Cicatricial pemphigoid and carcinoma of the pancreas. Carcinoma of the pancreas has been associated with both cicatricial and bullous pemphigoid. We report a case of a 53-year-old man with cicatricial pemphigoid who died within months of the diagnosis from metastatic pancreatic-carcinoma. All three reported cases were complicated by venous thrombosis, a well recognized but uncommon feature of pancreatic cancer.


Herpesvirus serology, aberrant specific immunoglobulin G2 and G3 subclass patterns and Gm allotypes in individuals with low levels of IgG3. One objective of this study was to determine whether IgG3-deficient individuals have an increased frequency of reactivated herpesvirus infections. Serum titres to Epstein-Barr virus (EBV) and human herpesvirus-6 were examined in 10 healthy and in 10 symptomatic persons with serum IgG3 < 0.1 g/l. Atypical titres were found in 16% of the IgG3-deficient individuals. Reactivations of these viruses thus do not seem common in IgG3 deficiency. Antigen-specific IgG responses were also determined. A lowered frequency of IgG3 to an EBV-derived peptide was found only in symptomatic, IgG3-deficient individuals. Levels of IgG2 to a bacterial polysaccharide were lowered in the same group, despite normal serum levels of total IgG2. A functional IgG2 deficiency may contribute to symptoms in IgG3 deficiency. The G3(g) allotype, known to be associated with low total IgG3, dominated in IgG3-deficient persons (13/17) independently of presence or absence of symptoms. A linkage of G3(g) to the G2(n) negative allotype, associated with low IgG2, was equally common irrespective of symptoms. G3(g) and absence of G2(n) seem to be one prerequisite for most of IgG3 deficiency combined with low specific IgG2.


Cytokine receptors: structure and signal transduction. In the past 2-3 years, a number of cytokine receptors have been partly characterized and the cDNAs for the ligand binding chains cloned. This has revealed that cytokine receptors are complex. Many are known to be multichain receptors (e.g. IL-2) and since their mechanism of signal transduction is not obvious, it is likely that other proteins yet to be defined take part in the signalling process. The cloning of the receptor ligand binding chain has revealed that (unlike cytokines), there are major families of receptors. Some are members of the Ig supergene family (e.g. IL-1 receptor), others are members of the nerve growth factor receptor family (e.g. TNF), but the majority are members of the haematopoietic growth factor family (e.g. IL-3, GM-CSF). Yet other cytokine receptors do not belong to a family, e.g. IFN-gamma.


Inhibition of NO synthesis has an additive effect on hypertension induced by ACTH in conscious rats. 1. The haemodynamic and metabolic effects of oral intake of approximately 30 mg/kg per day N-nitro-L-arginine (NOLA) were examined in sham and adrenocorticotrophin (ACTH, 0.5 mg/kg per day) treated conscious Sprague-Dawley rats (n = 33). 2. NOLA administration produced an increase in systolic blood pressure of 24 +/- 6 mmHg (P < 0.001), but did not alter food or water intake, urine volume or electrolyte excretion in rats not treated with ACTH. 3. Compared with sham injection, ACTH-treated rats demonstrated an increase in systolic blood pressure (water + sham, 3 +/- 1 mmHg; water + ACTH, 16 +/- 3 mmHg; P < 0.001), loss of bodyweight, and increases in water intake and urine volume. 4. The magnitude of the blood pressure rise in ACTH-treated rats was greater in those receiving NOLA than in those drinking water only (water + ACTH, 16 +/- 3 mmHg; NOLA + ACTH, 37 +/- 3 mmHg; P < 0.05). Metabolic changes were similar. 5. Inhibition of nitric oxide is unlikely to be a major determinant of ACTH-induced hypertension in the rat, since NOLA increased blood pressure whether or not ACTH was administered, indicating an additive effect of ACTH and NOLA administration.


Do opioid receptors participate in the regulation of atrial natriuretic peptide (ANP) secretion in hypertensive patients? Experimental and clinical studies seem to prove that both endogenous opioids and atrial natriuretic peptide (ANP) are involved in blood pressure regulation. This raised the question, whether these two factors are functionally interrelated to each other. We tried to answer this question by assessing plasma ANP levels in 15 patients with II degrees essential hypertension and in 15 healthy subjects under water immersion (WI) conditions. In all subjects two WI tests were performed--one without pretreatment with naloxone, and a second one after blockade of opioid receptors by this opioid receptor antagonist. Parallel to ANP, plasma renin activity (PRA), aldosterone (ALD) and vasopressin (AVP) were assessed. In hypertensive patients significantly higher basal plasma ANP levels were found than in control subjects. WI induced a significant increase of plasma ANP in both examined groups which became markedly reduced after blockade of opioid receptors by naloxone. Naloxone did not influence the WI induced decrease of PRA, ALD and AVP respectively. From results presented in this study we conclude, that a.) opioid receptors seem to influence regulation of ANP secretion both in healthy normotensive subjects and patients with essential hypertension, and b.) that WI induced alterations of ANP on the one side and of PRA, ALD and AVP on the other side are not interrelated.


Discordant hepatic uptake of Tc-99m NGA and Tc-99m PMT in a patient with hepatoma. The authors report discordant hepatic uptake of Tc-99m NGA and Tc-99m PMT in a patient with hepatoma. Tc-99m PMT uptake was delayed and Tc-99m NGA concentrated in another area, thereby demonstrating that the uptake mechanisms for Tc-99m NGA and Tc-99m PMT are different. Tc-99m NGA imaging may be useful in characterizing the focal hepatic lesion of Tc-99m IDA or Tc-99m PMT concentration.


Seat belt-related thyroiditis documented with thyroid Tc-99m pertechnetate scans. A 64-year-old man presented with clinical unilateral thyroiditis after chronic left neck trauma from his car seat belt. Thyroid function tests were normal. The initial thyroid Tc-99m pertechnetate scan demonstrated decreased uptake in the entire left lobe of the thyroid. The follow-up scan 1 month later showed a more normal uptake in the left lobe. This patient's clinical course, laboratory values, and nuclear medicine scans are compatible with thyroiditis secondary to trauma sustained from his seat belt.


Evaluation of Klippel-Trenaunay syndrome with radionuclide total body angiography. A case report. A 21-year-old Italian woman with extensive Klippel-Trenaunay syndrome (KTS) developed recurrent pulmonary embolism in spite of the insertion of a Greenfield filter in the inferior vena cava. Clinical and radiologic diagnostic tests failed to demonstrate the pathway of the emboli. Radionuclide venography and intravenous radionuclide total body arteriography were performed. These radionuclide procedures helped to evaluate the extent of KTS and to detect the route of the emboli. This is the first case of KTS studied with intravenous total body arteriography reported in the literature.


Positron emission tomography for treatment evaluation and recurrence detection compared with CT in long-term follow-up cases of lung cancer. Two cases of lung cancer were studied with positron emission tomography (PET) using L-[methyl-C-11]methionine (C-11 Met) and CT scans five to six times during long-term follow-up after radiotherapy. In a large cell carcinoma with mediastinal invasion, C-11 Met tumor uptake showed a rapid decrease after radiotherapy, corresponding to clinical improvement, and detected recurrence at 11 months, as confirmed by biopsy. Tumor volume by CT showed no significant changes during this time. A squamous cell carcinoma of the superior sulcus (Pancoast type) showed rapid changes in C-11 Met tumor uptake and similar changes in tumor volume during two courses of radiotherapy and recurrence over a period of 25 months. PET evaluation of tumor viability seems to be valuable for treatment evaluation, and results match the tumor volume changes measured by CT.


Rifabutin absorption in humans: relative bioavailability and food effect. The relative bioavailability of the capsule dose form (150 mg) and the effect of high-fat food were assessed in a randomized, three-way crossover trial of rifabutin in 12 healthy male volunteers. Each subject received a single 150 mg dose as a solution (treatment A, fasted) or a capsule with food (treatment B) and without food (treatment C), with a 2-week washout period. Serial plasma and urine samples were obtained for 168 and 48 hours, respectively, and rifabutin and its active metabolite, 25-O-deacetyl-rifabutin, quantitated by a validated HPLC procedure. The mean +/- SD maximum concentration for rifabutin in plasma was 238 +/- 65, 156 +/- 52, and 188 +/- 50 ng/ml, time to reach peak concentration was 2.5 +/- 0.4, 5.4 +/- 1.6, and 3.0 +/- 1.1 hours, and the area under the plasma concentration-time curve from zero to infinity [AUC(0-infinity)] was 2989 +/- 726, 2640 +/- 891, and 2516 +/- 601 ng.hr/ml for the solution and the capsule during the fed and fasted states, respectively. Percentage of dose excreted in the urine as unchanged rifabutin was 11.0% +/- 2.4%, 11.4% +/- 4.9%, and 9.1% +/- 2.1% for treatments A, B, and C, respectively. The corresponding AUC(0-infinity) values for the equiactive metabolite 25-O-deacetyl-rifabutin, were 400 +/- 184, 361 +/- 187, and 298 +/- 102 ng.hr/ml.(ABSTRACT TRUNCATED AT 250 WORDS)


Demographic factors influencing cyclosporine pharmacokinetic parameters in patients with uremia: racial differences in bioavailability. The impact of several demographic and blood biochemistry factors on the pharmacokinetics of the immunosuppressive drug cyclosporine were studied in 187 patients with uremia. All patients underwent a pharmacokinetic evaluation including a 3 mg/kg intravenous dose of cyclosporine and a 14 mg/kg oral dose of cyclosporine. Cyclosporine was analyzed by specific monoclonal radioimmunoassay on whole blood samples. Statistical analysis included univariate analyses and stepwise multiple regression analysis. Major findings were as follows: The bioavailability (F) of cyclosporine was significantly lower in black patients than in white patients (mean values of 30.9% +/- 12.3% and 39.5% +/- 16.5%, respectively; p < 0.001). This difference was noted both before transplant and at 1 week after kidney transplantation, at which time the corresponding mean values were 28.6% +/- 15.5% and 36.1% +/- 15.5%, respectively (p < 0.01). Other factors that correlated with F were serum triglyceride (positively) and blood hemoglobin concentrations (inversely). Patients with diabetes displayed a longer mean absorption time than other patients and a larger volume of distribution of cyclosporine at steady state (VSS). Other factors that correlated with VSS were serum albumin concentration and patient height. Cyclosporine clearance (CL) decreased with patient age and also with increasing concentrations of serum triglycerides and blood hemoglobin. It was lower in patients with the pretransplant diagnosis of nephrosclerosis than in patients with other diseases. Several pharmacokinetic parameters correlated with the level of substances that can potentially bind cyclosporine in the blood. Serum triglycerides correlated with maximum concentration, time to maximum concentration, F, and CL. Blood hemoglobin concentration and blood hematocrit correlated with F, CL, and intravenous mean residence time. Although several relationships were observed between demographic factors and cyclosporine pharmacokinetics, the racial difference in F is of great clinical significance and may contribute to the poorer outcome observed after kidney transplantation in black patients.


