21, were applied for ploidy detection. RESULTS: Eighty-four (87%) blastomeres of the 73 embryos analyzed showed clear signals. Six of the blastomeres were lost during spreading. Two of the embryos were destroyed following biopsy. No nucleus was found in five of the blastomeres, while in nine, more than one nucleus was verified. Transfer was performed in 10 patients (32 embryos). Two pregnancies were achieved. Two healthy babies were born. Fifty-seven percent of the fast-dividing embryos demonstrated normal signals. In two groups of embryos of unequal pronuclei size following conventional insemination and intracytoplasmic sperm injection, 50 and 11.4% demonstrated normal signals. CONCLUSIONS: The efficiency of fluorescence in situ hybridization for aneuploidy detection is 87 and 97% for autosomes and gonosomes, respectively. The preimplantation genetic diagnosis is suitable for selected in vitro fertilization cases including fast-dividing embryos and embryos with unequal pronuclei size following regular in vitro fertilization.

Adult↗

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

HLA-B38 and clozapine-induced agranulocytosis in Israeli Jewish schizophrenic patients.

To further substantiate reports of an association between the major histocompatibility complex subtypes and clozapine-induced agranulocytosis, HLA typing was performed in 61 Jewish Israeli schizophrenic patients, in 11 of whom agranulocytosis developed following clozapine treatment and in 50 (controls) of whom it did not. Of the 11 agranulocytosis patients, seven (63%) were of Ashkenazi origin and four (37%) of Sephardi origin. There was no difference in ethnic origin between the arganulocytosis and non-agranulocytosis groups (chi 2 = 2.4, d.f. = 1, P = 0.11), although the agranulocytosis patients had a higher frequency of the HLA B38 antigen (8/11 or 72% vs. 6/50 or 12%; chi 2 = 18.7, d.f. = 1, P < 0.001). These results suggest that major histocompatibility complex gene products could be involved in clozapine-mediated haematological complications.

Adult↗

PubMed1998

Association between multiple suicide attempts and negative affects in adolescents.

OBJECTIVE: To compare the level of negative emotions-anxiety, depression, aggression, and impulsivity-in hospitalized adolescents with a history of either a single or multiple suicide attempts. METHOD: Thirty-two adolescents hospitalized for a first suicide attempt, 19 hospitalized for a repeated attempt (fifth or more), 109 nonsuicidal psychiatric inpatients, and 85 community controls were assessed for level of depression, anxiety, aggression, and impulsivity with the Beck Depression Inventory, the State-Trait Anxiety Inventory, the Multidimensional Anger Inventory, and the Suicide Potential Scale. RESULTS: Both suicidal groups demonstrated higher levels of most of the negative emotions than both the normal controls and the nonsuicidal inpatients. When the first attempters were compared with the multiple attempters, similarly high levels were noted for most dimensions of anxiety and depression. A trend toward increased aggression was noted among the multiple suicide attempters on all parameters evaluated; some of these differences were significant. CONCLUSION: In already highly anxious and depressed suicidal inpatients, a high level of aggression might significantly increase the risk of recidivism.

Adolescent↗

PubMed1998

Clinico-tremorgraphic features of neuroleptic-induced tremor.

Instrumental tremorgrams have been used to improve the diagnostic accuracy of various movement disorders, including tardive akathisia. The aim of the present work was to evaluate their place in the diagnosis of neuroleptic-induced tremor and to determine whether they can help to differentiate this disorder from other neuroleptic-induced movement disorders and from other types of tremor. Fourteen psychiatric patients treated with various neuroleptic medications were diagnosed as having neuroleptic-induced tremor on the basis of clinical criteria. They underwent accelerometric recordings following diagnosis. All patients demonstrated upper-limb tremor; four also had involvement of the lower limbs, jaw or tongue. Most demonstrated both resting and postural tremor, the latter being the more prominent. The tremor was mainly rhythmic, regular and sinusoidal. It did not significantly interfere with activities of daily living in the majority of patients, but four did exhibit some degree of impairment. Repeated accelerometric recordings showed constant and regular waveforms and frequencies (between 4 and 7 Hz) in each patient. We conclude that the presence of repeated constant waveforms and frequencies on accelerometric tracings may serve as confirmation of the diagnosis of neuroleptic-induced tremor. In light of the findings of this and other studies, we suggest that tremorgrams may be helpful in differentiating neuroleptic-induced tremor from other neuroleptic-induced movement disorders (e.g., tardive dyskinesia and tardive akathisia) and from psychogenic tremor. Although these techniques may also assist in the differentiation of neuroleptic-induced tremor from some tremor disorders (e.g., asterixis or ataxic tremor), their overall potential to distinguish it from other types of organic tremor is more limited.

Adult↗

PubMed1998

Surgical variables affecting speech in treated patients with oral and oropharyngeal cancer.

