Biomedical subjects

T W Smith

Publications and source records attributed to T W Smith.

At least 19 recordsLinked to original sources

PubMed1992

Transcriptional regulation in cardiac muscle. Coordinate expression of Id with a neonatal phenotype during development and following a hypertrophic stimulus in adult rat ventricular myocytes in vitro.

The transcriptional regulatory mechanisms in heart muscle that direct cardiac development and allow for a flexible, adaptive response to physiologic stress are not well understood. We demonstrate that a negative regulator of gene transcription termed Id that has been described predominantly in proliferating cell lines and in undifferentiated tissue during growth, is expressed in freshly isolated terminally differentiated adult rat ventricular myocytes, in contrast to most other tissues in the adult rat. Id mRNA expression is regulated in ventricular myocytes during post-natal development, peaking at the transition from hyperplastic to hypertrophic growth at day 17 in the rat, declining subsequently to lower, stable levels in adult myocytes. Although Id mRNA becomes undetectable in adult ventricular myocytes 48 h following isolation in the absence of serum, it can be rapidly reinduced by an alpha-adrenergic agonist, accompanied by increased protein synthesis and the reexpression, in defined media, of the neonatal genes prepro-ANP and skeletal muscle alpha-actin. Thus, the differential regulation of Id during cardiac development, the presence of Id mRNA in normal cardiac myocytes, and its increased expression following a hypertrophic stimulus all suggest a role for this transcriptional regulator in the control of cardiac muscle cell phenotype.

Aging↗

PubMed1992

The use of digoxin-specific Fab fragments for severe digitalis intoxication in children.

BACKGROUND: Because life-threatening digitalis intoxication is unusual in children, treatment with digoxin-specific-antibody Fab fragments (Fab) has rarely been reported. We describe the efficacy of Fab in the treatment of children with severe digitalis intoxication. METHODS: Twenty-nine children with intoxication due to digoxin (28) or digitoxin (1) received Fab at 21 participating hospitals between 1974 and 1986. Data were gathered about the patients' medical illnesses, doses and serum concentrations of digitalis, responses to Fab therapy, and outcomes. RESULTS: In the infants and young children with acute digoxin intoxication, the digoxin doses ranged from 0.30 to 0.96 mg per kilogram of body weight; two adolescents had severe intoxication after doses of only 0.20 and 0.26 mg per kilogram. The serum digoxin concentrations ranged from 3.0 to greater than 100 ng per milliliter (mean, 13.8). Atrioventricular block (present in 22 patients [76 percent]) was the most common sign of toxicity. All the patients in this series had severe disturbances of cardiac rhythm, hyperkalemia (mean serum potassium concentration, 5.4 mmol per liter), or both. In 27 patients (93 percent), digitalis toxicity resolved after the administration of Fab. Of the 19 patients for whom data were available on the timing of the response to Fab, 15 responded within 180 minutes. Three patients required retreatment with Fab. Seven died of complications unrelated to the administration of Fab. CONCLUSIONS: We recommend that Fab be used in the treatment of digitalis poisoning in infants and young children who have ingested greater than or equal to 0.3 mg of digoxin per kilogram, who have underlying heart disease, or who have a serum digoxin concentration of greater than or equal to 6.4 nmol per liter (greater than or equal to 5.0 ng per milliliter) in the elimination phase; and who also have a life-threatening arrhythmia, hemodynamic instability, hyperkalemia, or rapidly progressive toxicity. Adolescents, who are more sensitive to the toxic effects of digoxin than younger children, may require treatment with Fab after ingesting lower doses.

Acute Disease↗

PubMed1992

Recognition and management of digitalis toxicity.

