Search PubMed⌕ Search

Biomedical subjects

H Weinstein

Publications and source records attributed to H Weinstein.

At least 73 records · Page 4Linked to original sources
PubMed1995

Comparison of iodine-125-BMIPP and thallium-201 in myocardial hypoperfusion.

UNLABELLED: Radiolabeled fatty acids such as 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) have unique metabolic properties of potential use as myocardial perfusion tracers. Accordingly, we compared the in vivo pattern of uptake of BMIPP and 201Tl in hypoperfused rabbit myocardium. METHODS: Animals were intubated, ventilated and their arterial pressures monitored. A left thoracotomy was performed. After ligation of a major branch of the circumflex artery, an intravenous injection of BMIPP or BMIPP/201TI was given. Radiolabeled microspheres were used to document the area of risk. After the circulation period, the animals were killed. Tracer deposition within the hearts was determined by either dual-tracer autoradiography (Protocol I) or by segmental tissue analysis (Protocol II). RESULTS: Dual-tracer autoradiographic activity profiles for BMIPP were comparable to those of 201TI. Moreover, the two tracers yielded similar values for normal-to-defect contrast and defect size. The myocardial activity concentration of BMIPP for both protocols correlated strongly with coronary blood flow and compared favorably with 201TI. CONCLUSION: BMIPP and 201TI accurately delineate areas of hypoperfusion distal to a coronary occlusion. Therefore, differences in the myocardial distribution of BMIPP and 201TI in clinical studies may be related to cellular fatty acid metabolism.

Animals↗
PubMed1994

Polarity conserved positions in transmembrane domains of G-protein coupled receptors and bacteriorhodopsin.

The polarity of residues at certain positions in the transmembrane domains of G-protein coupled receptors (GPCR) is found to be conserved, and to indicate the pattern of specific helix-helix packing of the helices. A concept of polarity conserved positions (PCP) is proposed to describe this conserved property, and is applied to obtain insight into the structural features of the transmembrane proteins. The common pattern of PCPs for GPCRs indicates that they share a similar packing arrangement of their transmembrane helix bundles. For proteins in the bacteriorhodopsin family the PCP pattern suggests a common packing arrangement that differs from that of GPCRs, in agreement with experimental data. This difference in the packing arrangement underscores the shortcomings of a BR template for the construction of molecular models of GPCRs.

Amino Acid Sequence↗
PubMed1994

Clonality analysis of childhood ALL in remission: no evidence of clonal hematopoiesis.

We studied 98 female patients in remission (2-240 months) from childhood ALL to determine the clonality status of their hematopoiesis. Thirty-one (31.6%) were heterozygous at the PGK locus for the BstX1 endonuclease restriction site, permitting X-linked clonality assays to be performed. Two patients were in relapse at the time of study and were excluded. We used the PGK-PCR clonality assay (PPCA) to analyze DNA from PMN and mononuclear cells of the remaining 29 female patients. All (29/29) patients demonstrated polyclonal hematopoiesis. These data show that remission from childhood ALL involves reestablishment of polyclonally derived hematopoiesis in all patients studied.

Adolescent↗
PubMed1994

Ligand-induced domain motion in the activation mechanism of a G-protein-coupled receptor.

Rapidly accumulating information about the structures and functions of transmembrane proteins in the class of G-protein-coupled receptors is facilitating the exploration of molecular details in the processes of cellular signal transduction. We have described recently a 3-D molecular model of the transmembrane portion of the 5-HT2A type of receptor of the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT), constructed from such convergent empirical and theoretical considerations, and have used it for a computational simulation of the mechanisms of ligand-induced receptor activation and signal transduction. The molecular dynamics (MD) simulation of the interaction between the receptor model and ligands of different pharmacological efficacies pointed to a set of specific conformational changes propagated from the ligand binding site to a distal region of the receptor that is essential for signal transduction. The ligand-induced changes were found to correlate well with the known pharmacological properties, but it remained unclear how the binding of the small 5-HT2A receptor agonist molecules in the distal binding pocket could give rise to the specific conformational changes in a distant part of the receptor. As the MD simulations showed the secondary structure of the helical transmembrane domains of the receptor to be well maintained, and the conformational changes to involve mainly translations and rotations of the helices in the bundle relative to one another, an algorithm was developed to treat the ligand-induced conformational changes as rigid domain movements of transmembrane helices.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed1994

Phase I trial of continuous infusion carboplatin and etoposide in children with refractory acute leukemia: a Pediatric Oncology Group study.

