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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.

Ethylisopropylamiloride (EIPA) is a potent inhibitor of Na(+)-H+ exchange in many tissues and is frequently used to study cellular regulation of pH, but the electrophysiologic effects of EIPA on cardiac cells have not been studied previously. The use-dependent effects of EIPA on the sodium current (INa) of cultured embryonic chick atrial myocytes were investigated using standard whole-cell patch-clamp techniques. With 150-ms depolarizations from -140 to 0 mV, applied at 1-3 Hz in the presence of 10 microM EIPA, a decrement in INa was observed. This use-dependent reduction equaled 31 +/- 6% of control INa at steady state during 1-Hz stimulation. Inhibition increased with stimulation rate and with depolarization of the holding potential to -100 mV, but there was no effect of pulse duration on the EIPA-induced inhibition over the range of 20-500 ms. Moreover, repetitive depolarizations to potentials that did not activate macroscopic current but that did yield pronounced channel inactivation did not result in a decrement in INa. The effect of EIPA increased over the concentration range of 1-30 microM so that with 3-Hz stimuli steady-state inhibition increased from 3 +/- 1 to 85 +/- 5%. Amiloride, which slows repolarization of the cardiac action potential, was at least 100-fold less potent than EIPA in reducing INa. We conclude that EIPA is an "open-channel" blocker of the cardiac sodium current at concentrations comparable to those of many type I antiarrhythmic agents.

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.

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.

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.

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)

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)

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.

Previous in vitro studies have yielded conflicting results concerning the physiological effects of alpha-bungarotoxin (alpha-BTX) at avian autonomic ganglia. In the present study heart rate change was classically conditioned in pigeons immobilized with alpha-BTX to assess the effects of this agent on autonomic function in the intact animal. When compared with non-immobilized controls, alpha-BTX had no significant effect on basal heart rate or on the rate of acquisition, magnitude or dynamics of conditioned heart rate change. Furthermore, a significant difference in performance between groups receiving conditioning and sensitization paradigms clearly indicated the establishment of conditioned responding. It is concluded that alpha-BTX has little or no effect on the cardiac innervation at doses sufficient to block neuromuscular transmission. The irreversible blockade of neuromuscular transmission by alpha-BTX without the side-effects produced by most other paralytics makes it an ideal choice as an immobilizing agent in acute preparations.

Visually conditioned heart rate change in the pigeon has been developed as a vertebrate model system for the cellular neurophysiological analysis of associative learning. In previous studies of the "final common path," it was shown that both the vagal and sympathetic cardiac innervations contribute to this response. The present experiments indicate that, prior to any behavioral training, the visual stimulus elicits a small decrease in the discharge of vagal cardiac neurons. During conditioning, this stimulus evokes a progressively greater decrease in discharge that parallels the acquisition of the conditioned cardioacceleration. In contrast, nonassociative control animals show habituation of the initial decrease in discharge. These data confirm the involvement of the vagal cardiac innervation in conditioned heart rate change, indicate that the vagal innervation acts synergistically with the sympathetic to produce cardioacceleration, and suggest that a short-latency pathway mediates the conditioned response.

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.

We have studied the properties of Cl- channels in Müller cells of the lamprey brain, which are activated by two putative neurotransmitters, glycine and gamma-aminobutyric acid (GABA). Previous studies have shown that in these cells the two ligands act through different receptors, and it was of interest to determine whether or not the two receptors, in turn, activate separate channels having different properties. We have shown previously that the channels activated by glycine have large conductances which decrease rapidly as the intracellular Cl- concentration [Cl-]i is increased above normal. We show here that GABA-activated channels have much smaller conductances which are independent of [Cl-]i over the experimental range and also that the response to a saturating application of glycine is not occluded by simultaneous GABA application. These observations indicate that the glycine and GABA receptors are coupled to separate Cl- channels having different characteristics.

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.

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.