The most important step in the management of toxicity due to any of the cardiac glycosides is its recognition. Despite the development of an accurate clinical assay for serum levels of digoxin greater than 20 years ago, digitalis toxicity remains common and difficult to confirm, even if suspected, due primarily to 2 factors. First, the signs and symptoms of digitalis toxicity, most commonly an abnormal electrocardiogram showing ventricular or atrial arrhythmias, with or without some degree of concurrent atrioventricular block, often also occur in patients with congestive heart failure (CHF) and underlying coronary atherosclerosis who are not receiving a cardiac glycoside. Second, due to digoxin's narrow therapeutic ratio, the marked degree of variability in the sensitivity of individual patients to its toxic effects, and the common problem of obtaining blood samples inappropriately during the early distribution phase following dosing, a serum digoxin concentration often does not serve as a reliable indicator of toxicity. Despite these difficulties in diagnosis, the management of digoxin toxicity has been made much more effective with the widespread availability of F(ab) fragments of anti-digoxin antibodies. This drug provides the clinician with a rapidly acting, safe antidote for all commonly used digitalis preparations. Conventional therapy for digoxin toxicity remains the maintenance of serum potassium levels greater than or equal to 4 mEq/liter, reversal of decompensated CHF or overt myocardial ischemia, attention to serum magnesium levels and the patient's acid-base status, appropriate antiarrhythmics in the event of ventricular arrhythmias, and a temporary pacemaker for high-grade atrioventricular block. Nevertheless, the high specificity and documented safety of the antibody preparation provides a needed safety net for the continuing use of cardiac glycosides as first-line inotropic agents in the modern therapy of chronic CHF.

Digitalis Glycosides↗

PubMed1992

Modulation of dihydropyridine-sensitive calcium channels in heart cells by fish oil fatty acids.

The highly unsaturated n-3 fatty acids from fish oils, eicosapentaenoic acid [EPA; C20:5 (n-3)] and docosahexanoic acid [DHA; C22:6 (n-3)], prevent the toxicity of high concentrations of the cardiac glycoside ouabain to isolated neonatal rat cardiac myocytes. Arachidonic acid [C20:4 (n-6)] lacks such protective action. The protective effect of the n-3 fatty acids is associated with their ability to prevent high levels of cytosolic free calcium from occurring in response to the ouabain. This in turn results, at least in part, from a 30% reduction in calcium influx rate induced by the n-3 fatty acids. This protective effect is simulated by nitrendipine, a dihydropyridine inhibitor of the L-type calcium channels in cardiac myocytes. Nitrendipine (0.1 mM) alone, however, inhibits myocyte contractility, as do verapamil (10 microM) and diltiazem (1.0 microM). EPA or DHA (5 microM) blocks the inhibitory effects of nitrendipine but not those of verapamil or diltiazem. Bay K8644, a known dihydropyridine agonist of L-type calcium channels, produces a ouabain-like effect that is also prevented by EPA or DHA. Specific binding of [3H]nitrendipine to intact myocytes is noncompetitively inhibited by EPA or DHA in a manner that reduces the number of high- and low-affinity binding sites (Bmax) and increases their affinities. The fish oil fatty acids prevent calcium overload from ouabain and Bay K8644. They also prevent a calcium-depleted state in the myocytes caused by the L-type calcium channel blocker nitrendipine. The protective effects of the n-3 fatty acids appear to result from their modulatory effects on nitrendipine-sensitive L-type calcium channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1992

Suspected low-grade glioma: is deferring treatment safe?

Deferring therapeutic intervention may worsen outcome in patients with low-grade glioma. To address this issue, we searched our records and located 26 patients who presented with a transient event (most often seizures), who had radiographic evidence strongly suggestive of a low-grade primary supratentorial neoplasm, and for whom all therapy (except anticonvulsants) was withheld until deemed necessary (WAIT Group). For comparison, 20 patients who presented similarly, but for whom immediate intervention was elected, served as a comparison group (NOWAIT Group). Fifteen patients in the WAIT Group required eventual surgery or radiation therapy at intervals ranging from 4 to 123 months (median, 29 months) between radiographic diagnosis and therapeutic intervention; reasons for such intervention included increasing tumor size, uncontrollable seizures, or malignant transformation of tumor. At surgery, there was an increased number of anaplastic tumors noted in the patients in the WAIT Group (p less than 0.02); nevertheless, if the rate of malignant transformation was examined from time of diagnosis, no differences were noted between the patients in the two groups. Similarly, no difference in survival or quality of life could be demonstrated from time of radiographic diagnosis. Therefore, we could not demonstrate that deferring therapy worsens outcome for these patients.

Brain Neoplasms↗

PubMed1992

Family support, physical impairment, and adherence in hemodialysis: an investigation of main and buffering effects.

Patient noncompliance is a pervasive problem among end-stage renal disease (ESRD) patients. Previous studies have implicated social support as an important correlate of adherence behavior in other chronic illness groups, but little research has examined this relationship in a hemodialysis population. The present study examined the main and interactive effects of social support in the family and illness-related physical impairment with regard to patient compliance in a sample of 78 hemodialysis patients. Results indicated that patients holding perceptions of a more supportive family environment exhibited significantly more favorable adherence to fluid-intake restrictions than did patients reporting less family support. Family support was not associated with adherence to dietary restrictions. The effect of family support on fluid-intake adherence was not moderated by level of physical impairment. This pattern suggests that the influence of support on adherence is more attributable to a main or direct effect, as opposed to a buffering process in the face of increased physical impairment.

