Response to symptom-limited exercise in patients with the hepatopulmonary syndrome

OBJECTIVE: To study the response to symptom-limited exercise in patients with the hepatopulmonary syndrome (HPS). DESIGN: The response to maximal cardiopulmonary exercise (CPX) was studied in 5 patients with HPS and compared with 10 case control (normoxemic, NC) cirrhotics (matched for age, gender, etiology and severity of liver disease, tobacco use, and beta-blocker therapy) and 9 hypoxemic control cirrhotics (HC) without clinical evidence of HPS. SETTING: Cardiopulmonary exercise physiology laboratory in a tertiary care referral center. PATIENTS: Cirrhotics referred for CPX as part of their preliver transplantation evaluation. MEASUREMENTS: Standard pulmonary function tests and echocardiography were performed to assess resting pulmonary and cardiac function. Peak oxygen consumption (VO2), minute ventilation, arterial blood gases, and dead space (VD/VT) were determined during symptom-limited maximal CPX. RESULTS: Resting spirometry and lung volumes were similar between HPS and NC subjects, while HC subjects had restrictive physiology. Differences existed in diffusing capacity corrected for hemoglobin and alveolar volume percent predicted (HPS, 45+/-2 vs NC, 68+/-3, p<0.05; vs HC, 70+/-4, p<0.05), PaO2 (HPS, 70+/-5 mm Hg; HC, 79+/-3 mm Hg, vs NC, 102+/-3 mm Hg, p<0.05) and alveolar-arterial (A-a) O2 gradient (HPS, 42+/-8 mm Hg vs HC, 27+/-2 mm Hg, p<0.05; vs NC, 6+/-2 mm Hg, p<0.05). During CPX, HPS patients achieved a lower peak VO2 percent predicted (HPS, 55+/-6 vs NC, 73+/-3, p<0.05; vs HC, 71+/-5, p<0.05) and VO2 at the ventilatory threshold as percent predicted peak VO2 (HPS, 36+/-2 vs NC, 55+/-4, p<0.05; vs HC 55+/-5, p<0.05). While no differences existed in heart rate and breathing reserve, HPS patients had significantly lower PaO2 (HPS, 50+/-5 mm Hg vs NC, 97+/-4 mm Hg, p<0.05; vs HC, 87+/-6 mm Hg, p<0.05), wider A-a O2 gradient (HPS, 73+/-5 mm Hg vs NC, 13+/-3 mm Hg, p<0.05; vs HC, 31+/-5 mm Hg, p<0.05) and higher VD/VT (HPS, 0.36+/-.03 vs NC, 0.18+/-.02, p<0.05; vs HC, 0.28+/-.02, p<0.05) at peak exercise. For HPS patients, VO2 was negatively correlated with VD/VT (r2=0.9) and positively correlated with PaO2 (r2=0.41) at peak exercise. Conclusions: Patients with HPS demonstrate a severe reduction in aerobic capacity, beyond that found in cirrhotics without syndrome. The significant hypoxemia and elevated VD/VT at peak exercise suggest that an abnormal pulmonary circulation contributes to further exercise limitation in patients with HPS.     

Tricarboxylic acid cycle intermediates during incremental exercise in healthy subjects and in patients with McArdle's disease

