Lactate release and uptake in hepatoma 7288CTC perfused in situ with L-[(U)-14C]lactate or D-[(U)-14C]glucose

Arteriovenous differences (AVD) for glucose and lactic acid measured across tissue-isolated rat tumors in vivo have shown that individual tumors with similar rates of glucose consumption may either release or utilize lactic acid. The experiments described here investigated the relationships among arterial blood lactate concentrations and tumor lactate and glucose balances. AVDs for lactate, pyruvate, glucose, 14CO2, PO2, PCO2, pH, and lactate specific activities were measured across 17 tissue-isolated 7288CTC hepatomas perfused in situ with arterial blood containing 2.5 to 14.4 mmol/L lactate and either L-[(U)-14C]lactic acid or D-[(U)-14C]glucose. Measurements were made over a range of blood flow rates from 60% to 200% of the mean in vivo rate, 0.11 mL/min. Data collected during steady states were compared by regression analysis. Tumor lactate balance and the arterial blood lactate concentration were directly related (r = .895, n = 22, P < .01). Net negative and positive balances occurred below and above approximately 6.5 mmol/L arterial blood lactate, respectively. The mean intratumor lactate concentration for all tumors was 6.9 +/- 1.0 mmol/L (mean +/- SD, n = 13). Rates of 14C-lactate oxidation to 14CO2 (r = .716, n = 18, P < .01) and tumor venous/arterial blood 14C-lactate specific activity ratios (r = .845, n = 19, P < .01) were low during lactate release and were increased during lactate uptake. Total arterial blood lactate removal estimated from chemical and isotopic analyses was 23.1% +/- 11% and 43.0% +/- 16% (P < .05), respectively, for six lactate-utilizing tumors. Perfusions performed with 14C-glucose showed that approximately 50% of the glucose consumed during net negative lactate balance was released as 14C-lactate to the tumor venous blood, whereas only 5% was released as 14C-lactate during net positive lactate balance. The data support the following conclusions: Arterial blood lactate controls net lactate balance in solid tumors; high concentrations increase uptake. Lactate uptake inhibits lactate formation from glucose without changing the glucose balance. Lactate is release during net lactate uptake. Since lactate uptake may exceed glucose uptake, arterial blood lactate can be a substrate for tumor energy metabolism and growth.     

Comparison of the one-gram d-[14C]xylose breath test to the [14C]bile acid breath test in patients with small-intestine bacterial overgrowth

In twelve patients with culture-proven bacterial overgrowth of the small intestine, the ability of a newly-developed one-gram d-[14C]xylose breath test to detect bacterial overgrowth was compared to that of the [14C]bile acid breath test. All patients manifested excessive production of breath 14CO2 after the administration of one gram [14C]xylose, with 83% of the patients being abnormal within the first hour of testing. In contrast, during the [14C]bile acid breath test, four of the twelve patients had no period of excessive 14CO2 production (above the 95% confidence range of controls). Nutrient malabsorption (fat, cobalamin, xylose) was seen with both true-positive and false-negative bile acid breath tests. The one gram [14C]xylose breath test, utilizing a substrate with more predominant absorption in the proximal small intestine and which can be catabolized by Gram-negative aerobic bacteria, appears to have a greater degree of sensitivity and specificity than the bile acid breath test in detecting the presence of small-intestine bacterial overgrowth.     

O-ethyl 14C]phenacetin O-deethylase activity in human liver microsomes

The activity of human liver microsomal cytochrome P450 1A2 (CYP1A2) is readily estimated by following the O-deethylation of [O-ethyl 14C]phenacetin (PODase). The basis of the assay is the quantitative measurement of [14C]acetaldehyde, remaining in the supernatant of assay incubates, after extraction of unmetabolized [O-ethyl 14C]phenacetin with charcoal. In the presence of native human liver microsomes (K(m) = 54 +/- 27 microM; V(max) = 14 +/- 2.3 nmol/hr/mg; mean +/- SD; N = 3 different livers) and human B-lymphoblastoid cell microsomes containing cDNA-expressed CYP1A2 (K(m) = 46 microM; V(max) = 55 nmol/hr/nmol CYP), PODase activity conformed to monophasic Michaelis-Menten kinetics. Furthermore, PODase activity in a panel of microsomes prepared from a series of human livers was significantly correlated (r = 0.91; p < 0.001; N = 11) with CYP1A2-selective 7-ethoxyresorufin O-deethylase activity, and was markedly inhibited (> or = 92%) by furafylline (FURA, IC50 = 0.4 microM) and 7,8-benzoflavone (ANF, IC50 = 0.1 microM), two well known CYP1A2 inhibitors. Inhibitors selective for other forms of CYP (e.g. CYP3A, CYP2C, CYP2D6, CYP2E1) elicited a marginal effect (< or = 17% inhibition) at relatively high concentrations (> or = 10.K(i)). It is concluded that the inhibition of human liver microsomal CYP1A2 activity can be readily determined by using a charcoal-based radiometric method employing [O-ethyl 14C]phenacetin as substrate.     

