Showing papers by "Baylor College of Medicine published in 1985"

Flow effects on prostacyclin production by cultured human endothelial cells.

Abstract: Endothelial cell functions, such as arachidonic acid metabolism, may be modulated by membrane stresses induced by blood flow. The production of prostacyclin by primary human endothelial cell cultures subjected to pulsatile and steady flow shear stress was measured. The onset of flow led to a sudden increase in prostacyclin production, which decreased to a steady rate within several minutes. The steady-state production rate of cells subjected to pulsatile shear stress was more than twice that of cells exposed to steady shear stress and 16 times greater than that of cells in stationary culture.

Three-dimensional structure of calmodulin

Abstract: The three-dimensional structure of calmodulin has been determined crystallographically at 3.0 A resolution. The molecule consists of two globular lobes connected by a long exposed alpha-helix. Each lobe binds two calcium ions through helix-loop-helix domains similar to those of other calcium-binding proteins. The long helix between the lobes may be involved in interactions of calmodulin with drugs and various proteins.

Determination of parameters of left ventricular diastolic filling with pulsed Doppler echocardiography: comparison with cineangiography.

Abstract: To determine the relationship between Doppler-derived flow velocity through the mitral anulus and angiographic parameters of left ventricular filling, 30 patients were studied by two-dimensional echocardiography combined with pulsed Doppler echocardiography followed within 1 hr by left ventricular angiography. The average heart rate for each test was 69 beats/min. Doppler-derived parameters included: early peak diastolic velocity (E) and peak atrial velocity, peak filling rate computed as E X cross-sectional area of the mitral anulus derived from the annular diameter, normalized peak filling rate computed as peak filling rate divided by the left ventricular end-diastolic volume determined by two-dimensional echocardiography, and half filling fraction derived from the time-velocity integral of the Doppler-determined velocity curve. Frame-by-frame left ventricular volumes were obtained throughout diastole from single-plane cineangiograms. A volume-time curve with its derivative was generated by computer processing from which peak filling rate, normalized peak filling rate, and half filling fraction were measured. Morphologically, the Doppler-derived velocity profile resembled the derivative of the angiographic volume curve. In patients with reduced angiographic peak filling rates, early peak diastolic velocity was often decreased less than 45 cm/sec with a relative increase in peak atrial velocity resulting in an early peak diastolic velocity to peak atrial velocity ratio less than 1.0. There were no significant differences in mean values for peak filling rate, normalized peak filling rate, and half filling fraction by Doppler echocardiography vs angiography (296 vs 283 ml/sec, 1.9 vs 2.0 sec-1 and 0.55 vs 0.55, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Enhancement of recovery of myocardial function by oxygen free-radical scavengers after reversible regional ischemia.

Abstract: Reperfusion after reversible regional ischemia has been shown to result in delayed recovery of myocardial function, but the mechanism responsible for this phenomenon remains unknown. We explored the potential role of oxygen-free radicals as mediators of postischemic dysfunction in open-chest dogs undergoing a 15 min occlusion of the left anterior descending coronary artery (LAD) followed by 2 hr of reperfusion. Treated animals (n = 19) received an infusion of the oxygen free-radical scavengers superoxide dismutase (SOD; 15,000 U/kg) and catalase (CAT; 55,000 U/kg) for 1 hr starting 15 min before LAD occlusion, while control animals (n = 20) received an equal volume of saline. SOD and CAT produced no discernible effect on heart rate, aortic pressure, or left atrial pressure. Collateral flow to the ischemic zone (radioactive microspheres) was 0.07 +/- 0.01 ml/min/g in both groups. The size of the occluded bed as determined by postmortem perfusion was 26.1 +/- 1.2% of the left ventricle in the control group and 26.5 +/- 0.9% in the treated group. Systolic wall thickening (an index of regional function) was assessed with an epicardial pulsed-Doppler probe. The two groups exhibited comparable systolic thickening under baseline conditions and similar degrees of dyskinesia during ischemia. Nevertheless, recovery of function (expressed as percent of baseline) was considerably greater in the treated dogs, both at 1 hr (43.8 +/- 14.3 vs 12.8 +/- 11.6) and 2 hr of reperfusion (74.2 +/- 8.4 vs 31.6 +/- 9.8, p less than .005). This improved recovery of function obtained with SOD and CAT suggests that oxygen-free radicals play an important role in the genesis of myocardial dysfunction after a brief episode of regional ischemia.

Patterns of atherosclerosis and their surgical significance.

