The Part II examination: political exercise or national standard?
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Canada↗
Biomedical subjects
B Kennedy
Publications and source records attributed to B Kennedy.
Mutations sensitizing yeast cells to the start inhibitor nalidixic acid.
The regulatory step Start in the cell cycle of the budding yeast Saccharomyces cerevisiae is inhibited by nalidixic acid (Nal). To study this inhibition, mutations were identified that alter the sensitivity of yeast cells to Nal. Nal-sensitive mutations were sought because the inhibitory effects of Nal on wild-type cells are only transient, and wild-type cells naturally become refractory to Nal. Three complementation groups of Nal-sensitive mutations were found. Mutations in the first complementation group were shown to reside in the ARO7 gene, encoding chorismate mutase; tyrosine and phenylalanine synthesis was inhibited by Nal in these aro7 mutants, whereas wild-type chorismate mutase was unaffected, These aro7 alleles demonstrate 'recruitment', by mutation, of an innately indifferent protein to an inhibitor-sensitive form. The Nal-sensitive aro7 mutant cells were used to show that the resumption of Nal-inhibited nuclear activity and cell proliferation takes place while cytoplasmic Nal persists at concentrations inhibitory for the mutant chorismate mutase. Mutations in the second complementation group, nss2 (Nal-supersensitive), increased intracellular Nal concentrations, and may simply alter the permeability of cells to Nal. The third complementation group was found to be the ERG6 gene, previously suggested to encode the ergosterol biosynthetic enzyme sterol methyltransferase. Mutation or deletion of the ERG6 gene had little effect on the inhibition of Start by Nal, but prevented recovery from this inhibition. Mutation of ERG3, encoding another ergosterol biosynthetic enzyme, also caused Nal sensitivity, suggesting that plasma membrane sterol composition, and plasma membrane function, mediates recovery from Nal-mediated inhibition of Start.
Cell Cycle↗
Purification of baculovirus-overexpressed cytosolic phospholipase A2 using a single-step affinity column chromatography.
Cytosolic phospholipase A2 (cPLA2) plays a key role in the production of proinflammatory lipid mediators such as prostaglandins, thromboxane, and leukotrienes. cPLA2, an arachidonic acid-selective, 85-kDa protein has been purified, cloned, and partially characterized from a number of tissues. However, the purification schemes previously published by several groups are lengthy, involving several chromatographic steps and resulting in low yields of enzyme. Here we report the preparation of a novel affinity column (Affi-656) by immobilizing a competitive inhibitor of cPLA2, and a single-step purification of this enzyme. This column selectively retains cPLA2 activity from the cytosolic fractions of Sf9 cells infected with recombinant baculovirus which is eluted by a gradient of CHAPS in the elution buffer. Purification of cPLA2 to homogeneity can thus be accomplished in a single step. Moreover, mutant cPLA2 (Ser505/Ala505) which is no longer phosphorylated at Ser505 is also retained on Affi-656; mutation at this residue does not disrupt its binding to the affinity column. To our knowledge, this is the first report of cPLA2 affinity purification. Affi-656 is a convenient, reproducible, and high-capacity affinity column, and is a valuable tool for rapid purification of cPLA2 in large quantities.
Animals↗
Who's in the car? Passengers as potential interveners in alcohol-involved fatal crashes.
This article assesses the promise of motor vehicle passengers as interveners to prevent drinking and driving. It describes data from the U.S. Fatal Accident Reporting System (FARS), which indicate that most alcohol-involved fatally injured drivers (70% of males, 66% of females) were not accompanied by "adult" passengers (16 or older), and alcohol involvement among those passengers present appears to be high (80%). Nonetheless, in approximately 5% to 10% of cases it appears that sober or relatively "unimpaired" passengers could have served as interveners in alcohol-involved driving incidents. Passenger interveners may hold the most promise among teenagers, where passengers in general and unimpaired passengers in particular appear to be most prevalent.
Accidents, Traffic↗
Simian immunodeficiency virus infection of macaque primary placental cells.
We have characterized the ability of a simian immunodeficiency virus, SIVmne strain E11S, to infect macaque placental trophoblast and Hofbauer cells. These primary placental cells were permissive to SIVmne infection, regardless of gestational age. Virus production by the infected cells was determined as time-dependent viral core antigen p27 production, followed by verification of the proviral gag/LTR DNA sequences in the infected cells using a polymerase chain reaction assay. Of more than six placentas tested, SIVmne infection of placental cells at an early gestational age (i.e., days 55 or 78) produced more than 10-fold the amount of virus core antigen p27 than did placental cells infected at a late gestational age (i.e., days 135 or 165). In addition, SIVmne infection of trophoblast cells was inhibited by SIVmac neutralizing macaque serum but not by normal serum, indicating the specificity of virus infection. Furthermore, the amount of SIV core antigen p27 produced by the virus-infected trophoblast and Hofbauer cells was shown to be dependent on the multiplicity of virus infection. Collectively, our results indicate that macaque trophoblast and Hofbauer cells can be infected by SIV and that both gestational age and viral dose may play a role in the extent of viral infection.
