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Biomedical subjects

M R Gold

Publications and source records attributed to M R Gold.

At least 163 records · Page 9Linked to original sources
PubMed1991

Barriers to cholesterol testing in a rural community.

BACKGROUND: The purpose of this study was to investigate the factors that determine whether residents in a rural community have their cholesterol tested. METHODS: A population-based survey was conducted in 1987 as part of a community-oriented primary care project that sought to define and address the causes of and burden caused by increased cardiovascular disease in an economically depressed agricultural region of New York. All of the residents living in two towns in the region who were over 16 years of age and who lived in their homes year-round were surveyed. Demographic information was obtained from the participants, as well as information about previous cholesterol testing and their cardiovascular-risk knowledge and behaviors. The serum cholesterol of each participant was measured. RESULTS: Of the 557 households contacted, 508 (91%) households participated. A total of 1063 persons over 16 years of age were surveyed, and 973 (92%) were screened for cholesterol. Overall, 24% reported prior cholesterol testing. Logistic regression analysis identified several independent factors that were associated with a reduced likelihood of ever having had a cholesterol test. These factors included: (1) age under 45 years, (2) having less than 12 years of education, (3) having an income of less than $10,000, (4) not having health insurance, (5) not having visited a physician within the previous year, and (6) practicing three or more high-risk cardiovascular behaviors. The participants' cardiovascular knowledge made no independent contribution to having had their cholesterol levels tested. CONCLUSIONS: Many of the factors that prevent cholesterol testing are socially determined. The results of this study suggest that financial and social barriers are two of the major obstacles to residents of rural communities having their cholesterol levels tested.

Adolescent↗
PubMed1990

Stimulation of protein tyrosine phosphorylation by the B-lymphocyte antigen receptor.

Signalling by membrane immunoglobulin, the B-lymphocyte antigen receptor, regulates B-cell maturation and activation. Crosslinking of membrane immunoglobulin by antigen or by anti-immunoglobulin antibodies inactivates immature B cells, eliminating many of the B cells capable of producing auto-antibodies. By contrast, crosslinking of membrane immunoglobulin promotes activation of mature B cells for clonal expansion and antibody production against foreign antigens. Crosslinking membrane IgM on the immature B-cell line WEHI-231 induces growth arrest. This response may be analogous to the deletion or inactivation of immature B cells that is induced by antigen or anti-IgM antibodies. Membrane immunoglobulin crosslinking stimulates phosphoinositide hydrolysis, which leads to increases in intracellular calcium and activation of protein kinase C. The induced phosphoinositide breakdown is important for inhibiting WEHI-231 growth (ref. 7 and D. Page, M.R.G., K. Fahey, L. Matsuuchi and A.L.D., manuscript submitted for publication), but may not be sufficient, as agents that elevate calcium and activate protein kinase C cause only partial growth arrest. We now show that in both mature splenic B cells and the immature B-cell line WEHI-231 crosslinking membrane immunoglobulin also stimulates phosphorylation of protein tyrosine, a reaction that has been implicated as a key regulator of cell growth. Most of these phosphorylations were not a consequence of the phosphoinositide pathway. Thus, tyrosine phosphorylation is a second mode of transmembrane signalling by membrane immunoglobulin.

Animals↗
PubMed1990

The social origin of cardiovascular risk: an investigation in a rural community.

The effects of socioeconomic disadvantage on behavioral, psychosocial, and physiological risk factors for cardiovascular disease were investigated in an economically depressed agricultural area of New York State. After adjustment for age and sex, at least one and typically two of the three dichotomized socioeconomic factors (manual labor, lack of high school graduation, and poverty) were associated with an increased prevalence of smoking, obesity, frequent salt use, cholesterol consumption, low levels of leisure activity, and social isolation. Education and occupation also made independent contributions to systolic blood pressure. After adjustment for age, sex, behavioral, and social isolation variables, those with both risk factors (less than 12 years of school, and manual labor) had a higher mean systolic blood pressure than those with neither risk factor (9.5 mm Hg; 95 percent confidence interval = 5.5, 13.5). In contrast, after adjustment for the other variables, those with the two risk factors, less than 12 years of school and income below the poverty level, had a lower mean serum cholesterol than those with neither risk factor (11 mg/100 ml; 95 percent confidence interval = 3.1, 18.9). The policy implications of these pervasive social gradients of cardiovascular risk and the paradoxical relationship with serum cholesterol are discussed.

