Biomedical subjects
J M Hughes
Publications and source records attributed to J M Hughes.
Reduced alveolar-capillary membrane diffusing capacity in chronic heart failure. Its pathophysiological relevance and relationship to exercise performance.
BACKGROUND: The pulmonary diffusing capacity for carbon monoxide (DLCO) is reduced in chronic heart failure (CHF) and is an independent predictor of peak exercise oxygen uptake. The pathophysiological basis for this remains unknown. The aim of this study was to partition DLCO into its membrane conductance (DM) and capillary blood volume components (Vc) and to assess if alveolar-capillary membrane function correlated with functional status, exercise capacity, and pulmonary vascular resistance. METHODS AND RESULTS: The classic Roughton and Forster method of measuring single-breath DLCO at varying alveolar oxygen concentrations was used to determine DM and Vc in 15 normal subjects and 50 patients with CHF. All performed symptom-limited maximal bicycle exercise tests with respiratory gas analysis; 15 CHF patients underwent right heart catheterization. DLCO was significantly reduced in CHF patients compared with normal subjects, predominantly because of a reduction in DM (7.0 +/- 2.6 versus 12.9 +/- 3.8 versus 20.0 +/- 6.1 mmol.min-1.kPa-1 in New York Heart Association class III, class II, and normal subjects, respectively, P < .0001), even when the reduction in lung volumes was accounted for by the division of DM by the effective alveolar volume. The Vc component of DLCO was not impaired. DM significantly correlated with maximal exercise oxygen uptake (r = .72, P < .0001) and inversely correlated with pulmonary vascular resistance (r = .65, P < .01) in CHF. CONCLUSIONS: Reduced alveolar-capillary membrane diffusing capacity is the major component of impaired pulmonary gas transfer in CHF, correlating with maximal exercise capacity and functional status. DM may be a useful marker for the alveolar-capillary barrier damage induced by raised pulmonary capillary pressure.
Trends in antimicrobial drug prescribing among office-based physicians in the United States.
OBJECTIVE: To assess changes in oral antimicrobial drug prescribing by office-based physicians from 1980 through 1992, with emphasis on the treatment of otitis media and sinusitis and on the possible impact of demographic variables on such use. DESIGN: The National Ambulatory Medical Care Survey is a sample survey of office-based physicians in the United States conducted by the National Center for Health Statistics, Centers for Disease Control and Prevention. SETTING: Physicians' offices. PATIENTS OR OTHER PARTICIPANTS: Physicians sampled for the 1980, 1985, 1989, and 1992 National Ambulatory Medical Care Surveys, which included groups of 2959, 5032, 2540, and 3000 physicians, respectively. Sample physicians responding in 1980, 1985, 1989, and 1992 reported data for 46,081, 71,594, 38,384, and 34,606 sample office visits, respectively, including information on antimicrobial drug prescribing. MAIN OUTCOME MEASURE: Trends in the antimicrobial drug prescription rates. RESULTS: From 1980 through 1992, increasing prescribing measured by the annual drug prescription rate per 1000 population, was found for the more expensive, broad-spectrum antimicrobial drugs, such as the cephalosporins; decreasing rates were observed for less expensive antimicrobial drugs with a narrower spectrum, such as the penicillins. No trend was found for trimethoprim-sulfamethoxazole, the erythromycins, or the tetracyclines. During the decade, an increasing trend in the visit rate to office-based physicians for otitis media was observed, while the visit rate for sinusitis among adults was found to be higher in 1992 than in each of the other study years. CONCLUSIONS: The increased use of broader-spectrum and more expensive antimicrobial drugs have implications for all patients because of the impact on health care costs and the potential for the emergence of antimicrobial resistance. The data suggest that the incidence of otitis media and sinusitis is increasing.
Plague in India: a new warning from an old nemesis.
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Silicosis risk: Canadian and South African miners.
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Measurement of the pulmonary vascular granulocyte pool.