1. The importance of the level of tricarboxylic acid cycle intermediates (malate, citrate and fumarate) for energy transduction during exercise has been investigated in six healthy subjects and in two patients with muscle phosphorylase deficiency (McArdle's disease). 2. Healthy subjects cycled for 10 min at low (50 W), moderate [130 +/- 6 W (mean +/- SEM)] and high (226 +/- 12 W) work rates, corresponding to 26, 50 and 80% of their maximal O2 uptake, respectively. Patients with McArdle's disease cycled for 11-13 min at submaximal (40 W) rates, and to fatigue at maximal work rates of 60-90 W. 3. In healthy subjects, phosphocreatine was unchanged during low work rates, but decreased to 79 and 32% of the initial level during moderate and high work rates. In patients with McArdle's disease, phosphocreatine decreased to 82 and 34% of the initial level during submaximal and peak exercise. Muscle lactate increased in healthy subjects during exercise at moderate and high work rates, but remained low in patients with McArdle's disease. 4. In healthy subjects, tricarboxylic acid cycle intermediates were similar at rest and at low work rates (0.48 +/- 0.04 mmol/kg dry weight), but increased to 1.6 +/- 0.2 mmol/kg dry weight and 4.0 +/- 0.3 mmol/kg dry weight at moderate and high work rates. The tricarboxylic acid cycle intermediate level in patients with McArdle's disease was similar to that in healthy subjects at rest, but was markedly reduced during exercise when compared at the same relative intensity. The peak level of tricarboxylic acid cycle intermediates in patients with McArdle's disease was 22% of that in healthy subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Airways responses to oral ethanol in normal subjects and in patients with asthma

The effect of oral ethanol on airflow was studied in 5 normal subjects and 5 patients with asthma. On 4 different study days, each subject was asked to drink 40 ml of either water or 20%, 40% or 60% ethanol, and measurements were made of specific airways conductance (sGaw), blood ethanol levels, pulse rate and blood pressure. In some subjects in both groups there was a significant immediate fall in sGaw after drinking ethanol (below 5% confidence limits). Once absorbed, ethanol had a slight bronchodilator effect in 2 normal subjects and in 3 patients with asthma (5% level). Sixty per cent ethanol, when drunk slowly, showed significant bronchodilatation in 4 out of 5 patients with asthma and in one normal subject (5% level) with no acute fall in sGaw. Pulse rate and blood pressure did not change after water, 20% and 40% ethanol in either group, but immediately after 60% ethanol normal subjects showed a significant rise in pulse rate (P less than 0.01) which was not seen in patients with asthma. The immediate changes in sGaw and pulse rate may be due to stimulation of irritant receptors in the upper airways. Ethanol may act directly on bronchial smooth muscle to produce bronchodilatation and may be useful as a bronchodilator when given intravenously.     

Effects of smoking tobacco on exercise tolerance in healthy subjects

The aim of the study was to investigate the effects of smoking on exercise tolerance in middle aged smokers. Sixty two healthy subjects 55 males and 7 females with mean age 35 +/- 7 years were studied. There were 47 smokers (smoking 21.5 cigarettes per day for a mean of 16 years) and 15 non-smokers (control group). Resting pulmonary function was normal in both groups, however smokers had significantly lower VC as well as MEF 50 and MEF 75. A maximal incremental exercise on cycloergometer using ramp protocol was performed. Ventilatory parameters (breath by breath method) together with transcutaneous oxygen saturation (every minute), heart rate (continuously) and blood pressure (every minute) were recorded. Significant differences in exercise tolerance in studied groups were observed. Smokers tolerated a lower maximal workload for a shorter time and deferred significantly in both maximal oxygen consumption and oxygen consumption at anaerobic threshold. Five persons, all smokers did not reach the anaerobic threshold. In five smokers a decrease in ECG ST segment was observed. No differences were found in breathing reserve, heart reserve or maximal oxygen pulse. It seems that a decreases exercise performance is due to cardiac limitation.     

Nasal response in subjects undergoing challenges by inhaling occupational agents causing asthma through the nose and mouth

