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Cardiac beta-adrenoceptor regulation and the effects of partial agonism. The in vivo effects of xamoterol on the regulation of rat cardiac beta adrenoceptors were investigated. Rats were implanted subcutaneously with osmotic minipumps and exposed to the following treatment regimens: (1) subcutaneous infusion of saline (control), isoprenaline or xamoterol for 6 days, (2) subcutaneous infusion of isoprenaline with co-administration of xamoterol for various periods up to 96 hours, and (3) subcutaneous infusion of xamoterol for up to 96 hours after previous treatment with isoprenaline for 72 hours. Xamoterol did not induce beta-adrenoceptor down-regulation after short-term (72-hour) or long-term (6-day) infusions. When coadministered with isoprenaline xamoterol did not affect the rate or extent of down-regulation induced by isoprenaline alone. In addition, recovery of beta adrenoceptors down-regulated by isoprenaline treatment was not influenced by xamoterol treatment. In all studies, doses of xamoterol were equivalent to those producing full functional responses to the drug in vivo.

Interrupting the adaptive changes in congestive heart failure. Circulating plasma concentrations of norepinephrine, renin, angiotensin and vasopressin are increased in congestive heart failure. By increasing ventricular afterload, heart failure is further worsened, which in turn--in a vicious cycle--stimulates neurohumoral vasoconstrictor mechanisms. Furthermore, because of the compensatory but excessive stimulation of the sympathomimetic system, a down-regulation and desensitization particularly of the myocardial beta 1 receptors and depletion of myocardial catecholamine occurs in chronic heart failure. These defects may be restored toward normal by interventions that attenuate the activity of the sympathetic nervous system. A direct approach to modify the excessive vasoconstriction is to administer systemic vasodilator drugs, but despite favorable short-term effects, tolerance developed to most of these drugs during long-term treatment. One reason for the loss of effectiveness is the reflex activation of the sympathetic system, which increases vasoconstrictor hormone concentrations. Activation of the renin-angiotensin system can be modified effectively by angiotensin-converting enzyme inhibitors that have shown favorable responses in patients with chronic heart failure. Beta-blocking agents interfere with endogenous sympathetic activation and have produced beneficial effects in patients with congestive cardiomyopathy. Long-term treatment is associated with up-regulation of the number of beta receptors and an improved responsiveness to catecholamines. Owing to the negative inotropic effects of beta-blocking agents, some of the patients with severe heart failure deteriorated hemodynamically and clinically. Theoretically, it should be advantageous to have a substance that combines protection against excessive beta stimulation with a mild inotropic support to prevent cardiac decompensation. This may be achieved by a selective beta 1-partial agonist like xamoterol.

