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Biomedical subjects

J Barzilay

Publications and source records attributed to J Barzilay.

At least 19 recordsLinked to original sources
PubMed1997

Mapping of the active site of recombinant human erythropoietin.

Recombinant human erythropoietin (rHuEPO) variants have been constructed to identify amino acid residues important for biological activity. Immunoassays were used to determine the effect of each mutation on rHuEPO folding. With this strategy, we could distinguish between mutations that affected bioactivity directly and those that affected bioactivity because the mutation altered rHuEPO conformation. Four regions were found to be important for bioactivity: amino acids 11 to 15, 44 to 51, 100 to 108, and 147 to 151. EPO variants could be divided into two groups according to the differential effects on EPO receptor binding activity and in vitro biologic activity. This suggests that rHuEPO has two separate receptor binding sites. Mutations in basic residues reduced the biologic activity, whereas mutations in acidic residues did not. This suggests that electrostatic interactions between rHuEPO and the human EPO receptor may involve positive charges on rHuEPO.

Amino Acid Sequence↗
PubMed1996

Fine-structure epitope mapping of antierythropoietin monoclonal antibodies reveals a model of recombinant human erythropoietin structure.

We have isolated and mapped the rHuEPO epitopes for three noncompeting anti-EPO monoclonal antibodies (MoAbs). The MoAb 9G8A recognizes a linear epitope that includes amino acids 13, 16, and 17. MoAb F12 recognizes a conformational epitope that includes amino acids 31 through 33, 86 through 91, and 138. MoAb D11 recognizes a conformational epitope that includes amino acids 64 through 78 and 99 through 110. MoAb D11 neutralizes rHuEPO activity which suggests that its epitope may contain the receptor binding domain. Analysis of the effect of mutations on folding allowed the identification of buried residues, alpha-helical, and non alpha-helical regions. This data along with epitope mapping data of anti rHuEPO monoclonals was used to model rHuEPO protein structure. A model consistent with the data is a 4-helix bundle with short and long interconnecting loops.

Amino Acid Sequence↗
PubMed1992

Risk for cardiovascular autonomic neuropathy is associated with the HLA-DR3/4 phenotype in type I diabetes mellitus.

OBJECTIVE: To identify risk factors for the development of cardiovascular autonomic neuropathy in patients with juvenile-onset type I diabetes mellitus. DESIGN: Cross-sectional examination of an inception cohort 15 to 21 years after the onset of diabetes. SETTING: Outpatient diabetes clinic. PATIENTS: Seventy-nine patients with type I diabetes who experienced onset of disease before 21 years of age and who were followed for 15 to 21 years. MEASUREMENTS: Autonomic nerve function was evaluated in all patients using deep breathing and tilt tests. On the basis of these tests, an index of cardiovascular autonomic neuropathy was derived and patients were classified as having intact, mildly impaired, or significantly impaired autonomic function. RESULTS: The group with significantly impaired function had a higher mean hemoglobin A1 at the time of examination than the group without impairment, yet the groups did not differ regarding glycemic control during the first decade of diabetes. The HLA-DR3/4 phenotype was present in more than 50% of the patients with significant autonomic dysfunction and conferred relative odds of 6.2 (95% CI, 1.7 to 23.3) for the development of autonomic neuropathy when compared with other HLA-DR phenotypes. Sex, percent ideal body weight, and smoking did not have a statistically significant effect on the development of autonomic neuropathy. CONCLUSIONS: The development of cardiovascular autonomic neuropathy in type I diabetes mellitus is strongly associated with the HLA-DR3/4 phenotype. Thus, genetic predisposition may play an important role in the development of this complication.

Adult↗
PubMed1992

Erosive spondyloarthropathy in primary hyperparathyroidism without renal failure.