Cholesterol↗
PubMed1990

A community-oriented primary care project in a rural population: reducing cardiovascular risk.

A controlled community-oriented primary care (COPC) program designed to reduce cardiovascular risk was conducted in two towns in a poor, rural area of New York State that have populations with high levels of cardiovascular mortality. In both towns, house-to-house visits were used to screen for blood pressure, gather information about cardiovascular risk knowledge and behavior, and provide a cardiovascular educational program. Persons with elevated blood pressure were advised to seek follow-up. Additional interventions, carried out in the study town only, included ongoing follow-up for those with elevated blood pressure and their providers, and sliding-fee medical services for those with financial barriers to care. At rescreening 2 years later, residents of the study population had an adjusted systolic blood pressure 3.1 mm Hg lower than those in the control population (95% confidence interval [CI] = 0.9, 5.3). Furthermore, those who were screened at both rounds had an adjusted systolic blood pressure 2.7 mm Hg lower than those who had not previously been screened (95% CI = 0.6, 4.8). Although knowledge of cardiovascular risk factors increased among those who were surveyed in both rounds, there was little demonstrable effect on cardiovascular risk behaviors. Difficulties were encountered in engaging the participation of all medical providers, and less use was made of the sliding-scale program than expected. While it appears feasible to implement the technical methodology of a COPC model in a rural setting, it is crucial to engage the support of the local and medical community.

Adolescent↗
PubMed1989

Signal transduction via the B cell antigen receptor: involvement of a G protein and regulation of signaling.

The antigen receptors on B lymphocytes, membrane forms of immunoglobulins, transduce signals regulating B cell growth and differentiation by activating a phosphoinositide-specific phospholipase C. In this report, we describe our recent work aimed at understanding this process in greater detail. We have shown that a GTP-binding component is a necessary cofactor in the stimulation of phospholipase C by mIgM. This component has a number of properties in common with the G protein family of receptor-effector coupling components seen in the adenylate cyclase and other signaling systems. For example, analogues of GTP that cannot be hydrolyzed stimulated mIgM-triggered phosphoinositide breakdown, and an analogue of GDP that cannot be converted to GTP inhibited the reactions. Furthermore, aluminum fluoride, which activates known G proteins, also stimulates phosphoinositide breakdown. The G protein that appears to link mIgM to phospholipase C is not one of the well characterized G proteins involved in the regulation of adenylate cyclase or cGMP phosphodiesterase (GS, Gi, and transducin), as judged by its insensitivity to two bacterial toxins that modify these G proteins, cholera toxin and pertussis toxin. Interestingly, analysis of pertussis toxin sensitivity indicates that there are at least 2 distinct G proteins that couple receptors to phospholipase C. For example, the G protein required for chemotactic peptide receptor signaling in neutrophils is sensitive to pertussis toxin, in contrast to the phosphoinositide signaling G protein in B cells. We have also begun to explore the mechanisms by which mIgM signal transduction can be modulated. Stimulation of protein kinase C with phorbol esters or synthetic DG was found to inhibit mIgM-triggered phosphoinositide breakdown. This regulation probably represents a feedback inhibition that would occur with DG produced by phosphoinositide breakdown. Alternatively, there appear to be other signaling pathways that generate DG33, and they could possibly inhibit phosphoinositide breakdown via protein kinase C. This could be an important locus of regulation during B cell activation. For example, other signals could increase or decrease the potency of this feedback inhibition, and thereby adjust the sensitivity of the B cell to antigen. Alternatively, other agents could stimulate protein kinase C directly, or could stimulate another protein kinase which can do the same thing in this regard, and thereby make the B cell insensitive to antigen by preventing antigen receptor signaling.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenylate Cyclase Toxin↗
PubMed1987

Involvement of a guanine-nucleotide-binding component in membrane IgM-stimulated phosphoinositide breakdown.

