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Biomedical subjects

J Abramson

Publications and source records attributed to J Abramson.

At least 19 recordsLinked to original sources

Regulation of mast cell secretory response to the type I Fcepsilon receptor: inhibitory elements and desensitization.

While the current understanding of the stimulus-response coupling networks triggered by the multi-chain immune-recognition receptors (MIRRs) has markedly advanced, knowledge of its control mechanisms is only emerging. Regulation of the secretory response of mast cells to the stimulus provided by the type I Fcepsilon receptor (FcepsilonRI) is our topic of interest. Several mast cell membrane receptors capable of inhibiting both immediate and late responses have so far been identified. However, their ligands and mechanism(s) of operation are only partly known. Moreover, desensitization of mast cells' response to the FcepsilonRI, a well-known and widespread control process of many neural or hormone receptors, is hardly understood in this case. In this brief report we describe results of recent experiments in which we studied both of these aspects of mast cells' response to the FcepsilonRI stimulus by an inhibitory receptor MAFA, as well as those where we have established that these cells are susceptible to physiological modes of FcepsilonRI desensitization caused by prolonged exposure to sub-threshold concentrations of FcepsilonRI clustering agents.

Animals↗

The epidemiology and control of anaemia among pre-ESRD patients with chronic kidney disease.

Anaemia is a common condition among pre-end-stage renal disease (pre-ESRD) patients with chronic kidney disease (CKD). Indeed, data from clinical studies indicate that anaemia may be present in as many as two-thirds of such patients. Use of recombinant human erythropoietin (EPO) provides an effective means of correcting anaemia in CKD patients and helps to reduce the risk of renal disease progression and related problems. Unfortunately, EPO therapy is underutilized in these persons. Consequently, anaemia remains a major problem in the pre-ESRD CKD population. Evidence suggests that anaemia in the presence of CKD can lead to an increased risk of a number of adverse outcomes, including mortality, progression of kidney disease, coronary heart disease, stroke, hospitalization, and decreases in quality of life. Anaemia's association with these adverse outcomes suggests that effective treatment of anaemia in pre-ESRD CKD patients is of great importance and that substantial efforts should be made to ensure that these patients receive appropriate therapy to correct anaemia.

Anemia↗

SH2 domain-containing inositol polyphosphate 5'-phosphatase is the main mediator of the inhibitory action of the mast cell function-associated antigen.

The mast cell function-associated Ag (MAFA) is a type II membrane glycoprotein originally found on the plasma membrane of rat mucosal-type mast cells (RBL-2H3 line). A C-type lectin domain and an immunoreceptor tyrosine-based inhibitory motif (ITIM) are located in the extracellular and intracellular domains of MAFA, respectively. MAFA clustering has previously been shown to suppress the secretory response of these cells to the FcepsilonRI stimulus. Here we show that the tyrosine of the ITIM undergoes phosphorylation, on MAFA clustering, that is markedly enhanced on pervanadate treatment of the cells. Furthermore, the Src homology 3 domain of the protein tyrosine kinase Lyn binds directly to a peptide containing nonphosphorylated MAFA ITIM and PAAP motif. Results of both in vitro and in vivo experiments suggest that Lyn is probably responsible for this ITIM phosphorylation, which increases the Src homology domain 2 (SH2) affinity of Lyn for the peptide. In vitro measurements established that tyrosine-phosphorylated MAFA ITIM peptides also bind the SH2 domains of inositol 5'-phosphatase (SHIP) as well as protein tyrosine phosphatase-2. However, the former single domain is bound 8-fold stronger than both of the latter. Further support for the role of SHIP in the action of MAFA stems from in vivo experiments in which tyrosine-phosphorylated MAFA was found to bind primarily SHIP. In RBL-2H3 cells overexpressing wild-type SHIP, MAFA clustering causes markedly stronger inhibition of the secretory response than in control cells expressing normal SHIP levels or cells overexpressing either wild-type protein tyrosine phosphatase-2 or its dominant negative form. In contrast, on overexpression of the SH2 domain of SHIP, the inhibitory action of MAFA is essentially abolished. Taken together, these results suggest that SHIP is the primary enzyme responsible for mediating the inhibition by MAFA of RBL-2H3 cell response to the FcepsilonRI stimulus.

