Biomedical subjects

M Levenstein

Publications and source records attributed to M Levenstein.

At least 19 recordsLinked to original sources

PubMed2001

Meta-analysis of studies using selective alpha1-blockers in patients with hypertension and type 2 diabetes.

This meta-analysis of published studies evaluated the effect of selective alpha1-blockers on lipid and carbohydrate profiles and blood pressure (BP) as well as tolerability in patients with hypertension and type 2 diabetes. Publications identified via MEDLINE were used. Text and bibliographies of retrieved articles were examined for additional references. Clinical trials with a randomised comparative structure (placebo and active treatment arms) and controlled studies with other structures were included. Of the 27 citations identified, 22 studies were selected for inclusion, and five were rejected. Efficacy and safety data, lipid and carbohydrate profiles, and study and patient characteristics were extracted by two investigators independently. The mean pooled results showed beneficial effects of selective alpha1-blockers on total serum cholesterol (TC), high-density lipoprotein (HDL) cholesterol, and systolic and diastolic BP. The results also showed doxazosin had beneficial effects on fasting glucose levels, insulin sensitivity, TC, HDL cholesterol, low-density lipoprotein (LDL) cholesterol, HDL/TC ratio, and systolic and diastolic BP. The risk difference was equivalent between the alpha1-blocker group and the control group for postural hypotension or syncope. This meta-analysis demonstrates a number of favourable effects of therapy with selective alpha1-blockers in hypertensive patients with type 2 diabetes. These agents provide an effective modality for reducing BP, with favourable effects on lipid, no deterioration in glycaemic control, and little risk of orthostatic hypotension.

Adrenergic alpha-Antagonists↗

PubMed1999

SZF1: a novel KRAB-zinc finger gene expressed in CD34+ stem/progenitor cells.

The identification and study of genes expressed in hematopoietic stem/progenitor cells should further our understanding of hematopoiesis. Transcription factors in particular are likely to play important roles in maintaining the set of genes that define the stem/progenitor cell. We report here the identification of a putative KRAB-zinc finger gene (SZF1) from a cDNA library prepared from human bone marrow CD34+ cells. Characterization of SZF1 implicates its role in hematopoiesis. The predicted protein contains a highly conserved KRAB domain at the NH2 terminus and four zinc fingers of the C2H2 type at the COOH terminus. Two alternatively spliced products of SZF1 were isolated, which predict proteins of 421 (SZF1-1) and 361 (SZF1-2) amino acids, differing from each other only at the carboxy terminus. The two transcripts of SZF1 have different expression patterns. SZF1-2 is ubiquitously expressed, as indicated by Northern blot, RNase protection, and reverse transcriptase polymerase chain reaction. SZF1-1 expression, in contrast, was detected only in CD34+ cells. We recently isolated the promoter region for the stem/progenitor cell expressed FLT3/FLK-2/STK-1 gene and used this region to generate a reporter construct to test the effect of SZF1 expression. Cotransfection of the reporter construct with SZF1 constructs showed that SZF1-2 repressed transcription three- to fourfold, whereas SZF1-1 showed a lower level of repression. The expression pattern of SZF1 transcripts and the transcriptional repression of a CD34+-specific promoter demonstrate a possible role for SZF1 in hematopoietic stem/progenitor cell differentiation.

Alternative Splicing↗

PubMed1998

Safety of long-acting dihydropyridine calcium channel blockers in hypertensive patients.

Issues raised recently concerning the safety of calcium channel blockers (CCBs) prompted an analysis of the occurrence of cardiovascular events and death in the Pfizer Inc. hypertension clinical trial databases for amlodipine (Norvasc) and nifedipine in the gastrointestinal therapeutic system (GITS) formulation (Procardia XL). Prospectively defined analyses of data from comparative and noncomparative trials of amlodipine and nifedipine GITS were conducted. Outcome measures included cardiovascular and noncardiovascular deaths, and adverse cardiovascular events including new/worsened angina, myocardial infarction (MI), serious arrhythmia, stroke, congestive heart failure, and bleeding. Among all amlodipine-treated patients (n = 32,920), the incidence rates for all-cause death, MI, and new/worsened angina were 3.0, 3.3, and 1.6/1,000 patient-years of exposure, respectively. Among those in comparative trials alone (n = 4,126), the all-cause death rate was 4.1/1,000 patient-years, which was comparable to that of other non-CCB agents and significantly less than that of other CCBs (23.8/1,000 patient-years, p = 0.015), although the difference in rates represents only 2 deaths. Among all nifedipine-GITS-treated patients (n = 2,645), the rate of all-cause death was 4.1/1,000 patient-years, of MI 6.5/1,000 patient-years, and of new/ worsened angina 5.7/1,000 patient-years. The incidence rates for MI and other cardiac events were low in these hypertension trials, and did not differ among treatment groups in either the amlodipine or nifedipine GITS comparative analyses. In the clinical trial databases analyzed, there is no signal suggesting excessive risk of death or cardiovascular events for hypertensive patients treated with amlodipine or nifedipine GITS.

