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Biomedical subjects

M Kotler

Publications and source records attributed to M Kotler.

At least 55 records · Page 3Linked to original sources
PubMed1998

Human immunodeficiency virus type 1 Vif-derived peptides inhibit the viral protease and arrest virus production.

Human immunodeficiency virus type 1 (HIV-1) Vif protein is required for productive HIV-1 infection of peripheral blood lymphocytes and macrophages in cell culture and for pathogenesis in the SCID-hu mouse model of HIV-1 infection. Vif inhibits the viral protease (PR)-dependent autoprocessing of truncated HIV-1 Gag-Pol precursors expressed in bacterial cells and efficiently inhibits the PR-mediated hydrolysis of peptides in cell-free systems. The obstructive activity of Vif has been assigned to the 92 amino acids residing at its N'-terminus (N-Vif). To determine the minimal Vif sequence required to inhibit PR, we synthesized overlapping peptides derived from N-Vif. These peptides were then assessed, using two in vitro and two in vivo systems: (i) inhibition of purified PR, (ii) binding of PR, (iii) inhibition of the autoprocessing of the Gag-Pol polyprotein expressed by a vaccinia virus vector, and (iv) inhibition of mature virus production in human cells. The peptides derived from two regions of N-Vif encompassing residues Tyr-30-Val-65 and Asp-78-Val-98, inhibited PR activity in both the in vitro and the in vivo assays. Thus, these peptides can be used as lead compounds to design new PR inhibitors.

Amino Acid Sequence↗
PubMed1998

Characterization of human immunodeficiency virus type-1 (HIV-1) particles that express protease-reverse transcriptase fusion proteins.

We have selectively mutagenized specific residues at the junction between the protease (PR) and reverse transcriptase (RT) genes of human immunodeficiency virus type 1 (HIV-1) to study the effects of PR-RT fusion proteins in the context of a full-length, infectious proviral construct. Mutant viruses derived from COS-7 cells transfected with this construct were analyzed in regard to each of viral replication, maturation, and infectivity. Immunoblot analysis revealed that the mutation prevented cleavage between the PR and RT proteins and that both existed as a PR-RT fusion protein in each of cellular and viral lysates. Interestingly, intracellular PR that existed within the PR-RT fusion protein remained functionally active, whereby HIV-1 precursor proteins were processed efficiently. Furthermore, the RT component of the fusion protein also retained its enzymatic activity as shown in RT assays. Electron microscopy revealed that the mutant viruses containing the PR-RT fusion protein possessed wild-type morphology. These viruses also displayed wild-type sensitivities to inhibitors of each of the HIV-1 PR and RT activities. However, viruses containing the PR-RT fusion protein were 20 times less infectious than wild-type viruses. This defect was further pronounced when mutated Gag-Pol proteins were overexpressed as a consequence of an additional mutation that interfered with frameshifting. Thus, unlike cleavage site mutations at the N terminus of PR, a cleavage site mutation between PR and RT did not affect the enzymatic activities of either PR or RT and viruses containing PR-RT fusion proteins were viable.

Animals↗
PubMed1998

Analysis of heart rate variability in posttraumatic stress disorder patients in response to a trauma-related reminder.

BACKGROUND: Spectral analysis of heart rate variability has recently been shown to be a reliable noninvasive test for quantitative assessment of cardiovascular autonomic regulatory responses, providing a dynamic map of sympathetic and parasympathetic interaction. In a prior study exploring the state of hyperarousal characterizing the posttraumatic stress disorder (PTSD) syndrome, the authors described standardized heart rate analysis carried out in 9 PTSD patients at rest, which demonstrated clear-cut evidence of a baseline autonomic hyperarousal state. METHODS: To examine the dynamics of this hyperarousal state, standardized heart rate analysis was carried out in 9 PTSD patients compared to a matched control group of 9 healthy volunteers. Twenty-minute recordings of electrocardiogram in response to a trauma-related cue as opposed to a resting state were performed and analyzed. The PTSD patients were asked to recount the presumed triggering traumatic event, and the control subjects recounted a significant stressful negative life event. RESULTS: Our results show that, whereas the control subjects demonstrated significant autonomic responses to the stressogenic stimulus supplied by the recounting of a major stressful experience, the PTSD patients demonstrated almost no autonomic response to the recounting of the triggering stressful event. The PTSD patients demonstrated a degree of autonomic dysregulation at rest which was comparable to that seen in the control subjects' reaction to the stress model. CONCLUSIONS: The lack of response to the stress model applied in the study appears to imply that PTSD patients experience so great a degree of autonomic hyperactivation at rest, that they are unable to marshal a further stress response to the recounting of the triggering trauma, as compared to control subjects.