Cross-linking of membrane immunoglobulin, the B cell receptor for antigen, activates the phosphoinositide signal transduction pathway. The initial event in this pathway is the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdInsP2) by phospholipase C. This reaction yields two intracellular second messengers, diacylglycerol, which activates protein kinase C, and inositol trisphosphate, which causes an increase in cytoplasmic Ca2+. The experiments reported here demonstrate that activation of phospholipase C by membrane IgM (mIgM) involves a guanine nucleotide-dependent step. Saponin was used to permeabilize WEHI-231 B lymphoma cells and permit direct manipulation of nucleotide and Ca2+ concentrations. Very high levels of Ca2+ (greater than 100 microM) activated the phospholipase maximally without a requirement for cross-linking of mIgM. However, at much lower, physiologically relevant Ca2+ concentrations (100 to 500 nM), receptor-stimulated PtdInsP2 hydrolysis could be demonstrated. The ability of anti-IgM antibodies to activate phospholipase C in permeabilized WEHI-231 cells was greatly increased by nonhydrolyzable guanosine 5'-triphosphate (GTP) analogues (guanosine-5'-O-(3-thiotriphosphate) or 5'-guanylylimidodiphosphate), but not by guanosine diphosphate or guanosine diphosphate analogues or by a nonhydrolyzable analogue of adenosine triphosphate. This specificity for GTP analogues is consistent with the hypothesis that a GTP-binding regulatory protein analogous to those that couple receptors to adenylate cyclase is involved in the activation of phospholipase C by mIgM in WEHI-231 B lymphoma cells. In order to characterize this putative GTP-binding component, we examined the ability of pertussis toxin and cholera toxin to affect anti-IgM-stimulated inositol phosphate production. These bacterial toxins covalently modify and modulate the activity of various GTP-binding regulatory proteins and in some cell types can block receptor-stimulated PtdInsP2 breakdown. In WEHI-231 B lymphoma cells, neither toxin blocked signaling by mIgM. Thus mIgM appears to be coupled to the phosphoinositide signaling pathway by a GTP-dependent component that is insensitive to both pertussis toxin and cholera toxin.

Adenylate Cyclase Toxin↗
PubMed1987

Phorbol esters and dioctanoylglycerol block anti-IgM-stimulated phosphoinositide hydrolysis in the murine B cell lymphoma WEHI-231.

Cross-linking of membrane IgM (mIgM) on both normal resting B cells and on the murine B cell lymphoma WEHI-231 activates the phosphoinositide signal transduction pathway. The initial event in this pathway is the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdInsP2), which results in the generation of two second-messengers: inositol trisphosphate (InsP3), which can cause the release of Ca2+ from intracellular stores, and diacylglycerol (DG), which activates protein kinase C. In examining the effects of exogenous activation of protein kinase C on WEHI-231 cells, we found that phorbol esters blocked some of the biologic effects of anti-IgM on WEHI-231 cells. The mechanism of this effect was investigated. Phorbol ester treatment of WEHI-231 cells blocked the ability of anti-IgM to stimulate production of inositol phosphates and accumulation of phosphatidic acid, the phosphorylated product of DG. Phorbol esters also blocked the ability of anti-IgM to cause an increase in intracellular Ca2+. Thus, it is clear that phorbol esters block anti-IgM-stimulated PtdInsP2 hydrolysis in WEHI-231 cells. In addition, a synthetic DG, dioctanoylglycerol (diC8), also blocked anti-IgM-stimulated inositol phosphate production and the anti-IgM-stimulated rise in cytoplasmic Ca2+. The ability of phorbol esters and diC8 to block mIgM-mediated signaling may reflect a feedback inhibition mechanism by which activated protein kinase C limits the magnitude and duration of receptor signaling.

B-Lymphocytes↗
PubMed1986

Growth regulation of the B lymphoma cell line WEHI-231 by anti-immunoglobulin, lipopolysaccharide, and other bacterial products.