BACKGROUND: Subjects with occupational asthma (OA) often report nasal symptoms, but nasal reactions to inhalation challenges with occupational agents have not been well characterized. METHODS: Fifteen subjects with OA (eight due to high-molecular-weight agents--flour and guar gum--and seven due to isocyanates) underwent inhalational challenges using closed-circuit devices (dry particles for high-molecular-weight agents and gas generator for isocyanates) on two occasions, 2-4 weeks apart in a random fashion. On one occasion, they inhaled through the nose and, on another, through the mouth. The FEV1 was monitored for up to 8 h afterward, and symptoms were documented with a standardized questionnaire on nasal symptomatology, assessment of nasal resistance by rhinomanometry, and nasal lavage for the examination of cells and mediators. RESULTS: Inhaling through the mouth and through the nose: 1) yielded similar asthmatic responses (25+/-8% and 22+/-10% maximum changes in FEV1) 2) more than doubled the peak nasal symptoms and nasal resistance when the maximum daily response was compared with prechallenge results. This increase occurred on the days of inhalational challenges through the mouth and through the nose. There were some significant responses assessed by nasal lavage in terms of cells and mediators, again with no differences between the days of challenges through the mouth and through the nose. CONCLUSIONS: Inhaling occupational agents of high or low molecular weight, including isocyanates, whether through the mouth or nose: 1) results in a similar asthmatic response 2) causes a significant nasal response in terms of symptoms and an increase in nasal resistance 3) causes some significant changes in inflammatory cells and mediators.     

The pharmacokinetics of teniloxazine in healthy subjects and patients with hepatic cirrhosis

The single-dose and steady-state pharmacokinetics of teniloxazine, an investigational drug with antidepressant and anti-anoxic properties, were compared in 12 healthy volunteers and 12 cirrhotic patients, following oral administration of 80 mg teniloxazine maleate every 12 h for 7 days. In healthy volunteers, an increase in oral clearance, CLo (from a mean (s.d.) value of 14.6 (3.9) to 18.0 (6.6) ml min-1 kg-1; mean % ratio between the two values (95% CI), 123 (94-151)) and a significant shortening of t 1/2 (from 6.2 (2.7) to 4.8 (1.4) h; mean % ratio (95% CI), 78 (58-98)) were observed upon repeated administration, suggesting autoinduction of teniloxazine metabolism. In cirrhotic patients, the pharmacokinetic parameters of teniloxazine remained essentially invariant with time. Compared with normal subjects, CLo was about halved in cirrhotic patients, whereas t 1/2 was more than doubled. As a consequence of these modifications, the multiple-dose regimen resulted in a two-fold mean drug accumulation in cirrhotic patients, compared with virtually no accumulation in healthy volunteers. Although no adverse events were noted in either study group, it is suggested that maintenance doses for patients with liver dysfunction should initially be at the lower end of the therapeutic range.     

Coagulation and fibrinolysis after moderate and very heavy exercise in healthy male subjects

OBJECTIVES To correlate renal function with the site of the ectopic orifice in patients with a single ectopic ureter and to evaluate the role of ureteric reimplantation in the preservation of renal function. PATIENTS AND METHODS: Forty-four patients (41 female, age 1.5 months to 20 years) with a single ectopic ureter have been managed in our institution in the last 21 years. The classical symptom of continuous wetting with intermittent normal micturition was reported in most of the female patients. The investigative evaluation included intravenous urography (i.v.U), cysto-urethroscopy, vaginoscopy with retrograde ureteric catheterization, micturating cysto-urethrography (MCU) and ultrasonography. Diuretic renography was carried out in four patients after it became available in 1992. Renal function was assessed in relation to urinary tract anomalies and with outcome after ureteric re-implantation. RESULTS: Thirty-eight patients (two males) had a unilateral ectopic ureter; the ectopic orifice was vaginal in 12, vestibular in 11, urethral in nine, at the bladder neck in two, the seminal vesicle in one and undetermined in three. Twenty-one patients had renal and/or ureteric abnormalities, with reflux detected on MCU in three ureters. Associated anomalies included hypospadias (two, one female), skeletal anomalies (two), anorectal malformations (three), cryptorchidism (two), and unilateral cystic ovary (one). Two patients had preoperative hypertension. In 15 patients, renal function was considered sufficient to justify ureteric reimplantation, 14 of whom regained continence. One girl had suprapubic leakage from the bladder and died during secondary nephroureterectomy. Another girl had persistent incontinence; she was found to have contralateral duplex ureters with a vestibular ectopic orifice and was cured after upper polar heminephroureterectomy. i.v.U and renography carried out in two patients each within 4 weeks of surgery showed a moderate improvement in renal function. Eight patients reported for follow-up after ureteric reimplantation (mean duration 11 months); none had hypertension or urinary infection. Twenty-three patients with rudimentary kidneys underwent nephroureterectomy. Histopathological examination of the excised kidneys showed moderate to severe dysplasia with chronic pyelonephritis. Six patients (one male) had bilateral single ectopic ureters, with normal renal function in the five females. Unilateral reimplantation in the boy resolved the symptoms; one girl died before surgery and the other four underwent bilateral ureteric reimplantation, after which one was dry for up to 3 h while the other three were incontinent, one of whom subsequently underwent urinary diversion. CONCLUSIONS: There was no clear correlation of renal function with the site of the ectopic ureteric orifice, as most of the patients with a vaginal ectopic ureter had sufficient renal function to justify renal preservation. Ureteric reimplantation preserved renal function, although the improvement after surgery was determined by the degree of renal dysplasia.     