We have developed a technique for measuring the pulmonary granulocyte pool (PGP) as a fraction of the whole body total blood granulocyte pool (TBGP). The technique "captures" a dose of 99mTc-labeled granulocytes in a region of interest (ROI) over the lung during first pass by integrating an input time-activity curve from an ROI over the pulmonary artery, superior vena cava, or right ventricle. The ratio of the estimated first-pass count rate and the count rate in the same lung ROI after equilibration of the cells between the circulating and pulmonary pools (15-30 min) represents the PGP/TBGP. The technique was validated in eight subjects by using 99mTc-labeled macroaggregated human serum albumin. With corrections for background and injected doses, the ratios of first-pass granulocyte-to-macroaggregated human serum albumin count rates given by the three input ROIs were close to unity [superior vena cava 0.98 +/- 0.079 (SD), right ventricle 1.01 +/- 0.070, and pulmonary artery 0.97 +/- 0.073]. Significant increases in PGP/TBGP were demonstrated in systemic inflammation. Thus, in patients with inflammatory bowel disease, it was 0.22 +/- 0.07 (n = 7) compared with 0.08 +/- 0.01 (n = 5) in control subjects. It was also elevated in patients with systemic vasculitis (0.34 +/- 0.07; n = 5), in transplant recipients (0.33 +/- 0.08; n = 5), and in patients with osteomyelitis (0.15 +/- 0.06; n = 4). We conclude that this is a valid technique for quantifying the PGP that is expanded in several conditions associated with systemic inflammation.
The effect of inhalation of platelet-activating factor on the pulmonary clearance of 99mTc-DTPA aerosol.
Platelet-activating factor (PAF) is a short-acting, lipid-soluble autocoid, inhalation of which causes an immediate pulmonary vascular sequestration of granulocytes and a peripheral neutropenia. We investigated the effect of PAF inhalation on the pulmonary clearance rate of inhaled 99mTc-DTPA in order to test the hypothesis that the pulmonary sequestration of granulocytes results in acute lung injury. In nine normal nonsmoking adults, the rate of clearance of DTPA, corrected for background activity, was 1.5 (SD 0.7) %/min over the first 10 min after inhalation. Inhalation of 4.8 micrograms PAF abruptly increased the clearance rate to a mean value of 2.3 (1.4) %/min (p < 0.05). No increase in clearance was observed in four nonsmoking subjects who inhaled vehicle only. The mean overall increase after PAF was 87% of the baseline clearance, significantly different (p < 0.05) from the corresponding change in the control group, which was -17%. After PAF, the clearance rate returned to baseline values within 10 min in all subjects. In all subjects who inhaled PAF, but in none who inhaled vehicle, there was an immediate neutropenia of 51 (SD 25) % of the baseline value (p < 0.01). This neutropenia persisted longer than the corresponding accelerated DTPA clearance and was still 74 (36) % of the baseline value at 10 min. Furthermore, there was no correlation between the increase in DTPA clearance induced by PAF inhalation and the decrease in peripheral blood granulocyte count. We conclude that PAF inhalation results in an increase in pulmonary DTPA clearance, probably not mediated by pulmonary vascular granulocyte sequestration.
Clinical case seminar: a 33-year-old woman with a pituitary mass and panhypopituitarism.
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Pulmonary arteriovenous malformations: results of treatment with coil embolization in 53 patients.