Amlodipine↗

PubMed1997

Oropharyngeal candidiasis in patients with AIDS: randomized comparison of fluconazole versus nystatin oral suspensions.

A total of 167 human immunodeficiency virus (HIV)-infected patients with oropharyngeal candidiasis were randomly assigned to receive 14 days of therapy with liquid suspension fluconazole (100 mg once daily) or liquid nystatin (500,000 U four times daily). At day 14, 87% of the fluconazole-treated patients were clinically cured, as opposed to 52% in the nystatin-treated group (P < .001). Fluconazole eradicated Candida organisms from the oral flora in 60%, vs. a 6% eradication rate with nystatin (P < .001). The fluconazole group had fewer relapses noted on day 28 (18%, vs. 44% in the nystatin group; P < .001). This relapse difference no longer existed by day 42. Fluconazole oral suspension as a systemic therapy was more effective than liquid nystatin as a topical therapy in the treatment of oral candidiasis in HIV-infected patients and provided a longer disease-free interval before relapse.

AIDS-Related Opportunistic Infections↗

PubMed1997

JAK3: expression and mapping to chromosome 19p12-13.1.

We cloned JAK3, the most recently described member of the JAK family of intracellular tyrosine kinases, from normal human CD34+ RNA. JAK3 is involved in the signal transduction pathways of the IL-2, IL-4, IL7, IL-9, and IL-15 receptors by association with their common gamma-chain (gamma[c]). JAK3 is critical to lymphoid development, as recently established by the linking of mutations in JAK3 to a subgroup of patients with SCID and the generation of JAK3-null mice with severe disruptions in normal lymphocytic development. However, JAK3 expression is not restricted to the lymphocytic compartment of bone marrow but is found in a wide range of tissues of both hematopoietic and non-hematopoietic origin. Northern blot analysis indicates that JAK3 is also expressed in adult placenta, lung, liver, kidney, pancreas, spleen, thymus, ovary, and small intestine. RNAse protection assays and RT-PCR indicate that JAK3 is expressed in a variety of leukemic-derived hematopoietic cell lines with myeloid and/or lymphoid phenotypes. In normal human bone marrow, JAK3 is expressed in the CD34+/lineage- fraction, which is highly enriched in hematopoietic stem/progenitor cells. In addition, we found a splice variant of JAK3 which is formed by the splicing of JAK3 with exon II of the leydig insulin-like (LEY I-L) hormone. RT-PCR and RNAse protection assay analyses indicate that this variant (termed I-JAK3) is normally expressed in almost all hematopoietic and non-hematopoietic tissues shown to express JAK3. Using fluorescence in situ hybridization we have localized JAK3 to 19p12-13.1, the same region of chromosome 19 to which the LEY I-L hormone maps (19p12-13.2).

Adult↗

PubMed1996

Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias.