Postoperative speech function may be influenced by a number of treatment variables. The objective of this study was to examine the relationships among various treatment factors to determine the impact of these measures on speech function. Speech function was tested prospectively in 142 patients with surgically treated oral and oropharyngeal cancer 3 months after treatment. Each patient's speech was recorded during a 6- to 7-minute conversation and while performing a standard articulation test, producing speech outcome measures of percent correct consonant phonemes and percent conversational understandability. Correlational analyses were used to determine the relationships among the speech outcome measures and 14 treatment parameters. Speech function was mildly to moderately negatively correlated with most surgical resection variables, indicating that larger amounts of tissue resected were associated with worse speech function. Overall measures of conversational understandability and percent correct consonant phonemes were related to extent of oral tongue resection, floor of mouth resection, soft palate resection, and total volume of tissue resected. These relationships varied depending on the method of surgical closure. Method of surgical reconstruction had a profound impact on postoperative speech function 3 months after treatment and was an important factor in determining how oral tongue resection influenced articulation and intelligibility. The combination of closure type, percent oral tongue resected, and percent soft palate resected had the strongest relationship with overall speech function for patients with surgically treated oral and oropharyngeal cancer 3 months after treatment.

Adult↗

PubMed1998

The association between attitudes toward suicide and suicidal ideation in adolescents.

The aims of this study were to determine whether adolescent attitudes to suicide could be grouped into distinct factors, and then to examine the relationship between these factors and the psychosocial parameters known to be associated with suicide, and between attitudes towards suicide and suicidal ideation. A questionnaire designed to assess attitudes to suicide was distributed to a total of 525 Israeli adolescents. Statistical analysis indicated that the attitude items could be grouped into four distinct factors: the right of society to prevent suicide; suicide as a symptom of mental illness; the right of the individual to talk about suicide; and taking suicidal behaviour seriously. Each factor was differentially associated with the various psychosocial parameters examined. The association between the attitude factors and subjects' suicidal ideation was significant and at least as strong as that of the psychosocial parameters normally associated with adolescent suicide, namely gender and exposure to suicide. A generally approving attitude towards suicide was correlated with a high level of suicidal ideation.

Adolescent↗

PubMed1998

Demonstration of a relaxin receptor and relaxin-stimulated tyrosine phosphorylation in human lower uterine segment fibroblasts.

To elucidate the mechanism of relaxin action, we studied the binding characteristics of human relaxin and its effects on intracellular concentrations of cAMP and tyrosine phosphorylation of cellular proteins in a model system of human cervix, human lower uterine segment fibroblasts. Human relaxin labeled with 125I bound specifically to a single class of high-affinity relaxin binding sites, distinct from insulin receptors, with a mean (+/-SEM) dissociation constant (Kd) of 4.36 +/- 1.7 x 10(-9) M and a mean of 3220 +/- 557 binding sites per cell in human lower uterine segment fibroblasts. Relaxin, in quantities that were shown previously to stimulate intracellular levels of cAMP in other cell types, had no effect on intracellular levels of cAMP in human lower uterine segment fibroblasts even in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (IBMX). Incubation of the cells with relaxin caused a significant increase in tyrosine phosphorylation of a protein with an apparent Mr of approximately 220 kDa in these cells. In concert with results of recent studies that demonstrated that the Mr of the relaxin receptor is approximately 220 kDa, our data suggest that the phosphorylated protein is likely to be the relaxin receptor.

1-Methyl-3-isobutylxanthine↗

PubMed1998

The Dorsal-related immunity factor (Dif) can define the dorsal-ventral axis of polarity in the Drosophila embryo.

In Drosophila embryos, dorsal-ventral polarity is defined by a signal transduction pathway that regulates nuclear import of the Dorsal protein. Dorsal protein's ability to act as a transcriptional activator of some zygotic genes and a repressor of others defines structure along the dorsal-ventral axis. Dorsal is a member of a group of proteins, the Rel-homologous proteins, whose activity is regulated at the level of nuclear localization. Dif, a more recently identified Drosophila Rel-homologue, has been proposed to act as a mediator of the immune response in Drosophila. In an effort to understand the function and regulation of Rel-homologous proteins in Drosophila, we have expressed Dif protein in Drosophila embryos derived from dorsal mutant mothers. We found that the Dif protein was capable of restoring embryonic dorsal-ventral pattern elements and was able to define polarity correctly with respect to the orientation of the egg shell. This, together with the observation that the ability of Dif to restore a dorsal-ventral axis depended on the signal transduction pathway that normally regulates Dorsal, suggests that Dif protein formed a nuclear concentration gradient similar to that seen for Dorsal. By studying the expression of Dorsal target genes we found that Dif could activate the zygotic genes that Dorsal activates and repress the genes repressed by Dorsal. Differences in the expression of these target genes, as well as the results from interaction studies carried out in yeast, suggest that Dif is not capable of synergizing with the basic helix-loop-helix transcription factors with which Dorsal normally interacts, and thereby lacks an important component of Dorsal-mediated pattern formation.

Animals↗