Amino Acid Sequence↗

Pulse pressure and risk of cardiovascular events in the systolic hypertension in the elderly program.

Pulse pressure has been related to higher risk of cardiovascular events in older persons. Isolated systolic hypertension is common among the elderly and is accompanied by elevated pulse pressure. Treatment of isolated systolic hypertension may further increase pulse pressure if diastolic pressure is lowered to a greater extent than systolic pressure. Little is known regarding pulse pressure as a predictor of cardiovascular outcomes in elderly persons with isolated systolic hypertension, and the influence of treatment on the pulse pressure effect. We assessed the relation between pulse pressure, measured throughout the follow-up period, and the incidence of coronary heart disease (CHD), heart failure (HF), and stroke in 4,632 participants in the Systolic Hypertension in the Elderly Program, a 5-year randomized, placebo-controlled clinical trial of treatment of isolated systolic hypertension in older adults. In the treatment group, a 10-mm Hg increase in pulse pressure was associated with a statistically significant 32% increase in risk of HF and a 24% increase in risk of stroke after controlling for systolic blood pressure and other known risk factors, as well as with a 23% increase in risk of HF and a 19% increase in risk of stroke after controlling for diastolic blood pressure and other risk factors. Pulse pressure was not significantly associated with HF or stroke in the placebo group, nor with incidence of CHD in either the placebo or treatment group. These results suggest that pulse pressure is a useful marker of risk for HF and stroke among older adults being treated for isolated systolic hypertension.

Aged↗

Depression and risk of heart failure among older persons with isolated systolic hypertension.

BACKGROUND: Investigators have shown that depression is associated with an increased risk of coronary heart disease in general and myocardial infarction in particular. However, it is unknown whether depression, independent of its association with myocardial infarction, is a risk factor for heart failure. METHODS: This study examined whether depression was a predictor of incident heart failure among 4538 persons aged 60 years and older with isolated systolic hypertension who were enrolled in the Systolic Hypertension in the Elderly Program (SHEP). Depression was defined as a score of 16 or more at baseline on the Center for Epidemiological Studies Depression Scale (CES-D). The relationship between depression and heart failure was assessed using Cox proportional hazards regression. RESULTS: The average follow-up was 4.5 years. Heart failure developed in 138 (3.2%) of 4317 nondepressed persons and in 18 (8.1%) of 221 depressed persons. After controlling for age; sex; race; history of myocardial infarction, diabetes, or angina; blood pressure; cholesterol levels; electrocardiographic abnormalities; smoking; disability; and SHEP treatment group, depressed persons had more than a 2-fold higher risk of developing heart failure compared with nondepressed persons (hazard ratio, 2.59; 95% confidence interval, 1.57-4.27; P<.001). After additional adjustment for the occurrence of myocardial infarction during follow-up, depressed persons remained at elevated risk of heart failure (hazard ratio, 2.82; 95% confidence interval, 1.71-4.67; P<.001). CONCLUSIONS: Depression is independently associated with a substantial increase in the risk of heart failure among older persons with isolated systolic hypertension. This association does not appear to be mediated by myocardial infarction.

Aged↗

Structure of cytochrome c oxidase: a comparison of the bacterial and mitochondrial enzymes.

It has been almost 5 years since the first structures of cytochrome c oxidase, from Paracoccus denitrificans and bovine heart mitochondria, were revealed. Since then many different proton pumping mechanisms have been proposed for the enzyme; however, no definitive conclusion has been achieved. In this article, we revisit the original structures of bacterial and mitochondrial oxidases and try to clarify similarities as well as differences between the two structures.