Normal expression of the hematopoietic growth factor receptor FLT3 (STK-1@Flk2) is limited to CD34+ stem/progenitor cells. We have evaluated the expression of FLT3 by RNase protection assay and Western blotting in 161 primary bone marrow (BM) samples from patients with leukemia. FLT3 RNA was found to be expressed at a higher level than in normal BM controls in 33 of 33 B-lineage acute leukemias, 11 of 12 acute myeloid leukemias (AMLs), and 3 of 11 T-cell acute leukemias (T-ALLs). Expression of FLT3 RNA was also observed in some cases of blast crisis CML. The FLT3 signal resulted from expression on the leukemic blasts, and was not caused by increased FLT3 expression on normal CD34+ stem/progenitor cells in the leukemic samples. To determine if FLT3 protein was also overexpressed, proteins were extracted from leukemic BM samples and screened by Western blotting with anti-FLT3 antisera. FLT3 protein was not detected in normal BM controls, but was found in 14 of 14 B-lineage ALLs, 36 of 41 AMLs, and 1 of 4 T-ALLs. Stimulation of patient samples with FLT3 ligand resulted in autophosphorylation of the FLT3 receptor, suggesting the receptor is functional in these cells. These data show that FLT3 RNA and protein are aberrantly expressed by AML and ALL cells in that CD34 expression and FLT3 expression are no longer synchronous, and suggest the possibility that overexpression of FLT3 could play a role in the survival and/or proliferation of malignant clones in acute myeloid and lymphoid leukemias.

Antigens, CD34↗

PubMed1996

Principal results of the Hypertension and Lipid Trial (HALT): a multicenter study of doxazosin in patients with hypertension.

The Hypertension and Lipid Trial (HALT) was undertaken to assess the efficacy and safety of doxazosin, a selective alpha 1- adrenergic blocker, in patients with hypertension in a clinical practice setting. The effects of doxazosin on office blood pressure, changes in lipid profiles, and theoretic coronary disease risk were studied. In an open, noncomparative, multicenter trial, 851 patients were studied for a maximum of 16 weeks. Doxazosin significantly reduced mean sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 15.2/12.5 mm Hg and standing SBP and DBP by 16.1/12.7 mm Hg in the total study population (n = 807; p = 0.0001), with no significant effect on heart rate. Mean total cholesterol levels were significantly reduced by 2.7%, low-density lipoprotein cholesterol levels by 2.4%, and mean triglyceride levels by 3.4% (all p values < 0.05). High-density lipoprotein (HDL) cholesterol levels were essentially unchanged. The mean ratio of total to HDL cholesterol was significantly reduced (p < 0.05). Mean predicted 5-year coronary disease risk was significantly reduced with doxazosin therapy by 14.7% in previously untreated patients (p < 0.0001) and by 1.7% in patients who were previously receiving antihypertensive therapy (p < 0.05). The drug was well tolerated. This study demonstrates that antihypertensive therapy with doxazosin can favorably affect coronary disease risk factors and reduce predicted coronary disease risk.

Adult↗

PubMed1994

STK-1, the human homolog of Flk-2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells.

We cloned the cDNA for stem cell tyrosine kinase 1 (STK-1), the human homolog of murine Flk-2/Flt-3, from a CD34+ hematopoietic stem cell-enriched library and investigated its expression in subsets of normal human bone marrow. The cDNA encodes a protein of 993 aa with 85% identity and 92% similarity to Flk-2/Flt-3. STK-1 is a member of the type III receptor tyrosine kinase family that includes KIT (steel factor receptor), FMS (colony-stimulating factor 1R), and platelet-derived growth factor receptor. STK-1 expression in human blood and marrow is restricted to CD34+ cells, a population greatly enriched for stem/progenitor cells. Anti-STK-1 antiserum recognizes polypeptides of 160 and 130 kDa in several STK-1-expressing cell lines and in 3T3 cells transfected with a STK-1 expression vector. Antisense oligonucleotides directed against STK-1 sequences inhibited hematopoietic colony formation, most strongly in long-term bone marrow cultures. These data suggest that STK-1 may function as a growth factor receptor on hematopoietic stem and/or progenitor cells.

Amino Acid Sequence↗

PubMed1994

Nighttime dosing of doxazosin has peak effect on morning ambulatory blood pressure. Results of the HALT Study. Hypertension and Lipid Trial Study Group.

In this study the effects of a single daily dose (average 8.9 mg) of doxazosin (an alpha-adrenergic blocker) given at night were evaluated in 111 patients with mild hypertension. Patients were studied first on no medication, and a second time after being treated for up to 16 weeks with doxazosin. Blood pressure was measured by noninvasive ambulatory monitoring at the beginning and end of the study. There was a sustained reduction of both systolic and diastolic pressure throughout the day and night, but the greatest reduction occurred in the morning hours. Since the peak treatment effect was later than predicted from previous pharmacokinetic studies, it is suggested that the timing of the peak effect may depend on the prevailing level of alpha-adrenergic tone, as well as on the pharmacokinetics of the drug.

