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Biomedical subjects

S Gottlieb

Publications and source records attributed to S Gottlieb.

At least 217 records · Page 12Linked to original sources
PubMed1996

Cellular actions of etretinate in psoriasis: enhanced epidermal differentiation and reduced cell-mediated inflammation are unexpected outcomes.

Retinoids are potent cell growth and differentiation modulators, but cellular effects of therapeutic retinoids in psoriasis are unknown. We studied the effects of etretinate on pathological activation of keratinocytes and lymphocytes in patients treated systemically with this agent for 8 weeks. Ten patients with extensive psoriasis vulgaris were treated with etretinate at 0.75 mg/kg for 8 weeks. Skin biopsies obtained before and at 8 weeks of treatment were studied using immunohistochemical markers for keratinocyte proliferation or differentiation and for the presence of T-lymphocyte subsets or associated inflammatory proteins. During 8 weeks of treatment, the clinical severity decreased by a mean of 64% (p < 0.001). Compared to a similar group of patients treated with bath PUVA, psoriatic plaque erythema resolved more slowly and less completely (p < 0.05), but improvements in plaque thickness and scale were not significantly different between etretinate and PUVA treatments. Etretinate produced a 44% decrease in epidermal thickness (p < 0.001) and a 62% reduction in keratinocyte proliferation (p < 0.001) after 8 weeks of treatment. Unexpectedly, keratinocyte differentiation was enhanced following etretinate treatment as indicated by increased filaggrin production, increased number and size of keratohyaline granules, greater abundance of keratin filaments, and increased secretion of intercellular lipids from Odland bodies. The stratum corneum in resolving psoriatic lesions was unusually thin, probably caused by retinoid-induced shedding of corneocytes. "Regenerative" epidermal growth was maintained during etretinate treatment, as marked by continued expression of keratin 16 and alpha 3-integrin by suprabasal keratinocytes. Surprisingly the inflammation-associated proteins HLA-DR and ICAM-1 were no longer produced by epidermal keratinocytes following etretinate treatment, and CD3+, CD8+, and CD25+ T-lymphocyte subsets were reduced by 50-65% in lesional tissue (p < 0.01). Etretinate shows unexpected anti-inflammatory and pro-differentiation actions in psoriasis. Etretinate appears to function as a disease suppressive agent which improves hyperplasia, keratinocyte differentiation and tissue inflammation mediated by cellular immune elements.

Cell Differentiation↗
PubMed1996

Modulation of epidermal differentiation, tissue inflammation, and T-lymphocyte infilitration in psoriatic plaques by topical calcitriol.

Psoriasis is characterized by immune activation, increased proliferation and abnormal differentiation of keratinocytes. The reported anti-psoriatic mechanisms of action in vivo of vitamin D analogues include reduction of keratinocyte proliferation and induction of keratinocyte terminal differentiation. We investigated whether the anti-psoriatic effect of the natural active vatamin D analogue, calcitriol, applied topically, is due to direct effects on keratinocytes alone or also due to immunoregulatory effects of calcitriol. Psoriasis patients were treated with topical calcitriol (0.005%) and a vehicle control for 8 weeks. Disease activity was assessed by a severity index and quantitative histopathological markers. In vitro studies of lymphocyte proliferation and gamma interferon secretion and of keratinocyte proliferation complemented the clinicohistopathologic studies. A heterogeneous response to calcitriol treatment could be segregated based upon elimination of K-16 keratin expression. Calcitriol treatment decreased keratinocyte proliferation, normalized keratinocyte differentiation and decreased immune activation in plaques. The histologic response to vitamin D treatment of psoriasis includes suppression of both immune and keratinocyte activation in situ. These studies provide a basis for rational combination of anti-psoriatic treatments and for the design of new vitamin D analogues to treat psoriasis.

Administration, Topical↗
PubMed1995

Relations between heart failure, ejection fraction, arrhythmia suppression and mortality: analysis of the Cardiac Arrhythmia Suppression Trial.