Response to exercise in patients after repair of tetralogy of Fallot

Cardiac catheterization and submaximal exercise testing was performed in 38 patients after repair of tetralogy of Fallot (TF), and compared to 6 control patients who had functional murmurs. Cardiac index, heart rate, and stroke volume index were significantly lower in the TF group than in the control group. Right and left ventricular end-diastolic pressure increased significantly during exercise, which was not found in the control group. Total pulmonary vascular resistance (TPVR), which decreased significantly with exercise in the control group, did not change remarkably during exercise. TPVR was significantly higher in the TF group than in the control group both at rest and during exercise. Several factors were compared between patients with good cardiac index (> 5.0 l/min/m2; Group 1) and poor cardiac index (< 5.0 l/min/m2; Group 2) during exercise. Stroke volume index, right ventricular ejection fraction at rest were significantly higher in Group 1 than Group 2. TPVR, right and left ventricular end-diastolic and end-systolic volume index were significantly lower in Group 1 than in Group 2. There was no significant difference in heart rate, left ventricular ejection fraction, residual pulmonary stenosis, right to left ventricular systolic pressure ratio, and severity of pulmonary regurgitation between two groups. These findings indicate that abnormalities of exercise tolerance in patients after repair of TF were related to poor response of heart rate, pulmonary vascular resistance, and systolic and diastolic ventricular function.     

Angiotensin-converting enzyme activity in stools of healthy subjects and patients with celiac disease

Angiotensin-converting enzyme (ACE) is a dipeptidylcarboxypeptidase that occurs in three types of cells: endothelial, epithelial, and neuroepithelial. ACE activity is present in plasma, urine, and vascular endothelium. High levels of ACE are found in the brush border of human small bowel. The aim of this study was to evaluate ACE activity in human stools and to find a correlation with the intestinal loss of epithelial cells. Fifteen healthy subjects (HS) (8 males, 7 females; age range 6-56 years), 20 patients with celiac disease (CD) (11 males, 9 females; age range 15-53 years), and 18 patients with CD in remission after a gluten-free diet (CD-GFD) (8 males, 10 females; age range 14-54 years) were enrolled in the study. The fecal ACE activity was measured in all groups. Fecal samples were kept at -20 degrees C for a subsequent test. In HS, fecal ACE activity was 21.03 +/- 16.17 nmol/min/100 g (mean +/- SD). In patients with CD with subtotal mucosa atrophy, ACE activity was significantly higher (113 +/- 88.94) than in HS and CD on GFD (36.65 +/- 23.9). We have demonstrated ACE activity in human stools. ACE activity in stools seems to derive from the microvilli of the intestinal mucosa, thus suggesting the potential usefulness of ACE determination as an index of enterocyte damage.     