Effect of timing of administration on the plasma ACE inhibitory activity and the antihypertensive effect of quinapril. To assess whether timing of administration can influence the antihypertensive effect of quinapril, 18 patients with hypertension were studied with noninvasive ambulatory blood pressure monitoring. Quinapril, 20 mg, was given at 8 AM or 10 PM for 4 weeks in a double-blind crossover fashion. To study the pattern of angiotensin converting enzyme (ACE) inhibition with the two treatment regimens, plasma ACE activity was measured in seven subjects 2, 4, 8, 12 and 24 hours after quinapril administration. The 24-hour blood pressure profiles showed a more sustained antihypertensive action with the evening administration of quinapril compared with the morning administration of quinapril; as with the morning administration, a partial loss of effectiveness was observed during nighttime hours. Measurement of ACE activity showed that evening administration caused a less pronounced but a more sustained decline of plasma ACE. These findings show that 20 mg quinapril given once daily is effective in lowering blood pressure levels throughout a 24-hour period. The evening administration seems to be preferable because it causes a more favorable modulation of ACE inhibition and therefore determines a more homogeneous 24-hour blood pressure control.


Analysis of factors limiting maximal exercise performance in cystic fibrosis. 1. Maximal exercise capacity in cystic fibrosis is influenced by both pulmonary and nutritional factors: lung disease by limiting maximal achievable ventilation, and malnutrition through a loss of muscle mass. The associated reduction in everyday activities may result in peripheral muscle deconditioning. 2. We studied 14 stable patients with cystic fibrosis (six males, eight females) and 14 healthy control subjects (seven males, seven females) in order to assess the influence of these factors on exercise performance. Subjects underwent anthropometry to estimate muscle mass, spirometry to assess ventilatory capacity, a 30 s sprint on an isokinetic cycle ergometer to assess maximal leg muscle performance, and progressive cycle ergometry to assess overall exercise capacity. 3. Compared with control subjects, the patients with cystic fibrosis were of similar age and height but weighed proportionately less [% ideal weight (mean +/- SD): 94.3 +/- 9.64 versus 109.5 +/- 11.82] and showed evidence of airflow limitation [forced expiratory volume in 1.0 s (FEV1.0) 72.5 +/- 24.78 versus 112.6 +/- 14.25% of predicted]. 4. The patients with cystic fibrosis did less absolute (5.1 +/- 1.89 versus 7.3 +/- 1.97 kJ) but similar relative maximal (11.5 +/- 3.41 versus 13.1 +/- 3.55 kJ/kg lean body mass) sprint work. During progressive exercise, the group with cystic fibrosis achieved lower absolute [maximal O2 consumption (VO2max.) 1.8 +/- 0.527 versus 3.0 +/- 0.655 litres/min] and relative (VO2max./kg lean body mass: 40.5 +/- 9.23 versus 53.0 +/- 11.62 ml min-1 kg-1) work levels.(ABSTRACT TRUNCATED AT 250 WORDS)


Responses of airway rapidly adapting receptors to bradykinin before and after administration of enalapril in rabbits. 1. The present study was performed in anaesthetized, artificially ventilated, open-chested rabbits to examine whether (a) the rapidly adapting receptors of the airways were stimulated by exogenously administered bradykinin, and (b) if this sensitivity could be enhanced by the angiotensin-converting-enzyme inhibitor, enalapril. 2. Rapidly adapting receptor activity (n = 8) was recorded from the cervical vagus. Bradykinin was injected intravenously (0.25-1.0 microgram/kg) and a dose-response curve relating receptor activity to bradykinin was elicited. In the control state, the threshold dose of bradykinin required for stimulation of rapidly adapting receptors was 0.53 +/- 0.11 microgram/kg. Five minutes after the administration of enalapril maleate (2 mg intravenously), the dose-response curve was shifted to the left significantly (P < 0.01). 3. In seven other rapidly adapting receptors, enalapril (2 mg) increased the resting activity significantly (P < 0.05) over a period of 60 min. This increase was significantly different from the spontaneous variation in neural activity of rapidly adapting receptors (n = 7) recorded over a period of 60 min. 4. Bradykinin either alone (0.25-1.0 microgram/kg) or in the presence of enalapril did not stimulate the slowly adapting receptors (n = 5) of the airways. 5. These results show that (a) exogenous bradykinin stimulates the rapidly adapting receptors, (b) the sensitivity of rapidly adapting receptors to bradykinin is enhanced by enalapril and (c) enalapril increases the resting activity of rapidly adapting receptors. It is suggested that the cough reported after the administration of enalapril may be due to stimulation of rapidly adapting receptors of the airways.


Decreased faecal exoglycosidase activities identify a subset of patients with active Crohn's disease. 1. alpha 1-Proteinase inhibitor (alpha 1-antitrypsin) is excreted in a deglycosylated form (M(r) 38,000) in the faeces of healthy subjects and in patients with quiescent Crohn's disease. By contrast, in most patients with active Crohn's disease, alpha 1-proteinase inhibitor is excreted in a glycosylated form (M(r) 51,000). 2. Faecal extracts containing deglycosylated alpha 1-proteinase inhibitor are able to deglycosylate alpha 1-proteinase inhibitor by an exoglycosidic process. Conversely, we demonstrate that in faecal extracts from patients excreting glycosylated alpha 1-proteinase inhibitor, glycosidase activities, such as N-acetyl-beta-glucosaminidase (EC 3.2.1.30), alpha-mannosidase (EC 3.2.1.24) and particularly beta-galactosidase (EC 3.2.1.23), are strongly decreased. 3. Degradation of glycosidases by proteases could not explain the decreased glycosidase activity in these faecal extracts. 4. Our data suggest that a modification of the bacterial colonic flora (or of its metabolic activity) occurs in most patients with active Crohn's disease and could be responsible for an impaired colonic salvage of carbohydrates.


Effects of spermine on water absorption, polyethylene glycol 4000 permeability and collagenase activity in rat descending colon in vivo. 1. The effects of spermine in the concentration range 0-10 mmol/l on (a) the fluid absorption, (b) the polyethylene glycol permeability, (c) the release of collagenase activity activity into the lumen and (d) the histological appearance of rat descending colon were examined. 2. Spermine (5 mmol/l) decreased fluid absorption from 48.83 +/- 2.98 (n = 7) to 23.98 +/- 2.32 (n = 6) microliters h-1 cm-2 (P < 0.01); polyethylene glycol 4000 permeability was increased from 0.030 +/- 0.001 (n = 7) to 0.047 +/- 0.003 (n = 6) cm/h (P < 0.01) and luminal collagenase activity increased from a negligible control value to 250 +/- 39 (n = 6) units/ml (P < 0.001). Spermine also caused oedema formation within the mucosal interstitial fluid, without inducing an overt breakdown of the mucosa at the luminal surface. 3. Polyamine-free dialysed seminal plasma had no effect on polyethylene glycol 4000 permeability, although it still caused a significant decrease in colonic fluid absorption from 48.83 +/- 2.98 (n = 7) (control) to 31.41 +/- 2.08 (n = 5) microliters h-1 cm-2 (P < 0.01). 4. Low-molecular-mass heparin (600 units/ml) prevented the spermine (5 mmol/l)- and whole-semen-induced increase in colonic polyethylene glycol 4000 permeability and reduced the effect of semen on fluid absorption by 63% (P < 0.001) and that of spermine by 56% (P < 0.01). 5. The Zn2+ chelator and collagenase inhibitor o-phenanthroline reduced the effect of spermine on fluid absorption and polyethylene glycol 4000 permeability by 100% (P < 0.001) and on interstitial oedema formation. o-Phenanthroline also reduced the effects of whole semen on fluid absorption (by 70%, P < 0.01) and on polyethylene glycol 4000 permeability by 95%, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)


Contribution of soluble aluminium species to absorption of aluminium from the rat gut in situ. 1. Rat gut perfusion studies in vivo at pH 4, 6 or 8 using aluminium chloride or equimolar aluminium chloride and sodium citrate showed that elevated plasma aluminium concentrations were associated with aluminium solubility in the perfusion. Elevated plasma aluminium levels and soluble aluminium in the perfusate occurred with perfusion of equimolar aluminium chloride and sodium citrate at all three pH values. 2. Partitioning studies in vitro, utilizing water and ethyl acetate, revealed that uncomplexed aluminium exhibited maximum partitioning into the ethyl acetate phase at pH 2.5. When complexed with citrate, aluminium exhibited partitioning over a much broader pH range, pH 2.5-8.0. 3. A direct linear relationship was observed between the soluble aluminium concentration of the perfusate and the increase in the plasma aluminium level, suggesting that soluble aluminium is absorbed by a passive diffusion mechanism.


Effect of citrate on plasma aluminium concentration and aluminium excretion in the rat. 1. Plasma aluminium concentration and urinary aluminium excretion were monitored for 4.5 h in rats after the administration of 25 micrograms or 800 micrograms of aluminium as an intravenous bolus, either as aluminium chloride or as aluminium citrate (i.e. aluminium chloride together with sodium citrate). 2. Immediately after the bolus aluminium administration, the plasma aluminium concentration was higher in the groups given aluminium chloride than in those which received aluminium citrate, although the difference was significant (P < 0.05) only for the 25 micrograms dose. This difference between aluminium chloride and citrate indicates that the citrate form has a higher volume of distribution (i.e. is able to leave the plasma). The calculated volume of distribution for the 25 micrograms of aluminium chloride (17.5 ml) was similar to the plasma volume of the rats used (15 ml). 3. In experiments in vitro, the ultrafilterability of aqueous solutions of aluminium chloride and aluminium citrate were compared. Only 1.05 +/- 0.09% of the aluminium chloride solution was ultrafilterable (aluminium concentration 28,200 +/- 730 ng/ml), whereas 97.3 +/- 2.4% of the aluminium citrate was ultrafilterable (aluminium concentration 42,000 +/- 370 ng/ml). When the filterability of aluminium in plasma was examined, the aluminium chloride ultrafilterability was identical with that in aqueous solution (1.06 +/- 0.13%, aluminium concentration 19,800 +/- 2956 ng/ml), but the aluminium citrate was 79.8 +/- 7.1% ultrafilterable (aluminium concentration 10,125 +/- 591 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)


Plasma concentrations and comparisons of brain natriuretic peptide and atrial natriuretic peptide in normal subjects, cardiac transplant recipients and patients with dialysis-independent or dialysis-dependent chronic renal failure. 1. We have developed a radioimmunoassay for the measurement of immunoreactive brain natriuretic peptide (1-32) in human plasma. Simultaneous measurements of atrial natriuretic peptide have also been carried out to allow for direct comparison between circulating brain natriuretic peptide and atrial natriuretic peptide. Plasma levels of immunoreactive brain natriuretic peptide (means +/- SEM) were 1.1 +/- 0.1 pmol/l in 36 normal healthy subjects and were significantly elevated in cardiac transplant recipients (18.8 +/- 3.9 pmol/l, n = 12) and in patients with dialysis-independent (8.8 +/- 1.5 pmol/l, n = 11) or dialysis-dependent (41.6 +/- 8.8 pmol/l, n = 14) chronic renal failure. Similarly, in these groups of patients plasma levels of atrial natriuretic peptide were also significantly raised when compared with those in the group of normal healthy subjects. 2. The plasma level of atrial natriuretic peptide was significantly higher than that of brain natriuretic peptide in normal subjects and in patients with dialysis-independent chronic renal failure, with ratios (atrial natriuretic peptide/brain natriuretic peptide) of 2.8 +/- 0.2 and 2.2 +/- 0.3, respectively. However, in both cardiac transplant recipients and patients on dialysis plasma levels of atrial natriuretic peptide and brain natriuretic peptide were similar, with ratios of 1.3 +/- 0.2 and 1.0 +/- 0.1, respectively, in these two groups. 3. Plasma levels of brain natriuretic peptide and atrial natriuretic peptide were significantly correlated in the healthy subjects and within each group of patients. When all groups were taken together, there was an overall correlation of 0.90 (P < 0.001, n = 73).(ABSTRACT TRUNCATED AT 250 WORDS)


