Dramatic resolution of skin lesions associated with porphyria cutanea tarda after interferon-alpha therapy in a case of chronic hepatitis C.
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Adult↗
Biomedical subjects
R A Wright
Publications and source records attributed to R A Wright.
Do back support belts cause gastroesophageal reflux?
A competent lower esophageal sphincter (LES) prevents gastroesophageal reflux disease (GERD) in the setting of increased abdominal pressure. Therefore, we have assessed whether a back support belt causes gastroesophageal reflux (GER). Ten healthy volunteers underwent esophageal manometric studies to locate the LES. Subsequently, each subject underwent two separate 8-hour intra-esophageal pH monitor studies on different days, the first without wearing a back support belt, and the subsequent one wearing a back support belt. A symptom diary and continuous intra-esophageal pH data were obtained during both study periods. The mean LES pressure (LESP) was 14 +/- 3.6 mm Hg without a back support belt and 15.8 +/- 4.3 mm Hg with a back support belt which was not significantly different. There were no significant differences in total episodes of GER, esophageal acid exposure, or any other parameters monitored. Symptoms of GER were the same comparing the back support belt with no back support belt. We conclude that healthy people with normal LESP do not have increased GER as a result of wearing a back support belt.
Abdomen↗
Do parotid duct abnormalities occur in patients with chronic alcoholic pancreatitis?
OBJECTIVE: Several studies have suggested that ethanol affects the pancreas and parotid gland. We performed a prospective study to determine whether ductal lesions of ethanol-induced chronic pancreatitis occur in the parotid. METHODS: Parotid sialograms were performed in 11 alcoholic patients who had endoscopic retrograde pancreatograms. Sialograms and pancreatograms were examined in all subjects for ductal abnormalities. RESULTS: Seven of nine patients (77.8%) with ductal lesions of the pancreas had coexistent ductal abnormalities of the parotid gland (Kendall's tau = 0.578, p = 0.035). CONCLUSIONS: Chronic ethanol intake induces ductal alterations in the parotid gland similar to those seen in the pancreas. These results suggest a common histopathological effect of alcohol in the ductal system of the parotid gland and pancreas and raise the possibility that the parotid sialogram could be useful as an adjunct in the diagnosis of ethanol-induced chronic pancreatitis.
Adult↗
A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension.
OBJECTIVE: To determine the best therapeutic strategy for the use of midodrine in patients with neurogenic orthostatic hypotension (NOH). BACKGROUND: Midodrine is a peripherally acting alpha-adrenergic agonist useful in the treatment of NOH. However, neither the most effective dosage of midodrine nor the required frequency of administration is established. DESIGN/METHODS: Midodrine dose-blood pressure response, pharmacokinetics, and duration of action were examined in a double-blind, placebo-controlled, four-way crossover trial. Twenty-five patients with NOH were randomized to receive on successive days placebo or midodrine 2.5, 10, or 20 mg. Blood pressures of patients in the supine and standing positions were measured sequentially. A global assessment of the patient's overall symptom improvement after each leg of the study was performed. Blood levels of midodrine and its active metabolite, desglymidodrine, were assayed. RESULTS: Midodrine significantly increased standing systolic blood pressure, with the increase peaking at 1 hour. There was a significant linear relation between midodrine dosage and mean systolic blood pressure. The mean score for global improvement of symptoms was significantly higher for midodrine (10 and 20 mg) compared with placebo. The half-life of desglymidodrine was approximately 4 hours. CONCLUSION: A 10-mg dose of midodrine prescribed two to three times daily is effective in increasing orthostatic blood pressure and ameliorating symptoms in patients with NOH.
Adrenergic alpha-Agonists↗
Design, synthesis, and pharmacological characterization of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties.