Acute and chronic hemodynamic effects of xamoterol in mild to moderate congestive heart failure. Xamoterol, a new beta 1 partial agonist, has the potential to modulate cardiac response to variations in sympathetic tone in patients with heart failure. Its properties should result in beta-receptor stimulatory effects at low levels of sympathetic tone and beta-receptor protective effects at higher levels of sympathetic tone. The acute effects of intravenous (i.v.) xamoterol on hemodynamics at rest and during exercise were studied in 30 patients with mild to moderate heart failure (13 patients in New York Heart Association class II; 17 in class III) due to ischemic (n = 24) or cardiomyopathic (n = 6) heart disease. Cardiac index, stroke volume and stroke work index at rest were significantly improved after i.v. administration of xamoterol and consistent with net agonist effects. During exercise, heart rate and double product were significantly reduced (net antagonist effects), but with preservation of the expected increases in cardiac index and systolic blood pressure. These hemodynamic findings confirm the ability of xamoterol to modulate cardiac response to variations in sympathetic tone. Tachyphylaxis and arrhythmogenicity limit the chronic use of drugs with full beta-agonist properties as positive inotropes in heart failure. The patients were therefore entered into a 6-month double-blind, placebo-controlled, crossover study of chronic oral xamoterol therapy, 200 mg twice daily, and the hemodynamic responses to i.v. xamoterol were repeated at the end of the trial. No impairment in either resting or exercise effects was observed, indicative of a maintained response and absence of tachyphylaxis after chronic therapy. Furthermore, 24-hour ambulatory electrocardiographic monitoring showed no change in ventricular arrhythmias during oral treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Local cardiac responses--alternative methods of control. Much attention has been paid to the influence of the beta-adrenoceptor system on cardiac function in heart failure. Full agonists and partial agonists acting on cardiac beta 1 receptors have been widely investigated, as has the density of these receptors in the failing heart. However, other cardiac control mechanisms may play important roles in the normal heart as well as in heart failure. The Frank-Starling mechanism of enhanced cardiac contraction produced by mechanical stretching of the ventricular myofibrils is well known. When treating patients with heart failure with diuretics, vasodilators and other drugs that influence preload, it is important to consider their overall effects in relation to the Starling curves. Atrial stretching also produces compensatory responses which are currently being intensively studied. Reflex release of atrial natriuretic factor after stimulation of atrial receptors has important physiologic effects in heart failure. The atria, but not the ventricles, are innervated by the vagus; the influence of the parasympathetic nervous system on the heart and circulation is often overlooked. The initial increase in heart rate during exercise is primarily due to withdrawal of vagal influence. Besides acetylcholine, the parasympathetic transmitter, many other local hormones may affect cardiac function; these include prostaglandins, 5-hydroxytryptamine and histamine. Although the activity of the sympathetic nervous system is mediated primarily through beta 1 adrenoceptors, both beta 2 and alpha receptors are also found in the heart. Myocardial alpha 1 receptors, which mediate a positive inotropic effect, have been identified, and prejunctional alpha 2 receptors may mediate inhibition of norepinephrine release from sympathetic nerves.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary alpha-linolenic acid is as effective as oleic acid and linoleic acid in lowering blood cholesterol in normolipidemic men. The effect of dietary oleic acid (OA), linoleic acid (LA), and linolenic acid (LNA) on plasma lipid metabolism was studied in eight normolipidemic men. A mixed-fat diet composed of conventional foods was fed during 6-d pre- and post-experimental periods. The same basic diet but with 75% of the fat (26% of total energy) provided by sunflower and olive; canola; soybean; and sunflower, olive, and flax oils was fed during four 18-d experimental periods. Mean plasma total cholesterol (-18%), low-density-lipoprotein-cholesterol, (-22%) and very-low-density-lipoprotein-cholesterol (-41%) concentrations were significantly (P less than 0.004) lower after the experimental diets than after the mixed-fat diet. Mean serum apolipoprotein B (-19%) and apolipoprotein A-I (-9%) concentrations were also significantly (P less than 0.0007) lower after the experimental diets. The experimental diets were equally effective in lowering total and lipoprotein cholesterol and apolipoprotein concentrations in plasma, indicating that dietary OA, LA, and LNA were equally hypocholesterolemic.

Depression of thymus-dependent immunity in wasting protein-energy malnutrition does not depend on an altered ratio of helper (CD4+) to suppressor (CD8+) T cells or on a disproportionately large atrophy of the T-cell relative to the B-cell pool. We report cell numbers within major subsets of lymphocytes in the spleen, mesenteric nodes, and recirculating pool of weanling mice subjected to protein-energy malnutrition (PEM). PEM and thymus (T)-dependent immunodepression were induced in male C57BL/6J mice by a low-protein (LP) diet fed ad libitum. Recirculating lymphocyte numbers were estimated by enumerating labeled and unlabeled cells after equilibration of a known number of fluorescein isothiocyanate-labeled C57BL/6J donor lymphocytes within well-nourished or LP recipients. Involution of the recirculating lymphocyte pool of the LP group was proportionately less than the lymphoid atrophy of the spleen and mesenteric nodes. The LP protocol exerted no influence on the ratio of helper (CD4+) to suppressor (CD8+) T cells and increased the ratio of T cells to B cells in the secondary lymphoid organs and recirculating pool. These results challenge two established concepts: that T-dependent immunodepression in PEM depends on a reduced CD4(+)-CD8+ ratio and that PEM induces greater involution within the T-cell system than within the B-cell system.