Determinants of intra-individual variation in kidney function in normoalbuminuric insulin-dependent diabetic patients: importance of atrial natriuretic peptide and glycaemic control. 1. In order to investigate the modulation of kidney function in insulin-dependent diabetes mellitus, intraindividual variation in glomerular filtration rate, renal plasma flow, urinary albumin excretion rate and mean arterial blood pressure was assessed in 22 normoalbuminuric patients [age 31 +/- 8 years, duration of diabetes 9 +/- 5 years, mean arterial blood pressure 90 +/- 5 mmHg (means +/- SD), urinary albumin excretion rate 5.4 x/divided by 1.6 micrograms/min]. The variation in these parameters was calculated from the results of two clearance studies (continuous infusion of [125I]-iothalamate and 131I-hippuran as markers for glomerular filtration rate and renal plasma flow, respectively) and was subsequently analysed in relation to individual variation in plasma concentrations of atrial natriuretic peptide, arginine vasopressin, angiotensin II and aldosterone and measures of glycaemic control. 2. Simple correlation analysis showed a significant association between intra-individual variation in glomerular filtration rate and atrial natriuretic peptide (sigma = 0.66, P = 0.003). Besides variation in atrial natriuretic peptide, multiple regression analysis identified variation in glycated haemoglobin (P = 0.026) and arginine vasopressin (P = 0.057) as variables having independent association with variation in glomerular filtration rate [R2 with the three variables included (adjusted for degrees of freedom) = 0.50, analysis of variance: P = 0.002]. 3. With respect to variation in renal plasma flow, differences in fasting blood glucose concentration and mean arterial blood pressure were suggested as determinants (R2 = 0.36, analysis of variance: P = 0.009). 4. Variation in urinary albumin excretion rate (after log transformation) was statistically associated with variation in glycated haemoglobin.(ABSTRACT TRUNCATED AT 250 WORDS)


Study of the actions of human recombinant erythropoietin on rat renal haemodynamics. 1. Studies were undertaken to examine the effect of acute and chronic administration of human recombinant erythropoietin on kidney cortical and papillary perfusion in the anaesthetized rat using laser-Doppler flowmetry. 2. Thirty minutes after erythropoietin (50 and 150 units/kg intravenously), blood pressure, cortical perfusion and papillary perfusion were unchanged. 3. In animals treated chronically with erythropoietin over 7 days (three doses of 150 units/kg subcutaneously) blood pressure was similar to that of vehicle-treated animals, whereas cortical perfusion and papillary perfusion were reduced by 23% and 20%, respectively (both P < 0.05), and the packed cell volume (51.1 +/- 0.7%) was significantly (P < 0.01) greater than in vehicle-treated animals (46.2 +/- 0.6%). 4. Bolus doses of vasopressin and phenylephrine increased blood pressure (by between 10% and 40%) and decreased cortical and papillary perfusion (by between 10% and 20%), while angiotensin II caused similar increases in blood pressure and decreases in cortical perfusion but not papillary perfusion. The magnitude and pattern of these responses were comparable after both acute and chronic administration of erythropoietin. 5. Erythropoietin given acutely at therapeutic levels has a marginal effect on cortical and papillary perfusion. However, the chronic treatment indicated that there was a sustained reduction in both cortical and papillary perfusion, reflecting a vasoconstriction. This reduction in renal haemodynamics could contribute to the increase in blood pressure observed when this hormone is administered in man.


2,3-Dinor metabolites of thromboxane A2 and prostacyclin in urine from healthy human subjects: diurnal variation and relation to 24h excretion. 1. Urinary levels of the 2,3-dinor metabolites of thromboxane A2 (2,3-dinor-thromboxane A2, Tx-M) and prostacyclin (2,3-dinor-6-keto-prostaglandin F1 alpha, PGI-M) are frequently analysed as indices of platelet and endothelial activity and interaction in vivo. Despite this, little is known about the possible diurnal variations in urinary Tx-M and PGI-M in healthy human subjects, and how the urinary levels of Tx-M and PGI-M in single samples reflect their respective 24 h excretion rates. We addressed this by determining Tx-M, PGI-M and creatinine in consecutive portions of urine collected during 24 h in 15 healthy non-smoking subjects. 2. The total 24 h excretion of Tx-M and PGI-M did not differ between men (223 +/- 31 and 132 +/- 27 ng, respectively) and women (215 +/- 44 and 127 +/- 29 ng, respectively). Neither the excretion of Tx-M nor that of PGI-M displayed any significant diurnal variation. 3. The excretion of Tx-M during a 3 h period and the Tx-M/creatinine ratio in a urine sample accurately reflected the 24 h excretion of Tx-M (correlation coefficient ranges 0.74-0.94 and 0.74-0.86, respectively). The excretion of PGI-M during a 3 h period and the PGI-M/creatinine ratio in a urinary sample were accurate measures of 24 h excretion of PGI-M (correlation coefficient ranges 0.76-0.94 and 0.72-0.83, respectively). Urinary Tx-M and PGI-M expressed as simple concentrations were poor indices of their respective 24 h excretion. 4. We conclude that time-related excretions of Tx-M and PGI-M may be the best indices ex vivo of the cardiovascular formation of thromboxane A2 and prostacyclin, but that urinary creatinine-related concentrations of Tx-M and PGI-M in a urine sample are accurate measures as well.


Vasopressin and angiotensin II in the conscious dog: synergistic effects on renal excretory parameters? 1. The renal effects of angiotensin II were investigated (a) with and without acute blockade of the effects of aldosterone and (b) with and without concomitant infusion of vasopressin. Angiotensin II (2 ng min-1 kg-1) and/or vasopressin (5 pg min-1 kg-1) was infused intravenously into conscious water-diuretic dogs and the effects were quantified by measurements of renal excretion of water, Na+ and K+, as well as determination of plasma renin activity and plasma levels of atrial natriuretic peptide and catecholamines. 2. Angiotensin II alone increased blood pressure by 7% (P < 0.05), decreased effective renal blood flow markedly and reduced urine flow and osmolar and free water clearances. Na+ and K+ excretion did not change significantly. Aldosterone blockade with canrenoate increased Na+ excretion by a factor of 10; subsequent infusion of angiotensin II decreased Na+ excretion by about 50%, the other renal effects being qualitatively similar to those seen without blockade. As expected, vasopressin also decreased diuresis and free water clearance substantially; however, the effect of combined infusion of angiotensin II and vasopressin was not compatible with the notion of additive effects of the two peptides. 3. Angiotensin II alone or in combination with vasopressin did not change the plasma concentrations of atrial natriuretic peptide, adrenaline, noradrenaline, or dopamine. Vasopressin alone exerted its antidiuretic effect without affecting plasma renin activity, plasma aldosterone concentration or renal excretion of Na+ and K+.(ABSTRACT TRUNCATED AT 250 WORDS)


Relative effects of fat-, carbohydrate- and protein-containing liquid diets on cardiac output in healthy adult subjects. 1. Nine healthy adult subjects consumed four types of proprietary liquid diet of similar volume and calorific value but of different nutritional composition. The effects on resting cardiac output, mean blood pressure and pulse rate were measured. 2. A significant rise in cardiac output occurred with the balanced, protein and carbohydrate diets but not with the fat diet. The greatest rise was seen with the balanced diet. Water alone had no effect on cardiac output. 3. The average time taken to reach peak cardiac output was shortest with the carbohydrate diet and longest with the fat diet. 4. The increases in cardiac output resulted from a rise in both pulse rate and stroke volume. The carbohydrate diet produced the most sustained rise in pulse rate but the least sustained elevation in stroke volume. 5. No significant changes were seen in mean blood pressure when each liquid meal was compared with water. 6. Our data show that the increase in cardiac output with liquid ingestion is related to the dietary components. These effects are additive.


Ageing and the response of plasma insulin, glucose and C-peptide concentrations to intravenous glucose in postmenopausal women. 1. Eighty-six apparently healthy postmenopausal women not receiving hormone replacement therapy were given an intravenous glucose tolerance test. Plasma glucose, insulin and C-peptide concentrations were determined in fasting and post-glucose challenge samples. 2. Using a multivariate regression model, with predictor variables of chronological age, menopausal age and body mass index, neither chronological age nor menopausal age correlated with fasting or post-challenge plasma glucose or C-peptide concentrations. In contrast, menopausal age was positively associated with fasting plasma insulin concentration (P = 0.038, model r2 = 0.107), insulin area (P = 0.01, model r2 = 0.236) and incremental insulin area (P = 0.024, model r2 = 0.243). This relationship could not be explained by differences in lifestyle variables of alcohol consumption, physical activity, previous duration of oral contraceptive usage, history of cigarette smoking or body mass index. 3. Our findings suggest that loss of ovarian function is associated with hyperinsulinaemia, possibly via alterations in the clearance of circulating insulin from the plasma. The hyperinsulinaemia observed may contribute to the increased risk of cardiovascular disease seen in postmenopausal women.