Adult↗

PubMed1994

Differential effects of doxazosin on clinic and ambulatory pressure according to age, gender, and presence of white coat hypertension. Results of the HALT Study. Hypertension and Lipid Trial Study Group.

In this study the effects of a single daily dose of doxazosin (an alpha-adrenergic blocker) given at night were evaluated in 112 patients with mild hypertension. Patients were studied first on no medication, and a second time after being treated for up to 16 weeks with doxazosin. Blood pressure (BP) was measured by noninvasive ambulatory monitoring at the beginning and end of the study. Before treatment, the white coat effect (clinic-ambulatory BP) was greater in women than in men (significant for systolic pressure but not diastolic), and greater in elderly (aged over 65 years) than in younger patients (significant for both systolic and diastolic pressure). Clinic and ambulatory BP were reduced to a similar extent in men and women by doxazosin, but in the elderly the fall in clinic BP was associated with a much smaller fall of ambulatory BP. In patients with white coat hypertension (elevated clinic but normal ambulatory BP) doxazosin lowered clinic but not ambulatory BP, while in those with sustained hypertension it lowered both.

Adult↗

PubMed1992

Influence of gender on survival in patients with stage I malignant melanoma.

BACKGROUND: Women with stage I malignant melanoma (MM) have a survival advantage over men as judged by univariate analysis. However, on multivariate analysis, gender was found to be an independent predictor of survival in only 8 of 14 published studies. OBJECTIVE: This study attempts to explain the disparate findings for gender as a prognostic factor in different multivariate analyses. METHODS: Univariate and multivariate analyses were performed on 832 patients with stage I MM in the New York University Melanoma Cooperative Group (NYU-MCG) data base. The results were compared with those of 14 similar studies. RESULTS: In the NYU-MCG data base, gender, age of the patient, and number of mitoses per square millimeter were not independent factors on multivariate analysis, whereas thickness, anatomic site, and presence of ulceration were. The statistically significant difference in survival by gender on univariate analysis, in the NYU-MCG data base, could be explained by the differences in thickness and anatomic site of the MMs in the sexes. Comparison of these results with the reviewed reports from the literature consistently shows thickness and ulceration to be independent prognosticators of survival. Likewise, most authors agree that age is not an independent predictor. However, there is no consensus with respect to gender and site, each of which was found to be an independent predictor of survival in only about half the studies reviewed. CONCLUSION: The disparate findings for gender in different multivariate analyses are explained by a gender-related difference in anatomic distribution of MM. Gender and site appear to have a similar influence in multivariate analysis and thus either one or the other is a dominant factor in different multivariate analyses.

Adult↗

PubMed1990

Clinical characteristics of malignant melanomas developing in persons with dysplastic nevi.

A total of 452 patients with dysplastic nevi (DN) were followed prospectively by repetitive, complete cutaneous examinations in order to determine the clinical features of early malignant melanomas (MM) arising in them. Sixteen patients (3.5%) developed 18 newly diagnosed MM during an average follow-up period of 27 months. Twelve of the 18 MM were in situ and all of the primary invasive MM diagnosed prospectively in this follow-up were less than 0.89 mm in Breslow thickness, implying an excellent prognosis. The principal clinical clue to the diagnosis of MM was change in a preexisting pigmented lesion. Total-body photographs were very useful in helping to identify the early MM in these patients.

Adolescent↗

PubMed1990

Does a history of melanoma correlate with the clinical presentation of dysplastic nevi?

In order to determine the prevalence of key features concerning nevocytic nevi (NN) in 150 consecutive Caucasian patients with dysplastic nevi (DN), total-body photographs were reviewed that revealed the following: 74% had greater than or equal to 100 NN, 73% had NN 8 mm or more in diameter, and 81% had atypical NN. The patients were then divided into two subsets, those with a personal and/or family history of malignant melanoma (MM) and those without, to see if the proportion of these three features differed in these two groups. There were no statistically significant differences between the MM-history-positive and MM-history-negative subsets.

Adult↗

PubMed1989

Efficacy and safety of Minipress XL, a new once-a-day formulation of prazosin.