Nutritional status of gastric cancer patients after total gastrectomy

A number of causes of malnutrition after total gastrectomy have been proposed. The purpose of this study was to assess nutritional status and to determine the cause of malnutrition after total gastrectomy. We studied 20 gastric cancer patients who had undergone total gastrectomy and immunochemotherapy and 6 normal controls. Nutritional status was assessed by dietary history, anthropometric methods, and serologic measurements. Malabsorption tests included the fecal fat excretion test, D-xylose absorption test, glucose tolerance test, vitamin B12 absorption test using dual isotopes, bacterial culture of jejunal aspirates, and jejunal biopsy. Weight loss was compared to the preoperative status in all patients (average 15%: 59.0 +/- 9.9 vs. 50.2 +/- 7.8 kg, preoperatively vs. postoperatively). Average daily calorie intake was 1586.2 kcal, which is lower than the normal intake of Korean adults (1838 kcal). Malnutrition of skeletal and visceral protein was not found. There was, however, severe fat malnutrition and a deficit of body fat. Postoperatively the body mass index was considerably lower than that preoperatively (22.2 +/- 0.4 vs. 18.9 +/- 0.4 kg/m2; preoperatively vs. postoperatively). With malabsorption tests, the daily excreted amount of fecal fat was 28.6 +/- 3.4 g (mean +/- SD) in patients and 6.9 +/- 0.2 g in controls. There was no significant malabsorption of carbohydrates. In 64.3% (9/14) of patients, vitamin B12 absorption was abnormal; and the serum concentration of vitamin B12, which was significantly related to malabsorption of this vitamin, was lower than normal in 73.7% (14/19). Bacterial overgrowth was not found, and there were no abnormal histologic findings in the jejunal mucosa. These results suggest that poor oral intake and fat malabsorption following total gastrectomy cause malnutrition and that fat malabsorption may be related to relative pancreatic insufficiency.     

The effects of various diphosphonates on a rat model of cardiac calciphylaxis

Compartmental analysis of the disappearance curve of serum cholesterol specific activity after an intravenous administration of a tracer does of cholesterol-4-14C was carried out in five patients with resection of the distal small intestine, cecum, and proximal colon. The data fit best a two compartment model in all five cases with the rapidly exchangeable pool of 16.6+/-3.2 g (mean +/- SD, 60% of the mean of 15 normal subjects) and the slowly exchangeable pool of 31.5 +/- 10.9 g (65%). The reduction of the pool sizes was associated with a shorter mean transit time of cholesterol, 22.15 +/- 8.07 days (40%) and increased turnover rate, 2.42 +/- 0.72g/ day (172%). Direct fecal analysis for the neutral sterols and bile acids derived from the exchangeable pool confirmed the turnover rate obtained from the compartmental analysis. The increased fecal excretion was mainly in the bile acid fraction. The study suggests that the ileal and proximal colon resection results in bile acid malabsorption which, in turn, increases hepatic cholesterol and bile acid synthesis. The synthetic rates, however, could not compensate totally for the excretory rate. Therefore, the pool size decreased to a new low steady state of equilibrium.     

Evaluation of the use of beta-sitostanol as a nonabsorbable marker for quantifying cholesterol absorption