OBJECTIVES: We studied the relations between heart failure, ejection fraction, arrhythmia suppression and mortality. BACKGROUND: Both left ventricular ejection fraction and functional class of heart failure are strongly associated with mortality after acute myocardial infarction. Both are also related to the presence of ventricular arrhythmias and have been identified as factors related to the ability to suppress ventricular arrhythmias. Little has been reported about the relations between these two factors and arrhythmia suppression or mortality. METHODS: Baseline data from the Cardiac Arrhythmia Suppression Trial were used to define several categories of heart failure and to relate both the resulting categories and ejection fraction to arrhythmia suppression and mortality using logistic and survival regression analytic methodologies. RESULTS: Regardless of the prospective baseline definition of heart failure used, the data consistently showed that heart failure was a more powerful predictor of subsequent congestive heart failure events and arrhythmia suppression and was equally powerful in predicting death. However, each variable provided incremental information when included in the prediction model. Heart failure and ejection fraction appeared to be independent predictors of death. Interactions were observed: A low ejection fraction was more predictive of failure of arrhythmia suppression in patients with than without evidence of heart failure before or at baseline; a low ejection fraction was more predictive of subsequent congestive heart failure events in patients without than with evidence of heart failure before or at baseline. CONCLUSIONS: Although heart failure as a prognostic feature appears to be somewhat superior to ejection fraction, both are powerful predictors of arrhythmia suppression and cardiac events in patients with ventricular arrhythmia after myocardial infarction. Each provides incremental prediction.

Arrhythmias, Cardiac↗
PubMed1995

Effect of pressure on echocardiographic videodensity from sonicated albumin: an in vitro model.

The effect of different pressures (0, 10, 30, 60, 80, 100, 120, or 180 mm Hg) on the ultrasound contrast effect obtained from sonicated albumin was evaluated by videodensity decay curves in an in vitro model immersed in a water tank. Decay rates and half-times were calculated from the videodensity decay curves at each pressure. A significant (P < 0.0001) relation was found between contrast disappearance and pressure: the higher the pressure the more rapid the contrast disappearance. Release of pressure did not result in contrast reappearance. Contrast decrease with pressure may result from microbubble destruction or alteration in acoustic properties by pressure. These findings may help explain the limited success of sonicated albumin for systemic ultrasonographic arteriography and myocardial perfusion imaging after intravenous injection. An ideal contrast agent for contrast echo studies should be stable at physiologic pressures.

Albumins↗
PubMed1994

Influence of gender in the therapeutic management of patients with acute myocardial infarction in Israel. The Israeli Thrombolytic Survey Group.

A national study was performed in early 1992 in the 25 operating coronary care units in Israel, which enabled the assessment of whether the therapeutic management of patients with acute myocardial infarction was affected by patient gender. During a 2-month period, 1,014 consecutive patients with acute myocardial infarction were hospitalized. Thrombolytic therapy was given to 47% of men (362 of 769), and 43% of women (106 of 245) (p = NS). After adjustment for age, no gender differences in the administration of thrombolytic therapy were noted (odds ratio 0.95; 95% confidence interval 0.73-1.23). Coronary angiography was more frequently performed in men (22%) than in women (16%) (p < 0.05). However, no gender differences in the use of angioplasty or coronary bypass surgery performed during the index hospitalization were found (10% in men, and 8% in women). The main reasons for ineligibility for thrombolytic therapy were: late hospital arrival, absence of qualifying ST-T changes on admission electrocardiogram, and contraindications to thrombolytic therapy. Hospital death was significantly lower in patients receiving thrombolytic therapy (37 of 456; 8%) than in those excluded from thrombolysis (70 of 540;13%) (p < 0.01). This difference was significant for men, but not for women. The 1-year postdischarge mortality was 4% in patients treated compared with 12% in those ineligible for thrombolysis (p < 0.01). This significant difference persisted among men and women.

Aged↗
PubMed1994

Feasibility of recanalization of human coronary arteries using high-intensity ultrasound.

To investigate the feasibility of ultrasonic recanalization of obstructed human coronary arteries in vitro, high-intensity ultrasound was applied to 16 coronary arteries obtained at autopsy, using a prototype instrument enabling insonification through a catheter tip. It was a 119 cm long, 0.95 mm thick wire in an 8Fr catheter connected to an external ultrasonic transformer and power generator. A 5 MHz phased-array 2-dimensional echocardiography instrument was used to determine minimal luminal diameter and percent diameter narrowing before and after ultrasound application. The ultrasonic energy was delivered at 21.5 kHz and with a 52 +/- 19 micrometer average amplitude of tip displacement. The mean percent luminal diameter narrowing, flow rate and mean pressure gradient before ultrasound exposure were 74 +/- 11%, 97 +/- 61 ml/min, and 92 +/- 18 mm Hg, respectively. After recanalization, the mean percent luminal diameter narrowing decreased to 45 +/- 17% (p < 0.001), the mean flow rate increased to 84 +/- 92 ml/min (p < 0.001), and the mean pressure gradient was reduced to 45 +/- 24 mm Hg (p < 0.001). Of the debris particles, 95% had a diameter < 9 microns (range 5 to 12). Arterial perforation occurred in 5 of 16 arteries (31%) and all 5 occurred due to stiff wire manipulation and without ultrasound application. Mechanical fracture of the wire occurred in 8 cases (50%). No signs of thermal injury were found on histology. Thus, ultrasonic recanalization of human coronary arteries in vitro is feasible. It may reduce obstruction and improve blood flow. Debris sizes are sufficiently small to minimize the hazard of peripheral embolization.