Mild intraoperative hypothermia increases duration of action and spontaneous recovery of vecuronium blockade during nitrous oxide-isoflurane anesthesia in humans. We compared the duration of action and recovery times for vecuronium in normothermic and mildly hypothermic patients. Ten patients were actively cooled to a central body temperature near 34.5 degrees C, and ten were maintained at a normothermic central temperature (greater than 36.5 degrees C); temperature was measured in the distal esophagus. Vecuronium 0.1 mg/kg was administered as an intravenous (iv) bolus to all patients, and the evoked mechanical response to train-of-four stimulation was recorded. Five hypothermic and five normothermic patients were allowed to recover spontaneously. In the remaining five in each group, neostigmine (40 micrograms/kg) and atropine (20 micrograms/kg) was administered when the first twitch (T1) height spontaneously recovered to 10% of control (T1 = 10% of the pre-vecuronium twitch tension). Vecuronium's duration of action (from injection of drug until T1 = 10%) was 28 +/- 4 and 62 +/- 8 min during normothermia and hypothermia, respectively (P less than 0.05). The corresponding values for spontaneous recovery from T1 = 10% to TOF ratio greater than 75% were 37 +/- 15 and 80 +/- 24 min (P less than 0.05), and for neostigmine-induced recovery were 10 +/- 3 and 16 +/- 11 min (difference not significant). We conclude that mild hypothermia increases the duration of action of and time for spontaneous recovery from vecuronium-induced neuromuscular blockade.

Vecuronium neuromuscular blockade at the adductor muscles of the larynx and adductor pollicis. The differences between neuromuscular blockade of the adductor muscles of the vocal cords and the adductor pollicis were examined in 20 adult women anesthetized with fentanyl and propofol. Vecuronium 0.04 or 0.07 mg/kg was given as a single bolus by random allocation. The force of contraction of the adductor pollicis was recorded. Laryngeal response was measured as pressure changes in the cuff of the tracheal tube positioned between the vocal cords. Train-of-four stimulation was applied to the recurrent laryngeal nerve at the notch of the thyroid cartilage and to the ulnar nerve at the wrist. Neuromuscular blockade had a faster onset, was less intense, and recovered more rapidly at the vocal cords. With 0.04 mg/kg, maximum blockade of first twitch (T1) was 55 +/- 8 (mean +/- standard error of the mean [SEM]) and 88 +/- 4% at the vocal cords and the adductor pollicis, respectively (P = 0.006). Onset time was 3.3 +/- 0.1 and 5.7 +/- 0.2 min, respectively (P = 0.000001), and time to 90% T1 recovery was 11.3 +/- 1.6 and 26.1 +/- 1.8 min, respectively (P = 0.001). With 0.07 mg/kg, onset time was unchanged; maximum blockade was more intense, being 88 +/- 4 and 98 +/- 1%, respectively (P = 0.04 between muscles); and time to 90% T1 recovery was 23.3 +/- 1.8 min at the vocal cords versus 40.3 +/- 2.9 min at the adductor pollicis (P = 0.001). Approximately 1.73 times as much vecuronium was required at the larynx compared with the dose required at the adductor pollicis for the same intensity of blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of a histamine type-2 receptor antagonist (BMY-25368) on gastric secretion in horses. The effects of a potent new histamine-2 (H2) receptor antagonist, BMY-25368, were studied on gastric acid secretion in 5 foals from which food was withheld. Doses of 0.02, 0.11, 0.22, and 1.10 mg/kg of body weight were administered IM in a randomly assigned treatment sequence. Following BMY-25368 administration, hydrogen ion concentration was decreased and mean pH was higher than baseline values in a dose-response pattern. At the 0.22 and 1.10 mg/kg doses, the high pH was sustained for greater than 4 hours. The BMY-25368 thus may be useful for treating gastric ulcer disease in horses.