A patient with erosive spondyloarthropathy (ESA) and primary hyperparathyroidism is described. In the past, ESA has been described exclusively in patients with chronic renal failure (CRF) and has been attributed to crystal deposition, amyloidosis, severe secondary hyperparathyroidism, or other abnormalities of chronic renal failure. This patient with normal renal function suggests that secondary hyperparathyroidism plays the major pathogenetic role in ESA in patients with renal failure.

Female↗
PubMed1992

Predisposition to hypertension: risk factor for nephropathy and hypertension in IDDM.

Less than a quarter of the patients with juvenile-onset IDDM develop diabetic nephropathy during the first 20 years of diabetes. To study the determinants of this complication, we selected patients who had come with newly diagnosed IDDM to the Joslin Clinic between 1967 to 1972, and we examined them in 1986 to 1988, that is, 15 to 21 years after onset of diabetes. Using a case control design we compared three groups of cases, that is, advanced nephropathy (N = 43), only microalbuminuria (N = 41), and hypertension alone (N = 17), with a group of controls who remained normoalbuminuric and normotensive despite the long duration of IDDM (N = 61). In comparison with controls, patients with advanced nephropathy had more parents with hypertension (odds ratio 3.8), higher Vmax values of Na/Li countertransport in red blood cells (odds ratio 10.0 for the highest tertile), and higher mean arterial pressure during adolescence and early adulthood (odds ratio 3.1 for those above the median). They also had significantly poorer glycemic control during their first 12 years of diabetes. Patients with hypertension alone were similar to those with advanced nephropathy with regard to markers of predisposition to hypertension but differed from them with regard to glycemic control, having the best glycemic control of all the study groups. Patients who developed only microalbuminuria during 15 to 21 years of IDDM (some of whom will progress to overt proteinuria later) did not differ significantly from controls with regard to predisposition to hypertension. In conclusion, predisposition to hypertension is a major risk factor for the development of advanced diabetic nephropathy and essential hypertension during the first 20 years of IDDM.

Aging↗
PubMed1992

Risk of early-onset proliferative retinopathy in IDDM is closely related to cardiovascular autonomic neuropathy.

Determinants of proliferative diabetic retinopathy (PDR) that occur during the 2nd decade of insulin-dependent diabetes mellitus (IDDM) (early-onset PDR) were investigated in a nested case-control study. From an inception cohort of patients with juvenile-onset IDDM that now has 15-21 yr diabetes duration, the patients with PDR (cases, n = 74) were selected for study along with a random sample of the patients in the cohort without PDR (control subjects, n = 88). The risk of PDR was associated with poor glycemic control during the first 12 yr of diabetes. Relative to patients in the first quartile of the index of hyperglycemia, those in higher quartiles and nonattenders had a four- to fivefold risk of developing PDR. A striking relationship with cardiovascular autonomic neuropathy (CAN) was found. Relative to patients without CAN, patients with significant and mild CAN had odds ratios of 77.5 and 34.6, respectively. Patients with albumin excretion rates greater than 30 micrograms/min had moderately increased risk of PDR (ranging from 4-fold for microalbuminuria to 7-fold for proteinuria). In contrast, patients with impaired renal function had an extremely high risk of PDR. All 20 of these patients were cases, therefore the odds ratio was infinite. All three factors (poor glycemic control, CAN, and various stages of nephropathy) were associated with PDR in multiple logistic regression analysis. However, in models including glycemic control, the association between microalbuminuria or proteinuria and PDR was weakened. In conclusion, our findings are consistent with a hypothesis that the level of glycemia is a primary determinant of early-onset PDR.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Benign and malignant tumors in patients with acromegaly.