PURPOSE: The purpose of this phase I study was to determine the toxicities and response to continuous infusion carboplatin in combination with a fixed dose of etoposide (VP-16) in children with refractory acute leukemia. PATIENTS AND METHODS: From January 1989 to February 1992, 20 patients received 28 courses of treatment. Each course of treatment consisted of a 1-hour intravenous (IV) infusion of VP-16 100 mg/m2/d for 5 days, followed by a 23-hour IV infusion of carboplatin each day. The initial, total 5-day dose of carboplatin (1,000 mg/m2) was escalated by 250- to 375-mg increments to a final, total dose of 1,875 mg/m2 over 5 days. RESULTS: Significant marrow suppression was observed in all patients, with prolonged marrow aplasia at the 1,875-mg/m2 dose level. Grade III diarrhea occurred in three patients; 10 patients experienced life-threatening infection and three had severe thrombocytopenic bleeding. Major marrow responses (two complete remissions and two partial remissions) occurred in four patients (20%). CONCLUSION: In view of the apparent antileukemic efficacy and minimal extramedullary toxicity, carboplatin deserves further study in a phase II trial.

Acute Disease↗
PubMed1994

A reciprocal mutation supports helix 2 and helix 7 proximity in the gonadotropin-releasing hormone receptor.

Activation of the pituitary gonadotropin-releasing hormone receptor, a member of the seven-transmembrane G protein-coupled receptor (GPCR) family, triggers a cascade of events leading to gonadotropin release and stimulation of the reproductive system. An unusual feature of this receptor, observed in mice, rats, and humans, is the presence of Asn87 in the second putative transmembrane helix at the location of a highly conserved aspartate in the GPCR family and of Asp318 in the putative seventh transmembrane helix where nearly all other GPCRs have asparagine. The possibility that these residues interact was suggested by this reciprocal pattern and by a three-dimensional model of the gonadotropin-releasing hormone receptor and was investigated by site-directed mutagenesis. Replacing Asn87 in the second transmembrane domain by aspartate eliminated detectable ligand binding. A second mutation, generating the double-mutant receptor Asp87Asn318, recreated the arrangement found in other GPCRs and re-established high affinity agonist and antagonist binding. The restoration of binding by a reciprocal mutation indicates that these two specific residues in helices 2 and 7 are adjacent in space and provides an empirical basis to refine the model of the transmembrane helix bundle of the receptor.

Amino Acid Sequence↗
PubMed1993

Wide-field radiation therapy with or without chemotherapy for patients with Hodgkin disease in relapse after initial combination chemotherapy.

BACKGROUND: Patients with Hodgkin disease who have relapses after initial chemotherapy (CT) appear to have a poor prognosis, especially if the duration of the first complete remission (CR) was short. The authors performed a retrospective analysis of patients with Hodgkin disease whose relapse after combination CT was limited to nodal sites; their aim was to study the prognosis of this selected subgroup of patients. METHODS: In 28 patients with Hodgkin disease who had relapses in nodal sites after combination CT alone, the disease was restaged carefully to rule out simultaneous extranodal recurrences. Then the patients were treated with wide-field, high-dose radiation therapy (RT) with or without additional CT with curative intent between 1971 and 1987 at the Joint Center for Radiation Therapy. Fourteen patients were in first relapse and were treated with combination CT followed by RT. The remaining 14 patients (8 who were in first relapse and 6 who were in second relapse) were treated with RT alone. RT techniques were similar to those recommended for early-stage disease. RESULTS: The 7-year actuarial freedom from relapse and survival rates for the patients retreated with CT and RT were 93% and 85%, respectively, as compared with 36% and 36% for patients retreated with RT alone. There was a significant difference for freedom from relapse (P = 0.002) and survival (P = 0.03), favoring patients retreated with both CT and RT. CONCLUSIONS: This retrospective study demonstrates that RT combined with second-line CT can result in a high percentage of durable remissions in patients who have relapses primarily in nodal sites after original treatment with combination CT alone. These durable remissions are seen even in patients who have only a brief CR after initial CT.