Platelet-activating factor causes hypoketonaemia in starved rats. 1. The aim of this work was to examine whether platelet-activating factor could mimic the hypoketonaemia seen in septic and endotoxic experimental animals. Platelet-activating factor was administered either by the intraperitoneal (high dose) or intravenous (jugular vein, low dose) routes. 2. Intraperitoneal injection of platelet-activating factor (25 micrograms/kg body weight) decreased the blood ketone body concentration (acetoacetate plus 3-hydroxybutyrate) transiently (30 min after injection) in starved rats. Continuous intravenous infusion of platelet-activating factor (40 ng min-1 kg-1 for 5 h) caused comparable hypoketonaemia. 3. The hepatic acetoacetate concentration also decreased transiently after injection of platelet-activating factor and there was an increase in the 3-hydroxybutyrate/acetoacetate ratio. The hepatic ATP concentration decreased at 15 and 30 min after injection of platelet-activating factor. Infusion of platelet-activating factor caused a similar decrease in hepatic ketone body concentration, but no significant change in the 3-hydroxybutyrate/acetoacetate ratio or adenine nucleotide concentrations. 4. Platelet-activating factor administered by infusion, but not by injection, decreased the plasma non-esterified fatty acid concentration. The plasma glycerol concentration also decreased after infusion of platelet-activating factor, suggesting decreased lipolysis in adipose tissue. 5. Changes in plasma insulin concentration or white adipose tissue blood flow did not appear to contribute to the decrease in the plasma non-esterified fatty acid concentration after infusion of platelet-activating factor. However, there was a significant decrease in blood flow to interscapular brown adipose tissue in both the infused and injected groups.(ABSTRACT TRUNCATED AT 250 WORDS)


Spontaneous release of interleukin-I and interleukin-6 by peripheral blood mononuclear cells after oophorectomy. 1. We studied the changes in interleukin-1 and interleukin-6 secretion by peripheral blood mononuclear cells from 12 premenopausal women after oophorectomy and seven premenopausal women who had undergone simple hysterectomy. 2. The results showed that 1 month after surgery interleukin-1 secretion increased by 414 +/- 171% (mean +/- SEM) and interleukin-6 secretion increased by 1354 +/- 481% in oophorectomized women, whereas only non-significant fluctuations in the secretion of both cytokines (-9% +/- 29% for interleukin-1 and -31% +/- 19% for interleukin-6) were seen in the women who had undergone simple hysterectomy. The difference between the two groups was significant (P = 0.035 for interleukin-1 and P = 0.003 for interleukin-6). In addition, oophorectomy, but not simple hysterectomy, was followed by significant increases in plasma ionized calcium concentration (P < 0.05), plasma alkaline phosphatase activity (P < 0.01) and plasma osteocalcin concentration (P < 0.02), and a reduction in plasma parathyroid hormone level (P < 0.01). 3. We conclude that ovary ablation may modify cytokine secretion by peripheral blood mononuclear cells. If this phenomenon occurs in the bone microenvironment, it could be important in the loss of bone observed after oophorectomy. However, the possibility of an independent alteration induced by the lack of gonadal hormones but unrelated to bone turnover cannot be excluded.


Indirect pathway of liver glycogen synthesis in humans is predominant and independent of beta-adrenergic mechanisms. The relative contribution of the direct and indirect pathways to liver glycogen formation was assessed in humans by using a combined tracer-hepatic vein catheterization technique. An oral glucose load (75 g) labelled with 1-14C-glucose was administered to five subjects (control group) and 4.5 h later hepatic glycogen was flushed with glucagon and analysed to determine the randomization of 14C. The specific activity (SA) of the glycogen derived glucose (1-14C-glucose SA+recycled 14C-glucose SA) was 61 +/- 7% of the mean blood glucose SA of the interval 0-180 min after the oral glucose load. The relative values due to 1-14C-glucose and recycled 14C-glucose were 33 +/- 7 and 28 +/- 3%, respectively. The data indicate that the indirect pathway of glycogen formation is not only active in humans but contributes substantially (at least 50%) to liver glycogen formation. In order to investigate whether the basal adrenergic tone plays a role in the maintenance of the indirect pathway, the same protocol was also performed in a second group of subjects (n = 5) who received propranolol before the oral glucose load (propranolol group). The SA of the glycogen-derived glucose was considerably smaller than that of the control group (18 +/- 5 vs. 61 +/- 7%, P < 0.001), suggesting lesser glycogen formation. However, the ratio of 1-14C to recycled-14C in the glucose molecule was similar in the control (1.3 +/- 0.4) and propranolol group (1.9 +/- 1.2). We conclude that the basal adrenergic tone does not play any role in the operation of the indirect pathway of liver glycogen synthesis.


In vitro activity of various antimicrobial agents against Staphylococcus aureus isolates including fluoroquinolone- and oxacillin-resistant strains. To determine susceptibility to 31 old and new antimicrobials, 44 strains of Staphylococcus aureus, most resistant to oxacillin and ciprofloxacin and isolated in a community hospital, were tested in vitro. For the peptide/peptide-derivative compounds, with the exception of mersacidin, all strains were inhibited by less than or equal to 2 micrograms/ml. Minimum inhibitory concentration (MIC)90 values indicated mupirocin, teicoplanin, and MDL 62211 to be fourfold more active than vancomycin, ramoplanin, and decaplanin. For fluoroquinolones, ciprofloxacin-resistant S. aureus exhibited high-level cross-resistance to ofloxacin, norfloxacin, fleroxacin, enoxacin, and Ro 23-9424. WIN 57253, a new fluorinated naphthyridine, showed good activity against these strains. Among the beta-lactams, the penem-derivative compounds (imipenem, meropenem, FCE 22101, and HRE 664) had the greatest activity, although resistance to each compound was detected among oxacillin-resistant S. aureus. The presence of tazobactam reduced the piperacillin MIC90 fourfold. Oxacillin-susceptible strains were susceptible to cephalosporins/cephamycins, whereas most oxacillin-resistant strains exhibited resistance. This study has shown that certain old and new quinolones and peptide-derivative compounds have good in vitro activity against multiply resistant strains of S. aureus.


In vitro activity of CP-74667 compared with four other fluoroquinolones. CP-74667 is a new, novel C-7 diazabicyclo-fluoroquinolone. Its spectrum of activity includes the Enterobacteriaceae, most nonenteric Gram-negative bacilli, and Gram-positive cocci. Particularly high activity was demonstrated against Xanthomonas maltophilia (MIC50, 1 microgram/ml), Staphylococcus spp. (MIC50s, 0.06-0.12 micrograms/ml) and enterococci (MIC50s, 0.5-4 micrograms/ml). Several staphylococci resistant to ciprofloxacin had potentially susceptible range MICs for CP-74667, for example, less than or equal to 2 micrograms/ml. Fluoroquinolones with this C-7 modification appear promising and worthy of continued pharmaceutical investigation.


In vitro activity of l-ofloxacin against norfloxacin-resistant coagulase-negative staphylococci. The in vitro activity of l-ofloxacin was determined against coagulase-negative staphylococci that were induced to norfloxacin resistance. l-Ofloxacin was the most active agent tested with an MIC90 of 4 micrograms/ml compared with greater than 128, 32, and 128 micrograms/ml for norfloxacin, ciprofloxacin, and enoxacin, respectively. Rifampin-resistant, coagulase-negative staphylococci were not cross-resistant to the quinolones tested. Among the rifampin-resistant organisms tested, l-ofloxacin was also the most active agent with an MIC90 of 0.25 micrograms/ml.


Immunosuppression in goats by dexamethasone and cyclophosphamide. The influence of dexamethasone and cyclophosphamide on the goat immune system was investigated. Seven goats, with a previous contact with caprine herpesvirus type 1 (CHV-1), were used. All had been vaccinated with live Mycobacterium paratuberculosis vaccine. Six goats were injected intravenously (i.v.) with dexamethasone daily for 5 days (2.5-4 mg/kg BW per day). Three also received 25 mg/kg BW of cyclophosphamide on day 0. The seventh goat was not treated. Dexamethasone alone caused depression, slight lymphopenia and fall in tuberculin reaction. Dexamethasone plus cyclophosphamide caused a severe clinical reaction, marked leukopenia (lymphopenia and polymorphopenia), fall in tuberculin reaction and significant increase in CHV-1 neutralizing antibody titres. M. paratuberculosis antibody reaction was variable and thus difficult to be assessed. CHV-1 was not isolated.


Effects of pseudorabies virus infection upon cytotoxicity and antiviral activities of porcine alveolar macrophages. Alveolar macrophages (AM) infected with Pseudorabies virus (PRV) were compared to noninfected AM for cytotoxicity against foreign or transformed cells and production of interferon (IFN). Five PRV strains were used to infect AM including strains that are known to be highly virulent for pigs, i.e. strain 4892 and strain S-62 as well as strains that are regarded as mild or nonvirulent, i.e. BUK and Bartha. The multiplicity of infection ranged from 0.005 to 0.05 TCID50/cell. The target cells in the cytotoxicity assays were either chicken red blood cells, PRV-infected vero cells, or human myeloblastoma cells (K562 cell line). For the production of IFN, AM cultures were treated with polyinosinic:polycytidylic acid (Poly I:C) diluted in tissue culture media at a concentration of 5 micrograms/10(6) cells. Culture supernatants were collected at various times poststimulation and tested for antiviral activity using the Vesicular Stomatitis Virus replication inhibition test. Swine AM were able to lyse chicken red blood cells in an antibody-independent way but not in an antibody-dependent way, whereas lysis of PRV-infected vero cells was accomplished both ways. The cytotoxicity against chicken red blood cells was reduced in the PRV-infected AM as compared to noninfected cells, particularly in AM infected with virulent PRV strains. Specific 51Cr release values for AM infected with S-62 and 4892 strains were 14 and 19, while the noninfected AM had values of 36. Similarly, in the antibody-dependent cytotoxicity assay against PRV-infected vero cells there was no activity of AM against K562 cells. The production of IFN was readily stimulated with Poly I:C. The optimal time for supernatant collection was between 12 and 16 h poststimulation. The antiviral activity was abrogated by treatment of the supernatant with antiserum against human leukocyte IFN; it was therefore considered to be due to interferon-alpha (IFN alpha) released from the macrophages. The antiviral activity present in supernatants of PRV-infected AM was reduced compared to noninfected AM. The difference between AM cultures infected with virulent strains of PRV and noninfected AM cultures was statistically significant at P < or = 0.025. The results provide support to the premise that the role of AM in lung defense can be compromised by PRV infection.


Effects in calves of mixed infections with bovine viral diarrhea virus and several other bovine viruses. The objective of this study was to verify whether a mixed infection in calves with bovine viral diarrhea virus (BVDV) and other bovine viruses, such as bovid herpesvirus-4 (BHV-4), parainfluenza-3 (PI-3) and infectious bovine rhinotracheitis (IBR) virus, would influence the pathogenesis of the BVDV infection sufficiently to result in the typical form of mucosal disease being produced. Accordingly, two experiments were undertaken. In one experiment calves were first infected with BVDV and subsequently with BHV-4 and IBR virus, respectively. The second experiment consisted in a simultaneous infection of calves with BVDV and PI-3 virus or BVDV and IBR virus. From the first experiment it seems that BVDV infection can be reactivated in calves by BHV-4 and IBR virus. Evidence of this is that BVDV, at least the cytopathic (CP) strain, was recovered from calves following superinfection. Moreover, following such superinfection the calves showed signs which could most likely be ascribed to the pathogenetic activity of BVDV. Superinfection, especially by IBR virus, created a more severe clinical response in calves that were initially infected with CP BVDV, than in those previously given the non-cytopathic (NCP) biotype of the virus. Simultaneous infection with PI-3 virus did not seem to modify to any significant extent the pathogenesis of the experimentally induced BVDV infection whereas a severe clinical response was observed in calves when simultaneous infection was made with BVDV and IBR virus.


Response of pups with maternal derived antibody to modified-live canine parvovirus vaccine. The AA reports the results of vaccination against canine parvovirus (CPV) of pups with maternal antibody, utilizing a modified-live virus (MLV) CPV vaccine having a titer of 10(7) TCID50/dose. This vaccine was shown to be effective also when HI antibody titers of pups were < or = 1:80.