OBJECTIVE: The purpose of this study was to determine the effects of percutaneous transcatheter coil embolization of pulmonary arteriovenous malformations on arterial oxygen saturation, pulmonary gas exchange, anatomic right-to-left shunt, and lung function and to assess the complications of the procedure. SUBJECTS AND METHODS: Fifty-three patients were included in the study: 42 (79%) had associated hereditary hemorrhagic telangiectasia. Nineteen (36%) had neurologic problems compatible with paradoxical embolization. During 102 separate embolization procedures, all malformations with feeding vessels > or = 3 mm in diameter were embolized with steel coils. Arterial oxygen saturation at rest and on exercise and the intrapulmonary right-to-left shunt fraction (99mTc-macroaggregate injection), forced expiratory volume in 1 sec, vital capacity, diffusing capacity for carbon monoxide, and transfer coefficient were measured before and after embolization. Complications of the procedure were recorded and investigated. RESULTS: Before treatment, all patients had hypoxemia in the supine posture (SaO2, 89 +/- 1% [standard error of the mean]), which fell a further 6% (absolute) on standing. Mean values for transfer coefficient and diffusing capacity for carbon monoxide were reduced, at 85 +/- 3% and 78 +/- 3% (predicted value), respectively. After embolization, the mean values for supine and erect SaO2 rose to 94 +/- 1% and 93 +/- 1%. Transfer coefficient increased by a mean of 5.4% of predicted value. The mean shunt fraction fell from 23 +/- 2% preembolization to 9 +/- 1% postembolization. In 102 procedures, there were 18 complications, 12 mild, two moderate, and four potentially serious (systemic coil embolization in two patients, cerebrovascular accident [transient], and myocardial puncture), but there were no lasting sequelae. CONCLUSION: Our results show that coil embolization is an effective and well-tolerated method for treatment of pulmonary arteriovenous malformations. Improvements in pulmonary gas exchange and lung function and a decrease in right-to-left shunting occurred after treatment. The procedure was well tolerated and had a low complication rate.
Pathology and emerging infections--quo vadimus?
There have been dramatic changes in the occurrence of infectious diseases throughout the world in the previous two decades. The emergence of new microbial agents, and the reemergence of infections previously believed to be controlled, threatens the health of all populations. The emergence of these infectious diseases has occurred during a period of breakdown in the capabilities of the public health surveillance systems, prevention programs, and disease control efforts. Expertise in pathology is critical to provide a strong national control program for emerging and reemerging infectious diseases. Despite the many significant achievements made by pathologists in improving understanding of the pathogenesis and diagnosis of infectious diseases, the field of pathology remains largely oriented toward neoplastic diseases, and has not yet identified infectious disease diagnosis as an important component of anatomic pathology training and research, even in the face of the current threats posed by microbial agents. In addition, there is currently a dearth of infectious disease pathologists in the United States and elsewhere in the world, and the use of the autopsy, a prime pathological tool for diagnosis of emerging infections, is on the wane. The most serious problem is that no formal training program for infectious disease pathology currently exists in the United States or elsewhere in the world. As a consequence of this lack of training opportunities, there is a severe deficiency of young, well-educated pathologists with infectious disease expertise. This article explores the historical linkages between the disciplines of infectious diseases and pathology, and suggests that infectious disease pathology as a subspecialty be strengthened and training programs be initiated.
Pulmonary studies using positron emission tomography.
The detailed investigation of regional differences in lung function at a local level began when suitable gamma-ray emitting isotopes and focused external radiation detectors (especially the Anger gamma-camera) became available. A major recent advance has been the development of positron emission tomography (PET), which provides a powerful combination of highly accurate tomographic reconstruction of radioisotope concentration with a potentially unlimited list of biological compounds to be labelled with the positron emitting isotopes of oxygen, carbon and fluorine. Early studies using PET focused on the inhalation of 11CO (or C15O) and 19Ne gases and the intravenous injection of 13N in saline and H215O for the measurement of relatively simple aspects of regional lung function, such as tissue, blood and gas volumes, blood flow, ventilation and ventilation/perfusion (V'A/Q'). More recent work has been directed towards the more challenging areas of regional endothelial permeability, carbohydrate utilization, enzyme and receptor binding assays, and in vivo pharmacokinetics. The short physical half-lives of the isotopes (17 s to 2 h) and the noninvasive nature of PET allows serial measurements to be made on patients (within the constraints of permitted radiation doses) to assess the effect of physiological and therapeutic interventions.
Management of mitochondrial disease on an intensive care unit.