For over a decade investigators have quantified cholesterol absorption by comparison of dietary intake and fecal excretion of isotopic cholesterol with that of beta-sitosterol as a "nonabsorbable" marker. However, beta-sitosterol might not be ideal due to its potential for absorption. We therefore carried out two studies to evaluate a new marker with less potential for absorption, [3H]beta-sitostanol. In the first study (Study I, n = 22), we compared absorption of [3H]beta-sitostanol and [14C]beta-sitosterol in a simultaneous dual-label continuous feeding ("phytosterol absorption") experiment. We observed a consistently higher ratio of [3H]beta-sitostanol/[14C]beta-sitosterol in the stool relative to diet on the first day of fecal collection (6.1% +/- 3.2% loss of [3H]beta-sitosterol, range 3-12%), but thereafter, the ratio in stool was similar to that in diet. In Study II (n = 23), we compared cholesterol absorption directly using [3H]beta-sitosterol and [14C]cholesterol, and, separately, [3H]beta-sitostanol and [14C]cholesterol. We found that mean absorption between the two methods was similar (45% +/- 11% versus 44% +/- 10%, respectively, P difference = 0.40), and the two methods correlated well with one another (r = 0.83) when samples from all available days were used. Variability between the two methods was greater in individuals who absorbed more than 40% of cholesterol. Cholesterol loss on day 2 estimated from use of beta-sitostanol as a nonabsorbable marker was predictive of absorption using ratios from days 4-6 (r = 0.80). These results suggest that, for the majority of subjects, beta-sitosterol is a valid nonabsorbable marker for cholesterol absorption.     

MR guidance of laser disc decompression: preliminary in vivo experience

BACKGROUND: The mechanism of atrial natriuretic peptide (ANP) release has been difficult to demonstrate in patient studies because of inaccuracies in measuring atrial volumes using conventional techniques. METHODS: Magnetic resonance imaging was performed in 28 clinically stable patients (New York Heart Association class 3) with chronic heart failure to determine right atrial (RA), left atrial (LA), and ventricular volumes. In addition, right heart catheterization was serially performed and plasma ANP levels (in picograms per milliliter) were drawn from the right atrium. RESULTS: Five patients had to be excluded from data analysis for technical reasons. The remaining 23 patients had the following hemodynamic measurements (mean +/- SD): RA mean pressure 7+/-5 mm Hg, pulmonary artery mean pressure 28+/-10, pulmonary capillary wedge pressure 21+/-8 mm Hg, and cardiac index 2.9+/-1.4 (L/min/m2), respectively. Plasma ANP levels were significantly elevated at 162+/-117 (normal range 20 to 65 pg/ml, p < 0.05), as were LA and RA volumes compared with healthy controls (RA volume 128+/-64 ml vs 82+/-25 ml, p < 0.05; LA volume 157+/-54 ml vs 71+/-24 ml, p < 0.01, respectively). ANP showed a stronger relation with atrial volumes (RA volume, r = 0.91, p = 0.0001; LA volume, r = 0.80, p = 0.001) than with atrial pressures (RA mean pressure, r = 0.45, p = 0.03; pulmonary capillary wedge pressure, r = 0.67, p = 0.001). A subgroup analysis of patients with increased RA or LA volumes (>1 SD of mean of controls) revealed a stronger relation between ANP and RA volumes than between ANP and LA volumes. CONCLUSIONS: These data suggest that increased right heart volume with subsequent increased atrial stretch is the major determinant for ANP release in patients with stable CHF.     

Managing complex orthodontic problems: the use of implants for anchorage

In congestive heart failure captopril modifies the left ventricular filling pattern mainly by unloading the heart. We investigated whether the structural characteristics of the left ventricle may influence the acute effects of captopril on this pattern in patients with untreated hypertensive (H group, 6 patients) or idiopathic (I group, 14 patients) cardiomyopathy. We evaluated changes of pulsed Doppler mitral flow, of systemic arterial and wedge pulmonary pressures 40 min after 25 mg captopril administered sublingually, and correlated these changes with the M-mode echocardiographic relative wall thickness index (h/r). Baseline mean arterial pressure (H = 137 +/- 20 mm Hg, mean +/- SD, I = 95 +/- 19 mm Hg; p < 0.001), and h/r (H = 0.38 +/- 0.03, I = 0.28 +/- 0.09; p < 0.05) were greater in the high blood pressure group; wedge pressure, echocardiographic biplane ejection fraction, and Doppler indexes of the left ventricular filling were similar in the two populations. After captopril, ejection fraction did not change significantly, mean arterial pressure decreased significantly in hypertensive patients (H group, baseline = 137 +/- 20, captopril = 119 +/- 10, p = 0.02; I group, baseline = 95 +/- 19, captopril = 90 +/- 24, p = nonsignificant), and the wedge pressure was reduced by the same extent in both groups (H group, baseline = 27.7 +/- 3, captopril = 21 +/- 7, p < 0.05; I group, baseline = 20 +/- 12, captopril = 15 +/- 8, p < 0.05). In the H group early mitral flow increased [(E wave integral) x (mitral annulus area)] by 38 +/- 15%, and was almost steady in the I group (-1.3 +/- 30%; group H vs. I = p < 0.01); late mitral flow [(A wave integral) x (mitral annulus area)] showed a pattern exactly opposite to this (H = +0.4 +/- 40%, I = +38 +/- 19; p < 0.01). In the whole population there was a significant correlation between the early/late flow ratio variations and baseline h/r (r = 0.6, p < 0.05). In chronic congestive heart failure, changes in left ventricular filling with captopril are related to h/r: a higher index, as recorded in the H group, is associated with "true normalization' of the filling pattern after captopril; a lower index, as recorded in the I group, is associated with "pseudonormalization' despite a similar decrease of left ventricular filling pressure.     