Animals↗
High muscle blood flows are not attenuated by recruitment of additional muscle mass.
Recent studies have demonstrated that single-leg knee extensor (KE) exercise elicits high mass-specific blood flow (Q) which, if incremented toward maximum, in the presence of additional muscle recruitment would soon outstrip the heart's pumping capacity and blood pressure would fall. Thus incremental KE exercise provides the opportunity to determine the intensity at which, if at all, quadriceps muscle hemodynamics are altered during incremental exercise that involves a substantially greater muscle mass. Leg Q was measured during incremental KE exercise and again with superimposed incremental two-legged knee extensor exercise with incremental arm cranking (A+L) in trained subjects (n = 5). Leg Q and vascular conductance (VC) increased with work rate (WR) to reach high levels [Q = 385.7 +/- 26 and 342.3 +/- 15 ml.min-1.100 g-1 for KE and A+L exercise, respectively; VC at 90% of maximum WR (WRmax) = 79 +/- 5 and 75 +/- 6 ml.min-1. mmHg-1 for KE and A+L exercise, respectively], but the Q/WR and VC/WR relationships in KE and A+L exercise were not different. Maximum O2 consumption (VO2max) and the VO2max/WR relationship of the quadriceps were also unaffected by the additional muscle mass recruited. Despite a significantly greater net femoral venous norepinephrine (NE) outflow at both 90 and 100% of WRmax in A+L exercise (WRmax = 4,216 +/- 1,601 and 901 +/- 99 ng/ml for A+L and KE exercise, respectively; P < 0.05), leg Q continued to rise linearly with WR.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Chromogranin A in human hypertension. Influence of heredity.
Multiple heritable traits are associated with essential (genetic) hypertension in humans. Because chromogranin A is increased in both human and rodent genetic hypertension, we examined the influence of heredity and blood pressure on chromogranin A in humans. In estimates derived from among- and within-pair variance in monozygotic versus dizygotic twins, plasma chromogranin A displayed significant (F15,18 = 2.93, P = .016) genetic variance (sigma 2 g), and its broad-sense heritability was high (h2B = 0.983). Plasma chromogranin A was increased in essential hypertension (99.9 +/- 6.7 versus 62.8 +/- 4.7 ng/mL, P < .001) but was influenced little by genetic risk for (family history of) hypertension (in normotensive or hypertensive subjects), by race, or by several antihypertensive therapies (angiotensin-converting enzyme inhibitor, diuretic, or beta-adrenergic antagonist). In normotensive subjects at genetic risk for essential hypertension, neither basal nor sympathoadrenal stress-evoked chromogranin A differed from values found in subjects not at risk. In established essential hypertension, plasma chromogranin A responses to adrenal medullary (insulin-evoked hypoglycemia) or sympathetic neuronal (dynamic exercise) activation were exaggerated, whereas responses to sympathoadrenal suppression (ganglionic blockade) were diminished, suggesting increased vesicular stores of chromogranin A and an adrenergic origin of the augmented chromogranin A expression in this disorder. We conclude that plasma chromogranin A displays substantial heritability and is increased in established essential hypertension. Its elevation in established hypertension is associated with evidence of increased vesicular stores of the protein and with adrenergic hyperactivity but is influenced little by customary antihypertensive therapies. However, the chromogranin A elevation is not evident early in the course of genetic hypertension.
Adrenal Medulla↗
Nonadrenal epinephrine-forming enzymes in humans. Characteristics, distribution, regulation, and relationship to epinephrine levels.