Animals↗

Depressive symptoms and risk of functional decline and death in patients with heart failure.

OBJECTIVES: We sought to examine whether depressive symptoms are associated with poorer prognosis in patients with heart failure. BACKGROUND: Depression is an established risk factor for poor outcome in patients with coronary heart disease (CHD). Little is known of its role in patients with heart failure. METHODS: We prospectively followed 391 patients > or =50 years of age who met criteria for decompensated heart failure on hospital admission. The outcome of the study was death or decline in activities of daily living (ADL) at six months, relative to baseline. Depressive symptoms were measured at baseline by means of the Geriatric Depression Scale, Short-Form, with 6 to 7 symptoms, 8 to 10 symptoms and > or =11 symptoms indicating mild, moderate and severe levels of depressive symptoms, respectively. RESULTS: There was a strong and graded association between the severity of depressive symptoms at baseline and the rate of the combined end point of either functional decline or death at six months. After adjustment for demographic factors, medical history, baseline functional status and clinical severity, patients with > or =11 depressive symptoms, compared with those with <6 depressive symptoms, had an 82% higher risk of either functional decline or death, whereas the intermediate levels of depressive symptoms showed intermediate risk (p = 0.003 for trend). A similar graded association was found for functional decline and death separately; however, after multivariate analysis, the association with mortality was less strong and no longer statistically significant. CONCLUSIONS: An increasing number of depressive symptoms is a negative prognostic factor for patients with heart failure, just as it is for patients with CHD.

Aged↗

Hematopoietic stem cell transplantation for Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry.

The Diamond Blackfan Anemia (DBA) Registry of North America is a detailed database of patients with DBA from the United States and Canada. To date, 354 patients have been registered. From this database an analysis of the outcome of hematopoietic stem cell transplantation for DBA was undertaken. Of the 20 transplanted patients who met criteria for the diagnosis of DBA, eight underwent an allogeneic HLA-matched sibling hematopoietic stem cell transplant (SCT) and 12 an alternative donor SCT. The median age at transplant for all patients was 6 years 2 months; 3 years 10 months vs 9 years 1 month for HLA-matched sibling and alternative donor SCT, respectively. All of the HLA-matched sibling transplants were done using a non-irradiation-containing regimen, whereas the majority of alternative donor transplants were performed using total body irradiation. The survival for HLA-matched sibling vsalternative donor transplant was 87.5% +/- 11.7% vs 14.1% +/- 12.1% at greater than 5 years from SCT (P = 0.015). The use of HLA-matched sibling SCT should be considered for all patients with suitable donors. However, alternative donor SCT in DBA must be approached cautiously, the potential for severe aplastic anemia (SAA) or hematopoietic malignancy not withstanding.

Adolescent↗

Thyroid antibodies and fetal loss: an evolving story.

This article reviews the literature on thyroid antibodies and miscarriage. In 1990, in a study designed to determine the incidence and etiology of postpartum thyroiditis, a serendipitous finding emerged revealing an association between thyroid antibodies and spontaneous miscarriage. Subsequently, four other studies, performed on three different continents, have confirmed the correlation. Six studies have evaluated the relationship between thyroid antibodies and recurrent abortion, defined as three or more spontaneous miscarriages. The majority of the studies (67%) reported a statistically significant increase in the incidence of thyroid antibodies in the recurrent abortion group as compared to controls. Four intervention trials have evaluated the impact of immunosuppressive therapy in women with thyroid antibodies. Although all of the trials revealed a decrease in the incidence of recurrent abortion, each study was limited by methodological concerns. A recently developed murine model of pregnancy has also demonstrated increased fetal loss in female mice immunized with thyroglobulin when mated with allogeneic males. The implications of these data generated over the last decade are discussed.

Abortion, Habitual↗

Fusion protein approach to improve the crystal quality of cytochrome bo(3) ubiquinol oxidase from Escherichia coli.