Prednisone as adjunctive therapy in the management of pulmonary tuberculosis. Report of 12 cases and review of the literature

A retrospective chart review was conducted over a 5-year period (1988 to 1993) in a tertiary inpatient care center on the effects of the addition of prednisone to the treatment regimens of 12 patients with pulmonary tuberculosis who continued to spike high temperatures and lose weight while showing bacteriologic response to effective antituberculosis therapy. After exclusion of other causes of fever, all patients were treated with 20 to 60 mg of prednisone daily until normalization of temperature and clinical improvement. Analyzed data included twice weekly sputum bacillary count, temperature record every 4 h, weekly patient weight, serum albumin level, liver function tests, and chest roentgenogram. The patients continued to spike temperatures of 38.3 degrees C to 40.5 degrees C (mean +/- SD = 39.6 degrees C +/- 0.6 degrees C) even after 18 to 53 days (mean +/- SD = 33.9 +/- 9.8 days) of antituberculosis therapy. Within 24 h after the addition of oral prednisone, temperature decreased in all 12 patients from a daily highest spike mean of 39.6 degrees C +/- 0.6 degrees C (SD) to 38.1 degrees C +/- 0.6 degrees C (SD) (p = 0.0022). The duration of required prednisone therapy was 20.1 +/- 9 days (mean +/- SD). During this period patients' appetites improved, and their weight increased from a mean (+/- SD) of 53.6 +/- 5.7 kg to 58.1 +/- 6.4 kg (p = 0.0022). The serum albumin level increased from a mean (+/- SD) of 2.51 +/- 0.4 g/dL to 3.21 +/- 0.4 g/dL (p = 0.0033). All the patients also showed clinical evidence of a decrease in toxic reactions associated with tuberculosis. There were no side effects from the addition of prednisone. This study shows the need for randomized controlled clinical trials to clarify the role of prednisone as adjunctive therapy in the management of pulmonary tuberculosis.     

Proximal tubular basement membrane width in insulin-dependent diabetes mellitus

Although glomerular structure has been studied, careful evaluation of tubular basement membrane (TBM) structure in diabetes in humans has not been done. We measured proximal TBM width, glomerular basement membrane (GBM) width, mesangial fractional volume [Vv(Mes/glom)], mesangial matrix fractional volume [Vv(MM/glom)], and cortical interstitial fractional volume [Vv(Int/cortex)] in 35 insulin-dependent diabetic (IDDM) patients and 20 controls. The patients' mean age was 28 +/- 10 years (X +/- SD) and IDDM duration was 17 +/- 8 years. Twenty-five patients were normoalbuminuric, four microalbuminuric, and six had overt proteinuria. Tubular basement membrane and GBM widths were measured by the orthogonal intercept method and mesangial and interstitial parameters by point counting. The TBM width was 915 +/- 320 nm in IDDM patients and 558 +/- 116 nm in controls (P = 0.0005); the TBM width was also increased in normoalbuminuric patients (849 +/- 297 nm, P = 0.0005). The TBM width was strongly directly related to GBM width (r = 0.67, P < 0.001), Vv(Mes/glom) (r = 0.52, P < 0.01), and Vv(MM/glom) (r = 0.61, P < 0.001), but only weakly to Vv(Int/cortex) (r = 0.29, NS). The TBM width (r = 0.65, P < 0.001) and GBM width (r = 0.65, P < 0.001) were strongly related to hemoglobin A1C (HbA1C), while the Vv(Mes/glom) (r = 0.35, P < 0.05) and Vv(Int/cortex) (r = 0.30, NS) were only weakly related to HbA1C. Thus, increased proximal TBM width is an integral component of early nephropathology in IDDM patients. This study suggests that the metabolic disturbances of diabetes are strong determinants of the constellation of structural abnormalities occurring in human diabetic nephropathy.     