Animal studies indicate that nonadrenal tissues may synthesize epinephrine (E). Here we demonstrate phenylethanolamine N-methyltransferase (PNMT) and/or nonspecific N-methyltransferase (NMT) enzymatic activity in human lung, kidney, heart, liver, spleen, and pancreas. There was a significant overall correlation (r = 0.34) between tissue PNMT and E. PNMT and NMT in human tissues differed in substrate and inhibitor specificity, thermal stability, and antigenicity. By these criteria, PNMT in human lung and in human bronchial epithelial cells were indistinguishable from adrenal PNMT. PNMT and/or NMT activity were present in red blood cells (RBCs), and cancer cell lines. Human kidney, lung, and pancreas showed immunohistochemical staining with an antibody to adrenal PNMT. RBC PNMT activity was lower in males than females and was increased in hyperthyroidism and decreased in hypothyroidism. PNMT activity in a human bronchial epithelial cell line was dramatically increased by incubation with dexamethasone. E and 3H-E levels in plasma and urine during an intravenous infusion of 3H-E into humans indicated that kidney may synthesize half of urinary E. We conclude that PNMT and NMT are widely distributed in human tissues, that they may synthesize E in vivo and are influenced by glucocorticoid and thyroid hormones.
Adrenal Glands↗
Compassion for new MDs.
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Attitude of Health Personnel↗
Comparison of stimulable phosphor technology and conventional screen-film technology in pediatric scoliosis.
One hundred consecutive patients being investigated for scoliosis were studied using a double cassette containing a conventional film screen and a stimulable phosphor plate. The images were separated, randomised and scored thrice by three radiologists for anatomic structure visualisation. The exposure to the plate and film and repeat rate were measured. Scoliosis angles were comparable on both sets of images, however, visualisation of vertebrae, vertebral end plates, pedicles, spinous processes and other structures were significantly improved (p < 0.0001). Intra- and inter-observer reliability was high with good intraclass correlation. There was a 40% potential exposure reduction, and retakes were decreased from 3 to 0%. We conclude that stimulable phosphor images give better anatomic structure visualisation with potential radiation exposure reduction and lower repeat rate.
Child↗
Does chromostatin influence catecholamine release or blood pressure in vivo?
Although the structure of chromogranin A (CgA) is now known, its ultimate physiological role remains elusive. Recently, an interior fragment of CgA [CgA(124-143)], also called chromostatin, was reported to suppress catecholamine release from chromaffin cells in vitro. We therefore explored chromostatin's biological actions when administered in vivo to anesthetized rodents with normal (Wistar-Kyoto rats) or elevated blood pressure (spontaneously hypertensive rats). Neither mean arterial pressure nor plasma epinephrine concentrations were significantly altered following either chromostatin or vehicle administration. Plasma norepinephrine, on the other hand, tended to rise throughout all studies, with the rise reaching statistical significance only in the SHR subgroup receiving chromostatin. We conclude that, unlike its actions in vitro, chromostatin does not appear to suppress catecholamine release or modulate blood pressure in vivo.
Animals↗
Patient knowledge of anaesthesia and peri-operative care.
One hundred and sixty six patients were questioned by means of a multiple choice questionnaire, to determine their knowledge of peri-operative care, anaesthesia and the rôle of anaesthetists. In general, knowledge was good, but there were some important misconceptions; in particular, 28.3% of respondents thought that fasting referred to food only, and not to fluid intake. In addition, 47.6% of respondents considered pain to be a necessary part of the healing process and 38.6% believed that it was something that just had to be endured. When forthcoming anaesthesia is discussed, anaesthetists need to ascertain that patients really do understand the language used.
Adult↗
Sympatho-adrenal secretion in humans: factors governing catecholamine and storage vesicle peptide co-release.
1. In postganglionic sympathetic neurones and adrenal chromaffin cells, catecholamines are co-stored in vesicles with soluble peptides, including chromogranin A (CgA) and neuropeptide Y (NPY), which are subject to exocytotic co-release with catecholamines. 2. Plasma catecholamine, CgA and NPY responses to stimulators and inhibitors of sympatho-adrenal catecholamine storage and release were measured in humans. Short-term, high-intensity dynamic exercise, prolonged low-intensity dynamic exercise, and assumption of the upright posture, in decreasing order of potency, predominantly stimulated noradrenaline (NA) release from sympathetic nerve endings. Only high-intensity exercise elevated CgA and NPY, which did not peak until 2 min after exercise cessation. Stimulated NA correlated with plasma CgA 2 min after exercise, and with NPY 5 min after exercise. 3. Insulin-evoked hypoglycaemia and caffeine ingestion, in decreasing order of potency, predominantly stimulated adrenaline (AD) release from the adrenal medulla. During insulin hypoglycaemia AD and CgA rose, but NPY was unchanged. Neither NPY nor CgA were altered by caffeine. The rise in CgA after intense adrenal medullary stimulation was greater than its rise after intense sympathetic neuronal stimulation (1.4-versus 1.2-fold, respectively). 4. Infusion of tyramine, which disrupts sympathetic neuronal vesicular NA storage, elevated systolic blood pressure and NA, while NPY and CgA were unchanged. After reserpine, another disruptor of neuronal NA storage, NA transiently rose and then fell; NPY and CgA were unaltered. After the non-exocytotic adrenal medullary secretory stimulus glucagon. AD rose while NA, CgA and NPY did not change. After amantadine, an inhibitor of protein endocytosis, both CgA and fibrinogen rose, while NA and NPY remained unaltered. Neither CgA, NPY, nor catecholamines were altered by the catecholamine uptake and catabolism inhibitors desipramine, cortisol, and pargyline. 5. Human sympathetic nerve contained a far higher ratio of NPY to catecholamines than human adrenal medulla, while adrenal medulla contained far more CgA than sympathetic nerve. 6. It is concluded that peptides are differentially co-stored with catecholamines, with greater abundance of CgA in the adrenal medulla and NPY in sympathetic nerve. Activation of catecholamine release from either the adrenal medulla or sympathetic nerves, therefore, results in quite different changes in plasma concentrations of the catecholamine storage vesicle peptides CgA and NPY. Only profound, intense stimulation of chromaffin cells or sympathetic axons measurably perturbs plasma CgA or NPY concentration; lesser degrees of stimulation perturb plasma catecholamines only. Neither CgA nor NPY are released during non-exocytotic catecholamine secretion.