Growth hormone and its principal mediator insulinlike growth factor I are known promoters of normal growth. To determine whether excessive secretion of growth hormone is associated with an increased occurrence of benign and of malignant tumors, we studied records of 87 patients with acromegaly seen in the Lahey Clinic Medical Center (Burlington, Mass) from 1957 to 1988 and compared the rate of tumor occurrence with a control group of patients with pituitary tumors (198) and with findings from a cancer registry. Patients with acromegaly had a 2.45-fold increased rate of malignant tumors (95% confidence interval, 0.98 to 5.04) compared with findings from the tumor registry. Female patients had a higher rate than male patients. The rate of carcinoma of the thyroid was excessive and previously underscribed, but the rate of carcinoma of the colon was not increased as reported by others. Among benign lesions, goiters, predominantly nodular, were seen in 25% of patients in addition to a large number of mesenchymal lesions.

Acromegaly↗
PubMed1989

Spontaneous hematoma of a parathyroid adenoma.

A patient with long-standing, asymptomatic, primary hyperparathyroidism developed pain in the anterior neck area, with cough, dysphagia and increasing shortness of breath. This led to respiratory insufficiency, which required endotracheal intubation and respirator assistance. During the ensuing hours the patient developed an area of ecchymosis on the anterior chest. Chest x-ray showed widening of the superior mediastinum, and CT scan showed a large mass with a fluid level. Surgery revealed a large hematoma originating from a mediastinal parathyroid adenoma with a hemorrhagic infarct. Serum calcium, previously elevated, decreased to normal with the onset of neck pain, and the patient remains normocalcemic. Previous reported cases of this rare complication of parathyroid adenomas are reviewed. Hemorrhagic infarct of a parathyroid adenoma may present with a rapidly enlarging mediastinal mass, and/or hypercalcemic crisis. Surgical removal of the infarcted adenoma can return the serum calcium to normal.

Adenoma↗
PubMed1988

Increased expression of Fc gamma receptor in cancer patients and tumor bearing mice.

In this study we report on some lines of ongoing research performed in our laboratory, in relation to the increased expression of FcR on tumor cells, as well as on cells present in the tumor-bearing host, and its possible role in tumor progression. In a previous study we have shown that a Polyoma virus (PyV)-induced anaplastic carcinoma (SEYF-a tumor) contained an FcR-expressing subpopulation of tumorigenic cells. We tested the effect of in vivo passaging of FcR-expressing and of non-FcR-expressing sub-populations of SEYF-a tumor cells on the expression of FcR, as revealed by the ability of these cells to bind the 2.4G2 monoclonal antibody, which is directed against mouse Fc gamma 2b/gamma 1R. It was found that upon in vivo passaging these two sub-populations became practically identical in their ability to bind anti-Fc gamma R antibody. On the other hand, in vitro passaging of FcR-expressing SEYF-a cells resulted in a gradual decrease in the expression of Fc gamma R. These results, indicating that the expression of Fc gamma R on tumor cells, per se, is dependent on a factor present in the in vivo environment were confirmed using 3T3 cells transformed in vitro by PyV (C) and forming tumors at first injection to mice (CTC). C cultures of various clones did not express Fc gamma R, while CTC cultures (cultures from tumors) became positive. We also detected an increase in the level of a soluble form of Fc gamma 2b/gamma 1R in the circulation of mice bearing PyV induced tumors. This increase paralleled the appearance of palpable tumors. A similar pattern of increase was observed in mice inoculated with the c-H-ras transformed tumorigenic clone 8/F/5, but not in mice inoculated with non-tumorigenic 3T3 cells. Data published by us show that metastatic breast cancer patients had significantly elevated Fc gamma R levels on their peripheral blood mononuclear cells (PBMC). Experiments presented here indicate a direct correlation between increased Fc gamma R levels on PBMC and tumor mass in colon, ovary and lung metastatic carcinoma patients. The possibility that malignantly transformed cells have the potential to cause proliferation of Fc gamma R expressing T cells was tested. It was found that extract derived from r-H-ras transformed 3T3 cells triggers the proliferation of a T cell hybridoma expressing Fc gamma R.

Animals↗
PubMed1988

The c-fos proto-oncogene in murine 3LL carcinoma clones controls the expression of MHC genes.