Abstract: The records of 13,827 patients admitted on one or more occasions to The Methodist Hospital in Houston on the service of the senior author for the treatment of arterial atherosclerotic occlusive disease from 1948 to 1983 were analyzed. The data derived from this analysis are believed to support the concept that atherosclerotic occlusive disease tends to assume characteristic patterns that may be classified, by predominant site or distribution of the disease, into five major categories: (I) the coronary arterial bed, (II) the major branches of the aortic arch, (III) the visceral arterial branches of the abdominal aorta, (IV) the terminal abdominal aorta and its major branches, and (V) a combination of two or more of these categories occurring simultaneously. Category IV had the highest proportion of patients (about two-fifths), Category I the second highest (almost one-third), and Category III had the lowest percentage (3%). Atherosclerotic occlusive disease in all categories tends to be well localized and usually occurs in the proximal or midproximal portions of the arterial bed. Such lesions are amenable to effective surgical treatment directed toward restoration of normal circulation. Less commonly, however, the occlusive disease in all categories occurs predominantly in the distal portions of the arterial bed, and such lesions are usually not amenable to effective surgical treatment. Patients in Categories I and III were significantly younger than those in the other categories and, although males predominated in all categories, Categories II and III contained significantly more female patients than did the other categories. In general, however, female patients behaved like male patients in virtually all aspects of the study. The rates of progression of the disease may be classified into: rapid (0 to 36 months), moderate (37 to 120 months), and slow (more than 120 months). The rapid and moderate rates of progression occurred most frequently in Categories II and IV, and the moderate and slow rates occurred most frequently in Category I. The possibility for development of recurrence or progression of disease in the same category and in a new category was significantly greater in younger patients. The patient's sex had no significant influence in this regard. Among the various categories, patients in Category IV had the highest incidence of development of disease in a new category, and Category I had the lowest incidence. Patients originally in Category II had a somewhat greater tendency to development of disease in Category IV, and patients originally in Category IV, for development of disease in Category II.(ABSTRACT TRUNCATED AT 400 WORDS)

Sleep and epilepsy.

Abstract: Summary: Epileptic mechanisms in the brain are subject to long-duration, time-ordered neuromodulatory processes controlled by endogenous oscillators which are responsible for appropriately phased modulation of various normal physiological processes, including the 24-h sleep/wakefulness cycle and the ultradian 100-min cycle of rapid eye movement/non-rapid eye movement sleep. Both focal and generalized types of epileptiform activity in humans are subject to biorhythmic modulation, and the various modulation patterns observed are in accord with a model which explains these patterns as a consequence of the interaction of two endogenous modulatory processes: one with a period of about 24 h, the other with a period of about 100 min. Differences in the phase angle between the two cyclic processes, determined by time of sleep onset, explain the various modulatory patterns observed. The mechanisms involved in the genesis and elaboration of electrical epileptiform activity in animal models are examined in relation to known processes involved in the physiology of sleep, and compared with data derived from long-term studies of the time distribution of epileptic events in humans. In infantile spasms, clinical seizure activity and the ictal and interictal EEG patterns in relationship to the phases of the sleep cycle, the significant defects in the quality and quantity of sleep in this disorder, and the changes that take place in all of these when seizures are abolished by effective treatment, suggest that pontine mechanisms responsible for the sleep cycle may be involved in the elaboration of infantile spasms and hypsarrhythmia.

Relationship of plasma lipoprotein Lp(a) levels to race and to apolipoprotein B

Abstract: Lipoprotein Lp(a) is an atherogenic subfraction of plasma lipoproteins which has been studied predominantly in white populations. We quantified Lp(a) by electroimmunoassay in plasma from 105 black and 134 white healthy men and women. Results were correlated with clinical variables and plasma levels of lipids, other lipoproteins, and apolipoprotein (apo) B determined by radioimmunoassay. Black subjects had levels of Lp(a) that averaged twice those of whites (p less than 0.001). Among blacks, Lp(a) levels showed a bell-shaped frequency distribution, while among whites the distribution was strongly skewed, with the highest frequencies at low levels. Contrary to previously published results, the apo B levels in our study correlated significantly, though weakly, with Lp(a) (r = 0.21, p = 0.001 among whites, and r = 0.15, p = 0.02 among blacks, Kendall rank correlation). The regression slopes and variances suggested that apo B in the Lp(a) lipoprotein could account for the correlation. Lp(a) levels did not correlate significantly with any other plasma lipoprotein or lipid levels. The implications of this study are as follows: Despite the high levels of Lp(a) among blacks in the Houston area, these blacks do not experience greatly increased atherosclerotic progression and mortality. Thus, the atherogenicity of Lp(a) in blacks must be decreased or counterbalanced by other factors. The correlation between Lp(a) and apo B should be taken into account when analyzing atherogenic risk, but this correlation is not strong enough to dispute the independence of Lp(a) and apo B as risk factors.