Crystals of cytochrome bo(3) ubiquinol oxidase from E. coli diffract X-rays to 3.5 A and the structure determination is in progress. The limiting factor to the elucidation of the structural detail is the quality of the crystals; the diffraction spots from the crystals are diffused which leads to difficulties in processing the data beyond 4.0 A. Weak protein-protein contacts within the crystal lattice is assumed to be the cause of this problem. To improve these contacts, we have introduced protein Z to the C-terminal end of the subunit IV of cytochrome bo(3) and expressed both proteins as a single fusion. We have successfully obtained crystals of this fusion protein. The spot shape problem has clearly been solved in the crystals of the fusion protein although further optimization is necessary to obtain higher resolution. We also discuss the potential applications of this approach to the crystallization of membrane proteins in general.

Bacterial Proteins↗

Affinity partitioning of a poly(histidine)-tagged integral membrane protein, cytochrome bo3 ubiquinol oxidase, in a detergent--polymer aqueous two-phase system containing metal-chelating polymer.

A system has been developed for selective partitioning of membrane proteins. For the first time, an integral membrane protein, cytochrome bo3 ubiquinol oxidase from Escherichia coli, has been affinity partitioned in an aqueous two-phase system. The systems used were different detergent/polymer aqueous two-phase systems containing a metal-chelating polymer, such as poly(ethyleneglycol)-iminodiacetic acid-Cu(II) as well as dextran-iminodiacetic acid-Cu(II). Many non-ionic detergents, such as alkyl(polyethyleneoxide) (CmEOn), Triton, Tween and alkylglucosides, form two-phase systems in mixture with polymers, such as dextran and poly(ethyleneglycol), i.e., a micelle-enriched phase in equilibrium with a polymer-enriched phase are formed. In general, membrane proteins partition strongly to the micelle phase. We show that it is possible to selectively partition a poly(histidine)-tagged integral membrane protein into the polymer phase by metal affinity partitioning, with a shift in the partitioning coefficient from 0.015 to 4.8 (300-fold). The affinity partitioning was characterized and the effects of ligand concentration, pH, time, salts, buffer type, imidazole and charged detergent are discussed. Thus, a fast and mild affinity procedure for the purification of integral membrane proteins can be developed in affinity detergent/polymer aqueous two-phase systems, and the method is especially suitable for the purification of labile integral membrane proteins, such as receptors.

Chelating Agents↗

The structure of the ubiquinol oxidase from Escherichia coli and its ubiquinone binding site.

Cell respiration is catalyzed by the heme-copper oxidase superfamily of enzymes, which comprises cytochrome c and ubiquinol oxidases. These membrane proteins utilize different electron donors through dissimilar access mechanisms. We report here the first structure of a ubiquinol oxidase, cytochrome bo3, from Escherichia coli. The overall structure of the enzyme is similar to those of cytochrome c oxidases; however, the membrane-spanning region of subunit I contains a cluster of polar residues exposed to the interior of the lipid bilayer that is not present in the cytochrome c oxidase. Mutagenesis studies on these residues strongly suggest that this region forms a quinone binding site. A sequence comparison of this region with known quinone binding sites in other membrane proteins shows remarkable similarities. In light of these findings we suggest specific roles for these polar residues in electron and proton transfer in ubiquinol oxidase.

Amino Acid Sequence↗

Purification, crystallization and preliminary crystallographic studies of an integral membrane protein, cytochrome bo3 ubiquinol oxidase from Escherichia coli.

Cytochrome bo(3) ubiquinol oxidase has been successfully purified for crystallization. Single crystals of this integral membrane protein diffract X-rays to 3.5 A resolution and belong to the orthorhombic space group C222(1). From the diffraction data, the unit-cell parameters were determined to be a = 91.3, b = 370.3, c = 232.4 A. The crystals have a solvent content of 59% and contain two molecules per asymmetric unit. A search model generated from the structures of cytochrome c oxidase from Paracoccus denitrificans and the extrinsic domain of cytochrome bo(3) ubiquinol oxidase from Escherichia coli was used for molecular-replacement studies, resulting in a solution with sensible molecular packing.