Serum placental protein 14 (PP14) levels in patients with threatened abortion

Serum placenta protein 14 (PP14) were significantly lower serum levels in patients with threatened abortion at 10 to 20 weeks controls than in normal (normal group, n = 133, median: 52,0 microgram/l [16-83, SD: 17,9],risk group: n=20, median: 34,0 microgram/l [13-63, SD: 13,7]).     

Factors affecting the respiratory ratio during cardiopulmonary by-pass

Despite the wide use of hypothermic cardiopulmonary bypass (CPB) during open heart surgery there is little information about the patient metabolism. In particular no complete studies addressed the assessment of the respiratory ratio (RR) during CPB at different core temperatures. Therefore a clinical study was performed in order to evaluate the oxygen consumption (VO2) and carbon dioxide production (VCO2) in adult patients with valvular or coronary heart disease undergoing CPB. Twenty-five patients (16 male, 9 female) aged between 26 and 76 (54.2+/-12.4 mean +/- SD) were the subjects of this study. Measurements (102) were taken at various perfusion flow rates (from 1.6 to 2.9 L/min(-1) x m(-2)) and temperatures (from 24 to 37 degrees C). Arterial and mixed venous gas analyses were performed and O2 and CO2 concentrations were calculated, including the carbamate contribute. We calculated VO2, VCO2 and then RR from artero-venous differences in O2 and CO2 contents. Both VO2 and VCO2 showed a positive linear correlation with temperature (r = 0.82 and r = 0.59 respectively) and with blood flow rate (r = 0.61 and r = 0.29 respectively). The mean RR was 0.78+/-0.28 and more than 84% of RR values fell in the range 0.5-1.2. No significant correlation between RR and temperature and blood flow rate was observed. VCO2 and RR showed a positive linear correlation with the gas to blood flow rate ratio (r = 0.37 and r = 0.49 respectively).     

Correlation of nicotinic binding with neurochemical markers in Alzheimer's disease

The loss of neocortical synapses that occurs in Alzheimer's disease (AD) has been shown to correlate with cognitive decline. In addition, marked losses in the cholinergic system in AD, specifically choline acetyltransferase (ChAT) activity and high affinity presynaptic neuronal nicotinic cholinergic receptors (nAChRs), have also been described. We hypothesized that in AD, the loss of [3H]-ligand binding to nAChRs, which are largely presynaptic, would correlate with changes in two other presynaptic markers: synaptophysin (Syn), a measure of synaptic density, and ChAT activity. The midfrontal (MF) cortex of 36 autopsy confirmed (NIA and CERAD criteria) AD patients (mean death age +/- SD 80.1 +/- 8.4 years) who met NINDS-ADRDA criteria for a clinical diagnosis of probable or possible AD, and 11 nondemented controls (mean death age +/- SD 77.9 +/- 8.0) were examined. Synapse counts were quantified by a dotimmunobinding assay for Syn. ChAT activity was assessed by standard biochemical assays. Nicotinic cholinergic receptor binding was assayed using the high affinity nicotinic agonist [3H]-(+/-)-epibatidine ([3H]-EPI). The mean +/- SD Syn in AD (83.4 +/- 31.9 arbitrary units (AU)/mg protein) was significantly lower than controls (126.1 +/- 19.9, p = 0.0003; t-test). The mean ChAT activity in AD (139.0 +/- 75.6 nmol ACh/hr/100 mg protein) was significantly lower than controls (219.6 +/- 70.8, p = 0.004). The mean [3H]-EPI total binding in AD (6.2 +/- 2.8 fmol/mg protein) was significantly lower than controls (14.8 +/- 3.2; p < 0.0001). Syn correlated with [3H]-EPI binding in AD (r = 0.48, p = 0.006; Pearson) but ChAT did not (r = -0.20, p = 0.34). We conclude that loss of high affinity nAChR binding correlates with loss of synapses in AD. The lack of correlation between [3H]-EPI binding and ChAT activity suggests that the targeted receptor populations may not be located exclusively on cholinergic neurons.     