Epileptiform activity induced by changes in extracellular potassium in hippocampus.

Abstract: Using extra- and intracellular recording techniques, we investigated the induction and frequency modulation of spontaneous epileptiform activity produced by changes in the concentration of extracellular potassium ([K+]o). This paper describes a quantitative relationship between [K+]o and the frequency of spontaneously occurring epileptiform events. Recordings were made from the CA3 subfield of the rat in vitro hippocampal slice preparation. Intracellular microelectrodes were filled with 2 M Cs2SO4 and connected to a 3-kHz, time-share, single-electrode current- and voltage-clamp device. The frequency of spontaneous epileptiform (interictal) discharges was determined from extracellular recordings as a function of [K+]o. Current- and voltage-clamp techniques were used to characterize the intracellular correlate of these epileptiform events. The frequency of bicuculline-induced spontaneous epileptiform discharges was dependent on [K+]o. Below 4 mM [K+]o, spontaneous discharges occurred sporadically in the presence of 10 microM bicuculline. Increasing [K+]o from 5 to 10 mM caused a fivefold increase in the rate of spontaneous discharges. Spontaneous epileptiform discharges also occurred in the absence of bicuculline when [K+]o was increased above 6.5 mM. The rate of these discharges was dependent on [K+]o in much the same way as the discharges induced by bicuculline. For any given [K+]o concentration greater than 6.5 mM, however, the resultant discharge rate was faster than that obtained when bicuculline was present in the bathing solution. Simultaneous intra- and extracellular recordings revealed that the spontaneous high-[K+]o-induced interictal discharge was accompanied by a large depolarization of the membrane potential that appeared similar to the paroxysmal depolarizing shift (PDS) seen with other convulsants. The intracellularly recorded event fulfilled the criteria for a synaptically mediated PDS. The waveform of the PDS was complex and dependent on the membrane potential. When the membrane potential was held at 0 mV, spontaneously occurring hyperpolarizing potentials were noted during the inter-PDS interval. These events were blocked by picrotoxin or bicuculline and were probably spontaneous inhibitory postsynaptic potentials. The complexity of the PDS waveform suggested that more than one synaptic conductance was involved in the generation of the PDS. The mean measured reversal potential of the depolarizing phase was -10.7 mV. Voltage-clamp techniques were used to measure the conductance underlying the depolarizing phase of the high-[K+]o-induced PDS. The mean measured conductance was 51.5 nS, with a reversal potential of -7.9 mV.(ABSTRACT TRUNCATED AT 400 WORDS)

Beta-adrenergic stimulation reverses postischemic myocardial dysfunction without producing subsequent functional deterioration☆

Abstract: The prolonged myocardial dysfunction observed after reversible ischemia (stunned myocardium) has been postulated to result from an inability of the myocytes to replenish ATP stores. Accordingly, one would expect inotropic stimulation to result in minimal increase in contractile function, or possibly even further deterioration. To test this hypothesis, studies were performed in open-chest dogs undergoing a 15-minute occlusion of the left anterior descending coronary artery (LAD) followed by 4 hours of reperfusion. Systolic wall thickening, an index of regional myocardial function, was measured in the LAD-dependent territory with ultrasonic crystals. Thickening fraction was 20.8 ± 3.0% (mean ± standard error of the mean) under baseline conditions, decreased to −18.6 ± 1.6% during LAD occlusion, and was still severely depressed after 3 hours of reperfusion (2.6 ± 3.4%). Thickening fraction remained stable between 3 and 4 hours of reperfusion in 5 untreated control dogs. In 9 treated dogs, isoproterenol (0.1 μg/kg/min intravenously for 30 minutes starting 3 hours after reperfusion) increased thickening fraction to values (24.8 ± 4.5%) that were similar to those at baseline. Thirty minutes after discontinuation of isoproterenol administration, thickening fraction had returned to pre-isoproterenol levels. Thus, reperfused, severely depressed myocardium responds dramatically to β-adrenergic stimulation without subsequent adverse effects on function in the short-term. These findings imply that the stunned myocardium can generate ATP, and therefore do not support the view that an inability to replenish ATP stores is the cause of postischemic dysfunction. More important, this study suggests that postischemic dysfunction in humans may be effectively reversed with inotropic therapy without short-term deleterious sequelae.

Occupational low-back pain in hospital nurses.