Adolescent↗
PubMed1993

Pediatric stage IV Hodgkin disease. Long-term survival.

BACKGROUND: The optimal treatment for Stage IV Hodgkin disease (HD) remains uncertain, particularly the role of radiation therapy (RT). METHODS: A retrospective review of 43 children, 18 years of age or younger, who were seen and treated for Stage IV HD between June 1970 and June 1988, was performed. All patients were treated with combination chemotherapy (CT), and 20 patients received RT after CT (combined-modality therapy, CMT). CT consisted of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) in 41 patients and both MOPP and doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH), bleomycin, vinblastine, and dacarbazine in two patients. RT was added for patients who had a partial response (PR) to CT (n = 11) and/or for initial bulky thoracic disease (n = 12). RESULTS: With a median follow-up of 83 months, the 7-year actuarial freedom from progression (FFP) and survival rates for all patients were 69% and 78%, respectively. For patients achieving a complete response (CR) to CT, the 7-year FFP rate was 73% and for patients with a PR it was 90% (P value not significant). The actuarial overall survival rates at 7 years were 88% for patients with CR versus 80% for patients with PR. In contrast, patients with either no response (one patient) or progressive disease (four patients) after CT had a significantly worse prognosis than patients with CR, with a 7-year actuarial survival rate of 40% (P = 0.006). FFP after CT alone was significantly more prevalent in patients with Stage IVA (11 of 13 patients) than in patients with Stage IVB disease (2 of 10 patients; P = 0.003). For these symptomatic patients, failures were almost exclusively (seven of eight patients) in sites of initial nodal disease. The addition of adjuvant RT improved the progression-free survival for patients with B symptoms: 2 of 13 patients had relapses after CMT versus 8 of 10 patients treated with CT alone (P = 0.003). CONCLUSIONS: This retrospective analysis of MOPP alone compared with MOPP plus RT showed a significant difference in FFP in patients with Stage IVB HD favoring CMT.

Adolescent↗
PubMed1993

Prognostic factors for patients with Hodgkin disease in first relapse.

BACKGROUND: This study aims to identify factors that predict outcome after salvage therapy for patients with Hodgkin disease (HD) in first relapse. METHODS: Between 1969 and 1985, 627 patients with Pathologic Stage IA-IIIB HD were treated at the Joint Center for Radiation Therapy. With a median follow-up time for survivors of 135 months, 138 patients (22%) have experienced relapse. One hundred twenty-seven of these were retreated with curative intent and form the basis of this report. RESULTS: The complete response (CR) rate after retreatment was 79%. The 10-year actuarial freedom from second relapse (FSR) was 53%, and the 10-year survival rate from the time of first relapse was 57%. For patients experiencing relapse after initial radiation therapy (RT) alone (n = 110), the 10-year FSR and overall survival rates were 58% and 62%, respectively. Histologic type was the single most important prognostic factor for second CR rate, FSR, and survival. Patients with nodular sclerosis or lymphocyte predominant (NS/LP) histologic type had a 91% second CR rate, 67% 10-year FSR rate, and 75% 10-year survival rate, compared with 66%, 44%, and 43%, respectively, for patients with mixed cellularity or lymphocyte depleted (MC/LD) histologic type. For patients who experienced relapse after initial combined modality therapy (CMT; n = 17), the 10-year FSR and overall survival rates were 13% and 24%, respectively. CONCLUSION: This study demonstrates that patients who experience relapse after RT alone can be effectively salvaged with combination chemotherapy. The implications of these results for clinical decision making are discussed.

Adult↗
PubMed1993

Rapid redistribution of teboroxime.