Uncomplicated asthma in adults: comparison of CT appearance of the lungs in asthmatic and healthy subjects

A study was undertaken to define the computed tomographic (CT) appearance of the lungs in subjects with uncomplicated asthma and to compare the prevalence of bronchial dilatation at CT in asthmatic and healthy subjects. Clinical features, pulmonary physiologic findings, chest radiographs, and high-resolution CT scans of 48 asthmatic subjects were reviewed. Forty-one (85%) of the 48 asthmatic subjects were undergoing bronchodilator therapy, 28 (58%) were undergoing steroid therapy, and 21 (44%) were cigarette smokers. Twenty-seven healthy control subjects underwent limited high-resolution CT. At selected CT levels, any bronchus with an internal diameter greater than that of the accompanying pulmonary artery was considered dilated. In the asthmatic subjects, 153 (36%) of 429 bronchi evaluated met criteria for bronchial dilatation compared with 37 (26%) of 142 bronchi in the control group (P < .05). Because bronchial dilatation demonstrated at CT did not correlate with clinical data, the authors conclude a bronchus larger in diameter than the adjacent vessel is not sufficient evidence to diagnose cylindric bronchiectasis.     

Echocardiographic evaluation of the Valsalva Maneuver in healthy subjects and patients with and without heart failure

The Valsalva maneuver was evaluated by echocardiography in three groups: A) 10 normal volunteers, B) 10 patients with no history of heart failure and normal ejection fractions, and C) 10 patients with heart failure and depressed ejection fractions. Groups A and B had a significant fall in left ventricular internal dimensions and calculated stroke volume by end strain which returned rapidly to baseline in recovery without significant overshoot. Arterial pressure showed a signoidal strain pattern with a normal overshoot in early recovery in all group B patients. In group C ventricular dimensions did not diminish during strain; arterial pressures showed a "square wave" pressure elevation during strain without an overshoot in recovery. Echocardiography allows a new approach to evaluate further the left ventricular response to the Valsalva maneuver. Patients with severely depressed ejection fractions, unlike those with normal ventricular function, are unable to alter stroke output in response to acutely increased intrathoracic pressure. A square wave pressure response is a likely consequence of a fixed stroke output during the strain maneuver.     

The kinin system in rhinitis and asthma

During detailed visual function testing, pattern-reversal visual evoked potentials (VEP), generated by different spatial frequencies (3 c/d, 1 c/d and 0.6 c/d) and visual contrasts (100% and 10%) were recorded in 21 adolescent and young adult phenylketonuric (PKU) patients (11 females and 10 males; mean age 14.8 years, range 9-22.8) on and off diet. In 14 of the 21 patients, disease had been detected at neonatal screening and in 7 later. Ten age-matched healthy subjects acted as controls. Recordings in more than 40% of eyes in the whole group and 30% of eyes in the screening subgroup showed a prolonged P100 latency. All visual pattern stimuli elicited a significantly longer P100 latency in PKU patients than in controls. VEP latencies to 3 c/d, 1 c/d and 1 c/d with 10% contrast--but not to 0.6 c/d--were longer in patients off diet than in patients on diet. No differences were found between VEP latencies in early- and later-detected subjects. To study the link between biochemical variables and VEP latencies, we envisaged either a linear relationship between recent exposure to phenylalanine (Phe) and VEP abnormalities or a threshold model considering phenylalanine (Phe) concentrations among the factors influencing VEP latencies. The correlation analysis detected an association between plasma Phe concentrations and abnormal VEP latencies, predicting that plasma Phe concentrations > 901 mumol/L would prolong VEP latencies to 1 c/d; concentrations > 879 mumol/L would prolong latencies to 3 c/d; and concentrations > 898 mumol/L would prolong latencies to 1 c/d with 10% contrast.     

Regulation of hepatic glucose production in healthy subjects and patients with non-insulin-dependent diabetes mellitus

The regulation of endogenous glucose production is central to the control of blood glucose concentrations. In non-insulin-dependent diabetes mellitus (NIDDM), increased endogenous glucose production contributes to fasting hyperglycaemia. Gluconeogenesis appears to be exaggerated in NIDDM, and it may be hypothesized that an enhanced release of gluconeogenic precursors is responsible for increased total glucose output. However, it would appear that substrate-induced stimulation of gluconeogenesis fails to increase total glucose production in healthy humans and NIDDM patients. This autoregulation of endogenous glucose production may be attained by inhibition of glycogenolysis and/or gluconeogenesis from endogenous substrate. It has also been observed that stimulation of intrahepatic disposal of neoformed glucose (mainly as glycogen synthesis) contributes to autoregulation. These observations support the concept that intrahepatic disposal of glucose-6-phosphate plays a major role in the control of endogenous glucose production.     

