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Biomedical subjects

H Weinstein

Publications and source records attributed to H Weinstein.

At least 91 records · Page 5Linked to original sources
PubMed1992

Planar myocardial perfusion imaging with technetium-99m-teboroxime: comparison by vascular territory with thallium-201 and coronary angiography.

Myocardial perfusion agents labeled with 99mTc offer improved physical imaging properties compared to 201TI. Teboroxime is a new 99mTc-labeled compound for myocardial perfusion imaging that shows a high myocardial extraction and rapid clearance. Sixty-seven patients underwent planar teboroxime imaging with a rapid acquisition protocol. Agreement of teboroxime and 201TI for the presence or absence of disease occurred in 56/65 patients (86%). There was agreement (normal or abnormal) between the two agents in 156/195 vessels (80%) and 457/585 segments (78%). When abnormal segments (ischemia or infarction) were compared, teboroxime showed significantly more ischemic segments (89/135, 66%) than did 201TI (73/135, 54%, p < 0.05). Teboroxime offers accuracy comparable to 201TI for the diagnosis of coronary artery disease and may improve the detection of ischemic or viable myocardium. In addition, its rapid myocardial clearance permits stress/rest imaging in 60-90 min.

Coronary Angiography↗
PubMed1991

Lymphokine profile in bone marrow transplant recipients.

Immune reconstitution after bone marrow transplantation (BMT) recapitulates immune ontogeny. At birth there is an imbalance in lymphokine production, with decreased production of interferon-gamma (IFN-gamma) compared with interleukin-4 (IL-4) and IL-2. We investigated whether a similar imbalance in lymphokine production occurs in BMT recipients within 6 months after transplantation. Our results show that BMT recipients not treated with immunosuppressive drugs have a decrease in IFN-gamma production and IL-2, in comparison with IL-4. This imbalance was likely to result from impaired signal transduction through surface receptors, because it was detectable on stimulation with Concanavalin A (ConA), but was overcome completely or largely by stimulation with phorbol myristate acetate (PMA) + ionophore, which bypass surface receptors and mimic the effects of second messengers. In contrast, lymphokine production in patients treated with immunosuppressive drugs (cyclosporine A, corticosteroids) was abnormal after stimulation with PMA and ionophore, as well as ConA. Thus, treated BMT recipients exhibit an additional deficit, which affects the signaling cascade down-stream of second messenger generation and results in impaired lymphokine production.

Adult↗
PubMed1991

Structural dynamics of calmodulin and troponin C.

We present the results of computational simulation studies of the structures of calmodulin (CAM) and troponin C (TNC). Possible differences between the structures of these molecules in the crystal and in solution were suggested by results from some recent experimental studies, which implied that their conformations in solution may be more compacted than the characteristic dumbbell shape observed in the crystal. The molecular dynamics simulations were carried out with the CHARMM system of programs, and the environment was modeled with a distance-dependent dielectric permittivity and discrete water molecules surrounding the proteins at starting positions identified in the crystals of CAM and TNC. Methods of macromolecular structure analysis, including linear distance plots, distance matrices and a matrix representation of hydrogen bonding, were used to analyze the nature, the extent and the source of structural differences between the computed structures of the molecules and their conformations in the crystal. Following the longest simulation, in which intradomain structure was conserved, the crystallographically observed dumbbell structure of the molecule changed due to a kinking or bending in the region of the central tether helix connecting the two Ca(2+)-binding domains which moved into close proximity. The resulting structure correlates with experimental observations of complexes between CAM and peptides such as melittin and mastoparan. Analysis of the corresponding pair distance distribution functions in comparison to experimental results suggests the dynamic existence of a non-negligible fraction of the compacted structure in aqueous solutions of CAM. In this more nearly globular shape, CAM reveals to the environment two interior pockets that contain a number of hydrophobic residues, in agreement with NMR data suggesting involvement of such residues in the binding of inhibitors and proteins to CAM.

Calcium↗
PubMed1991

Molecular mechanisms of radiation induced DNA damage: H-abstraction and beta-cleavage.

Quantum mechanical simulations of hydrogen abstraction by hydroxyl radical from methanol and ethanol yield barriers that agree very well with those measured experimentally. Analysis of the multiconfigurational wavefunction indicates that the strength of the C-H bond is the electronic parameter that has a major contribution to the barrier for H-abstraction. Similar analysis applied to 2-deoxy-D-ribose shows that the strength of a C-H bond together with the steric accessibility of the hydrogen determine that H4 is the most susceptible hydrogen for abstraction by a hydroxyl radical. Quantum mechanical simulations of beta-cleavage show that a concerted mechanism in which a water molecule assists in the bond breaking process is more likely than a SN1 mechanism. However, the polar transition state suggests that the environment of the DNA and the surrounding water will have an important effect on the reaction.