Antibody responses to Toxoplasma gondii antigens in aqueous and cerebrospinal fluids of cats infected with T. gondii and FIV. Antibodies to antigens of Toxoplasma gondii were measured in the aqueous and cerebrospinal fluid (CSF) of 16 specific-pathogen free kittens experimentally infected with feline immunodeficiency virus (FIV), T. gondii, or both pathogens. The results indicated that all cats infected with T. gondii had antibody responses to antigens of T. gondii in both aqueous fluids and CSF. Co-infection with FIV did not affect antibody levels. Aqueous fluids from eyes of cats with toxoplasmic retinochoroiditis did not necessarily have higher antibody levels than those from eyes without lesions. Antibodies to T. gondii were also detected in the CSF of two cats from whose brains no parasites were isolated by in vivo mouse inoculation. Total IgG did not increase significantly in the aqueous fluids and CSF of cats infected with T. gondii whether or not they were also infected with FIV.


In vitro activity of CP-74,667. A new fluoroquinolone compared with other quinolones. CP-74,667, a 6-fluoro-7-bridged piperazinyl-1-cyclopropyl-4 quinolone, inhibited 90% of staphylococci, beta-hemolytic streptococci, enterococci, Enterobacteriaceae, and Pseudomonas aeruginosa at less than or equal to 2 micrograms/ml. Ciprofloxacin-resistant, methicillin-resistant Staphylococcus aureus had minimum inhibitory concentration (MIC50) of 4 micrograms/ml and an MIC90 of 8 micrograms/ml. CP-74,667 was fourfold more active than ciprofloxacin against Streptococcus pneumoniae and St. pyogenes, but equal or less active than tosufloxacin against Gram-positive species. The MIC90 for P. aeruginosa was 5 micrograms/ml similar to temafloxacin. The CP-74,667 MIC90 for Bacteroides fragilis was 2 micrograms/ml, equal to tosufloxacin and temafloxacin. Activity was eight- to 16-fold less at pH 5.5 compared with pH 7.4 and also eight- to 16-fold less in urine. Magnesium ions markedly increased the CP-74,667 minimum bactericidal concentrations (MBCs). The development of resistance to CP-74,667 was similar to that found for other fluoroquinolones.


Cytochrome b of protozoan mitochondria: relationships between function and structure. 1. The sensitivity of ubiquinol:cytochrome c reductase to its most powerful inhibitors has been characterized in mitochondria from three ciliate and two trypanosome protozoans and compared with that in mitochondria of animals and plants. 2. Mitochondria of ciliates, particularly those of Tetrahymena pyriformis, are resistant to antimycin. 3. Mitochondria of trypanosomes are quite resistant to stigmatellin, as they exhibit a 40-fold higher titer than that in ciliate or animals mitochondria. 4. Both ciliates and trypanosomes are highly resistant to myxothiazol. 5. Correlations have been drawn between the natural resistance of the protozoan mitochondria to antimycin, stigmatellin and myxothiazol and peculiar features in the structure of their apocytochrome b, on the basis of an accurate alignment of the sequences of this protein.


Purification and characterization of cytoplasmic 5'(3')-nucleotidase from rabbit spleen: characteristic differences of the enzyme from the rat spleen nucleotidase. 1. A 5'(3')-nucleotidase, which preferably hydrolyzed 3'-dTMP and 3'-dUMP, was highly purified from rabbit spleen cytosol. 2. The enzyme also hydrolyzes 3'-UMP, 5'-dUMP and guanine nucleotides, but does not hydrolyze any adenine nucleotides or cytosine nucleotides. 3. The activity is dependent upon Mg2+, Co2+ or Mn2+; the addition of deoxyinosine stimulates the activity, and the pH optimum for the hydrolysis of 3'-dTMP is 7.0. 4. Although the catalytic properties of the enzyme are similar to the 5'(3')-nucleotidase from rat spleen, these nucleotidases differ in their molecular disposition. 5. The charge state of the rabbit enzyme is slightly basic, and the subunit M(r) is about 27 kDa, while the value of the rat enzyme is 26 kDa. 6. Immunochemical experiments with the use of antibodies against the purified nucleotidase indicate that enzymes from rabbit spleen and from rat spleen are composed of different polypeptides.


The new macrolactones: clarithromycin (Biaxin) and azithromycin (Zithromax). Clarithromycin and azithromycin are new macrolactone antibiotics which offer several advantages over erythromycin such as increased bioavailability secondary to better acid stability, excellent tissue and intracellular distribution, extended half-lives allowing for once-daily or twice-daily dosing, lower gastrointestinal intolerance, and greater microbiological activity against selected organisms (eg, H. influenzae). These new agents are significantly more expensive than erythromycin.


Retrospective serologic survey for the presence of feline immunodeficiency virus antibody: a comparison of ELISA and IFA techniques. A total of 878 samples from the New York State Diagnostic Laboratory (NYSDL), dating from January 1984 to May 1987, were examined to detect antibodies to feline immunodeficiency virus (FIV). We used 2 screening methods; an indirect immunofluorescence assay (IFA) and an enzyme-linked immunosorbent assay (ELISA). Of these, 211 samples were from cats that tested negative for feline leukemia virus (FeLV) and exhibited disease signs consistent with immunodeficiency disease; 19 (9.0%) serum samples were determined to be positive. An additional 508 samples were from cats that tested FeLV-negative and were asymptomatic; 6 (1.2%) sera were determined to be positive. The final 159 samples were from FeLV-positive cats and included symptomatic and asymptomatic animals; this population of cats produced 6 (3.8%) positives. Additionally, 521 samples from the Cornell Feline Health Center (CFHC) serum bank, dating back to 1966, were tested to determine the earliest sample in which FIV antibodies could be detected. Five (2.7%) 1971 and 3 (3.3%) 1969 CFHC samples tested positive. The IFA for FIV antibody proved to be a sensitive (97.4%) and specific (100%) test. The ELISA also had high sensitivity (100%) and specificity (99.6%); however, the IFA proved to be more specific than the ELISA when assaying FeLV-positive cats.


Exemplary data: sample size and power in the design of event-time clinical trials. In planning a complex clinical trial with time to event as the outcome, it is difficult to derive the power of the test statistic analytically. In this paper we describe an algorithm for generating exemplary data from an alternative hypothesis that can be used to compute the expected value of a logrank test statistic and its power under that alternative. Exemplary data are nonrandomly computer-generated data that are constructed from a complex stochastic process and have desirable characteristics such as distributional moments similar to those of the process. An algorithm for generating exemplary timed events data is presented and its use in evaluating power for the planning of clinical trials demonstrated. These data represent "expectations" of outcome, data censoring, and censoring event times. A test statistic, z, such as the logrank can be computed from the data. It is distributed asymptotically, N(mu A, 1), under the alternative hypothesis and its value is used to estimate mu A and the power of the test for a given trial scenario. The results compare favorably to results from analytical methods and Monte Carlo simulations published in the literature. The advantages of the method lie in the degree of flexibility in study design, choice of models that describe the timing of events, and the range of testing methods that can be used. Although Monte Carlo methods may appear to have similar flexibility, the exemplary algorithm is more practical because only one data set need be analyzed and the modifications can be achieved without reprogramming.


Rationale and design for the Asymptomatic Carotid Artery Plaque Study (ACAPS). The ACAPS Group. An NHLBI-sponsored randomized, double-masked, placebo-controlled, multicenter clinical trial is underway to test the efficacy of the lipid-lowering agent lovastatin and/or the antithrombotic agent warfarin in slowing the progression of early carotid atherosclerosis--as defined by ultrasonographic intimal-medial arterial wall thickening--in a high-risk, asymptomatic population consisting of 919 men and women aged 40-79 years with moderately elevated serum LDL-cholesterol. The Asymptomatic Carotid Artery Plaque Study's (ACAPS) factorial design permits evaluation of each of the two treatments alone as well as assessment of the treatments in combination with each other over a 2.5- to 3.0-year treatment period. Randomized participants receive either 20-40 mg/day lovastatin or lovastatin placebo and either 1 mg/day (minidose) warfarin or warfarin placebo. All participants were encouraged to take low-dose (81 mg/day) aspirin. The primary outcome is the ultrasonographic measurement of the mean of maximum intimal-medial thickness (IMT) across up to 12 preselected segments in the carotid arteries. The secondary outcome of the trial measures the single maximum IMT measurement among the same preselected carotid artery segments. This report describes the rationale for ACAPS, its design, and some baseline characteristics of the study population.


Recruiting children and their families for clinical trials: a case study. We describe the recruitment of 226 families for participation in a randomized trial examining the effectiveness of alternative strategies for the management of pediatric asthma. All families were members of a large health maintenance organization. Families of children identified through emergency room and hospital admission records were much more likely to participate in the study than were families of children identified only through outpatient prescription records. Specific details of the recruitment process are described.


Recruitment strategies in the studies of left ventricular dysfunction (SOLVD): strategies for screening and enrollment in two concurrent but separate trials. The SOLVD Investigators. SOLVD was a double-masked, placebo-controlled trial whose initial sample size goal was to randomize 6100 participants into two concurrent trials: treatment and prevention. The objective was to determine if participants with severe left ventricular dysfunction (left ventricular ejection fraction < or = 35%, with congestive heart failure (2569) and participants without overt heart failure (4228) had improved survival with angiotensin-converting enzyme inhibitors. Participants were identified from cardiac catheterization, echocardiography and radionuclide laboratories, and inpatient units. The treatment trial recruitment goal was attained 13 months ahead of schedule while recruitment for the prevention trial was extended 11 months beyond the scheduled time. Recruitment of relatively asymptomatic participants with a low ejection fraction in a hospital-based trial necessitated novel strategies. Coronary care units and clinics for follow-up of acute cardiac conditions, not typically employed in studies of chronic diseases, were useful recruitment sources. Different approaches to encourage participation also needed to be employed. Expanding selected entry criteria was evaluated and the success of varying strategies was reviewed. The authors recommend tailoring of strategies to the target population, staffing flexibility, principal investigator involvement, and broad entry criteria in recruitment activities.


Detection of herpes simplex virus type 1 latency-associated transcripts in corneal cells of inbred mice by in situ hybridization. We have previously recovered herpes simplex virus type 1 (HSV) from the corneas of latently infected mice by cultivation in vitro. It could be argued, however, that these data do not definitively distinguish between persistent and latent corneal infection. We have now used RNA hybridization in situ to resolve this question by determining the expression of HSV genes in the corneas of BALB/c mice during latent infection. Two to four months after topical corneal inoculation with HSV, when no active ocular disease or infectious virus was present, corneas were removed and digested with collagenase. Dissociated cells pooled from two corneas were hybridized with 3H- or 35S-labeled 2.6-kb single-stranded RNA probes to detect sense and antisense ICP-0 transcripts. Twenty-five percent of the pools hybridized with the probe for antisense ICP-0 (latency-associated transcript, LAT), while only 3% hybridized with the probe for ICP-0 (p less than 0.03). Of the cells in positive pools, 0.6-7.0% showed a positive hybridization signal for LAT. No infectious virus was found by culture of supernatants from the probed pools or control latently infected corneas. These data provide further evidence that HSV can establish a true latent infection in the mouse cornea.


Delayed onset of varicella keratitis.