Teboroxime, a new technetium-99m-labeled myocardial perfusion tracer, possesses rapid myocardial kinetics. Whereas this agent is routinely imaged after separate stress and rest injections, experimental data suggest that teboroxime may rapidly redistribute in the myocardium. Accordingly, we assessed 68 exercise teboroxime scintigrams in which immediate poststress, early delay (5 minutes) and rest images were acquired. Studies were categorized visually as ischemia, infarct or normal based on conventional stress-rest comparison. They were then evaluated for rapid teboroxime redistribution by comparing the stress and early delay images. Quantitative analysis was then performed on 537 myocardial segments. Segments were grouped as ischemia, infarct or normal based on stress-rest comparison, and the degree of normalization of stress-induced defects in the early delay images was determined for each group. Rapid teboroxime redistribution was observed in 20 of 46 scintigrams (48%) considered ischemic, and in 2 of 7 and 2 of 15 scintigrams deemed infarct and normal, respectively. The mean segmental intensity ratio (defined relative to the opposite segment) improved from 0.79 at stress to 0.88 at early delay (p < 0.005) in the group with ischemia and from 0.83 to 0.87 in the group with infarction. The most likely explanation for rapid redistribution of teboroxime is differential washout from the myocardium between areas of disparate flow. It is concluded that rapid redistribution of teboroxime occurs within 5 minutes of a stress injection, giving rise to potentially useful clinical information. Thus, teboroxime imaging should be completed expeditiously to detect areas of relative hypoperfusion.

Exercise Test↗
PubMed1993

Comparison of teboroxime and thallium for the reversibility of exercise-induced myocardial perfusion defects.

To determine the optimal technique for the scintigraphic detection of exercise-induced myocardial perfusion defects, we compared teboroxime scanning to both stress/redistribution thallium imaging and the thallium reinjection method following exercise in 35 patients. The overall concordance for the presence of a perfusion defect between teboroxime and thallium scanning was 91% (p < 0.01) and 89% when teboroxime was compared with stress/reinjection thallium imaging (p < 0.01). More segments per scan with fixed defects were observed with redistribution imaging than with teboroxime or thallium reinjection (2.9 vs 2.0 vs 1.9; p < 0.02). Additionally, more transient defects were present with teboroxime than thallium, but less than with reinjection imaging. One half of the 52 fixed perfusion abnormalities on stress/redistribution thallium imaging demonstrated reversibility with both teboroxime imaging and thallium reinjection scanning, but less than 50% of these segments were concordant. Teboroxime allows for improved detection of reversible perfusion defects compared with stress/redistribution thallium scanning, but more ischemia is noted with thallium reinjection. The variation in the detection of segmental ischemic defects between teboroxime scintigraphy and thallium reinjection scanning probably reflects different physiologic properties and imaging protocols of these perfusion agents.

Aged↗
PubMed1993

Effect of triphenyl tetrazolium chloride staining on the distribution of radiolabeled pharmaceuticals.

Myocardial tissue is routinely exposed to the vital stain triphenyl tetrazolium chloride (TTC) to delineate infarction in conjunction with myocardial isotope research. However, it is unknown whether TTC has a direct effect on tracer deposition. We evaluated this possibility in rabbit hearts injected with either teboroxime, sestamibi or 201Tl. The hearts were excised and treated as follows: (1) TTC or normal saline was perfused through the heart and the residual activity monitored; (2) hearts were sliced into 0.5-cm thick sections, counted and incubated in either TTC or normal saline for 10 min then recounted; and (3) the circumflex artery was ligated postmortem and TTC perfused. Autoradiographic images were produced from 30-microns slices to depict any disparity in activity concentration from the selective perfusion of TTC. Both perfusion and incubation by TTC resulted in a significant activity loss of both 201Tl and sestamibi, but not teboroxime, compared to normal saline. An independent octanol extraction experiment measured the change in the partition coefficient of labeled teboroxime and sestamibi induced by the addition of TTC. TTC was shown to liberate the radiolabel from sestamibi, but not from teboroxime. We conclude that histochemical staining techniques involving TTC can alter the distribution of radiolabeled pharmaceuticals. As a result, experiments using TTC with 201Tl and sestamibi should be interpreted cautiously.

Animals↗
PubMed1993

Teboroxime, sestamibi and thallium-201 as markers of myocardial hypoperfusion: comparison by quantitative dual-isotope autoradiography in rabbits.