Cardiopulmonary exercise testing in the evaluation of patients with occupational asthma and reactive airways dysfunction syndrome

Oxidative stress has been known to play important roles in various inflammatory diseases of lung such as allergic bronchitis, dust particle-induced inflammatory diseases, or chronic bronchitis. However, the effects of oxidants on Cl- secretion in tracheal epithelia have not been determined. To examine the effects of oxidants on Cl- secretion of the airway epithelia rat tracheal epithelial cells were cultured on porous filters and short circuit current (Isc) was measured in an Ussing chamber system. t-Butylhydroperoxide, which was widely used as a model substance to study the mechanism of cell injury resulted from oxidative stress, induced a transient increase in Isc by dose-dependent manner. The response was not observed in Cl(-)-free medium, and inhibited by 100 microM bumetanide. N(-Diphenyl-1,4-phenylene-diamine (DPPD, 5 microM), an inhibitor of lipid peroxidation, blocked the t-butylhydroperoxide response. When t-butylhydroperoxide was added after the administration of forskolin or H-89, a protein kinase A inhibitor, the t-butylhydroperoxide-induce Isc increase was abolished. Pretreatment of indomethacin (10 microM) completely inhibited the t-butylhydroperoxide response, but pretreatment of thapsigargin (1 microM) did not, t-Butylhydroperoxide induced gradual increases in cytosolic Ca2+ level, and increased [3H]arachidonic acid release in the presence of thapsigargin. These results indicate that t-butylhydroperoxide stimulates Cl-secretion via activation of phospholipase A2 and subsequent production of cyclooxygenase metabolities by Ca(2+)-dependent and -independent mechanisms.     

Submillimeter-resolution MR of the endolymphatic sac in healthy subjects and patients with Menière disease

PURPOSE: To evaluate the utility of submillimeter resolution MR imaging for direct depiction of functional soft-tissue components of the intraosseous endolymphatic duct and sac in healthy subjects and in patients with Menière disease. METHODS: Axial MR images were acquired of 14 patients with Menière disease and 14 healthy volunteers at 1.5 T with a short-echo-time steady-state 3-D gradient-echo sequence. Seven volunteers and eight patients were also studied with a T1-weighted 3-D spoiled gradient-echo sequence. T1/T2 relaxation times were estimated from studies with multiple flip angles. RESULTS: Independent of the acquisition method, intraosseous endolymphatic ducts and sacs were seen unambiguously in the ears of 20 of 21 healthy subjects but in only four of 12 asymptomatic and two of 10 symptomatic ears of patients with Menière disease. Other labyrinthine structures were well depicted in all subjects. Furthermore, shorter relaxation times were measured for the contents of the vestibular aqueduct than for other labyrinthine structures. CONCLUSION: In our high-resolution study, the intraosseous portions of the endolymphatic ducts and sacs were depicted in most of the healthy subjects. They were frequently not seen in either ear of patients with unilateral Menière disease, presumably because of their small size.     

Fasting values of carbohydrate--and lipid metabolism in healthy subjects and in patients with diabetes mellitus

In 106 healthy adults and 34 in-patients with diabetes mellitus the venous blood concentration of lactate, pyruvate, hydroxybutyrate and acetacetate was measured. In healthy men we found a lactate concentration of 7.7 mg/100 ml (7.11-8.15), a pyruvate level of 0.37 (0.34-0.44) mg/100 ml, a level of acetoacetate of 0.41 mg/100 ml(0.38-0.47) and a level of hydroxybutyrate of 0.47 mg/100 ml(0.29-0.70).