2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (9) was designed as a conformationally constrained analog of glutamic acid. For 9, the key torsion angles (tau 1 and tau 2) which determine the relative positions of the alpha-amino acid and distal carboxyl functionalities are constrained where tau 1 = 166.9 degrees or 202 degrees and tau 2 = 156 degrees, respectively. We hypothesized that 9 would closely approximate the proposed bioactive conformation of glutamate when acting at group 2 metabotropic glutamate receptors (mGluRs). The racemic target molecule (+/-)-9, its C2-diastereomer (+/-)-16, and its enantiomers (+)-9 (LY354740) and (-)-9 (LY366563) were prepared by an efficient, stereocontrolled, and high-yielding synthesis from 2-cyclopentenone. Our hypothesis that 9 could interact with high affinity and specificity at group 2 mGluRs has been supported by the observation that (+/-)-9 (EC50 = 0.086 +/- 0.025 microM) and its enantiomer (+)-9 (EC50 = 0.055 +/- 0.017 microM) are highly potent agonists for group 2 mGluRs in the rat cerebral cortical slice preparation (suppression of forskolin-stimulated cAMP formation) possessing no activity at other glutamate receptor sites (iGluR or group 1 mGluR) at concentrations up to 100 microM. Importantly, the mGluR agonist effects of (+)-9 are evident following oral administration in mice in both the elevated plus maze model of anxiety (ED50 = 0.5 mg/kg) and in the ACPD-induced limbic seizure model (ED50 = 45.6 mg/kg). Thus, (+)-9 is the first orally active group 2 mGluR agonist described thus far and is an important tool for studying the effects of compounds of this class in humans.
Administration, Oral↗
LY354740 is a potent and highly selective group II metabotropic glutamate receptor agonist in cells expressing human glutamate receptors.
The novel compound LY354740 is a conformationally constrained analog of glutamate, which was designed for interaction at metabotropic glutamate (mGlu) receptors. In this paper the selectivity of LY354740 for recombinant human mGlu receptor subtypes expressed in non-neuronal (RGT) cells is described. At human mGlu2 receptors, LY354740 produced > 90% suppression of forskolin-stimulated cAMP formation with an EC50 of 5.1 +/- 0.3 nM. LY354740 was six-fold less potent in activating human mGlu3 receptors (EC50 = 24.3 +/- 0.5 nM). LY354740 inhibition of forskolin-stimulated cAMP formation in human mGlu2 receptor-expressing cells was blocked by competitive mGlu receptor antagonists, including (+)-alpha-methyl-4-carboxyphenylglycine (MCPG) and LY307452 ((2S,4S)-2-amino-4-(4,4-diphenylbut-1-yl)-pentane-1,5-dioic acid). LY354740 had no agonist or antagonist activities at cells expressing human mGlu4 or mGlu7 (group III mGlu receptors) (EC50 > 100,000 nM). When tested at group I phosphoinositide-coupled human mGlu receptors (mGlu1a and mGlu5a), LY354740 did not activate or inhibit mGlu receptor agonist-evoked phosphoinositide hydrolysis at up to 100,000 nM. Electrophysiological experiments also demonstrated that LY354740 also had no appreciable activity in cells expressing human recombinant AMPA (GluR4) and kainate (GluR6) receptors. Thus, LY354740 is a highly potent, efficacious and selective group II (mGlu2/3) receptor agonist, useful to explore the functions of these receptors in situ.
Bridged Bicyclo Compounds↗
Effects of digoxin on time domain measures of heart rate variability in patients with stable chronic cardiac failure: withdrawal and comparison group studies.
The effect on heart rate variability of adding digoxin to a diuretic and ACE inhibitor was studied in patients with chronic stable cardiac failure. Digoxin was found to increase heart rate variability, especially those measures of heart rate variability thought to represent parasympathetic activity. The withdrawal of digoxin led to a decrease in heart rate variability to pre-treatment levels. Whilst digoxin in standard doses does not alter prognosis in chronic cardiac failure, it does have potentially beneficial neurohumoral effects. If the increase in heart rate variability, which represents beneficial neurohumoral modulation, can be divorced from the potentially detrimental effects, perhaps by using smaller doses, then there may be a role for digoxin in the treatment of chronic cardiac failure.