Crystallization↗

Space proton flux and the temporal distribution of cardiovascular deaths.

The influence of solar activity (SA) and geomagnetic activity (GMA) on human homeostasis has long been investigated. The aim of the present study was to analyse the relationship between monthly proton flux (> 90 MeV) and other SA and GMA parameters and between proton flux and temporal (monthly) distribution of total and cardiovascular-related deaths. The data from 180 months (1974-1989) of distribution in the Beilinson Campus of the Rabin Medical Centre, Israel, and of 108 months (1983-1991) from the Kaunas Medical Academy, were analysed and compared with SA, GMA and space proton flux (> 90 MeV). It was concluded: (1) monthly levels of SA, GMA and radiowave propagation (Fof2) are significantly and adversely correlated with monthly space proton flux (> 90 MeV); (2) medical-biological phenomena that increase during periods of low solar and/or geomagnetic activity may be stimulated by physical processes provoked by the concomitant increase in proton flux; (3) the monthly number of deaths related (positively or negatively) to SA are significantly and adversely related to the space proton flux (> 90 MeV).

Adult↗

Ocular manifestations of systemic infection.

Increased research and awareness of various systemic infections places a greater emphasis on the ophthalmologist's knowledge of ocular manifestations of these diseases. New advances in the diagnosis and treatment, as well as studies of the pathogenesis and histological features of different infectious processes are continually being reported. Recent publications focusing on ophthalmic findings of infectious diseases are reviewed. This article discusses new reports on herpes simplex, herpes zoster, Lyme disease, malaria, onchocerciasis, cysticercosis, and toxocariasis.

Eye Infections, Bacterial↗

The first report of familial adult T-cell leukemia lymphoma in the United States.

Two patients, a daughter and her father, developed the acute type of adult T-cell leukemia/lymphoma (ATLL) within a 3-month period. Antibodies against HTLV-I have been found in both wives of the father. The second wife acquired the infection from her husband within 3 years of marriage. The patients described represent the first cases of familial ATLL in the United States. ATLL continues to be frequently misdiagnosed in the United States. A positive family history consistent with this disease in a patient with a lymphoid malignancy may be a helpful clue for earlier diagnosis.

Adult↗

A new chromosomal abnormality in a patient with acute myelomonocytic leukemia.

A new chromosomal abnormality is being presented in a patient with acute myelomonocytic leukemia (AMMoL). The cytogenetic findings in this case can be described as 43, XY, t(12;17) (q12;p13), del (4) (q31), -5,-7. This patient developed a treatment-associated leukemia. The possible causal and clinical implications in such patients with unusual cytogenetic findings are stressed. In addition, basic biological as well as public health implications are discussed which are based on particular cytogenetic abnormalities.

Aged↗

Chromosomal abnormalities in adult T-cell leukemia/lymphoma (ATL). A report of six cases with review of the literature.

Chromosomal studies were performed on six patients with adult T-cell leukemia (ATL). Structural abnormalities of chromosome 3 were the most common. In one case a complete loss of the short arm of chromosome 10 (10 p-) was noted while in another case a balanced translocation involving chromosome 10p and 4q was found. These abnormalities have not been previously reported. After reviewing the literature, it was concluded that chromosomes 3, 6, 10, 13, 14, and X were most frequently involved in abnormalities. Specific and consistent chromosomal abnormalities were noted in each study. Therefore, it is hypothesised that the mutation rate for this virus may be higher than first expected. Furthermore, the relative consistency of heterogeneous findings in different localities may reflect a geographic clustering of specific chromosomal abnormalities which may in turn be related to specific and geographically associated viral mutations. To support these suggestions not only are more cytogenetic data required but a molecular evaluation of these patients must be carried out to establish a relationship, if any, between genetic abnormalities and the epidemiology of ATL.

Adult↗