Activities of Daily Living↗

PubMed1992

Coping processes as mediators of the relationship between hardiness and health.

Hardiness has been hypothesized to moderate the impact of stress on health by influencing coping responses, but little attention has been focused upon these associations. This study examined the relationship among hardiness, coping, and illness while attending to recent criticisms of the hardiness literature including the potential overlap with neuroticism, whether hardiness is a unitary construct, and the predominant use of male samples. Hardiness was found to be positively related to adaptive coping variables and negatively related to maladaptive coping variables. Problem-focused, support-seeking, and avoidant coping were found to mediate the hardiness-illness relationship. Although these hardiness-coping relationships were partially independent of the influence of neuroticism, the relationship of both coping and hardiness with self-reported illness appeared to result from the common influence of neuroticism. Consistent with previous research, the commitment and control components correlated most consistently with coping variables, and predicted hardiness effects were most consistently demonstrated for males.

Adaptation, Psychological↗

PubMed1992

The indusium griseum in Alzheimer's disease: an immunocytochemical study.

The immunocytochemical features of the indusium griseum (IG) were compared with the corresponding hippocampus in 5 patients with Alzheimer's disease (AD) and 5 age-matched nondemented individuals using antibodies against beta-amyloid, the A68 protein (Alz-50 antibody), tau, ubiquitin and synapsin I. beta-Amyloid-positive plaques were prominent in the AD hippocampus but were not present in the IG. Numerous Alz-50, tau and ubiquitin-positive neurofibrillary tangles and dystrophic neurites were observed in the AD hippocampus but were infrequent in the IG. Synapsin I immunoreactivity was significantly reduced in both the AD hippocampus and the AD IG when compared to age-matched patients. These findings suggest that the IG may be resistant to factors that trigger production of abnormal AD-associated proteins. Loss of synaptic input alone may not account for the AD-associated changes in the hippocampus since synaptic depletion was seen in both the hippocampus and the unaffected AD IG.

Aged↗

PubMed1992

Neuropathology of the spinal cord in the acquired immunodeficiency syndrome.

The neuropathologic findings in the spinal cord were reviewed in 138 consecutive autopsies of patients with the acquired immunodeficiency syndrome. In all cases both the brain and spinal cord were examined by conventional histologic techniques, and in 63 cases immunohistochemistry was used to detect human immunodeficiency virus (HIV), Toxoplasma gondii, cytomegalovirus, and JC papovavirus antigens. The most common observation was a normal spinal cord (60%). Vacuolar myelopathy (VM) was observed in 23 (17%) cases. Human immunodeficiency virus myelitis was evident in 8% of cases. Human immunodeficiency virus myelitis was associated with HIV encephalitis in 65% of the cases. Opportunistic infections of the spinal cord were uncommon, consisting of cryptococcosis (five cases), cytomegalovirus (four cases), toxoplasmosis (one case), and progressive multifocal leukoencephalopathy (one case), and almost always were seen with cerebral and/or systemic infection by these agents. Malignant lymphoma rarely involved the spinal cord (four cases); all were B-cell lymphomas and were associated with cerebral and/or systemic lymphoma. Other abnormalities rarely observed were Wallerian degeneration of the corticospinal tracts or posterior columns (6%) and focal microinfarcts. Most cases of VM (78%) were not associated with HIV myelitis, and in the five patients with both VM and HIV myelitis, HIV-infected cells were not found in the regions affected by VM. In contrast, 65% of cases with VM were associated with HIV encephalitis. The pathogenesis of VM remains unknown; it is probably not due to direct infection by HIV.

Acquired Immunodeficiency Syndrome↗

PubMed1992

Angiotropic lymphoma (intravascular large cell lymphoma) presenting with cauda equina syndrome.

A 50-year-old man developed cauda equina syndrome of unknown etiology that was stable for 20 months. Two months prior to sudden death, he experienced new back pain, confusion, seizures, and multiple cranial nerve palsies. Neuropathologic examination revealed angiotropic lymphoma without parenchymal involvement or infarcts in the brain, spinal cord, and muscle. In addition, nerve roots in the cauda equina contained angiotropic lymphoma and infarcts of various ages. Angiotropic lymphoma should be considered as a cause of cauda equina syndrome and of disorders that affect the central and peripheral nervous systems concurrently.