Adult↗
Ability analysis of gender relevance and sex differences in cardiovascular response to behavioral challenge.
Cardiovascular effects of gender-specific ability perceptions (ability perceptions linked to one's identity as being female or male) were examined under different task conditions. In Study I, participants were led to believe that either men (masculine task) or women (feminine task) tend to do well on a memory task and then were provided the chance to avoid noise by attaining a low or high performance standard. As expected, sex differences in systolic blood pressure response during performance depended not only on task type but also on the degree of challenge. In Study 2, high standard effects were strengthened and extended through the use of an appetitive procedure and the inclusion of conditions in which the performance standard was extreme. Findings are discussed in terms of an interactional analysis of ability percepts, task demand, and cardiovascular responsivity.
Adolescent↗
Long-term survival following pericardiectomy for Staphylococcus aureus pericarditis in an HIV-positive drug user.
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Adult↗
Rheumatoid constrictive pericarditis.
A 73-yr-old woman with a 4 yr history of rheumatoid arthritis presented with the clinical features of congestive cardiac failure. She had a good early response to standard therapy although she subsequently developed recurrent biventricular failure. The preservation of good ventricular function on echocardiography in the face of clinical evidence of myocardial insufficiency raised the possibility of constrictive pericarditis, which was confirmed on cardiac catheterization. Constrictive pericarditis should be considered in patients with rheumatoid arthritis who develop unexplained cardiac failure. Early diagnosis requires a high index of suspicion and cardiac catheterization may be necessary to confirm the diagnosis. Medical treatment is largely ineffective and pericardiectomy should be considered.
Aged↗
A performance evaluation system for primary care providers in a community health services program.
A performance evaluation system (PES) serves to motivate employees to provide desired behaviors that achieve organizational objectives. In 1989, Denver Health and Hospital (DHH), a publicly funded, integrated delivery system with a large primary care program, instituted a new PES. This report summarizes performance evaluation results for DHH's community health center program. The evaluation focused on the performance of primary care physicians, midlevel practitioners (i.e., physicians assistants, nurse practitioners, and dentists), over a 4-year study period (1990 to 1993). Category-specific performance ratings were based on a 5-point ordinal scale: unacceptable, expectations not met, meets expectations, exceeds expectations, and outstanding. Performance ratings were analyzed as variables that were dependent on several practice characteristics. Results demonstrated a relationship between performance ratings and specific practice characteristics. Based on the results, limitations of the new PES and implications for designing more effective evaluation systems are discussed.
Colorado↗
Nemaline myopathy: an unusual cause of ophthalmoparesis.
Ophthalmoparesis and ptosis are extremely rare in nemaline myopathy. A 45-year-old man with a long history of bilateral ptosis and a 1-year history of diplopia is reported. Leg and arm weakness and wasting had been present since childhood, with a very slow deterioration over time. On examination, there was nonfatigueable bilateral ptosis that was more marked on the right. There was diplopia on left gaze. Extraocular movements showed limitation of elevation and adduction of the right eye. There was bilateral facial weakness, as well as proximal and distal wasting and weakness in the arms and legs. Electromyography (EMG) showed a combination of myopathic and neurogenic changes. Triceps muscle biopsy showed small multiple collections of rod-like structures in > 50% of fibers. This patient presented with a clinical picture that did not primarily suggest nemaline myopathy. This case illustrates the heterogeneity of this disorder and the need for muscle biopsy to make an accurate diagnosis in patients with ptosis and progressive external ophthalmoparesis.
Biopsy↗
The linkage between immigration and internal migration in large metropolitan areas in the United States.