The c-fos proto-oncogene and H-2K class I major histocompatibility antigens are differentially expressed in low-metastatic Lewis lung carcinoma clones, but not in high-metastatic clones. Interferons induce mRNA expression of fos and H-2 in non-expressor cells and elevate mRNA steady state levels of expressor cells. Transfection of non-expressor cells by v-fos or c-fos genes induces the transcription of H-2K mRNA and elevates the levels of H-2 proteins, but not of other gene products. These results, correlated with observations in other cell systems, suggest that the c-fos proto-oncogene controls the expression of MHC genes coding for class 1 antigens.

Actins↗
PubMed1987

Leiomyosarcoma of kidney.

The case of a seventy-one-year-old woman with leiomyosarcoma of the kidney capsule is presented. Despite lack of invasion into surrounding tissues and few mitoses, the tumor recurred thirteen months after nephrectomy. A full subjective response and an almost complete objective regression lasting eight months were achieved using a short course of combination chemotherapy. The literature on leiomyosarcoma of the kidney is reviewed.

Aged↗
PubMed1987

Predictive value of premature ventricular contractions on the resting electrocardiogram for ventricular arrhythmias on 24 hour monitoring in asymptomatic young adults.

Between the years 1981-1984, 89 air-personnel, ages 18-45 years, underwent 24-hour ambulatory ECG monitoring at the Israel Air Force Aeromedical Center due to an incidental finding of one or more premature ventricular contractions (PVCs) on the resting supine 12-lead ECG. Complex ectopic arrhythmias (bigemini, trigemini, couplets, ventricular tachycardia, R on T phenomenon, or multifocal patterns) were observed during monitoring in 1.4% of 138 control subjects without PVCs, in 22% of those with 1 to 3 PVC X min-1 and in 68% of those with 4 or more PVC X min-1 on the resting ECG. Altogether 39(44%) of the 89 subjects with PVCs on the resting ECG had complex ectopic rhythms on monitoring. Of the 43 subjects with available follow-up data, 3 (7%) reported bouts of dizziness and light headedness which coincided with complex ectopic rhythms. In one of these three subjects, the bouts of dizziness coincided with runs of ventricular tachycardia during exercise testing.

Adult↗
PubMed1987

Expression of major histocompatibility class I genes in differentiating leukemic cells is temporally related to activation of c-fos proto-oncogene.

The relationship between the expression of the c-fos proto-oncogene and the expression of the class I major histocompatibility (MHC) antigens during the early stages of induced differentiation in three different leukemic cell lines was examined. In the U937 histiocytic lymphoma line TPA induced an increase in mRNA and cell surface MHC expression which followed induction of c-fos. In contrast, in the murine erythro-leukemia cell line, DMSO induced declining constitutive c-fos levels that were accompanied by declining mRNA and cell surface MHC expression. In the pluripotent HL60 promyelocytic line induction of macrophage differentiation with TPA led to c-fos induction and rising MHC levels, whereas induction of granulocyte differentiation with DMSO did not induce c-fos expression and was followed by declining MHC levels. Taken together, the results suggest that the c-fos proto-oncogene might be involved in the control of class I MHC antigen expression during differentiation.

Cell Differentiation↗
PubMed1987

Predictive value of the resting electrocardiogram for Mobitz type I atrio-ventricular block on Holter monitoring in Israeli air force personnel.

During 1981-1984, a total of 52 airpersonnel had 24-h continuous ambulatory electrocardiographic (ECG) monitoring at the Israel Air Force Aeromedical Center because of an incidental finding of a first or second degree atrio-ventricular block on a resting 12-lead ECG. There were 230 other airpersonnel without AV block on the resting ECG monitored during the same period. Altogether 17 cases of second degree Mobitz type I (Wenckebach) block were identified. Mobitz type I was detected on Holter monitoring in 2 (0.9%) of the 230 cases with a normal PR interval on the resting ECG, in 6 (15.4%) of 39 cases with a PR interval of 0.22-0.25 s, in 5 (55.5%) of 9 cases with a PR interval of 0.26 s or more, and in all 4 cases with Mobitz type I on the resting ECG. It is concluded that the PR interval on the resting ECG may be useful in predicting an intermittent Mobitz type I AV block on Holter monitoring.