Brain Neoplasms↗

PubMed1992

Differential antinociceptive effects of morphine and methylmorphine in the formalin test.

The antinociceptive activities of morphine, and its quaternary analogue methylmorphine, have been compared after intraperitoneal and intracerebroventricular administrations in the mouse paw formalin test. Systemic morphine inhibited both the early and late phases of the formalin-induced licking response and this activity was naloxone sensitive. In contrast, systemic methylmorphine inhibited only the late phase, and this activity was blocked by pre-treatment with methylnaloxone. Central administration of either morphine or methylmorphine inhibited the early phase of the licking response partially and the late phase completely. Systemic naloxone inhibited the central action of both opioids, whilst systemic methylnaloxone did not affect the central action of methylmorphine. The results indicate that the early phase of the response to formalin in the mouse may be inhibited by stimulation of central opioid receptors whilst inhibition of the late phase may involve both peripheral and central opioid receptors.

Analgesics↗

PubMed1992

Social influence, marriage, and the heart: cardiovascular consequences of interpersonal control in husbands and wives.

Human and experimental animal research suggests that social stress in general--and chronic, effortful attempts to exert social control in particular--may contribute to cardiovascular disease. We examined the effects of exerting social influence or control on cardiovascular responses in married couples. Compared to husbands discussing a problem with their wives, husbands attempting to influence or persuade their wives displayed larger increases in systolic blood pressure (SBP) before and during the discussion. Furthermore, these physiological effects were accompanied by increases in anger and a more hostile and coldly assertive interpersonal style. Although wives who engaged in social influence attempts displayed generally similar behavior, they did not show the elevated SBP response or anger. We discuss the results in terms of the social context of cardiovascular reactivity and potential marital factors in cardiovascular health.

Adaptation, Psychological↗

PubMed1992

Hostility and health: current status of a psychosomatic hypothesis.

Recent research has renewed interest in the potential influence of hostility on physical health. This review indicates that the evidence available from prospective studies, although not entirely consistent, suggests that hostile persons may be at increased risk for subsequent coronary heart disease and other life-threatening illnesses. Further, several plausible mechanisms possibly linking hostility and health have been articulated and subjected to initial evaluation. Hostile individuals display heightened physiological reactivity in some situations, report greater degrees of interpersonal conflict and less social support, and may have more unhealthy daily habits. Additional research is needed, and it must address a variety of past conceptual and methodological limitations. Perhaps the most central of these concerns are the assessment of individual differences in hostility and the role of social contexts in the psychosomatic process.

Coronary Disease↗

PubMed1992

Personality and health: advantages and limitations of the five-factor model.

Interest in the association between personality characteristics and physical health has been renewed in recent years. Theory and research in this area has also been complicated by conceptual and methodological limitations. The present article briefly reviews this literature and discusses the advantages and limitations of the five-factor model of personality as an integrating framework for studies of personality and health. The model has already been fruitfully applied in several contexts, and more possibilities exist. Although it has some potential limitations, the application of the five-factor model--as well as other aspects of current personality theory and research--is likely to facilitate progress in the study of how personality influences health.

Humans↗

PubMed1992

Peripheral analgesic activities of peptides related to alpha-melanocyte stimulating hormone and interleukin-1 beta 193-195.

1. The hyperalgesic effects of interleukin-1 beta (IL-1 beta) and prostaglandin E2 (PGE2) were measured in rats. 2. Hyperalgesic responses to IL-1 beta were inhibited in a dose-dependent manner by alpha-melanocyte stimulating hormone (alpha-MSH)-related peptides with the following order of potency: [N1(4),D-Phe7]alpha-MSH greater than alpha-MSH greater than Lys-D-Pro-Val greater than Lys-Pro-Val greater than Lys-D-Pro-Thr greater than D-Lys-Pro-Thr. 3. Hyperalgesic responses to PGE2 were not inhibited by Lys-D-Pro-Thr and D-Lys-Pro-Thr but were inhibited in a dose-dependent manner by the other peptides with the same order of potency as against IL-1 beta. 4. The potencies of [N1(4), D-Phe7]alpha-MSH and alpha-MSH were greatly diminished by deletion of their C-terminal tripeptide, Lys11-Pro-Val13. 5. Nor-binaltorphimine (Nor-BNI) largely reversed the analgesic effects of alpha-MSH, [N1(4), D-Phe7]alpha-MSH, Lys-Pro-Val and Lys-D-Pro-Val indicating that kappa-opioid receptors mediated the analgesic activity of these peptides. 6. Nor-BNI did not antagonize the inhibition by Lys-D-Pro-Thr and D-Lys-Pro-Thr of IL-1 beta evoked hyperalgesia indicating that these peptides were not acting via kappa-opioid receptors.