Adrenal Medulla↗
Plasma norepinephrine variations correlate with peripheral vascular resistance in resting humans.
Plasma levels of norepinephrine (NE) vary rhythmically in humans and animals with an ultradian (shorter than 1 day) periodicity. We repeatedly measured plasma NE levels, blood pressure, cardiac output, and total peripheral resistance in nine normal resting subjects over 5 h. Plasma NE correlated with total peripheral resistance (Z = 0.322, P < 0.0002) and inversely with cardiac output (Z = -0.276, P < 0.0002) for the nine subjects overall. The correlations were strongest in subjects with the most spontaneous variability in total peripheral resistance. These findings suggest that spontaneous oscillations in plasma NE levels reflect alterations in sympathetic nervous activity to resistance blood vessels. The negative correlation between cardiac output and plasma NE levels may result from the very minor cardiac NE spillover into plasma and the inverse relationship between cardiac output and total peripheral resistance.
Activity Cycles↗
A prospective study of the clinical outcome of femoral pseudoaneurysms and arteriovenous fistulas induced by arterial puncture.
PURPOSE: Although spontaneous thrombosis of femoral false aneurysms (FAs) and arteriovenous fistulas (AVFs) has been reported, the frequency of this occurrence is unknown. This prospective study was designed to establish the natural history of FA and AVF and to evaluate factors that might predict eventual thrombosis of these lesions. METHODS: Twenty-two patients with either femoral FAs (n = 16) or AVFs (n = 6) induced by percutaneous arterial punctures were evaluated prospectively. After an initial duplex scan, all patients were monitored with serial scans, either in hospital or weekly as outpatients, depending on the stability of the process. Operative repair was performed for the following indications: (1) a greater than 100% increase in size of a FA by duplex scan, (2) the development of symptoms, or (3) continued patency of the lesion after 2 months of observation. RESULTS: Nine of 16 FAs and four of six AVFs closed spontaneously; FAs greater than 6 cm3 (1.8 cm in diameter) required repair more often (p = 0.065). However, size was not an absolute predictor of the need for repair because two small aneurysms (1.6 and 0.7 cm3) remained patent, although both patients were discharged safely from the hospital, and two large aneurysms (13.2 and 10.7 cm3) thrombosed spontaneously. Three of seven patients whose aneurysms required repair received anticoagulation continuously from the time of catheterization until repair became necessary. None of the patients whose FAs closed spontaneously were receiving anticoagulants at the time of thrombosis (p = 0.02). Neither length of the FA neck, velocity in the FA cavity, size of original arterial puncture, nor velocity in the AVF correlated with thrombosis. CONCLUSIONS: We conclude that (1) all FAs do not thrombose spontaneously and at least one third require surgical repair, (2) patients receiving continuous anticoagulation should undergo aneurysm repair, (3) discharge of patients with FAs less than 6 cm3 is safe (the majority of these FAs will eventually thrombose spontaneously), and (4) many AVFs close spontaneously and repair is not required unless symptoms or signs of progressive enlargement develop.
Aneurysm, False↗
Immune function in offspring of nonhuman primates (Macaca nemestrina) exposed weekly to 1.8 g/kg ethanol during pregnancy: preliminary observations.