Mental disorders among alcoholics. Relationship to age of onset and cerebrospinal fluid neuropeptides. Eighty-one percent of 339 alcoholics participating in a research program were found to have associated mental disorders. Alcoholics with onset of heavy drinking before 20 years of age had significantly more antisocial personality traits, drug abuse, bipolar disorder, panic disorder, suicide attempts, and paternal alcoholism than alcoholics with onset after age 20 years. Alcoholics with onset before and after 20 years of age also differed significantly from each other for cerebrospinal fluid concentrations of diazepam-binding inhibitor and somatostatin. These results support the notion that age of onset may delineate subgroups of alcoholics with significant clinical and neurochemical differences.

Human T-cell leukemia/lymphoma viruses. Life cycle, pathogenicity, epidemiology, and diagnosis. Human T-cell leukemia/lymphoma virus type I (HTLV-I) was discovered in 1980, and it subsequently was found to be the cause of adult T-cell leukemia/lymphoma. A progressive neurologic disease known as tropical spastic paraparesis, or HTLV-I-associated myelopathy, has also been linked to infection with HTLV-I. A related virus, HTLV type II (HTLV-II), has been isolated from patients with hairy-cell leukemia, but it has not been proved to be the cause of any disease. In late 1988, US blood banks began screening all blood donations for antibodies to HTLV-I/II. This program has resulted in the identification of many unexpectedly seropositive blood donors and provided much information about the prevalence of HTLV-I/II in the United States. In this article, I review the replication of these agents, as well as their pathogenesis, diagnosis, and mechanisms of spread.

S100 protein-positive sustentacular cells in malignant and locally aggressive adrenal pheochromocytomas. The absence or presence of S100-positive sustentacular cells has been previously shown to be correlated with benign and malignant pheochromocytomas and paragangliomas. We evaluated a total of 17 malignant and recurrent or locally aggressive adrenal pheochromocytomas for their quantity of sustentacular cells. An absence of sustentacular cells was demonstrated in the majority of malignant cases, while the locally aggressive or recurrent group usually contained an abundance of these cells. However, in one malignant case a constant moderate number of sustentacular cells in the primary site and in two sequential metastases was found. We conclude that the absence of sustentacular cells in pheochromocytomas may indicate a lesion with a greater potential for metastasis and that sustentacular cells, when they are present in a malignant pheochromocytoma, are an integral part of the tumor.

The impact of ulcerogenic drugs on surgery for the treatment of peptic ulcer disease. To investigate the impact of ulcerogenic drugs on surgery for the treatment of peptic ulcer disease, we reviewed 150 surgical cases. Ulcerogenic drug use (steroids and/or nonsteroidal anti-inflammatory agents, including aspirin) increased from 15% between 1972 and 1977 to 37% between 1983 and 1988. While there was no correlation between ulcerogenic drug use and hemorrhage, obstruction, or intractable pain, 16 (52%) of the 31 perforations and 26 (38%) of the 69 emergency operations were associated with use of ulcerogenic drugs. The overall mortality rate was 11%. Death was correlated with age greater than 65 years and emergency operation, but not with ulcerogenic drug use or other variables. Of 12 patients with histories of peptic ulcer disease who were treated with ulcerogenic drugs without concomitant antiulcer prophylaxis, 11 (92%) required emergency operation to treat perforation or massive hemorrhage. Standard antiulcer medications or misoprostol should be prescribed to elderly patients and to those with histories of ulcers who require ulcerogenic drug therapy.