Adult↗
PubMed1994

Hormonal parameters and testicular volume in children and adolescents with unilateral varicocele: preoperative and postoperative findings.

Preoperative and postoperative testicular volume, serum testosterone, follicle-stimulating hormone and luteinizing hormone were determined in 25 patients 8 to 19 years old (mean age 13.2 +/- 1.63) with grades 2 and 3 unilateral varicocele. Testicular growth arrest was considered significant when volume loss was greater than 2 ml. in the ipsilateral testis compared to the contralateral side. Baseline serum testosterone, follicle-stimulating hormone and luteinizing hormone as well as post-gonadotropin releasing hormone stimulation were determined preoperatively and at 4 to 6 months postoperatively. Data are presented as mean plus or minus standard deviation. Results showed an increase in serum testosterone in Tanner's stages 1 (p < 0.028) and 2 to 3 (p < 0.008). No differences were recorded in basal luteinizing hormone and follicle-stimulating hormone, as well as maximal follicle-stimulating hormone levels before and after surgery. A decrease of maximal luteinizing hormone response to gonadotropin releasing hormone test was noted postoperatively in pubertal stages 4 to 5, when compared to preoperative values. Postoperative ipsilateral testicular volume increased in all Tanner stages (p < 0.045, p < 0.008 and p < 0.012, respectively). Our observations suggest that varicocele may be initially responsible for interstitial dysfunction with preservation of germinal function and unilateral testicular growth arrest, however reversible, after pubertal surgical correction. This study supports previous reports suggesting that varicocelectomy in children who show anatomic and functional changes is advisable.

Adolescent↗
PubMed1994

daf-2, daf-16 and daf-23: genetically interacting genes controlling Dauer formation in Caenorhabditis elegans.

Under conditions of high population density and low food, Caenorhabditis elegans forms an alternative third larval stage, called the dauer stage, which is resistant to desiccation and harsh environments. Genetic analysis of some dauer constitutive (Daf-c) and dauer defective (Daf-d) mutants has revealed a complex pathway that is likely to function in particular neurons and/or responding tissues. Here we analyze the genetic interactions between three genes which comprise a branch of the dauer formation pathway that acts in parallel to or downstream of the other branches of the pathway, the Daf-c genes daf-2 and daf-23 and the Daf-d gene daf-16. Unlike mutations in other Daf-c genes, mutations in both daf-2 and daf-23 cause non-conditional arrest at the dauer stage. Our epistasis analysis suggests that daf-2 and daf-23 are functioning at a similar point in the dauer pathway. First, mutations in daf-2 and daf-23 are epistatic to mutations in the same set of Daf-d genes. Second, daf-2 and daf-23 mutants are suppressed by mutations in daf-16. Mutations in daf-16 do not suppress any of the other Daf-c mutants as efficiently as they suppress daf-2 and daf-23 mutants. Third, double mutants between either daf-2 or daf-23 and several other daf-d mutants exhibit an unusual interaction. Based on these results, we present a model for the function of daf-2, daf-23 and daf-16 in dauer formation.

Animals↗
PubMed1994

Cigarette smoking and the age at onset of a first non-fatal myocardial infarction.

BACKGROUND: Smoking is a major risk factor for coronary heart disease. Discontinuance of smoking is associated with a reduction in the risk of coronary disease; this risk approaches the level among non-smokers after stopping smoking for periods ranging from 6 months to several years. We analyzed pertinent prospectively accumulated data from our multicenter postinfarction studies to gain further insight into the complex relationship between cigarette smoking and the premature occurrence of a first myocardial infarction. METHODS: Retrospective analysis of the relationship between the number of cigarettes smoked and the age at onset of patients experiencing their first non-fatal myocardial infarction was investigated in 2445 patients. The intensity of smoking was quantitated in terms of the average number of packs per day smoked during adult years, subcategorized in increments of a half-pack per day up to more than two packs per day. Ex-smokers were identified if they had stopped smoking 1 month before their index infarction. Analysis of variance was used to adjust for the effects of relevant confounding risk factors. RESULTS: The adjusted age for first non-fatal infarction progressively declined with increasing smoking exposure, with an average age reduction of 8.7 years (95% confidence interval; 7.2, 10.2) in those smoking more than two packs per day compared with non-smokers. The graded effect was somewhat more marked in women than in men. The number of cigarettes smoked before infarction had no effect on the severity of the acute infarction or on mortality from cardiac causes during more than 2-year post-hospital follow-up. Those who stopped smoking 1 month or longer before the infarction were significantly older at the time of first infarction than active smokers in all smoking categories. CONCLUSION: This study provides strong evidence that active smoking is associated with an earlier age at onset of first infarctions, with a striking inverse dose-response effect. Stopping smoking appears to reduce the premature occurrence of coronary events.