Delayed onset of varicella keratitis. Although varicella is one of the most common infectious diseases in the United States, systemic and ocular complications are rare. We report a patient who developed disciform edema followed by microdendritic keratitis 1 and 2 months, respectively, after resolution of the acute phase of varicella. Cultures were negative, but serologic analysis found positive antibodies against varicella zoster virus and negative antibodies against herpes simplex virus. Based on this case and on a review of the literature, we believe that this delayed onset of keratitis represents a distinct category of varicella corneal complications.


Cytochrome oxidase activity in rat retina after exposure to 404 nm blue light. Cytochrome oxidase (CYO), a key enzyme in the respiratory chain, was observed as an indicator of retinal metabolism after an in vivo blue light exposure. Thirty Sprague-Dawley rats were exposed to optic radiation of 404 nm with a retinal dose of 110kJ/m2. Immediately after exposure, the CYO activity in the pigment epithelium, in the outer and inner segments of photoreceptors, and in the outer plexiform layer of the exposed retina, was reduced to one-third-to-half of the control level. However, there was an increase in CYO activity in the exposed retina one day after exposure. One week after exposure, the CYO activity in the inner segment and the outer plexiform layer was higher, while the activity in the other two layers was lower, than that at one day, although still higher than in the control. Two weeks after exposure, the CYO activity in the four retinal layers returned to the level of the control retina, as did the activity four weeks after. After exposure, no ophthalmoscopically visible retinal change and no light-microscopically evident morphological alterations were found. There was no retinal edema or loss of photoreceptor cells. The observed alteration in CYO activity after blue light exposure may represent an inhibition of retinal metabolism. The inhibition was reversible. If this compensation mechanism is overwhelmed, retinal damage may occur.


Protein kinase C subspecies in rabbit corneal epithelium: increased activity of alpha subspecies during wound healing. Protein kinase C (PKC) has been implicated in cell proliferation and differentiation. Multiple forms of PKC have been isolated, principally from the brain where PKC is most abundant. In rabbit corneal epithelium, two distinct major peaks of PKC activity were resolved by hydroxyapatite column chromatography. Peak 2, with 65% of the total PKC activity, corresponds to alpha-PKC, based on its mobility in the column and Western blot analysis using specific monoclonal antibodies. Peak 1 did not react with either polyclonal or monoclonal antibodies to PKC alpha-, beta-, and gamma-isoforms suggesting the presence of isoforms specific to the corneal epithelium, or of another member of the PKC family. To investigate possible changes in the amounts of the various PKC subspecies during wound healing, the enzyme activities of the isolated subspecies were assayed 2, 5, and 7 days after corneal de-epithelialization. Two days after wounding, by which time the migratory limbal epithelium had covered the denuded area, total PKC activity was unchanged but alpha-PKC activity had increased to 77% of the total activity, compared with 65% in non-wounded epithelium. An increased proportion of alpha-PKC activity was also observed 5 and 7 days after wounding, during which time proliferation of epithelium continued. We hypothesize that alpha-PKC plays a role in long-term responses after injury such as gene expression and corneal epithelial proliferation. Moreover, these studies indicate that the cornea provides a good model of in vivo wound healing for PKC studies.


HLA-B27 as a receptor for cytomegalovirus. Acute anterior uveitis (AAU) is strongly associated with the genetic marker and cell membrane protein HLA-B27. Although also other genetic factors must play a pathogenetic role, the HLA-class I molecule B27 is up to now the only hold. The normal task of HLA class I molecules is to present endogenous, mostly viral, peptides to receptors on cytotoxic T cells. It is possible that HLA molecules at the cell surface serve as viral receptors. Human cytomegalovirus (HCMV) particles have been found to bind beta 2m. This might promote infectivity by a binding to HLA alpha-chains on cell membranes. We studied this mechanism using mouse fibroblasts transfected for human HLA class I molecules. Susceptibility of these cells for HCMV was compared by measuring of HCMV immediate early antigen (IEA) expression. Earlier we observed that cells transfected with HLA-B27 alpha-chains and beta 2m were significantly more infected than cells expressing HLA-A2 + beta 2m or HLA-B7 or HLA-B27 without beta 2m. However, studying another four, separately transfected, cell lines, all expressing HLA-B27 and beta 2m, three of the five B27 cell lines showed low IEA levels. The degree of infectivity was independent of the degree of B27 expression. These results do not support the previous suggestion that HLA-B27 might act as an HCMV receptor.


Initial combined cryotherapy and irradiation for unresectable non-small cell lung cancer. Preliminary results. In unresectable non-small cell lung cancer (NSCLC) with a patent mainstem bronchus, some studies of obstructive tumors, showed (1) a poor role for irradiation in obtaining efficient debulking and (2) an interest in preliminary laser treatment in these patients. Cryotherapy is another method to obtain debulking. Moreover, several studies showed that cryotherapy would increase the radiosensitivity of a tumor. We performed a preliminary protocol combining successively initial cryotherapy followed by irradiation in inoperable NSCLC (either for local or functional contraindications). Thirty-eight patients were included and treated first by cryotherapy performed under general anesthesia and then with external irradiation in a curative intent. The efficiency of cryotherapy assessed on bronchoscopy was found to be volume-efficient (VE) in 26 of the 38 patients and non-volume-efficient (NVE) in the other 12 patients. After irradiation in the VE group, 17 of the 26 patients had no bronchial residual tumor (NRT). In contrast, all of the patients in the NVE group had a bronchial residual tumor (RT). Survival in the VE group (median, 397 days) was significantly higher than the survival of the NVE group (median, 144 days). Survival was found to be independent of the surgical contraindication (local or functional). The best survival was associated both with the efficiency of the initial debulking (VE) by cryotherapy and with the local control (NRT) induced by the irradiation (median, 560 days). Local control was obtained in 65 percent (17/26) of the cases in the VE group and was never observed in the NVE group. In our study the VE group's local control is better than the 35 percent usually reported after irradiation alone. These results argue for the efficient potentiation of irradiation by cryotherapy.


Primary mediastinal germ cell tumors. Results of a French retrospective study. Eighty-seven patients with primary mediastinal germ cell tumors treated between 1983 and 1990 were studied. Among the 23 patients classified as pure seminoma, eight (35 percent) underwent surgery followed by radiotherapy (n = 6), radiotherapy and/or chemotherapy (n = 2); two patients underwent radiotherapy; 13 patients (57 percent) underwent induction cisplatin-based chemotherapy (ten complete responses) followed by radiotherapy (n = 9), second line chemotherapy (n = 2) and surgical resection of residual tumor (n = 2). On completion of treatment, 22 patients (96 percent) with seminoma were free of disease. The two-year Kaplan-Meier survival rate of these patients was 86 percent. Among the 64 patients with nonseminomatous germ cell tumor, 19 patients (30 percent) underwent surgery as first treatment (ten complete resections) followed by chemotherapy (n = 17) and radiotherapy (n = 5). On completion of treatment, 12 of 19 patients were disease free. Forty-five patients (70 percent) underwent induction cisplatin-based chemotherapy (ten complete responses), and 22 of them underwent resection of residual tumor (19 complete resections). Twenty-three patients were treated with first line chemotherapy without postchemotherapy surgery (three complete responses). In summary, 33 patients (52 percent) with nonseminomatous germ cell tumors became free of disease, and seven patients (21 percent) relapsed after achieving a complete response. The two-year Kaplan-Meier survival rate of the nonseminomatous germ cell tumor patients was 53 percent (87 percent if a complete response), with a median survival of 28 months. Despite a worse prognosis than nonseminomaous tumors from other primary sites, this series of mediastinal germ cell tumors has confirmed the efficacy of therapy.


Pretransplant pulmonary function predicts cytomegalovirus-associated interstitial pneumonia following bone marrow transplantation. To determine the value of pulmonary function tests (PFTs) in predicting the development of human cytomegalovirus (CMV)-associated interstitial pneumonia (IP) in allogeneic bone marrow transplant (BMT) recipients. Nonrandomized, prospective, open-trial study. Tertiary referral medical center. 66 evaluable CMV-seropositive patients with hematologic malignancies who were undergoing allogeneic BMT. FEV1, FVC, FEV1/FVC, TLC, Dcoc/VA, PaO2, and P(A-a)O2 were measured on days -13, +33, and +44 following BMT. CMV-IP was diagnosed when typical roentgenographic findings developed with confirmatory positive bronchoalveolar lavage (BAL) using standard cytologic and/or rapid culture techniques. Univariate logistic regression analysis to predict the development of CMV-IP revealed significant associations with the day -13 and +33 percent predicted FEV1, FVC, and TLC (p < 0.01) but no associations with other PFT parameters or with changes in these parameters. Stepwise logistic regression analysis demonstrated that only BAL positivity for CMV (odds ratio 14.8; p = 0.0002) and day -13 percent predicted FEV1 (odds ratio 0.92; p = 0.0004) were significant independent predictors of CMV-IP. Pretransplant lung function is a previously unrecognized strong predictor and risk factor for the subsequent development of CMV-IP in BMT recipients.


Electrophysiological basis for the bradycardic effects of 1-(1-pyrrolidinylmethyl)-2-naphthol in rodents. In anesthetized rats, intravenous injection of 1-(1-pyrrolidinylmethyl)-2-naphthol (TPY-beta, 0.1-1 mg/kg) induced a transient (less than 1 min) decrease in arterial blood pressure and heart rate (acute responses) followed by a delayed and sustained (greater than 10 min) bradycardic response. The electrophysiological mechanisms responsible for the bradycardic effect of TPY-beta were studied in sinoatrial tissues isolated from guinea-pig hearts. Transmembrane action potential (AP) and twitch force of atrial tissues were recorded with the conventional microelectrode techniques. In sinoatrial pacemakers active spontaneously in 4 mM [K]o Tyrode solution, TPY-beta (3-100 microM) depressed the diastolic slope and the rate of spontaneous discharges. When the non-automatic atrial tissues were driven at a fixed rate, TPY-beta (10-100 microM) inhibited the upstroke velocity of phase-0 depolarization and prolonged AP duration. In atrial fibers depolarized in high [K]o (24 mM), TPY-beta depressed the phase-0 upstroke of slow response AP and the twitch force in a concentration-dependent manner. The present results indicate that TPY-beta induced direct negative chronotropic and inotropic effects on guinea-pig atrial pacemakers and myocardial fibers. The underlying mechanisms involve a general inhibition of transmembrane of Ca, K and Na ion fluxes.