Ferrochelatase activities in patients with erythropoietic protoporphyria and their families

Ferrochelatase, estimated as zinc chelatase, was measured in the lymphocytes of 30 patients with erythropoietic protoporphyria (EPP), in 35 first- or second-degree relatives of patients with EPP, and in 50 healthy controls. In 30 EPP patients the zinc chelatase level (mean +/- standard deviation, SD) was 0.45 +/- 0.10 nmol of zinc protoporphyrin per hour per milligram of protein, in 14 EPP carriers the zinc chelatase level (mean +/- SD) was 0.42 +/- 0.09 and in 50 healthy controls the zinc chelatase level (mean +/- SD) was 0.84 +/- 0.27. All patients with EPP were also demonstrated to have an elevated protoporphyrin level in their red blood cells: the erythrocyte protoporphyrin levels were as follows EPP patients (mean +/- SD) 1300 +/- 758 nmol protoporphyrin/dl, EPP carriers (mean +/- SD) 60 +/- 24, and healthy controls (mean +/- SD) 50 +/- 25 (P < 0.001 for EPP patients compared to controls and EPP carriers). The families of 12 out of 15 EPP patients were examined with respect to the mode of inheritance of the disorder. Of 35 relatives, 14 were carriers of EPP, as characterized by reduced zinc chelatase activity in lymphocytes and by a normal protoporphyrin level in red blood cells. None of the 14 EPP carriers had presented with clinical symptoms of EPP. The mod of inheritance was autosomal dominant in seven of the 12 examined families, and autosomal recessive in two. In two families only one parent could be investigated, but we nevertheless concluded that the inheritance was autosomal dominant. Inheritance in one EPP family could not be elucidated as both parents showed normal zinc chelatase levels and did not demonstrate abnormal erythrocyte protoporphyrin levels.     

Physiological responses in nonheat acclimated horses performing treadmill exercise in cool (20 degrees C/40% RH), hot dry (30 degrees C/40% RH) and hot humid (30 degrees C/80% RH) conditions

The aim of the present study was to determine the effect of different environmental conditions on physiological response to exercise. Four winter acclimatised, nonheat acclimated horses of different breeds were exercised at 20 degrees C/40% RH (CD), 30 degrees C/40% RH (HD) and 30 degrees C/80% RH (HH). The exercise test was designed to represent the structure and intensity of a One star Speed and Endurance test (competition exercise test [CET]). All 4 horses were able to complete the full CET (60 min + 30 min active recovery) in CD and HD, but only one horse completed the CET in HH. Two horses were stopped because of pronounced general fatigue and one because of a right atrial temperature (TRA) of 43 degrees C. Oxygen uptake on each phase was not different between CD and HD, but was higher during Phases B, C and D in HH. Mean peak TRA at the end of Phase D was 40.3 +/- 0.2, 41.6 +/- 0.4 and 42 +/- 0.3 degrees C for CD, HD and HH, respectively. Corresponding, mean peak rectal temperatures (TREC) following Phase D were 39.5 +/- 0.1, 40.6 +/- 0.1 and 41.5 +/- 0.1 degree C for CD, HD and HH, respectively. Mean time to peak TREC was 9.3 +/- 1.1 (CD), 7.3 +/- 1.8 (HD) and 10.8 +/- 2.3 (HH) min and was not significantly different between conditions (P > 0.05). Heat dissipation amounted to 83 +/- 1, 73 +/- 2 and 70 +/- 1% of heat production in CD, HD and HH, respectively. Weight loss was significantly correlated with both body surface area (CD r = 0.85; HD r = 0.87; HH r = 0.81) and bodyweight (CD r = 0.97; HD r = 0.93; HH r = 0.94). The greatest weight loss recorded was 4.6% bodyweight in one horse in HD. The mean increase in exercise intensity over the whole CET (in terms of VO2) of HD and HH and HH compared with CD was 5 +/- 3 and 14 +/- 3% higher, respectively. The exercise induced hyperthermia and the reduced capacity for heat dissipation produced partial compensatory responses in minute ventilation (VE), particularly during Phase C, when the horses were trotting. In HD, the increase in VE was achieved mainly through an increase in frequency, whilst in HH it was achieved through an increase in tidal volume (VT). The horses demonstrated a high degree of tolerance to environmental heat load, suggesting a high thermoregulatory capacity. However, for unacclimatised animals exercising in severely hot and humid conditions, performance may be limited.     

Metabolism of [1-(14)C] and [2-(14)C] leucine in cultured skin fibroblasts from patients with isovaleric acidemia. Characterization of metabolic defects