Abstract: A survey of hospital staff nurses of a large tertiary care hospital was performed to investigate occupational low-back pain. Attack rates of 41% (37% "occupational") and 52% (occupational) were found using recall periods of two weeks and six months, respectively. Comparison with a control group suggests the validity of the work-relatedness of low-back pain in nurses. Factors associated with the disorder were also investigated, with results showing no differences due to nursing division assignment but significant association with specific tasks.

A comparison of pregnancy history recall and medical records. Implications for retrospective studies.

Abstract: Using data from the Diethylstilbestrol-Adenosis (DESAD) Project, a study of the effects of diethylstilbestrol (DES) exposure during fetal life, the authors compared prenatal records with obstetric history from mother's questionnaires completed 10 or more years after the birth of their daughters. Except for the history of hospitalization and trunk x-ray, no differences were observed in agreement (questionnaire compared with record) between the group of DES-exposed mothers identified through review of their prenatal records and the comparison group of mothers who were not exposed. The authors also compared data from mothers of DES-exposed daughters who initiated their own enrollment in the study (walk-ins and referrals). To obtain prenatal records for these women, physicians were contacted. They would usually supply drug exposure data but not the other obstetric history requested. Mothers of these walk-ins and referrals had slightly better agreement between questionnaire and records when compared with the two groups identified by review of prenatal records. In general, there was good to excellent agreement for all groups when mothers' recall of personal history (past miscarriage, past pregnancy, etc.) was compared with their medical records. However, for medical intervention such as drugs and x-rays, agreement was poor. Of the DES-exposed mothers identified through review of their prenatal records, 29% could not remember whether they took DES. An additional 8% said they did not take DES when it was recorded in their charts.

Impairment of caffeine clearance by chronic use of low-dose oestrogen-containing oral contraceptives.

Abstract: The effect of chronic (>3 months) administration of low-dose oestrogen-containing (<50 µg oestrogen) oral contraceptives (OCS) on the pharmacokinetics of caffeine has been examined in a treated females matched with 9 non-smoking, drug-free, healthy control females of similar age, weight and ethnic origin. Each subject received 162 mg caffeine base orally after an overnight fast. OCS subjects had a prolonged elimination half-life of caffeine, (mean 7.88 h vs 5.37 h in the controls). This was the result of marked impairment of the plasma clearance of caffeine (1.05 vs 1.75 ml/min/kg, respectively) with no change in apparent volume of distribution (0.685 in OCS vs 0.750 l/kg in the control group). The absorption parameters determined were peak plasma caffeine concentration (3.99 vs 4.09 µg/ml) and time to peak concentration after drug administration (1.52 vs 0.79), which was moderately prolonged in OCS users. Thus, caffeine clearance, previously reported to be a specific marker of cytochrome P-448 activity in man, is decreased by chronic OCS use. This suggests that OCS may cause significant impairment of this enzyme activity as assessed in vivo. With chronic caffeine consumption, OCS users are predicted to have an increased steady-state plasma caffeine concentration as compared to non-OCS users.

Effects of N-acetylcysteine on acetaminophen covalent binding and hepatic necrosis in mice.

Abstract: Experiments were designed to test whether the protective effect of N-acetylcysteine against acetaminophen hepatotoxicity precedes arylation of tissue or whether protection occurs after arylation of tissue. Investigation of potential postarylation actions showed that N-acetylcysteine was unable to attenuate the liver necrosis caused by acetaminophen or several other hepatotoxins that act through chemically reactive metabolites. Furthermore, varying the time and route of N-acetylcysteine treatment indicated that the late protection against acetaminophen mortality probably was a consequence of pharmacokinetic factors rather than postarylation intervention in the process of cell death. The antidote was found to inhibit covalent binding of acetaminophen by about 70% when N-acetylcysteine protected against liver necrosis. Treatment regimens that had no effect upon covalent binding also had no effect on acetaminophen hepatotoxicity. Previous failures to detect this relationship apparently occurred because of a failure to consider biological events important in the pathophysiology of acetaminophen-induced necrosis, particularly the marked intrahepatic hemorrhage and vascular congestion with liver engorgement by protein and fluid. These results support the hypothesis that sulfhydryl nucleophiles such as N-acetylcysteine act primarily through prearylation mechanisms to decrease the amount of reactive metabolite available for initiation of hepatic injury.

32P-postlabeling analysis of DNA adducts persisting for up to 42 weeks in the skin, epidermis and dermis of mice treated topically with 7,12-dimethylbenz[a]anthracene.