Aerospace Medicine↗
PubMed1987

The predictive value of the body mass index for systolic blood pressure 12-15 years later in young air force personnel.

The records of 719 male air force personnel, aged 18-30 in 1968, were searched for the results of the systolic blood pressure (SBP), and height and weight examinations at entry in 1968 and after 12-15 years follow-up. The body mass index (BMI = weight/height2) was calculated and an elevated value was defined as one in the upper quintile. An elevated blood pressure, defined as an SBP greater than or equal to 140 mm Hg, was found on follow-up in 4.7% of the entire cohort, in 6.0% (4/67) of those with an elevated SBP and a normal BMI at entry, in 10.2% (12/117) of those with a normal SBP and an elevated BMI at entry, and in 20.0% (7/35) of those with both elevated BMI and SBP greater than or equal to 140 mm Hg at entry. Of those with a normal SBP and BMI at entry, 2.2% (11/500) had an elevated SBP on follow-up. We conclude that BMI in young men can predict SBP 12-15 years later, and that this predictive value is at least as high as that of the resting blood pressure.

Adult↗
PubMed1987

Value of three annual blood pressure determinations in young adults as a predictor of elevated systolic blood pressure 15 years later.

The records of 726 male air force personnel aged 18 to 34 years in 1968 were searched for the results of examination of the systolic blood pressure (SBP) in 1968 and during the following 15 years ending in 1983. An elevated recent blood pressure (BP), defined as an SBP greater than or equal to 140 mm Hg on two or more of the last three follow-up examinations, done 13, 14, and 15 years after entry, was found in 3.2% of the cohort. An elevated recent BP was found in 12% of those with an SBP greater than or equal to 140 mm Hg on the first examination, in 31.7% (13 of 41 individuals) of those with an SBP greater than or equal to 140 mm Hg on two or more of the three initial annual examinations, and in 46.2% (6 of 13 men) of those with an SBP greater than or equal to 140 mm Hg on all three initial examinations. It is concluded that three annual determinations of SBP are better predictors of elevated SBP than a single causal BP measurement on entry. Still, their predictive value remains limited; 49% of those with an SBP greater than or equal to 140 mm Hg on two or more of the three initial annual examinations had a normal SBP on all of the last three annual examinations.

Adolescent↗
PubMed1986

Carcinoma of the nasopharynx. An analysis of 91 cases and a comparison of differing treatment approaches.

Ninety-one patients with malignant epithelial tumors of the nasopharynx seen in our department from 1970 to 1982 were evaluated. The 5- and 10-year actuarial survival rates were 62.0% and 42.0%, respectively. Patients seen from 1970 to 1979 were treated by radiotherapy to the primary site and upper neck, the lower neck being irradiated only in instances of massive disease. Those treated from 1980 to 1982 received elective irradiation of the whole neck, as well as adjuvant chemotherapy (consisting of cyclophosphamide, methotrexate, and either 5-fluorouracil or bleomycin) for 6 to 12 months after completion of radiotherapy. Comparison of 3-year actuarial survival (61.4% versus 83.3%) and disease-free survival (49.7 versus 77.0%) rates show significantly improved results (P less than 0.05) for those receiving combined therapy. In addition, significantly fewer (P less than 0.05) distant metastases appeared in the combined therapy group at 18 months. A retrospective analysis comparing those patients who received full-neck irradiation and adjuvant chemotherapy with those who received full-neck irradiation alone showed a significantly improved survival (P less than 0.02) and disease-free survival (P less than 0.05) for those patients with undifferentiated carcinomas, including lymphoepitheliomas, who received adjuvant chemotherapy.

Actuarial Analysis↗