A preliminary investigation of immune host response was conducted in a group of fetal alcohol-exposed nonhuman primates (Macaca nemestrina) who were part of a broader ongoing study of ethanol teratogenicity. The mothers of the offspring received weekly oral doses of ethanol (1.8 g/kg) for the first 3 or 6 or the entire 24 weeks of gestation. A control group received sucrose solution weekly throughout pregnancy. Four of the 18 ethanol-exposed animals (22%) died or were euthanized after infectious disease or failure to thrive during the first year of life; none of the seven control animals died. This imbalance in survival prompted the present review of immune function in the remaining offspring. Parameters assessed included: (1) white blood cell count (WBC), (2) peripheral blood leucocyte subsets (CD4+, CD8+, CD20+, and CD11c+), (3) T-cell proliferation after activation with phytohemagglutinin (PHA), staphylococcus enterotoxin B (SEB), and tetanus toxoid (TT), (4) phagocytic activity of monocytes, and (5) serum immunoglobulin levels and serum antibody titers after TT vaccination. Mean T-cell proliferation to TT was significantly decreased (p = 0.01) in all ethanol-exposed animals relative to controls, with near-significant decreases (p = 0.06) in response to SEB in the ethanol-exposed animals. Lymphocyte proliferation in response to PHA was not altered. Ethanol-exposed animals had significantly lower TT titers than controls after initial vaccination and booster. WBC, leukocyte subsets, serum immunoglobulins, and monocyte phagocytic activity were not significantly different from control values. These preliminary observations suggest that T-cell proliferation and antigen-specific memory responses may be altered in offspring exposed to weekly doses of ethanol in utero and warrant further evaluation for confirmation.
Animals↗
Glucocorticoid elevation of mRNA encoding epinephrine-forming enzyme in lung.
The epinephrine-forming enzyme phenylethanolamine N-methyltransferase (PNMT) is present in lung and its activity is increased by the glucocorticoid dexamethasone. Chronic administration of dexamethasone (0.5 mg/kg twice daily) doubled levels of mRNA coding for PNMT in rat lung. Administration of the glucocorticoid antagonist RU 486 after 7 days of dexamethasone treated reduced PNMT mRNA by about two-thirds within 24 h. Lung epinephrine (E) levels correlated with lung PNMT activity in these dexamethasone-treated and control rats. In a separate experiment, lung PNMT mRNA levels were nearly tripled 6 h after dexamethasone (1 mg/kg sc). In a third experiment chronic administration of the PNMT inhibitor SKF 64139 (50 mg/kg twice daily) reduced in vitro lung PNMT activity in chronically dexamethasone-treated adrenalectomized rats by approximately 96% and reduced lung E levels by approximately 75%. We conclude that glucocorticoids increase lung PNMT activity by increasing levels of mRNA coding for this enzyme. The data also suggest that a substantial fraction of lung E is locally synthesized. We speculate that enhanced lung E synthesis may participate in glucocorticoid-induced dilation of the bronchioles.
Adrenal Glands↗
Glucocorticoid hypertension and nonadrenal phenylethanolamine N-methyltransferase.
Several drugs that block epinephrine synthesis by inhibiting phenylethanolamine N-methyltransferase (PNMT) lower blood pressure in hypertensive rats. We investigated the mechanism by which these drugs lower blood pressure in rats made hypertensive with the glucocorticoid dexamethasone. We performed adrenalectomy or sham operation on several rats and then gave them either dexamethasone chronically or vehicle. The dexamethasone-treated adrenalectomized rats also received either the centrally acting PNMT inhibitor SKF 64139 chronically or an equal dose of the primarily peripherally acting PNMT inhibitor SKF 29661. Both SKF 64139 and SKF 29661 reduced blood pressure by more than 25 mm Hg. SKF 64139 also reduced PNMT activity in hypothalamus, medulla oblongata, skeletal muscle, and cardiac atria and ventricles; SKF 29661 inhibited PNMT in muscle and heart tissue by 40-75%, did not inhibit PNMT in hypothalamus, and inhibited PNMT by only 29% in medulla oblongata. PNMT activity in peripheral tissues was also more highly correlated with blood pressure than was PNMT activity in the brain areas studied. Neither drug reduced tissue epinephrine levels, but SKF 64139 elevated dopamine or norepinephrine levels or both in several tissues. We conclude that the blood pressure-lowering action of PNMT-inhibiting drugs in glucocorticoid hypertensive rats may be due to inhibition of peripheral nonadrenal PNMT. We speculate that elevations in nonadrenal PNMT may mediate glucocorticoid hypertension.
Adrenalectomy↗