Abstract: The initial and persistent levels of 7,12-dimethylbenz[a]-anthracene (DMBA)-DNA adducts in mouse skin, epidermis and dermis after topical carcinogen application were studied by 32P-postlabeling assay. In the major experiment, a single dose of 1.2 mumol of the carcinogen was applied to the shaved backs of adult female BALB/cANN mice, and DNA was isolated from epidermis and dermis, respectively, 24 h and 1, 2, 3, 4, 8, 16, 24, 36 and 42 weeks later. Total binding at 24 h was approximately 34 and approximately 28 adducts in 10(7) normal nucleotides for epidermal and dermal DNA, respectively. (One adduct in 10(7) nucleotides equals 0.3 fmol adduct/microgram DNA.) While initial binding was higher in epidermal DNA, the adducts were approximately 10 times more persistent in dermal DNA: at 42 weeks, total binding levels were approximately 0.17 and approximately 1.7 adducts in 10(7) nucleotides for epidermis and dermis, respectively. To quantitate low levels of DMBA-DNA adducts, 32P-postlabeling assays were run in the presence of a limiting amount of carrier-free [gamma-32P]ATP; this was found to favor labeling of the adducts, thereby leading to a 20- to 100-fold enhancement of the method's sensitivity for individual adducts. One of the three major DMBA-DNA adducts was more persistent than were the others; the level of this adduct remained constant at approximately 60% of the total in epidermal and dermal DNA during the last 18 weeks of the 42-week observation period. Since a [3H]thymidine-labeling experiment showed a normal epidermal DNA turnover 40 weeks after DMBA treatment, it was concluded that the bulk of the persistent adducts was present in subpopulations of dormant cells. We have hypothesized that such cells, in the absence of a promoting stimulus, are incapable of division because of the adduction and/or mutation of genes critical for growth (proto-oncogenes), and may thus correspond to the 'latent tumor cells', as defined by Berenblum and Shubik in their classical analysis of the attributes of tumor initiation and promotion.

Regulation of hormone receptors and adenylyl cyclases by guanine nucleotide binding N proteins.

Abstract: Publisher Summary Receptors that affect cyclic adenosine monophosphate (cAMP) are sub-classified into two subtypes: Rs receptors, which increase cAMP levels by stimulating the enzyme adenylyl cyclase, and Ri receptors, which decrease cAMP levels by inhibiting the cAMP-forming enzyme. This chapter discusses the transduction mechanism to which Rs- and Ri-type receptors couple to modulate adenylyl cyclase activity. At the center of this transduction mechanism are two oligomeric coupling proteins called N or G proteins. These proteins have properties to bind and hydrolyze guanosine triphosphate and regulate hormone affinity for receptors and the catalytic activity of the cAMP-forming enzyme. This complex receptor-coupling protein-adenylyl cyclase system is approached by first reviewing structural and functional aspects that regulate cAMP formation. The chapter also discusses the basic structure and regulation of adenylyl cyclase by nucleotides and magnesium. It also discusses action of hormones on the nucleotide-regulated system. It analyzes the known regulation of hormone-receptor interaction by the coupling proteins. The analysis of affinity regulation of receptors leads to conclusions that point toward the existence of at least two conformational states of receptors interacting with at least three conformational states or forms of the coupling proteins.

Syndromes with lissencephaly. II: Walker-Warburg and cerebro-oculo-muscular syndromes and a new syndrome with type II lissencephaly.

Abstract: Lissencephaly (smooth brain) is an abnormality of brain development characterized by incomplete neuronal migration and a smooth cerebral surface. At least two distinct pathological types occur, each associated with several recognized syndromes. In this paper, we report on the clinical and pathologic manifestations of four additional patients and classify and delineate three separate disorders with type II lissencephaly. We also report on a previously undescribed abnormality in one of the four patients--dilated rough endoplasmic reticulum cisternae containing an unknown osmiophilic secretory product, probably a glycoprotein.

Relation between testosterone concentration, sex role identity, and personality among females.

Abstract: Eighty-four undergraduate female students completed Baucom's Masculinity and Femininity Scales, the Bem Sex Role Inventory, and the Adjective Check List. Testosterone concentration was determined from saliva samples provided by the women. The results indicated that sex role type was related to level of testosterone concentration. More specifically, undifferentiated females had much higher levels of testosterone concentration than did the feminine-sex-typed females. Also, females with high levels of masculinity (androgynous and masculine-sex-typed females combined) had somewhat higher testosterone levels than did feminine-sex-typed females. Adjectival correlates indicated that females with higher testosterone concentrations perceive themselves as self-directed, action-oriented, resourceful individuals; women with lower testosterone concentration view themselves as conventional, socialized individuals, possessing a caring attitude coupled with an anxious and dejected mood.