The growth of WEHI-231, a murine immature B lymphoma cell line, was inhibited by anti-IgM antibodies. The inhibition of proliferation, as measured by [3H]thymidine incorporation, occurred between 16 and 28 hr after addition of anti-IgM. Moreover, the growth arrest was irreversible: cells that were cultured with anti-IgM for 18 hr and then recultured without it failed to recover the ability to proliferate, even though cells treated for up to 30 hr with anti-IgM remained viable, as measured by trypan blue exclusion. Three polyclonal B cell activators obtained from bacteria, lipopolysaccharide (LPS), peptidoglycan from Staphylococcus aureus, and gliding bacterial adjuvant from Cytophaga (GBA), were able to protect WEHI-231 cells from anti-IgM-induced growth arrest. The protection was transient, ending after approximately 56 hr. This transience was shown to be due to desensitization of the cells to the bacterial products. Interestingly, pretreatment of WEHI-231 cells with any of the bacterial products desensitized the cells to all of the bacterial products. The heterologous nature of this desensitization suggests that all three of these bacterial products may act through a common signaling pathway despite their diverse chemical natures.

Adjuvants, Immunologic↗
PubMed1985

Soluble non-cross-linked peptidoglycan polymers stimulate monocyte-macrophage inflammatory functions.

Soluble non-cross-linked peptidoglycan polymers are released by gram-positive bacteria when beta-lactam antibiotics are administered to humans. In this report, we show that this type of peptidoglycan can stimulate monocyte-macrophage functions that cause inflammation. Non-cross-linked peptidoglycan polymers from penicillin-treated Streptococcus faecium were purified and shown to stimulate the production of interleukin 1 by human monocytes and of colony-stimulating factors by a murine macrophage cell line. In addition, the release of plasminogen activator by human monocytes was inhibited by the soluble peptidoglycan. These in vitro results suggest that prolonged treatment with beta-lactam antibiotics, by causing the production of soluble peptidoglycan, may result in interleukin 1-mediated inflammatory reactions, excessive production of monocytes and granulocytes, and increased fibrin deposition.

Colony-Stimulating Factors↗
PubMed1984

Immunohistochemical localization of enkephalin- and ACTH-related substances in the pituitary of the lamprey.

The distributions of ACTH-, alpha MSH-, beta LPH-, and enkephalin-related substances were determined immunohistochemically in the pituitary of the brook lamprey, Lampetra lamotenii. an antiserum directed against the middle region of ACTH reacted chiefly with cells in the pro-adenohypophysis. An antiserum specific for alpha MSH reacted with all of the cells of the meta-adenohypophysis, but did not react with any of the middle ACTH-positive cells in the pro-adenohypophysis. Several antisera which crossreact with both beta LPH and beta-endorphin did not react with any region of the lamprey pituitary. However, an antiserum directed against gamma LPH did react with a small population of cells in the meso-adenohypophysis. This reactivity could be blocked following pre-absorption with mouse beta LPH but was not blocked by synthetic beta-endorphin (1-31). Antisera directed against either met-enkephalin or leuenkephalin reacted with fibers in the anterior neurohypophysis, cells in the pro-adenohypophysis, and all the cells of the meta-adenohypophysis. This crossreactivity could be blocked following pre-absorption with the appropriate enkephalin, but not by pre-absorption with synthetic beta-endorphin (1-31) or dynorphin (1-13). In addition, the enkephalin-like reactivity in the adenohypophysis of the lamprey was coincident with middle ACTH-like immunoreactivity in the pro-adenohypophysis and with alpha MSH-like immunoreactivity in the meta-adenohypophysis. The absence of beta LPH/beta-endorphin immunoreactivity coincident with ACTH immunoreactivity, and the presence of enkephalin-like material in the adenohypophysis are unique to the lamprey.

Adrenocorticotropic Hormone↗
PubMed1984

The discharge characteristics of vagal cardiac neurons during classically conditioned heart rate change.