Interrelationship between estradiol and thyroxine on the release of thyrotropin and prolactin in ovariectomized-thyroidectomized rats. The effects of estradiol and thyroxine (T4) on the spontaneous and thyrotropin-releasing hormone (TRH)-stimulated release of thyroid-stimulating hormone (TSH) and prolactin (PRL) in vitro from rat anterior pituitary glands (APs) were studied. Rats were ovariectomized (Ovx) and thyroidectomized (Tx) following injection of either thyroxine (20 micrograms/kg, sc) or saline and either estradiol benzoate (EB, 0.4 micrograms/kg, sc) or peanut oil daily for 42 days. Twenty hours after the last injection, all rats were decapitated. The blood samples were collected and the APs were bisected and incubated with or without TRH (1 or 1000 ng/ml) at 37 degrees C for 4 h. Serum TSH concentration was reduced by T4 injection but not altered by EB replacement. The concentration of serum PRL was increased by EB. Injection of both T4 and EB reduced the serum PRL level as compared with the PRL levels in Ovx-Tx rats injected with T4 or EB alone. The spontaneous release of TSH in vitro from APs of OVx-Tx rats was not altered by the replacement of T4, EB, or both. The TSH response to TRH (1000 ng/ml) was not influenced by EB treatment, but higher in T4-treated than in vehicle-treated group. Injection of both EB and T4 prevented the stimulatory effect of T4 alone on TSH response. Both spontaneous and TRH-stimulated releases of PRL in vitro were enhanced by EB injection. Administration of T4 did not affect the basal release of PRL, but stimulated the PRL response to TRH (1000 ng/ml). Injection of EB plus T4 caused a higher PRL response to TRH as compared with that in the rats injected with EB or T4 alone. These results suggest an antagonistic interaction between estradiol and thyroxine on the in vitro release of TSH in response to TRH and a synergetic interaction between these two hormones on PRL response to TRH. The interaction between estradiol and thyroxine on serum prolactin and TSH levels was not reflected by the interaction between these two hormones on the anterior pituitary gland.


Residential treatment: linkage with community drug treatment programs. The realization that the program and services offered at the residential treatment center were not fully effective for some clients with multiple problems was an emotionally wrenching, but unavoidable, process. As the need for outside community substance-abuse referrals continues, it is important that ongoing relationships among agencies be established and nurtured. Dilemmas in creating these relationships have to be expected by all involved. Ways to resolve these problems must be put in place as quickly as they occur. Windows of opportunity to help residential treatment center clients with drug and alcohol problems must be recognized early on in treatment to ensure optimal services. Agencies must coordinate and cooperate with each other to be in position to seize these opportunities when they arise.


Eukaryotic DNA helicases: essential enzymes for DNA transactions. DNA in its double-stranded form is energetically favoured and therefore very stable. However, DNA is involved in metabolic events and thus has a continuous dynamic. Processes such as DNA replication, DNA repair, DNA recombination and transcription require that DNA occurs transiently in a single-stranded form. This status can be achieved by enzymes called DNA helicases. These enzymes have the power to melt the hydrogen bonds between the base pairs by using nucleoside 5'-triphosphate hydrolysis as an energy source. A variety of different DNA helicases have recently been identified from eukaryotic viruses and cells. We focus on the current knowledge of these DNA helicases and their possible function in DNA transactions.


[Changes in serum endogenous digitalis-like factor concentration in patients with renal impairment]. Measurement of serum endogenous digitalis-like factor (EDF) concentration was carried out in 58 patients with renal impairment with radioimmunoassay. The results showed that serum EDF concentration in patients with renal impairment was markedly higher than that of normal cases. The serum EDF concentration was significantly elevated with decrease of renal function and was positively correlated with the levels of BUN and blood creatinine. The serum EDF concentration in patients with primary and secondary renal impairment was of no difference. It was found that the difference between patients with and without hypertension was statistically significant. The serum EDF concentrations were markedly decreased after hemodialysis but still higher than those of normal cases.


Immortalized hypothalamic gonadotropin-releasing hormone neurons. The neuroendocrine hypothalamus has been intensively studied using whole animals and tissue slices. However, it has been difficult to approach questions at the molecular and cellular level. By targeting expression of the oncogene product, simian virus 40 T antigen, in transgenic mice using the regulatory domain of the rat gonadotropin-releasing hormone (GnRH) gene, we have produced specific hypothalamic tumours. These tumours have been cultured to produce clonal cell lines (GT-1 cells) that express T antigen, GnRH and many other neuronal markers, but do not express other hypothalamic hormones. These immortal cell lines have a distinctive neuronal phenotype, process the GnRH peptide accurately and secrete GnRH in a pulsatile pattern. Thus, by targeting oncogenesis to a defined population of neurons using the regulatory region of a gene that is expressed late in differentiation of that cell lineage, we have succeeded in immortalizing hypothalamic GnRH neurons. The GT-1 cell lines are an excellent model for future molecular, cell biological, physiological and biochemical investigations into the mechanisms involved in regulation of GnRH and the characteristics of an isolated central nervous system neuron. Their derivation demonstrates the utility of targeting tumorigenesis to specific differentiated neurons of the central nervous system in transgenic mice.


Receptors and neural effects of oxytocin in the rodent hypothalamus and preoptic region. Vasopressin and oxytocin are produced in and secreted from not only hypothalamo-hypophysial neurons which shed their products into the circulation to act as hormones or releasing factors, but also from neurons whose axons form tracts which remain within the central nervous system. Using tritiated or radioiodinated ligands, binding sites for vasopressin and for oxytocin have been detected by in vitro autoradiography. In the rat hypothalamus binding sites for vasopressin are present in the suprachiasmatic, sigmoid and arcuate nuclei, and oxytocin receptors in the area of the ventromedial nucleus. Electrophysiological evidence obtained using single cell recordings in slices suggests that oxytocin-binding sites present in the ventromedial hypothalamus and in the bed nucleus of the stria terminalis mostly represent functional, neuronal receptors. The expression of these receptors (but not of the vasopressin receptors) depends on gonadal steroid hormones, as does that of uterine and mammary gland oxytocin receptors. Modifications of the hormonal status associated with, for example, puberty and lactation cause 'up-regulation' of central and peripheral oxytocin receptors. The central administration of oxytocin facilitates (and the administration of oxytocin agonists inhibits) maternal behaviour and the milk ejection reflex, therefore the hormonal and neural actions of oxytocin appear to be complementary in ensuring the birth and development of the offspring.


The relative importance of hypothalamic neurons containing corticotropin-releasing factor or vasopressin in the regulation of adrenocorticotropic hormone secretion. Corticotropin-releasing factor (CRF-41) and arginine vasopressin (AVP) are the two major factors that regulate adrenocorticotropic hormone (ACTH) secretion. The two neurohormones are co-localized in the parvocellular neurons of the paraventricular nuclei (PVN) of the hypothalamus and are capable of potentiating each others' action on freshly excised anterior pituitary fragments or cells in vitro. Transection of all axons entering the medial basal hypothalamus from anterior and lateral directions blocks ACTH release induced by either adrenalectomy or ether-surgery stress. Adrenalectomy-induced ACTH release is almost completely suppressed by a long-term lesion of the PVN. Stress-induced ACTH release is blocked for only a few days after PVN lesion and the pituitary-adrenal response to ether-surgery stress returns to a large extent by a few weeks after PVN lesioning. This remarkable plasticity can be observed also in the homozygous Brattleboro rat, therefore it is not dependent on mediation by AVP. When parvocellular CRF-41- and AVP-containing cells are present, and the anterior lobe ACTH cells are desensitized to the stimulating effects of AVP, the ACTH response to haemorrhage and immobilization is markedly decreased. This indicates that AVP may partially mediate ACTH release under normal conditions. The hypothalamic control of the pituitary-adrenocortical system has a remarkable degree of redundancy which may compensate, at least under stressful conditions, for disruption of the function of CRF-41-containing cells of the paraventricular nucleus, the major source of CRF-41 in the stalk-median eminence.


Quality of life after total proctocolectomy and ileal J-pouch-anal anastomosis. We investigated the daily life and opinions of patients after total proctocolectomy and ileal J-pouch-anal anastomosis. Eighty patients answered a questionnaire, completed Cattell's anxiety scale, and recorded bowel function for one month. Both colitis and polyposis patients defecated five times daily, had 1.6 episodes of nocturnal motions weekly, and soiled twice weekly. However, colitis patients were more satisfied with their bowel function and surgical outcome than were polyposis patients. This difference had a close relationship to the personality factors of ego strength and frustration. All patients with either disease who defecated less than three times daily, had no nocturnal motions, and had no soiling showed normal ego strength and frustration and were completely satisfied with their bowel status and operation. In contrast, patients defecating more than seven times daily or more than once per week nocturnally and soiling more than four times weekly had high frustration and were dissatisfied. Thus, satisfaction with surgery correlated not only with the objective outcome but also with personality and lifestyle.


Hepatitis C virus does not cause nonalcoholic steatohepatitis. The pathogenesis of nonalcoholic steatohepatitis (NASH) remains poorly understood. Since inflammation and fatty changes are associated with hepatitis C (HCV) infection, we have tested the role of HCV in the genesis of NASH. Five consecutive cases of classic NASH were tested by Abbott anti-c100-3 EIA and polymerase chain reaction (PCR) to detect HCV-RNA. All serum specimens were negative for anti-c100-3 (or anti-HCV EIA) and HCV PCR. Based on this study, we conclude that HCV does not play a causative or contributing role in the pathogenesis of NASH.


Systemic tumor necrosis factor-alpha production in experimental colitis. Tumor necrosis factor-alpha (TNF) is a cytokine released by mononuclear cells in response to inflammation and sepsis. Since the biological effects of TNF are consistent with the systemic and intestinal features of ulcerative colitis, the role of TNF was examined in a rabbit model of chronic colitis. Peripheral blood mononuclear cells were isolated, stimulated with lipopolysaccharide, and cultured supernatants assayed for TNF levels using a cytotoxic assay on mouse fibrosarcoma L929 cells. Basal levels of TNF production by mononuclear cells from 13 normal rabbits (124.3 units/ml +/- 27.1 units/ml, mean +/- SE) were not different from nine rabbits with colitis (83.6 units/ml +/- 24.4 units/ml, P > 0.05). Treatment with lipopolysaccharide (100 micrograms/ml) induced increased TNF production by mononuclear cells isolated from both normals (672.0 units/ml +/- 197.5 units/ml, P < 0.05) and rabbits with colitis (1114.0 units/ml +/- 489.6 units/ml, P < 0.05). However, at all lipopolysaccharide concentrations stimulated TNF levels were comparable in experimental and control groups (P > 0.05). In light of the role of leukotrienes in inflammation, a separate group of rabbits with colitis was investigated following treatment with an oral leukotriene B4 receptor antagonist. Serum TNF levels in 15 control rabbits (32.5 units/ml +/- 7.6 units/ml, mean +/- SE) were not significantly different from rabbits with colitis receiving either leukotriene B4 receptor antagonist (35.7 units/ml +/- 9.2 units/ml, N = 13) or vehicle alone (50.3 units/ml +/- 10.2 units/ml, N = 14) (ANOVA, P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Chronic intestinal pseudoobstruction in a patient with heart-lung transplant. Therapeutic effect of leuprolide acetate. After orthotopic heart-lung transplantation and immunosuppression, a patient developed intractable nausea and vomiting in association with chronic cytomegalovirus infection. Chronic intestinal pseudoobstruction was documented by antroduodenal manometric study. The patient was treated with leuprolide acetate with resolution of symptoms and improvement of intestinal motility abnormality. This case demonstrates an association of chronic viral infection with acquired intestinal motor disorders. Gastrointestinal complications that are common after organ transplantation might be due to acquired neuromuscular disease. The potential efficacy of leuprolide in such neuromuscular disorders provides a rationale for diagnostic motility studies in patients with "functional" gastrointestinal disorders.