Patients with mitochondrial disease may present to the Intensive Care Unit (ICU) with a variety of neurological and general medical disorders. Eleven patients were admitted to a neurological ICU between 1970 and 1992 because of respiratory insufficiency, status epilepticus and/or metabolic encephalopathy associated with mitochondrial disease. Respiratory impairment occurred in eight patients and was associated with nocturnal hypoventilation due to respiratory muscle weakness, aspiration due to bulbar weakness and abnormalities of central control leading to a reduced CO2 drive, irregular respiratory patterns and sleep apnoea. Seven patients received continuous respiratory support during the acute illness; three were subsequently weaned to domiciliary ventilation, and four died. Five patients had stroke-like episodes, which in two were recurrent. Four patients developed tonic-clonic grand mal epilepsy associated with myoclonic fits (2 patients), absences (2), focal fits (1) and status epilepticus (2). Encephalopathy was associated with recurrent lactic acidosis (2 patients), cardiac failure (2), hyponatraemia (2), renal abnormalities (3) and complete heart block (1). Although rare, mitochondrial disease should be considered in any patient with unexplained respiratory failure, intractable epilepsy, lactic acidosis or recurrent stroke.
Adult onset immunodeficiency caused by inherited adenosine deaminase deficiency.
Adenosine deaminase (ADA) deficiency is identified here as a cause of adult onset immunodeficiency. Two sisters who noted recurrent, predominantly chest infections in their twenties were found in their thirties to have CD4+ lymphopenia and lymphocyte ADA activity of approximately 5% of the lower limit of normal. Immune function, measured by proliferation of PBMCs in vitro to mitogens and specific Ags, was impaired. Inheritance of a polymorphic marker showed that both patients were heterozygous at the ADA locus. In the paternal allele there was a deletion resulting from homologous recombination between two alu elements that normally flank the first exon and the polymorphic marker. The recombination site was distinct from that in similar deletions described in two infants having severe combined immunodeficiency. This allele is predicted to result in a null phenotype. In the mutant allele inherited from the mother, a C to T transition in a CpG dinucleotide changed the codon for arginine 211, which lies in a conserved sequence close to the active site, to that for cysteine. This mutation has been observed previously in a child in whom the other allele was also a null mutation, but who was diagnosed as having partial ADA deficiency because immune function was apparently normal. The late onset of immunodeficiency in our patients suggests that immune function in children with partial ADA deficiency may deteriorate with time and that ADA deficiency should be regarded as a possible cause of adult onset immune dysfunction of unknown etiology.
Potency versus importance in fiber pathogenicity.
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Comparison of the effect of inhaled selective and non-selective adrenergic agonists on cardiorespiratory parameters in chronic stable asthma.
Increased hypoxia has been found after beta 2 adrenoceptor agonists (but not adrenaline) in asthmatics. Combined with hypokalaemia and sympathomimetic stimulation, this may predispose to cardiac arrhythmias. We have compared the effects of nebulized adrenaline and a selective beta 2 agonist (salbutamol) on the arterial oxygen saturation (SaO2), minute ventilation (VE), forced expiratory volume in 1 s (FEV1), plasma potassium and the electrocardiogram (ECG) in patients with chronic stable asthma. Six patients were studied according to a randomized, placebo-controlled, double-blind cross-over protocol. Adrenaline (5 mg), salbutamol (5 mg) and placebo were administered during 4 min tidal breathing using a nebulizer driven by air. There was a fall in SaO2 after both adrenaline (mean % fall (SEM) 3.3 (0.2)) and salbutamol (4.0 (0.7)) associated with an increase in FEV1, with no change in VE. Therefore, the fall in SaO2 must have been caused by increased ventilation-perfusion imbalance. There was an increased heart rate after both adrenaline and salbutamol and ventricular ectopic beats and a short run of parasystole were recorded on the ECG in one patient after adrenaline and in two patients after salbutamol. No change was found in plasma potassium levels. We conclude that both adrenaline and a selective beta 2 agonist salbutamol can cause a fall in SaO2 and ventricular ectopy in some asthmatic patients.
Adenosine deaminase (ADA) deficiency as the unexpected cause of CD4+ T-lymphocytopenia in two HIV-negative adult female siblings.
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Adenosine deaminase deficiency with altered biochemical parameters in two sisters with late-onset immunodeficiency.
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