DNA↗
PubMed1991

Molecular mechanisms of radiation induced DNA damage: H-addition to bases, direct ionization and double strand break.

Structures and properties of G.(-H) and of TH. were obtained from quantum mechanical calculations. New AMBER parameters for these radicals were obtained to fit their structures and charge distributions. Molecular mechanics simulations of the conformational changes induced in a 12-mer of DNA, d(CGCGAATTCGCG), by these radicals show that the distances between the base and the C2' of the sugar becomes shorter. Such changes suggest that the base radical can abstract the H2' and transfer the radical from the base to the sugar. Once the radical becomes centered on the sugar a strand break can follow. A simultaneous formation of guanine and thymine radicals on opposite strands may lead to a double strand break.

Base Sequence↗
PubMed1990

RAS gene mutations in childhood acute myeloid leukemia: a Pediatric Oncology Group study.

Mutations at codon 12, 13, and 61 of the HRAS, KRAS, and NRAS genes were evaluated in 99 cases of pediatric acute myeloid leukemia (AML) using oligonucleotide hybridization to polymerase chain reacted derived products. Twenty-four mutations were identified in the NRAS gene, 13 in the KRAS gene, and none in the HRAS gene. The mutations occurred in a broad spectrum of cases, and there was no specific association of RAS gene mutations with patient subsets defined on the basis of clinical or hematologic features. These data demonstrate that RAS gene mutations are at least as common in childhood AML as in adult AML and suggest that RAS gene mutations play a role in myeloid neoplasia in both age groups.

Adolescent↗
PubMed1990

Bone marrow transplantation (BMT) for the syndrome of pigmentary dilution and lymphohistiocytosis (Griscelli's syndrome).

We report the successful treatment of the syndrome of pigmentary dilution and immunodeficiency (Griscelli's syndrome) with allogeneic bone marrow transplantation. Griscelli's syndrome includes silvery hair, recurrent infections, hepatosplenomegaly, progressive neurologic deterioration, and lymphohistiocytosis and is uniformly fatal. We present a family in which four of seven children of consanguinous parents were affected. The affected children were all born with silvery hair. Microscopic examination of the hair showed large clumps of pigment in the hair shaft. Skin biopsy revealed an accumulation of melanosomes in the melanocytes. Three of the affected children were deceased before 20 months of age. Pathology of liver and lung in two of the siblings showed an infiltration of lymphocytes and histiocytes. Immunologic studies in one of these cases were notable for a decreased number of T cells and poor T-cell mitogen stimulation with concanavalin A (Con A) and pokeweed mitogen (PWM). Recently, a fourth sibling with silvery gray hair was referred to us at 3 months of age for evaluation. T-cell function studies were normal and she appeared in overall good health. Because of the expected fatal outcome, allogeneic bone marrow transplantation was performed at 4 months of age. Two years later the patient remains in excellent health. This suggests that cells of hematopoietic origin are responsible for the fatal outcome in Griscelli's syndrome and that bone marrow transplantation early in the course of the disease is an important modality for treatment of this syndrome.

Bone Marrow Transplantation↗
PubMed1990

Prognostic factors for positive surgical staging in patients with Hodgkin's disease.

Staging laparotomy was performed as part of the routine recommended diagnostic evaluation following clinical staging (CS) in 692 patients presenting with supradiaphragmatic Hodgkin's disease (HD). Various clinical factors were analyzed by multivariate analysis for prediction of abdominal involvement. Factors that were statistically significant for predicting disease below the diaphragm included CS III-IV disease (P less than .001), B symptoms (P less than .001), mixed cellularity (MC) or lymphocytic depletion (LD) histology (P = .017), number of supradiaphragmatic sites greater than or equal to 2 (P = .001), male sex (P = 0.034) and age greater than or equal to 40 years (P = .004). Separate analyses were performed for various subgroups of CS IA-IIA, CS IB-IIB, CS IIIA-IVA, and CS IIIB-IVB patients. Upstaging was seen in 0% to 55% of CS I-II patients based on subgroup. Male sex, B symptoms, and number of sites above the diaphragm greater than or equal to 2 all independently predicted for positive surgical staging in CS I-II patients. Sixty-four percent of CS I-II patients who were upstaged had extensive abdominal disease by positive lower abdominal nodes or multiple splenic nodules (greater than or equal to 5). Downstaging (to pathological stage [PS] I-II) was seen in 9% to 68% of patients with CS III-IV disease based on subgrouping. Age greater than or equal to 40, MC or LD histology, and B symptoms all independently predicted for positive surgical staging in CS III-IV patients. Downstaging was more frequently seen in CS IIIA-IVA patients (55%) than in patients who were CS III-IVB (22%). Four subgroups of patients who had a low probability (less than 10%) of stage or treatment change following laparotomy were identified. These included CS IA female patients, CS IA male patients with lymphocyte predominance histology or high neck presentations, and patients with CS IIIB-IVB disease and account for 21% of the study population. Staging laparotomy altered the stage and treatment of a significant number of the remaining 79% patients and should continue to be recommended for this group of patients.