Serum angiotensin-converting enzyme activity and active renin plasma concentrations in insulin-dependent diabetes mellitus. We report here the alterations of serum angiotensin-converting enzyme activity (S-ACE) and of active renin plasma concentrations (ARPC) in 41 insulin-dependent diabetes mellitus (IDDM) patients compared with those of 26 control subjects. The IDDM patients had S-ACE activity (54 +/- 16 I.E.) in the upper normal range (controls, 39 +/- 7). When the patients were subclassified according to their diabetic complications, a significant increase of S-ACE within the IDDM group compared to the controls was observed in patients with nephropathy (68 +/- 13, P less than 0.001) with persistent proteinuria and with retinopathy (63 +/- 14, P less than 0.001). A significant correlation was found between proteinuria and S-ACE (r = 0.98, P less than 0.001) and between retinopathy and S-ACE levels (r = 64, P less than 0.001). No correlation between blood pressure and S-ACE or between blood glucose and S-ACE was observed. The ARPC were within the normal range in the IDDM (21 +/- 9 ng/l) and in control (19 +/- 3) groups. No correlations between ARPC and blood pressure or blood glucose or the degree of diabetic complications were registered. These data show that S-ACE activity is elevated in IDDM patients with nephropathy-proteinuria and/or with retinopathy and the circulating renin may not represent the renal renin-angiotensin vascular system.


Arachidonic acid metabolites and alpha 2-adrenoceptor-mediated glucagon secretion in rats. Effects of phospholipase A2 inhibitor, cyclooxygenase inhibitor and lipoxygenase inhibitor on glucagon secretion induced by the alpha 2-adrenergic agonist clonidine were studied in the isolated perfused rat pancreas. The phospholipase A2 inhibitor mepacrine at 25 and 50 mumol/l significantly inhibited glucagon secretion induced by 0.1 mumol/l clonidine (P less than 0.01, respectively), whereas 5 mumol/l mepacrine did not affect clonidine-induced glucagon secretion. Also, both 100 mumol/l acetylsalicylic acid (cyclooxygenase inhibitor) and 100 mumol/l caffeic acid (lipoxygenase inhibitor) significantly inhibited clonidine-induced glucagon secretion (P less than 0.01, respectively), whereas neither 10 mumol/l acetylsalicylic acid nor 10 mumol/l caffeic acid affected clonidine-induced glucagon secretion. None of the drugs at the tested concentrations affected insulin secretion at a glucose concentration of 5.5 mmol/l. These results suggest that not only cyclooxygenase metabolites but also lipoxygenase metabolites are involved in the stimulation of glucagon secretion mediated through the alpha 2-adrenergic receptors in perfused rat pancreas.


Amantadine may facilitate detoxification of cocaine addicts. The effectiveness of amantadine hydrochloride was evaluated in a double-blind placebo controlled drug trial. The subjects were 42 cocaine dependent men enrolled in a day hospital program. Twenty-one patients were prescribed 100 mg/bid of amantadine to be taken over 10.5 days and 21 were prescribed an equivalent amount of placebo. The primary outcome measures were the Addiction Severity Index at 1 month after study entry and urines during the drug trial (end of weeks 1 and 2) and 1 month after study entry. Urines obtained at the end of the drug trial (2 weeks) indicated that the subjects receiving amantadine (93%) were more likely (P = 0.040) to be free of cocaine than the placebo (60%) subjects. Urine toxicology data at 1-month follow-up again indicated that more of the amantadine subjects (83%) were free of cocaine than the placebo (53%) subjects (p = 0.049); although no differences were found in self-reports of cocaine or other substance use in the past 30 days. The urine findings provided preliminary indication that amantadine may have some effectiveness in reducing cocaine use in cocaine dependent patients.


Weighing up the pros and cons: help-seeking by drug misusers in Baltimore, USA. Forty drug misusers receiving treatment in Baltimore completed questionnaires, originally administered to drug misusers in London, about their reasons for seeking help and their worries about the treatment. Seeking help was related to the experiences of addiction, loss of control over life and financial and family difficulties. The main fears were of failing treatment. These responses are similar to those obtained in the London group. There was little correlation between objective assessment and subjects' views of their problems. This study illustrates the complexities of coming for treatment and it emphasises the need for social and medical help.


Effects of acute and repeated alcohol ingestion on hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal functioning in normal males. We investigated the effects of acute and repeated alcohol ingestion on plasma levels of hormones associated with the functioning of the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) systems in normal males. In the first experiment, 7 normal male subjects were given ethanol (1.3 g/kg) in the form of a 43% alcohol solution of whiskey and water over a 30-min period (from 19:00 h to 19:30 h); blood samples were collected 30 min and immediately before the beginning of alcohol ingestion and then at intervals of 30 min for 180 min. Blood ethanol levels rose sharply and reached their maximum at 60 min, remaining above 1.0 mg/ml until 180 min. Prolactin levels increased, reaching a peak at 60 min, gradually returning to the initial value at 180 min. Decreased testosterone levels were observed only at 30 min. Luteinizing hormone (LH), adrenocorticotrophic hormone (ACTH) and cortisol levels did not show any increases. In the second experiment, 9 normal males were given the same dose of alcohol, but this was given on 7 consecutive evenings and the hormonal changes were examined on the 1st and 7th days, only at 30 and 60 min after alcohol ingestion began (during the period that blood ethanol levels were ascending to their peak). The results on the 1st day reconfirmed the findings in the first experiment and on the 7th day, the last alcohol ingestion produced increases in prolactin levels and decreases in testosterone levels at 30 and 60 min, but did not change other hormone levels.(ABSTRACT TRUNCATED AT 250 WORDS)


Attenuation of the effects of chronic ethanol administration in the brain lipid content of the developing rat by an oil enriched in gamma linolenic acid. Chronic ethanol administration to adult rats results in an increase in the linolenic (18:2) to arachidonic (20:4) acid ratios in brain phospholipids. Administration of a diet rich in essential fatty acids can reverse some of the effects of chronic ethanol administration on neuronal membranes. In this study we investigated the effect of ethanol on the neuronal membranes of rat pups and also the effect of the concomitant administration of gamma linolenic acid (18:3) as a component of Evening Primrose Oil (EPO). We found an increase in the concentration of several saturated fatty acids that are components of the phospholipids and a decrease in the mono- and polyunsaturated fatty acid content. EPO was found to attenuate the effect of ethanol in inhibiting the synthesis of polyunsaturated fatty acids. These effects of EPO are probably a direct consequence of the essential fatty acids in the oil circumventing the inhibitory effects of ethanol on polyunsaturated fatty acid synthesis.


[Osteoporotic vertebral fractures in systemic mastocytosis without skin involvement]. Radiological investigation of the vertebral column in two patients with low-back pain (53-year-old woman and a 52-year-old man) revealed unusually marked osteoporosis and sintering fractures of the 3rd, and 1st and 4th lumbar vertebrae, respectively. Biochemical tests failed to provide any evidence about metabolic or endocrinological abnormality. Iliac crest biopsy showed mastocytosis. There were no skin changes in either patient. Additional examinations excluded involvement of any internal organs. Despite treatment with calcium, sodium fluoride, vitamin D3 and calcitonin in the woman, and aspirin and chromoglycinic acid in the man the osteoporosis has slowly progressed during the last 7 and 5 years, but the disease has remained limited to the skeletal system. In a case of unusually marked osteoporosis, mastocytosis should be included in the differential diagnosis even in the absence of urticaria pigmentosa.


[Vaccination of sheep against Aujeszky's disease with a gI-deleted mutant]. The use of gl deleted live vaccines against Aujeszky's disease (AD) facilitates to differentiate vaccinated from field-virus infected animals. In this study different modes of vaccination were tried to find out how sheep can be protected from a lethal infection with ADV. It could clearly be demonstrated that Aujeszky disease virus (ADV) is spread by horizontal transmission from infected pigs to sheep. The nasal discharges of infected pigs contained a maximum of 10(8.75)TCID50/g mucus at days 3 and 4 p.i. and those of the contact-pigs 10(8.5)TCID50/g mucus at days 6 and 7 after contact. Non-vaccinated contact sheep were infected horizontally by the pigs. The highest titres ranged from 10(6.25) to 10(7.5)TCID50/g mucus. These animals were sacrificed at day 5 p.i. exhibiting acute symptoms of AD. The nasal discharge of vaccinated sheep contained much lower amounts of ADV (maximum: 10(4.25)TCID50/g mucus). All surviving animals had developed antibodies. Following challenge with the ADV-strain NIA3, no febrile response or virus-shedding was observed in sheep vaccinated 2x s.c. or 2x i.m. with a gl deleted live vaccine, whereas sheep, vaccinated only 1x i.m. (4 out of 4 animals) or 1x i.m. (3 out of 4 animals) or 1x i.n. and 1x i.m. (1 out of 4 animals) had to be sacrificed after showing acute symptoms of AD. In conclusion it can be stated that a double parental vaccination with a gl deleted live vaccine protects sheep against a field-virus AD infection.


[The effectiveness of cholecalciferol and flumethasone for the prevention of hypocalcemic parturient paresis in dairy cows]. Investigations on the efficacy of high doses of cholecalciferol and flumethasone for prophylaxis of hypocalcemic milk fever were performed in dairy cows. Only one cow in the group of 25 treated animals diseased by milk fever, but 5 of 25 control animals showed signs of hypocalcemia. A placenta retention was observed in three treated animals and in four control animals. The results show that the additional application of flumethasone for birth induction after the injection of vitamin D3 was unchanged.


Characterization of serum lysosomal enzymatic activities. II. Effect of lumpy skin disease in Egyptian cows. Clinical findings and lysosomal enzymes (LYE) in eight lumpy skin diseases (LSD) cows and same number of healthy ones were reported in Tal-El Baker village and Tal Alkabir centre, Ismailia province, Egypt. LSD began with fever, anorexia, skin lesions in form of nodules all over the body, which disappeared spontaneously or gathered to form large lumps. It was complicated with respiratory manifestation, corneal opacity, mastitis, dehydration and later on recumbency. It is noteworthy that the level of 3 LYE showed the same trend of significant reduction in acute stage of the disease (5 days after occurrence of LSD) probably due to injection of animals with a therapeutics dose of terramycin. Acid-phosphatase (ACP) enzyme is the sole that behaved very high significant increase in the serum in acute stage of LSD due to the damaged tissues caused by the virus. It underwent insignificant decrease in late stage of the disease (20 days after its occurrence) to restore the normal LYE level in control cows indicating recovery. Alpha-galactosidase (alpha-GAL) decreased perpetually by the progression of LSD because of the decreased bactericidal index which ist in concomitance with the secondary bacterial invader. N-acetyl-beta-glucosaminidase (beta-NAG) and beta-galactosidase (beta-GAL) in LYE had the same fluctuating manner. The activities showed very highly significant decrease in acute stage, followed by highly significant and significant increases (late LSD stage) respectively. The appreciable significant increase of beta-GAL may declare the effect of anorexia on LSD. In view of these findings, it can be postulated that LSD may be diagnosed and prognosed through LYE changes in the serum.