The scintigraphic assessment of myocardial hypoperfusion depends on the ability of imaging agents to delineate flow disparities. Accordingly, we compared the differential uptake of teboroxime, sestamibi and 201Tl in normal and hypoperfused myocardium using quantitative dual isotope autoradiography. Rabbits with acute coronary occlusions (n = 29) received dual isotope injections of teboroxime 201Tl or sestamibi 201Tl or single isotope tracer injections. A group of sham-operated controls (n = 15) received teboroxime and/or 201Tl. Multiple 30-mu short axis slices were collected from each heart and mounted on x-ray film along with tissue standards to independently generate separate 99mTc and 201Tl autoradiographs. Teboroxime and sestamibi produced greater normal-to-defect activity contrast than 201Tl in each dual isotope heart (range 8.4-48.9 [teboroxime] versus 2.6-12.3 [201Tl], p < 0.02 and 4.5-10.4 [sestamibi] versus 3.6-7.3 [201Tl], p < 0.03). Similar profiles were obtained in the single isotope hearts. Teboroxime produced larger autoradiographic defects than 201Tl in the dual-isotope hearts [16.0% +/- 5.6% (teboroxime) versus 12.9% +/- 5.3% (201Tl) of the LV, p < 0.02]. We conclude that the 99mTc-based perfusion agents teboroxime and, to a lesser extent, sestamibi, delineate hypoperfused myocardium more clearly than 201Tl. Teboroxime detects the largest area of hypoperfusion and may provide the most accurate assessment of myocardium at risk.

Animals↗
PubMed1992

On the use of the transmembrane domain of bacteriorhodopsin as a template for modeling the three-dimensional structure of guanine nucleotide-binding regulatory protein-coupled receptors.

The molecular architecture of bacteriorhodopsin (BR) is commonly regarded as a structural template for the three-dimensional structure of membrane receptors that are functionally coupled to guanine nucleotide-binding regulatory proteins (GPCR). More recently, specific molecular models of such GPCR were constructed on the basis of the functional and structural relation of rhodopsin to BR as well as the sequence homology between rhodopsin and the GPCR. Such models of GPCR leave unresolved the difficulty caused by the apparent lack of any significant degree of sequence homology between the seven transmembrane helices (TMH) of BR and the portions in the sequence of the various GPCR that are considered to constitute their transmembrane domains. Evolutionary arguments offered in favor of the structural relation between BR and the opsins, and hence the GPCR, prompted our investigation of the possibility that the sequence homology, including any similarity in the distribution of kink-inducing proline residues among the helices, might have been obscured by the assumption that the TMH maintained their sequential order from BR in the evolution of the mammalian proteins. With a definition of the TMH in the neurotransmitter GPCR guided by hydropathicity predictions, and additional criteria used to define the span of each helix, optimal alignment of each pair of sequences was determined with no gaps allowed in the matching. The resulting alignment proposed here reveals considerable homology between the TMH in BR and those in GPCR, if the sequential order of the helices is ignored. These findings suggest the possibility that exon shuffling could have occurred in the proposed evolution of the GPCR gene from BR and point to a modification of the BR template to account for the correct packing of the helices in the tertiary structures of GPCR. These findings could guide the construction of three-dimensional models of the neurotransmitter GPCR on the basis of specific interhelical interactions observed in BR.

Amino Acid Sequence↗
PubMed1992

Analysis and refinement of criteria for predicting the structure and relative orientations of transmembranal helical domains.

We are interested in modeling the membrane-spanning domain of the serotonin 5-HT1A G-protein coupled receptor. This superfamily of proteins is predicted to share the topology of the seven transmembrane helices of bacteriorhodopsin (BR), even though no significant sequence homology had been identified. We found significant homologies by allowing for helix shuffling corresponding to minimal exon shuffling during evolution. Consequently, our strategy for building the model for the 5-HT1A receptor has been to construct hypotheses concerning helix-helix interactions, their orientations, and arrangement in bundles surrounded by lipid, based on the 3.5 A resolution structure of BR. Inferences resulting from such models were tested against the 2.3 A resolution structure of the photosynthetic reaction center (PRC) from Rhodobacter Viridis. These comparisons led us to a reevaluation of current methods for the identification and topological orientation of membrane-embedded alpha-helices. We find that methods used currently in the construction of helical transmembrane domains could be misleading if used indiscriminately. These methods include the hydrophobicity profile, the hydrophobic moment, helix amphiphilicity, and charge neutralization. A refinement is proposed here, based on empirical observations, molecular modeling, and physicochemical considerations designed to overcome some of the shortcomings inherent in the use of the above mentioned methods. Here we present the analysis of two of the motifs identified in our study that led to the proposed refinements: the distribution of acidic and basic residues in the transmembranal domains, and the kink induced by a Pro residue in an alpha-helix.

Amino Acids, Diamino↗