Normothermic ischemic cardiac arrest in the isolated working rabbit heart: effects of dl-nebivolol and atenolol. The effect of pretreatment with selective beta 1-adrenoceptor blockers (dl-nebivolol or atenolol) on myocardial mechanical activity, mitochondrial function, morphology, and calcium cytochemistry was studied during normothermic ischemic arrest and reperfusion of isolated working rabbit hearts. The hearts subjected to 25 min of ischemia followed by 30 min of post-ischemic reperfusion showed typical signs of severe myocardial ischemic damage. The ultrastructural changes showed a good relation with the changes in mechanical activity and mitochondrial function. To determine whether these changes could be prevented or reduced by beta 1-adrenoceptor blockade, dl-nebivolol or atenolol (0.62 mg/liter) was added to the perfusate 30 min before the induction of ischemia. The results showed that dl-nebivolol exerted a protective effect on recovery of mechanical activity, on mitochondrial function during reperfusion as well as on the ultrastructure as examined at the end of the reperfusion period. On the other hand, atenolol failed to protect the myocardium against ischemia-reperfusion damage in the isolated working rabbit heart.

A model for collaborative service delivery for students with language-learning disorders in the public schools. Committee on Language Learning Disorders American Speech-Language-Hearing Association. Collaborative service delivery can augment traditional methods for serving students with language-learning disorders in the public schools. In collaborative service delivery, the speech-language pathologist is an integral member of a transdisciplinary team consisting of educators, parents, and the student. Team members collaborate to formulate a single educational program for each student. The team devises all treatment goals, assessment methods, intervention procedures, and documentation systems to enhance the student's academic and social functioning in the school environment. All team members are aware of the student's entire curriculum, and team members typically share responsibility for specific educational goals. Most special services, as well as regular instruction, take place within the classroom. Administrative support is crucial to the implementation of collaborative service delivery. Effective collaboration requires that team members be allotted time to meet outside of their classroom duties. In addition, cooperation among team members is essential. Potential team members must be willing to pool their expertise and abandon notions of professional "turf." The implementation of collaborative service delivery may require some adjustment in the way speech-language pathologists and other educators perceive their roles in public school settings. However, this service delivery model holds great promise for providing services to maximize the functional potential of students with language-learning disorders.

Effects of L-glutamine, glutaminase and glutamine synthetase on CAP threshold of cochlear nerve of guinea pig. Negative direct current (-DC 300 microA) stimulation was applied to the round window of the guinea pig cochlea to exhaust the pre-synaptic intracellular reserves of the transmitter in hair cells, and then the scala tympani was perfused respectively with L-glutamine, glutamine synthetase and glutaminase. Experimental results showed that the negative DC electrical stimulation applied to the round window elevated the CAP threshold of the cochlear nerve in the basal turn of the cochlea, which recovered over a period of approximately 17-39 min. The perfusion of L-glutamine apparently elevated the CAP threshold. The recovery of the CAP threshold following electrical stimulation, however, was accelerated by the perfusion of 10 mmol/L L-glutamine. The time for recovery only took about 5-6 min. The perfusion of enzyme glutamine synthetase elevated the CAP threshold by 50 dB, while glutaminase had little effect. These results suggest that the effect of L-glutamine on the CAP threshold in the cochlea of the guinea pig appears to be that of a potent depolarizing agent which accelerates the recovery of the CAP threshold during the depletion of the transmitter, and L-glutamine may be the candidate for the afferent excitatory transmitter.

Studies on DNA sequence specific binding proteins for 5' flanking upstream region of CPSI gene. Two specific carbamyl phosphate synthetase I gene binding nuclear proteins (M. W. 109 kD and 74 kD) have been determined in the rat liver by the protein blotting technique (Southwestern blot assay). The result shows that they are not present in the normal rat spleen and F-26 rat hepatoma cell. The Bal31 nuclease deletion in the CPSI gene 5' upstream region proves that the binding sites for 109 kD and 74 kD are respectively located in the regions of -38 bp to -4 bp and -113 bp to -38 bp. The binding proteins may be the liver-specific ones of the CPSI gene, which are related to hepatocyte differentiation and hepatocarcinogenesis.