Adult↗
PubMed1998

Inhibition of anxiety in rats by antisense to cholecystokinin precursor protein.

BACKGROUND: Cholecystokinin (CCK) and its analogs generates anxiety in humans and measurable anxiety-like behaviors in rats. CCK receptor blockers have had mixed results as a treatment approach for anxiety disorders. Since CCK is a peptide, we explored another strategy to reduce CCK levels in brain by antisense oligodeoxynucleotide inhibition of DNA transcription or messenger RNA (mRNA) translation for CCK precursor protein. METHODS: Antisense oligodeoxynucleotide complementary to the start coding region of rat CCK-precursor was intracerebroventricularly (icv) infused into rats three times at 24-hour intervals. Control groups received infusions of either a scramble sequence oligodeoxynucleotide or vehicle. On the fourth day, rats were assessed in the elevated plus maze paradigm. RESULTS: Compared to vehicle and scramble sequence oligodeoxynucleotide control, icv CCK-antisense exogenous administration for 3 days significantly diminished anxiety behavior in rats. CONCLUSIONS: Antisense inhibition of CCK-mediated anxiety could have therapeutic potential in human anxiety disorders.

Animals↗
PubMed1998

Backbone cyclic peptide, which mimics the nuclear localization signal of human immunodeficiency virus type 1 matrix protein, inhibits nuclear import and virus production in nondividing cells.

Here, we describe an application of the backbone cyclic (BC) proteinomimetic approach to the design and the synthesis of a BC peptide which functionally mimics the nuclear localization signal (NLS) region of the human immunodeficiency virus type 1 matrix protein (HIV-1 MA). On the basis of the NMR structure of HIV-1 MA, a library of BC peptides was designed and screened for the ability to inhibit nuclear import of NLS-BSA in digitonin-permeabilized HeLa and Colo-205 cultured cells. The screening yielded a lead compound (IC50 = 3 microM) which was used for the design of a second library. This library led to the discovery of a highly potent BC peptide, designated BCvir, with an IC50 value of 35 nM. This inhibitory potency is compared to a value of 12 microM exhibited by the linear parent HIV-1 MA NLS peptide. BCvir also reduced HIV-1 production by 75% in infected nondividing cultured human T-cells and was relatively resistant to tryptic digestion. These properties make BCvir a potential candidate for the development of a novel class of antiviral drugs which will be based on blocking nuclear import of viral genomes.

Anti-HIV Agents↗
PubMed1998

Melatonin decreases mRNA for histone H4 in thymus of young rats.

The antiproliferative properties of melatonin have been previously demonstrated for several normal and tumoral tissues. In a recent report we have shown that melatonin is able to inhibit programmed cell death in thymus both, in vivo and in vitro. Given that other authors have related programmed cell death and cell proliferation and that no previous reports on melatonin and cell division exist on thymus, we decide to study the possible antiproliferative effect of melatonin in this organ measured as the levels of mRNA for the histone H4. We found that melatonin inhibits cell division on thymus when administered chronically both, at high (500 microg/body weight) and low (50 microg/body weight) dose. We also found a circadian rhythm of the mRNA for histone H4, opposed to the one previously described for melatonin, supporting the negative regulation by this hormone of cell division on thymus. A single dose of melatonin (50 microg/body weight) was not able to decrease the levels of mRNA for H4 in the time-points studied but after two hours of its administration. Finally, we report the inhibitory effect of melatonin in the cell proliferation of Harderian gland, brain, lung and kidney.

Animals↗
PubMed1998

Cloning of cell-specific secreted and surface proteins by subtractive antibody screening.

To identify and clone genes that encode cell- or tissue-specific secreted and surface proteins, a polyclonal antiserum was raised against a complex mixture of surface or secreted proteins from the target cell, followed by immunodepletion of antibodies that recognize proteins from a nontarget cell or tissue. The depleted antiserum is used to screen bacteriophage cDNA expression libraries. Because of our interest in how adipocytes communicate with other cells, we have used this method to clone cDNAs encoding secreted and plasma membrane proteins that are induced during adipocyte differentiation. We describe several of these, including a novel plasma membrane-associated protein, S3-12.

3T3 Cells↗
PubMed1998

Melatonin increases gene expression for antioxidant enzymes in rat brain cortex.