Abdominal Neoplasms↗
PubMed1989

On the ion selectivity in Ca-binding proteins: the cyclo(-L-Pro-Gly-)3 peptide as a model.

Calcium plays a crucial role in many cellular processes. Its functions are directly dependent on the high specificity for Ca2+ exhibited by the proteins and ion carriers that bind divalent ions. To elucidate the basis for this specificity we have calculated the relative energies of solvation of calcium and magnesium ions in complexes with cyclo(-L-Pro-Gly-)3, a small synthetic peptide that binds Ca2+ with an affinity comparable to those of the naturally occurring proteins. The results show that the ion selectivity of the peptide resides in the difference in the solvation energies of the competing ions in water. Although the peptide is able to complex Mg2+ better than Ca2+ in the stoichiometries in which cyclo(-L-Pro-Gly-)3 binds divalent ions, it is not always able to provide as much stabilization for Mg2+ as water does. These results also explain why cyclo(-L-Pro-Gly-)3 binds Ca2+ and Mg2+ with different stoichiometries and indicate the source for expected differences in the structures of complexes of the two ions.

Calcium↗
PubMed1989

Stage IA-IIB Hodgkin's disease: staging and treatment of patients with large mediastinal adenopathy.

Ninety-two patients with clinically staged (CS) IA-IIB Hodgkin's disease (HD) with large mediastinal adenopathy (LMA) underwent three different staging and treatment approaches between April 1969 and December 1984. These approaches included: (1) staging laparotomy followed by radiation therapy (RT) alone; (2) staging laparotomy followed by combined RT and chemotherapy (CMT); or (3) clinical staging followed by CMT. Patients treated with CMT were more likely to have "B" symptoms, extension into extranodal sites, or stage III disease. Patients treated with RT alone had a significantly higher risk of relapse as compared to patients receiving CMT. No overall survival differences were seen between the three groups of patients. For patients treated with CMT without RT to the spleen or abdominal nodes, the risk of relapse in the abdomen was low (4%). These data suggest that for those CS I-II HD patients with LMA who are treated with CMT, the role for staging laparotomy and abdominal irradiation is limited. RT alone remains an option for some patients with LMA, but careful assessment of the anatomic extent of thoracic disease as well as staging laparotomy is essential if such treatment is recommended.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

A metactoid sensitization model to describe multiple receptors linked to a common response: application to histamine receptors coupled to [3H]cyclic AMP accumulation in guinea pig cortex.

A metactoid sensitization model was developed to describe and resolve the activities of different receptor subtypes coupled to second messenger interactions. The model was formulated for a system in which activation of one receptor potentiates the measured response to activation of another receptor but does not produce the same direct response on its own. For a case in which both direct and indirect components of the response could be activated by the same agonist, simulations based on the model reveal that the overall agonist EC50 of the measured response cannot be less than the EC50 of the direct response. Unless the indirect receptor is fully activated before agonist occupancy of the direct receptor, the EC50 of the overall response must be greater than the EC50 at the direct receptor. Inhibition of the response by antagonists acting at the direct receptor may not reveal the indirect component, even if the entire response is dependent on simultaneous activation of both receptors. The pattern of inhibition seen with competitive antagonists acting at the indirect receptor would be critically dependent on the difference between agonist affinities for its two receptors. These conditions may thus lead to the misclassification of the receptors through conventional pharmacological techniques. The model was applied to pharmacological data of histamine (HA)-stimulated [3H]cAMP accumulation in a vesicular preparation of guinea pig cerebral cortex. In this system, H1 receptors potentiate the [3H]cAMP response to H2 and/or adenosine receptor activation but have no measurable effect alone. Fitted HA EC50 values at both H1 and H2 receptors agreed well with independent experimental observations in this system. Values were similar in both the presence and absence of an interaction between the response to adenosine and the action of HA on H1 receptors. Similarly, affinity constants for both types of HA receptor antagonists, determined from fitting the pharmacological data to this model, were in agreement with literature values for these drugs. Thus, the metactoid sensitization model adequately describes this system, predicts the experimental data, and indicates experimental conditions for further testing and refinement of the model.

Adenosine↗