Classically conditioned heart rate change in the pigeon has been developed as a vertebrate model system for cellular analysis of associative learning. One aspect of this development involved characterizing in detail the "final common path" for the conditioned response, the "cardiac motoneurons." With this as a foundation it has been possible to investigate the discharge properties of these motoneurons during acquisition of the conditioned heart rate response, and in this paper we report such data for the vagal (parasympathetic) component of the conditioned response. The activity of single neurons was recorded in the intermediate zone of the dorsal motor nucleus of the vagus of the pigeon. Antidromic activation confirmed that these cells gave rise to efferent axons in the vagus nerve and allowed their classification on the basis of conduction velocity into three groups: A, B1 (cardiac), and B2 units. B1 and B2 units had low levels of irregularly maintained activity, whereas A units discharged more regularly at higher frequency. B1 units had a weak cardiac rhythm, no respiratory rhythm, and showed decreased discharge in response to visual stimulation or foot-shock. These stimulus-evoked decreases in the activity of cardiac cells were accompanied by increases in heart rate. B2 units were unresponsive to both visual stimulation and foot-shock, whereas A units were unresponsive to visual stimulation but possibly responsive to foot-shock. The activity of vagal cardiac neurons was recorded during or after classical conditioning (paired lights and foot-shocks) or sensitization (unpaired lights and foot-shocks) to characterize discharge changes associated with conditioned cardioacceleration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Inhibitory conductance changes at synapses in the lamprey brainstem.

Although the conductance and kinetic behavior of inhibitory synaptic channels have been studied in a number of nerve and muscle cells, there has been little if any detailed study of such channels at synapses in the vertebrate central nervous system or of the relation of such channels to natural synaptic events. In the experiments reported here, current noise measurements were used to obtain such information at synapses on Müller cells in the lamprey brainstem. Application of glycine to the cells activated synaptic channels with large conductances and relaxation time constants (70 picosiemens and 33 milliseconds, respectively, at 3 degrees to 10 degrees C). Spontaneous inhibitory synaptic currents had a mean conductance of 107 nanosiemens and decayed with the same time constant. In addition, the glycine responses and the spontaneous currents had the same reversal potential and both were abolished by strychnine. These results support the idea that glycine is the natural inhibitory transmitter at these synapses and suggest that one quantum of transmitter activates about 1500 elementary conductance channels.

Animals↗
PubMed1983

Characteristics of inhibitory post-synaptic currents in brain-stem neurones of the lamprey.

Voltage-clamp techniques were used to record spontaneously occurring inhibitory post-synaptic currents (i.p.s.c.s) from Müller cells in the brain stem of the lamprey. In normal bathing solution, the i.p.s.c.s in most cells had unimodally distributed amplitudes with a mean corresponding to a peak conductance of 107 nS and a coefficient of variation of about 15%. About 20% of the cells displayed, in addition, events of approximately twice the modal amplitude. The falling phase of the i.p.s.c.s was exponential with a mean time constant of about 32 msec. This is the same as the relaxation time constant of glycine-activated channels in these cells under comparable conditions (Gold & Martin, 1983b). When tetrodotoxin (TTX) was added to the bathing solution the spontaneous i.p.s.c.s disappeared, suggesting that they were due to release of transmitter by action potentials in presynaptic terminals. Spontaneous activity was also abolished by removing Ca2+ from the bathing solution. When extracellular Ca2+ was increased, or 4-aminopyridine (4-AP) was added to the bathing solution, the mean amplitude of the i.p.s.c.s increased and the amplitude distribution showed two or more distinct peaks. Analysis of the amplitude distributions suggested that the peaks represented single and multiple quantal events and that the release process obeyed binomial statistics. In TTX-blocked preparations, spontaneous i.p.s.c.s could be induced by raising extracellular K+. These had the same time constant of decay as in normal solution and a unimodal amplitude distribution, with the mean corresponding to a peak conductance of 45 nS. In solutions with raised extracellular K+ and reduced extracellular Cl-, the mean i.p.s.c. amplitude corresponded to a peak conductance of 67 nS. These variations in conductance corresponded closely to variations in conductance with extracellular K+ and Cl- of single glycine-activated channels. It is concluded that the i.p.s.c.s are produced by activation of conductance channels identical to those activated by glycine, and that in normal bathing solution i.p.s.c.s produced by individual presynaptic action potentials are the result of the release of one or, at most, two quanta of transmitter. Each quantum activates approximately 1500 elementary channels.