During the last years several reports have demonstrated that melatonin is a efficient free radical scavenger and general antioxidant. In addition, it has been shown that this neurohormone is able to increase the activity of glutathione peroxidase in rat brain cortex as well as the gene expression for some antioxidant enzymes in the Harderian gland of female Syrian hamster. Also, it is well known that brain cells are particularly exposed to free radicals, with antioxidant enzymes as the major defense mechanism that the brain uses to neutralize reactive oxygen species. The aim of the present study was to examine the influence of melatonin on gene expression for antioxidant enzymes in rat brain cortex. Our results clearly demonstrate that exogenously administered melatonin increases the levels of mRNA for glutathione peroxidase, copper-zinc superoxide dismutase, and manganese superoxide dismutase in this tissue. These stimulatory effects are observed after both acute and chronic treatment with this hormone, producing in the latter case the more marked increase. We therefore conclude that melatonin exerts an important role in providing indirect protection against free radical injury by stimulating gene expression for antioxidant enzymes. Consequently, melatonin could be considered as a potential therapeutic agent in some age-related neurodegenerative diseases where excessive free radical production has been implicated.

Animals↗
PubMed1998

Koro-like syndrome in a Bedouin man.

A case report is presented of a koro-like syndrome in a 34-year-old Bedouin man living in the Negev desert in Israel. The patient's disturbance is accompanied by voyeurism and the onset appears to be related to his sexual practices. This is the first reported case among Bedouins, who are an Arab nomadic tribe living in Asia and Africa.

Adult↗
PubMed1998

Outcomes of ultrarapid opiate detoxification combined with naltrexone maintenance and counseling.

Combining naltrexone and clonidine under general anesthesia is being used to shorten opiate detoxification. This study determined the one-year relapse rate of persons detoxified using this ultrarapid method in conjunction with naltrexone maintenance and counseling. Structured telephone interviews were held with 83 out of a random sample of 113 male patients who were detoxified via the ultrarapid method more than one year before the interview (average 1.5 years) and their significant others. Relapse was defined as at least two weeks of daily opiate use. According to patients and significant others, 57 percent of patients had not relapsed. This rate is better than rates obtained in studies of other detoxification methods.

Adult↗
PubMed1997

Compliance to naltrexone treatment after ultra-rapid opiate detoxification: an open label naturalistic study.

Studies have found that naltrexone, a long-acting opiate antagonist, owing to poor patient compliance, is of limited value in preventing relapse. The current study investigates compliance with a 9-month course of naltrexone (25-50 mg daily) given with counseling after ultra-rapid opiate detoxification which uses clonidine and naltrexone under general anesthesia. Eighty-three of 113 randomly selected patients (out of 640), who were detoxified more than 1 year prior (average 1.5 years), responded to phone interviews. Phone questionnaire asked about patients' compliance with naltrexone, counseling and drug use since detoxification. Similar interviews were also conducted with patients' significant other. Non-relapse patients (n = 47, 57%) took naltrexone an average of 2 months longer than did relapse patients (n = 36, 43%). About half of the non-relapse patients completed at least 5 months of naltrexone, 30% completed at least 7 months and about 20% completed 9 months. Fifty-five percent of the relapse patients stopped using naltrexone by the end of the 3rd month, and by the end of 7th month 10% continued to take it. After the first 2 months the decline in naltrexone compliance was about the same for relapse and non-relapse patients. These results are more encouraging about the use of naltrexone for relapse prevention than previous studies. This method of using naltrexone should be further tested in prospective random assignment controlled studies.

Anesthesia, General↗
PubMed1997

Personality differences between obsessive-compulsive disorder subtypes: washers versus checkers.

Personality differences between 'washer' and 'checker' subtypes of obsessive-compulsive disorder (OCD) were explored. Fifty-one OCD patients were recruited from several outpatient clinics in Central Israel. OCD was diagnosed according to DSM-III-R using the Structured Clinical Interview for DSM-III-R, and personality disorders were diagnosed using the Structured Clinical Interview for DSM-III-R Personality Disorders. Washers were much more likely to have personality disorders than checkers. Personality disorders were diagnosed in 12 of 13 washers vs. three of 11 checkers (chi 2 = 10.75, Fisher's exact test, P < 0.001, d.f. = 1, odds ratio = 32, CI = 2.8-365) and 21 of 27 patients with mixed OCD symptoms. The results support the validity of the washer-checker subdivision and might explain the relative refractoriness of washers to conventional intervention.

Adult↗
PubMed1997

Inositol has behavioral effects with adaptation after chronic administration.

Inositol is a simple dietary polyol that serves as a precursor in important second messenger systems. Inositol in pharmacological doses has been reported recently to be therapeutic in depression, panic disorder and obsessive compulsive disorder. We hereby report effects of inositol on the elevated plus maze model of anxiety. These results should allow development of new inositol analogs that could expand psychoactive drug development possibilities via second messenger manipulation.

Adaptation, Psychological↗