"This paper investigates the relationship between the internal migration of native-born workers and flows of immigrants to the United States using the 1980 and 1990 U.S. Census Bureau microsamples.... Based on the estimation of three sets of regression models for five overlapping samples of the largest metropolitan areas in the United States and five mutually exclusive segments of the labor force, this analysis shows that the finding of a significant linkage between internal migration and immigration depends critically on the empirical experiment used. In direct opposition to previous published research, we conclude that net migration of the native born for metropolitan areas is either positively related or unrelated to immigration. Our models show that the net migration loss of unskilled native workers from metropolitan areas is probably a function of those cities' population size rather than immigrant flow to them. We conclude that the net migration loss of native-born workers from large metropolitan areas is more likely the result of industrial restructuring than of competition with immigrants."
Americas↗
An in vivo model for the assessment of acute fibrinolytic capacity of the endothelium.
The effects on blood flow and plasma fibrinolytic and coagulation parameters of intraarterial substance P, an endothelium dependent vasodilator, and sodium nitroprusside, a control endothelium independent vasodilator, were studied in the human forearm circulation. At subsystemic locally active doses, both substance P (2-8 pmol/min) and sodium nitroprusside (2-8 microg/min) caused dose-dependent vasodilatation (p <0.001 for both) without affecting plasma concentrations of PAI-1, von Willebrand factor antigen or factor VIII:C activity. Substance P caused local increases in t-PA antigen and activity (p <0.001) in the infused arm while sodium nitroprusside did not. At higher doses, substance P increased blood flow and t-PA concentrations in the noninfused arm. We conclude that brief, locally active and subsystemic infusions of intraarterial substance P cause a rapid and substantial local release of t-PA which appear to act via a flow and nitric oxide independent mechanism. This model should provide a useful and selective method of assessing the in vivo capacity of the forearm endothelium to release t-PA acutely.
Adult↗
Synthesis of the four isomers of 4-aminopyrrolidine-2,4-dicarboxylate: identification of a potent, highly selective, and systemically-active agonist for metabotropic glutamate receptors negatively coupled to adenylate cyclase.
The four isomers of 4-aminopyrrolidine-2,4-dicarboxylate (APDC) were prepared and evaluated for their effects at glutamate receptors in vitro. (2R,4R)-APDC (2a), an aza analog of the nonselective mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (1S,3R)-ACPD, 1), was found to possess relatively high affinity for metabotropic glutamate receptors (mGluRs) (ACPD-sensitive [3H]glutamate binding IC50 = 6.49 +/- 1.21 microM) with no effects on radioligand binding to NMDA, AMPA, or kainate receptors up to 100 microM. None of the other APDC isomers showed significant mGluR binding affinity, indicating that this interaction is highly stereospecific. Both 1 and 2a were effective in decreasing forskolin-stimulated cAMP formation in the adult rat cerebral cortex (EC50 = 8.17 +/- 2.21 microM for 1; EC50 = 14.51 +/- 5.54 microM for 2a); however, while 1 was also effective in stimulating basal tritiated inositol monophosphate production in the neonatal rat cerebral cortex (EC50 = 27.7 +/- 5.2 microM), 2a (up to 100 microM) was ineffective in stimulating phosphoinositide hydrolysis in this tissue preparation, further supporting our previous observations that 2a is a highly selective agonist for mGluRs negatively coupled to adenylate cyclase. Microelectrophoretic application of either 1 or 2a to intact rat spinal neurons produced an augmentation of AMPA-induced excitation (95 +/- 10% increase for 1, 52 +/- 6% increase for 2a). Intracerebral injection of 1 (400 nmol) produced characteristic limbic seizures in mice which are not mimicked by 2a (200-1600 nmol, ic). However, the limbic seizures induced by 1 were blocked by systemically administered 2a in a dose-dependent manner (EC50 = 271 mg/kg, ip). It is concluded that (2R,4R)-APDC (2a) is a highly selective, systemically-active agonist of mGluRs negatively coupled to adenylate cyclase and that selective activation of these receptors in vivo can result in anticonvulsant effects.