4-Aminopyridine↗
PubMed1983

Analysis of glycine-activated inhibitory post-synaptic channels in brain-stem neurones of the lamprey.

Voltage-clamp techniques were used to measure fluctuations in membrane current produced by the application of glycine to Müller cells in the brain stem of the lamprey. The power density spectrum of the glycine-induced current 'noise' was consistent with the hypothesis that glycine activated a single population of conductance channels with open times determined by first-order kinetics. In normal bathing solution the channel conductance was 73 +/- 12 pS (mean +/- S.D.) and the channel open time 34 +/- 6 msec at 5 degrees C. The reversal potential for the response was 66 +/- 5 mV. Neither channel conductance nor mean open time was voltage-dependent. Replacement of Cl- in the bathing solution by isethionate and sulphate reversibly abolished the response to glycine. Increasing intracellular Cl-, either by using Cl- -filled micropipettes or by raising extracellular K+, decreased channel conductance. This unexpected decrease was a direct effect of intracellular Cl- and was not related to coincident changes in reversal potential. Channel open time was unaffected by intracellular Cl- concentration. Reducing extracellular Cl- concentration from 126.5 to 31 mM reduced channel conductance at all levels of intracellular Cl- without affecting open time. Increasing the temperature of the preparation resulted in increase in channel conductance and a decrease in mean open time. Q10S for the effects were of the order of 1.3 and -2.3 respectively in the range 4-14 degrees C.

Animals↗
PubMed1982

Intracellular Cl- accumulation reduces Cl- conductance in inhibitory synaptic channels.

Glycine increases Cl- conductance in neurones of the lamprey central nervous system and mimics the natural inhibitory transmitter pharmacologically. We have use current noise produce by glycine to examine in more detail the characteristics of inhibitory channels in Müller cells in the brain stem reticular formation. The channels have large conductances and mean open times consistent with large amplitudes and long durations of spontaneously occurring inhibitory synaptic currents. We now show that, unlike any post-junctional channels reported so far, their conductance decreases rapidly with increasing intracellular concentration of the permeant ion. This surprising behaviour is inconsistent with constant field theory and also with a single-site pore model such as proposed for cationic channels at the motor endplate, both of which predict an increase in conductance with concentration. In addition, the decrease in conductance cannot be explained quantitatively by a two-site, single-file pore model such as proposed for K+ channels and Na+ channels in nerve and for gramicidin channels. This property of the inhibitory channel may be functionally important in preventing intracellular Cl- accumulation during periods of intense synaptic activity when inhibition might otherwise convert progressively to excitation as the Cl- equilibrium potential became more and more positive.

Animals↗
PubMed1982

The effects of vasoactive intestinal peptide on neuromuscular transmission in the frog.

1. The effects of vasoactive intestinal peptide (VIP) on cholinergic transmission were studied at the neuromuscular junction of the frog.2. Bath application of VIP (10(-8)-10(-7) M) produced a dose-dependent increase in quantal content of the end-plate potential (e.p.p.), while having no effect on quantal size or on resting membrane potential of the muscle fibres.3. The increases in e.p.p. amplitude observed at end-plates blocked with Mg(2+) or curare were comparable.4. VIP increased miniature end-plate potential frequency when the nerve terminal was depolarized with K(+). This effect was abolished by removing Ca(2+) from the bathing solution.5. Ionophoretic application of VIP to the end-plate also increased quantal content, while having no effect on quantal size or on the input resistance and resting membrane potential of the fibres.6. Some possible mechanisms for the action of VIP are discussed, and it is proposed that it may act on some step involved in depolarization-secretion coupling.

Acetylcholine↗