The efficacy and safety of prazosin GITS (gastro-intestinal therapeutic system), a new extended-release once-a-day formulation, were assessed both as monotherapy in mild essential hypertension and in combination with a diuretic in moderate essential hypertension in two multicenter, double-blind, placebo-controlled trials. Prazosin GITS (Minipress XL) given once daily in doses of either 10 or 20 mg significantly reduced sitting and standing systolic and diastolic blood pressure compared with placebo in both mild and moderate essential hypertension. There were minimal, clinically insignificant changes in heart rate following prazosin-GITS treatment (2.5, 10, and 20 mg) compared with placebo treatment. Prazosin GITS was well tolerated; the most common adverse experiences reported were headache, dizziness, and fatigue. All adverse experiences in the moderate hypertension group and the majority (91 percent) in the mild hypertension group were mild-to-moderate in severity. The results from these multicenter trials demonstrate the efficacy and safety of this new extended-release once-a-day formulation of prazosin in the treatment of patients with mild and moderate essential hypertension.

Adult↗

PubMed1989

Dysplastic nevi. Markers for increased risk for melanoma.

A total of 452 white patients, classified into four dysplastic nevi groups, were followed prospectively by repetitive, complete cutaneous examinations using total-body photographs taken on entry into the study. Sixteen patients (3.5%) developed 18 newly diagnosed malignant melanomas (MM) during an average follow-up period of 27 months. Twelve of the 18 MM were in situ, and all of the six primary invasive MM diagnosed prospectively in this follow-up were less than 0.89 mm in Breslow thickness, implying an excellent prognosis. Compared with reference populations, the number of MM detected significantly exceeded the number estimated to occur in the comparable age-matched control groups. These data support the concept of repetitive follow-ups of all groups of patients with dysplastic nevi.

Adult↗

PubMed1988

Skin types in dysplastic nevus syndrome.

In order to determine if individuals with dysplastic nevi (DN) are relatively more sun-sensitive than controls who do not have DN, the sun-reactivity skin types (based on the Harvard classification) were determined in these two groups. Compared with controls, sun-sensitive types were significantly overrepresented in the DN group. This is consistent with the hypothesis that the fundamental defect in the dysplastic nevus syndrome is the genetically unstable melanocyte, which is susceptible to neoplastic transformation induced by sunlight.

Adult↗

PubMed1987

Prognostic index for malignant melanoma.

This report verifies the ability of a Prognostic Index (PI) to accurately predict 5-year survival rates for 879 Stage I cutaneous malignant melanoma (MM) patients seen at New York University Medical Center. The PI used in this study was first reported from Munich, West Germany, and is calculated from standard histologic sections by multiplying the MM thickness in millimeters (Breslow method) by the number of MM mitoses per square millimeter. A PI value of less than 19 versus greater than or equal to 19 was found to be a significant and independent prognostic variable for Stage I MM when compared with seven other predictive variables (including Breslow thickness). These PI intervals identified a subgroup of patients with MM of intermediate thicknesses (1.50-3.49 mm) whose significantly worse survival would not have been anticipated if prognosis were determined by Breslow thickness alone. For example, patients with MM 1.50 to 2.49 mm thick have a 5-year survival rate of 84.1% determined by Breslow thickness alone; however, among these patients exists a subgroup with PI greater than or equal to 19 whose survival rate is only 57.6%. This study verifies the additive usefulness of the PI in predicting survival rates of patients with Stage I cutaneous MM.

Age Factors↗

PubMed1986

Familial malignant melanoma.

Characteristics associated with familial compared with nonfamilial malignant melanoma were assessed. These data were obtained from consecutive prospectively completed questionnaires on 1169 cases of cutaneous malignant melanoma. Of these, 69 patients indicated a positive family history for this cancer. Among the various clinical and histological variables compared, those that significantly correlated with the familial occurrence of malignant melanoma include younger age at first diagnosis, smaller diameter of the lesion, lower Clark level, decreased frequency of nonmelanoma skin cancer, and reduced prevalence of noncutaneous cancer. Increased awareness of malignant melanoma among family members could account for some of these observations. Identification of the familial variety of malignant melanoma has practical implications concerning early detection and prompt intervention.

Age Factors↗