Antihypertensive effect of isradipine on blood pressure at rest and during exercise. After three months of treatment with isradipine, 20 patients with mild hypertension had reduced their resting blood pressure (BP) from 157/103 to 132/85 mm Hg and their BP during isometric exercise from 192/124 to 166/105 mm Hg. The isradipine dose necessary to normalize BP (both at rest and post-exercise) was 1.25 mg twice daily (2 x 1/2 tablet) in 50% of patients and 2.5 mg twice daily (2 x 1 tablet) in 25%. In the remaining 25% of patients, isradipine was combined with 1 mg/day bopindolol. There were virtually no accompanying side effects; in particular, reflex tachycardia was negligible or absent. It is concluded that isradipine is a reliable antihypertensive treatment in mild-to-moderate hypertension.

Lowered responsiveness of bronchoalveolar lavage T lymphocytes in hypersensitivity pneumonitis. We previously reported that Trichosporon cutaneum was the major causative antigen of summer-type hypersensitivity pneumonitis (HP) in Japan. In summer-type HP patients, we noticed that the proliferative responses of bronchoalveolar lavage (BAL) lymphocytes to phytohemagglutinin (PHA) and concanavalin A were significantly lower than those of the peripheral blood lymphocytes of the same patients. It was shown in this study that the low response of BAL lymphocytes was due to an intrinsic lowering of the responsiveness of the T cells. Results of the mixed culture experiments, in which the responses to mitogens of BAL and peripheral blood T cells mixed with either alveolar macrophages or blood monocytes were compared, indicated that the decreased proliferative response was due neither to the suppressive effect nor to defects in accessory function of the alveolar macrophages. BAL T cells did not act as suppressor cells when they were added to the culture of peripheral T cells. The decreased proliferative response was not due to the dominance of CD8+ T cells frequently seen in BAL cells of HP patients, because both CD4+ and CD8+ T cells separated from BAL cells of HP patients showed lower responsiveness than those of peripheral blood T cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute poisoning with a glyphosate-surfactant herbicide ('Roundup'): a review of 93 cases. Between 1 January 1980, and 30 September 1989, 93 cases of exposure to herbicides containing glyphosphate and surfactant ('Roundup') were treated at Changhua Christian Hospital. The average amount of the 41% solution of glyphosate herbicide ingested by non-survivors was 184 +/- 70 ml (range 85-200 ml), but much larger amounts (500 ml) were reported to have been ingested by some patients and only resulted in mild to moderate symptomatology. Accidental exposure was asymptomatic after dermal contact with spray (six cases), while mild oral discomfort occurred after accidental ingestion (13 cases). Intentional ingestion (80 cases) resulted in erosion of the gastrointestinal tract (66%), seen as sore throat (43%), dysphagia (31%), and gastrointestinal haemorrhage (8%). Other organs were affected less often (non-specific leucocytosis 65%, lung 23%, liver 19%, cardiovascular 18%, kidney 14%, and CNS 12%). There were seven deaths, all of which occurred within hours of ingestion, two before the patient arrived at the hospital. Deaths following ingestion of 'Roundup' alone were due to a syndrome that involved hypotension, unresponsive to intravenous fluids or vasopressor drugs, and sometimes pulmonary oedema, in the presence of normal central venous pressure.