Leucine metabolism in cultured skin fibroblasts from patients with isovaleric acidemia was compared with that in normal fibroblasts and in cells from patients with maple syrup urine disease using [1-(14)C] and [2-(14)C] leucine as substrates. Inhibitory effects of methylenecyclopropylacetic acid on leucine metabolism in normal cells were also investigated. Production of 14CO2 from [2-(14)C] leucine was very reduced (96-99%) in both types of mutant cells. Radioactive isovaleric acid accumulated in assay media with isovaleric acidemia cells but not in those with maple syrup urine disease cells. Unexpectedly, 14CO2 production from [1-(14)C] leucine was partially depressed (80%) in isovaleric acidemia cells whereas in maple syrup urine disease cells it was strongly depressed (99%) as expected. These two mutant cells were clearly distinguished by detection of 14C-isovaleric acid accumulation after incubation with [2-(14)C] leucine. A pattern of inhibition of leucine oxidation similar to that seen in isovaleric acidemia cells was induced in normal cells by the addition of 0.7 mM methylenecyclopropylacetic acid to the assay medium. The partial inhibition of [1-(14)C] leucine oxidation seen in isovaleric acidemia cells and also in normal cells in the presence of the inhibitor appears to be, at least in part, due to an accumulation of isovalerate in the cells. Isovaleric acid (5-10) mM) inhibited [1-(14)C] leucine oxidation 32-68% when added to the assay medium with normal cells. Addition of flavin adenine dinucleoside to culture medium or assay medium or both did not restore oxidation of either leucine substrate in isovaleric acidemia cells.     

L-[1-(13)C] Phenylalanine oxidation as a measure of hepatocyte functional capacity in end-stage liver disease

BACKGROUND: Liver disease is associated with impaired metabolism of these amino acids phenylalanine and tyrosine. Decreased metabolism of these amino acids leads to abnormal plasma elevations and impaired clearance rates. We have developed a noninvasive breath test that measures hepatic cytosolic enzyme activity. METHODS: The rate of hepatic phenylalanine metabolism was quantitatively calculated from the appearance of 13CO2 in the breath using the nonradioactive tracer L-[1-(13)C]phenylalanine. RESULTS: Normal controls (n = 47) oxidized phenylalanine more than twice that of end-stage liver disease patients (n = 117). Significant differences in the percent of phenylalanine oxidized per hour (mean +/- SEM) were found between controls (7.08% +/- 0.33%, 95% CI: 6.42%-7.74%) and Child Pugh classification patients, class A (4.96% +/- 0.69%, 95% CI: 3.50%-6.42%), class B (2.88% +/- 0.13, 95% CI: 2.39%-3.38%) and class C (1.75% +/- 0.13, 95% CI: 1.50%-2.01%). The phenylalanine breath test score significantly correlated with albumin levels, prothrombin time and total bilirubin. CONCLUSION: We have demonstrated that phenylalanine oxidation is significantly decreased with end-stage liver disease and is correlated with the best clinical measures of liver disease.     

Differential effects of anti-beta2-glycoprotein I and antiprothrombin antibodies on the anticoagulant activity of activated protein C

Antiprothrombin and anti-beta2-glycoprotein I (beta2-GPI) antibodies belong to the family of antiphospholipid (APL) antibodies and represent the phospholipid-dependent inhibitors of coagulation. They may be distinguished by analyzing the coagulation profiles generated by the comparison of the ratios of two coagulation tests, the Kaolin Clotting Time (KCT) and the dilute Russell's Viper Venom Time (dRVVT), commonly adopted for their diagnosis. The KCT profile is caused by antiprothrombin antibodies, whereas anti-beta2-GPI antibodies are responsible for the dRVVT coagulation profile. The presence of aPL antibodies is frequently associated with acquired resistance to activated Protein C (APC-R), but limited information is available regarding the role of the different antibodies in its development. We studied the time-course of activated Factor V (FVa) generation and inactivation in the plasma of 42 patients with well-defined phospholipid-dependent inhibitors of coagulation: 24 displayed the dRVVT coagulation profile, whereas the other 18 cases showed the KCT profile. In normal pooled plasma, the peak values of FVa (mean +/- standard deviation, [SD]: 16.307 +/- 4.372 U/mL) were reached in 4 to 5 minutes and an almost complete inactivation (0.088 +/- 0.123 U/mL) was obtained within 20 minutes. At this time point, values of residual FVa exceeding 2 SD the mean of controls (0.344 U/mL) were considered abnormal. Patients belonging to the KCT coagulation profile group reached the maximal amount of FVa in plasma (22.740 +/- 7.693 U/mL, P = not significant v controls) within 4 to 5 minutes; at 20 minutes, the residual amount of FVa in plasma ranged from 0 to 1.09 U/mL (0.293 +/- 0.298; P = .027), but it was found abnormal in only six of the 18 cases. The time-course of FVa in plasma of patients belonging to the dRVVT coagulation profile group differed from that of normal controls in that the peak values (10.955 +/- 5.092 U/mL) were reached at 10 minutes and the amount of residual FVa at 20 minutes ranged from 0.320 to 14.450 U/ml (2.544 +/- 3.580 U/mL; P = .0191 v normal controls and P = . 0114 v KCT group patients). Twenty of the 24 patients belonging to the dRVVT profile group had an abnormal inactivation of FVa (chi2 = 0.001 v KCT group patients). History of venous thrombosis was experienced by 15 patients: an abnormal rate of FVa inactivation was found in 11 of them (73%) versus 15 of the 27 cases without thrombosis (56%) (x2 = 0.2556). The effect of affinity-purified IgG phospholipid-dependent inhibitors of coagulation on the time-course of FVa generation and inactivation in normal plasma was also investigated. Anti-beta2-GPI, but not antiprothrombin antibodies, hampered the inactivation of FVa by endogenous APC, thus reproducing the behavior of the original plasmas. This effect was strictly beta2-GPI-dependent. In conclusion, our findings confirm that anti-beta2-GPI antibodies identify patients with phospholipid-dependent inhibitors of coagulation at increased risk of thrombosis and suggest acquired APC-R as a possible explanation of the pathogenesis of the thromboembolic events.     

Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators

BACKGROUND: Idiopathic bile acid malabsorption is a poorly recognized cause of chronic diarrhoea. The SeHCAT (75Selenium HomotauroCholic Acid Test) can accurately diagnose this condition. AIM: To identify patients with idiopathic bile acid malabsorption, to describe their clinical features, both qualitatively and quantitatively, and to assess the response to cholestyramine. METHOD: Idiopathic bile acid malabsorption was considered in all patients complaining of chronic diarrhoea. They were included in the study if their SeHCATs were positive (< 15% retention) and secondary causes of bile acid malabsorption were excluded. The response to therapy with cholestyramine was assessed. RESULTS: Nine patients were diagnosed with idiopathic bile acid malabsorption (median SeHCAT retention 8%, range 3-12.6). Their median daily faecal weight was 285 g (range 85-676) and median faecal fat output was 17 mmol/24 h (range 8.3-38.8). Six patients had an immediate response to cholestyramine. There was a marked reduction in stool frequency (median stool frequency pre-treatment 5/day vs. 2/day post-treatment, P = 0.03). Five patients had large volume diarrhoea (faecal weight > 200 g/day) and three had steatorrhoea. CONCLUSIONS: Idiopathic bile acid malabsorption, once suspected, especially by documenting true 'large volume' watery diarrhoea or steatorrhoea, is easily diagnosed and response to therapy is often very good. There is often a previous history of gastrointestinal infection and this condition should be considered in patients with chronic diarrhoea of undetermined origin, especially before they are labelled as having irritable bowel syndrome.     

Suppressed anti-aggregating and cGMP-elevating effects of sodium nitroprusside in platelets from patients with stable angina pectoris

Short bowel syndrome (SBS) in the newborn results in limited intestinal absorptive capacity, leading especially to fatty acid (FA) malabsorption. It is unknown whether adaptation occurs in time in FA absorption, and whether this adaptation is chain-length dependent. The aid of the present study was to prospectively evaluate FA absorption and excretion during SBS in the newborn. Twenty-one neonates who underwent small bowel resection (of variable length) for various reasons (necrotizing enterocolitis, intestinal atresia, meconium peritonitis, cloacal extrophy, etc) were studied. Eight neonates had SBS, defined as a small bowel remnant of less than 50% of the original small bowel length related to gestational age. The mean remaining small bowel length in the SBS group was 34% (24% to 42%). The non-SBS control group consisted of 13 neonates who had only minor small bowel resections. The mean remaining bowel length for the non-SBS group was 95% (70% to 100%). The results show that the total fractional excretion of FA (FE-FA) at 2 weeks and 1, 2, 3, and 4 months postsurgery was 51% +/- 37%, 33% +/- 24%, 51% +/- 65%, 53% +/- 27%, and 7% +/- 2% in patients with SBS, versus 12% +/- 8%, 24% +/- 10%, 9% +/- 3%, 8% +/- 3% and 17% +/- 14% in the non-SBS controls, respectively (P < .05 by ANOVA). There appeared to be an amelioration in time in FA absorption, especially in the SBS group, after 3 months. FE-FA was chain-length related, being considerably less for C10 and C12 than for C14 and longer amounts. An amelioration of absorption occurred in the SBS patients, especially with the longer-chain FA. On the basis of the study data, the authors conclude that in the initial adaptation phase shorter chain lengths are better absorbed than longer chain lengths; however, in the latter FA group, substantial adaptation occurs with time.