Age of Onset↗
PubMed1994

Improved survival of hospitalized patients with acute myocardial infarction from 1981-1983 to 1992 in Israel. The SPRINT Study Group and The Israeli Thrombolytic Survey Group. Secondary Prevention Israeli Nifedipine Trial.

BACKGROUND: This study compares in-hospital and 1-year mortality rates in two large cohorts of patients with acute myocardial infarction (AMI) who were admitted to coronary care units in Israel in 1981-1983 and in 1992. Since the late 1960s and early 1970s there has been a remarkable decline in mortality from cardiovascular causes in most Western countries; the reason for this decline is not completely understood. Although several studies have shown a significant decrease in in-hospital mortality from AMI between the 1960s and the 1980s, studies comparing survival after AMI between the 1980s and 1990s are relatively scarce. Over the past decade important medical treatments and procedures for the management of AMI were introduced. METHODS: Between August 1981 and July 1983, 5839 consecutive patients were admitted to 13 coronary care units in Israel with a confirmed diagnosis of AMI. Demographic and medical data from hospital charts were recorded. Mortality follow-up was complete for 99% of hospital survivors for a mean period of 10 years. A second cohort of 623 consecutive patients with AMI hospitalized during January and February of 1992 in the same 13 coronary care units were followed up for 1 year after discharge. RESULTS: Sex distribution and mean age were very similar in the two cohorts. Unadjusted in-hospital mortality was 18% in 1981-1983 versus 11% in 1992 (P < 0.001). After multiple regression analysis, the in-hospital mortality odds (adjusted for age, sex and history of previous infarction) declined from 1981-1983 to 1992 by 22-67%. The reduction in in-hospital mortality rates from 1981-1983 to 1992 was more pronounced among patients aged over 65 years. One-year survival was 91% and 92% in patients discharged in 1981-1983 and 1992, respectively; however, 1-year after discharge, the survival rate for patients older than 65 years was 85% in 1981-1983 versus 89% in 1992. None of the 5839 patients hospitalized in 1981-1983 received thrombolytic treatment or mechanical revascularization, whereas 46% and 9% of patients received these respective treatments in 1992. CONCLUSIONS: This study suggests that, over the past decade, changes in medical treatment, thrombolytic therapy and mechanical revascularization have significantly contributed to the improvement of the immediate prognosis of patients hospitalized as a result of AMI.

Aged↗
PubMed1994

Hemodynamic and neurohumoral effects of the angiotensin II antagonist losartan in patients with heart failure.

BACKGROUND: Losartan is a specific angiotensin II receptor antagonist with no agonist properties. This agent permits evaluation of the response to selective angiotensin II antagonism in patients with congestive heart failure. OBJECTIVE: A study was designed to assess the acute hemodynamic and neurohumoral response to losartan in a controlled, blinded fashion. DESIGN: Sixty-six patients in New York Heart Association functional class II, III or IV with a radionuclide ejection fraction of < 40% were randomly allocated to treatment with placebo and then sequentially to 5, 10, 25, 75 and 150 mg losartan. Hemodynamic and neurohumoral measurements were obtained at selected times for 24 h following ingestion of a single dose of losartan. RESULTS: Treatment with losartan led to dose-dependent vasodilation. Mean arterial pressure and systemic vascular resistance decreased progressively up to a dose of 25 mg. The higher doses of 75 and 150 mg did not produce additional vasodilation. Similarly, the decrease in pulmonary capillary wedge pressure was not greater with doses exceeding 25 mg. The increase in the cardiac index was modest and similar for all doses. No variation in the heart rate was observed at any dose. The hemodynamic changes were accompanied by marked neurohumoral changes. Large dose-related increases in plasma renin activity and angiotensin II levels were observed, especially following the 150-mg dose. Moderate reductions occurred in serum aldosterone and plasma noradrenaline. The peak effect for these parameters occurred 4-6 h after the dose, with persistent changes still evident 24 h after the dose. CONCLUSIONS: These data demonstrate that selective blockade of the angiotensin II receptor with losartan causes a favorable vasodilatory and neurohumoral response in patients with heart failure. Further studies are needed to determine the most effective dose in these patients. Nevertheless, losartan should be of substantial clinical use in the management of this large population.

Angiotensin Receptor Antagonists↗