Adenylyl Cyclases↗
Differentiation of group 2 and group 3 metabotropic glutamate receptor cAMP responses in the rat hippocampus.
The effects of group 2- versus group 3-selective metabotropic glutamate (mGlu) receptor agonists were examined against forskolin (10 microM)-, vasoactive intestinal peptide (VIP; 1 microM)- and 5'-N-ethylcarboxamidoadenosine (NECA; 10 microM)-stimulated cAMP accumulations in adult rat hippocampal slices (in the presence of adenosine deaminase). Group 2 mGlu receptor-selective ((1S,3R)-1-aminocyclopentane-1, 3-dicarboxylic acid (1S,3R-ACPD) and (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine (L-CCG I)) and group 3 mGlu receptor-selective (L-2-amino-4-phosphonobutyric acid (L-AP4) and L-serine-O-phosphate) agonists greatly inhibited forskolin-stimulated cAMP formation ( > 80% at maximally effective concentrations). In contrast, stimulation of cAMP by VIP or NECA was inhibited by group 3, but not by group 2, mGlu receptor agonists. In fact, group 2 mGlu receptor agonists greatly potentiated cAMP accumulation evoked by NECA. Both the inhibitory effects of 1S,3R-ACPD on forskolin-stimulated cAMP and the potentiating effects on NECA-stimulated cAMP accumulation were reversed by the competitive group 1/2 mGlu receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG). However, (+)-MCPG had no effects on L-AP4 inhibition of cAMP. Thus, the effects of group 2 versus group 3 mGlu receptor agonists on cAMP coupling can be pharmacologically as well as functionally differentiated in the rat hippocampus.
Adenosine↗
(2S,4S)-2-amino-4-(4,4-diphenylbut-1-yl)- pentane-1,5-dioic acid: a potent and selective antagonist for metabotropic glutamate receptors negatively linked to adenylate cyclase.
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Adenylyl Cyclases↗
The accuracy of a lead questionnaire in predicting elevated pediatric blood lead levels.
OBJECTIVES: To determine the prevalence of elevated blood lead levels and to evaluate the accuracy of a lead screening questionnaire in a western United States urban inner-city pediatric population. DESIGN: A convenience sample of children between the ages of 6 months and 6 years seen for a well-child visit were enrolled. Venous blood lead levels were measured and a lead screening questionnaire was completed. SETTING: The primary care clinics of the 10 community health centers of the city and county of Denver, Colorado. Approximately 85% of children receiving services are below the 150% poverty level and 54% are insured through the state's Medicaid program. SUBJECTS: A total of 2978 children seen for a well-child visit from February 1993 to January 1994. MAIN OUTCOME MEASURES: The prevalence of elevated blood lead levels and the operating characteristics of both the Centers for Disease Control and Prevention lead screening questionnaire and the complete questionnaire used in Denver, using venous blood lead levels as the criterion standard. RESULTS: The mean blood lead level was 0.20 mumol/L (4.19 micrograms/dL). Eighty-five children had blood lead levels of 0.48 mumol/L (10 micrograms/dL), representing 2.9% of the study group (95% confidence interval [CI], 2.3-3.5). Only 0.3% of the cohort had blood lead levels greater than 0.96 mumol/L (20 micrograms/dL). The sensitivity, specificity, and positive predictive value of the Centers for Disease Control and Prevention questionnaire was 57%, 51%, and 3%, respectively. The sensitivity, specificity, and positive predictive value of the complete questionnaire was 59.7%, 36%, and 2.6%, respectively. The marginal cost of identifying a child with a blood lead level greater than 0.96 mumol/L (20 micrograms/dL) was $4925. CONCLUSIONS: Few of the low-income children in this study had blood lead levels greater than 0.48 mumol/L (10 micrograms/dL). The questionnaire did little better than chance at predicting the presence or absence of elevated blood lead levels and cannot replace a blood lead level test for childhood lead screening in this community.
Adolescent↗