Amino Acid Sequence↗

PubMed1992

Neuropathology of immunosuppression.

Traditionally, the brain has been considered an "immunologically privileged" organ. Under normal conditions, the blood-brain barrier (BBB) is highly effective in preventing both cellular and humoral constituents of the blood from entering the brain parenchyma. In certain pathological conditions, such as viral infections and demyelinating disorders, the BBB may become altered, activated T cells and monocytes may gain access to the brain parenchyma, and microglia may assume the functions of antigen-presenting cells and macrophages. Naturally-occurring or clinically-induced immunosuppression may dramatically alter various cellular and/or humoral aspects of the immune system. Consequently, the brain may become susceptible to disorders that would otherwise be excluded or may develop more severe manifestations of diseases, such as certain infections. This review considers the neuropathologic aspects of various conditions that may be encountered in the setting of both acquired and inherited immunosuppression. The major categories include infectious, neoplastic, vascular, and metabolic disorders. The review also briefly addresses the neuropathology of complications of chemotherapeutic agents, radiotherapy, and organ transplantation inasmuch as they often occur in the clinical setting of acquired immunosuppression.

Animals↗

PubMed1992

Na+ efflux mechanisms in ventricular myocytes: measurement of [Na+]i with Na(+)-binding benzofuran isophthalate.

We characterized the Na(+)-sensitive dye benzofuran isophthalate (SBFI) with fluorescence microscopy in isolated, adult rat ventricular myocytes. When cells were loaded with SBFI by incubation with 10 microM of the acetoxymethyl ester, fluorescence excitation spectra were markedly attenuated below 340 nm and the isoemissive point was blue shifted by approximately 25 nm when compared with spectra from SBFI acid in buffered solutions. Fluorescence intensity (49 +/- 3%) was partially released by permeabilization of the sarcolemma with digitonin, suggesting that one-half of the dye molecules are sequestered subcellularly in a compartment shown most likely to be mitochondrial. Intracellular Na+ concentration ([Na+]i) was determined by in situ calibration using cation-selective ionophores and was found to be 14 +/- 2 mM in cells studied at 37 degrees C. The relative importance of Na+ efflux mechanisms in myocytes was investigated. Substitution of Ca2+ and Mg2+ with EGTA in the superfusing medium resulted in a reversible rise of [Na+]i from 13 +/- 2 to 31 +/- 5 mM, which was blocked by 1 microM verapamil. Cellular efflux of Na+ after loading in this manner was found to be insensitive to blockade of Na(+)-Ca2+ exchange but was abolished when Na(+)-K(+)-ATPase was inhibited with zero extracellular K+ concentration. We conclude that SBFI can be used to measure [Na+]i in ventricular cells nondestructively and without impalement. Na+ efflux after loading by Ca2+ and Mg2+ withdrawal is mediated by the Na+ pump with no measurable contribution from Na(+)-Ca2+ exchange.

Animals↗

PubMed1992

Endothelins. Myocardial actions of a new class of cytokines.

There is growing evidence to support the existence of a dynamic interaction in vivo between cardiac myocytes and adjacent microvascular endothelial cells in the regulation of both cardiac myocyte and possibly endothelial cell phenotype and function. Endothelins may be only one of several endogenous cytokines or autocoids that are released by the cardiac microvascular and/or endocardial endothelium and transported vectorially to adjacent myocytes that could modify cardiac contractile state, perhaps in response to changes in microvascular blood flow. Similarly, cardiac myocytes themselves could release cytokines that could directly affect endothelial cell proliferation or angiogenesis and indirectly elicit or modify the release of endothelium-derived cytokines and autocoids. Thus, in addition to modifying function, endothelial cell-cardiac myocyte interactions may also be of importance in the dynamic events that lead to myocardial wall remodeling and angiogenesis during hypertrophic growth and in the response to cardiac injury.

Amino Acid Sequence↗