The efficacy of DTPA treatment after deposition of thorium nitrate in the rat lung. The efficacy of CaDTPA and ZnDTPA, the chelating agents of choice for several actinide elements, have been evaluated after the deposition of thorium in the rat lung in widely different amounts. The results showed that: 1. When the initial mass concentration of thorium simulated human exposure to four times the annual limits on intake for 232Th, the prompt (300 or 1000 mumol kg-1 body weight at 0.02 d) or repeated (30 or 300 mumol kg-1 body weight at 0.02, 0.25, 1,2,3 d) administration of CaDTPA were at best only moderately successful for enhancing the elimination of thorium. By 7 d after exposure, the body contents of thorium were, respectively, about 74%, 65%, 90% and 74% of those present in untreated animals. 2. When the mass concentration simulated 1.7 x 10(-3) times the annual limits on intake for 232Th, the efficacy of treatment was not increased appreciably despite the substantial reduction in mass. After the repeated administration of CaDTPA at doses of 30 and 300 mumol kg-1 using the protocol above, the body contents of thorium by 7 d were, respectively, 69% and 51% of those in untreated animals. 3. Under comparable conditions, the efficacy of ZnDTPA was less than CaDTPA. The results suggest that more effective chelating agents are needed for the treatment of workers exposed to water soluble thorium compounds.

Evaluation of severity indexes of patients with paraquat poisoning. 1. Three indexes for evaluating the severity of paraquat poisoning based on plasma-paraquat concentration are presently in use; the curves of Proudfood et al. and Scherrmann et al. and the SIPP. Their effectiveness in determining the prognosis of patients with paraquat poisoning was evaluated. 2. To determine which index was more accurate, contigency tables of the three indexes were obtained and compared; Proudfoot's curve vs the SIPP Scherrmann's curve vs the SIPP. Proudfoot's curve and the SIPP were applied to patients admitted within 24 h after intoxication. Scherrmann's curve and the SIPP were applied to patients admitted more than 24 h after intoxication. The proportions of patients with true positive and true negative results to total patients were compared by a ratio test. 3. Proudfoot's curve was found to be more accurate than the SIPP for predicting the prognosis of patients admitted within 24 h (P less than 0.05). No significant difference, however, was noted between Scherrmann's curve and the SIPP in determining the prognosis of patients admitted after more than 24 h. 4. In conclusion, Proudfoot's curve proved a better index for predicting the outcome of patients who were admitted within 24 h. However, for the prognosis of patients admitted more than 24 h after the ingestion of paraquat, further study is required.

Distribution of ethylene oxide in human blood and its implications for biomonitoring. The distribution of radioactivity following the incubation of human blood with radio-labelled ethylene oxide was investigated in vitro. After incubation, the individual blood samples were separated into lymphocytes and high (Mr greater than 10,000) and low (Mr less than 10,000) molecular fractions of erythrocyte cytoplasm and blood plasma. The radioactivity was determined in each sample by liquid scintillation counting. In erythrocyte cytoplasm, the distribution of radioactivity showed marked interindividual differences and two distinct groups could be distinguished. The coincidence of these groups with 'conjugators' and 'non-conjugators', in terms of the enzymatic conjugation of methyl halides to glutathione in erythrocytes, suggests a common principle, such as enzyme polymorphism. Such polymorphism has been described for glutathione S-transferase mu in the human liver, an enzyme that efficiently conjugates epoxides. In the other blood compartments, the interindividual differences were either less significant or were not detectable. Binding products with various macromolecules in blood, such as haemoglobin or lymphocyte DNA, are being discussed as biological monitors for occupational exposure to ethylene oxide. The observation that erythrocytes exhibit interindividual differences as described above make binding products with haemoglobin less suitable for biological monitoring of ethylene oxide exposure than, for example, DNA adducts in lymphocytes.

Expression of N-acetyl transferase in a human monocytic cell-line, U937. 1. N-acetyl transferase (NAT) catalyses the acetylation of arylamine and hydrazine drugs and other xenobiotics. The activity of one isozyme (polymorphic NAT) varies amongst individuals but the other (monomorphic NAT) does not. 2. The human monocytic cell-line U937 transcribes the gene for monomorphic N-acetyl transferase. 3. Although the gene for polymorphic N-acetyl transferase is present in these cells, its expression is not detected. 4. It is concluded that U937 cells are a useful model for studying the metabolism of arylamines and hydrazines by human monomorphic N-acetyl transferase.

Oral pharmacokinetics of fluazifop-butyl in human volunteers. 1. Fluazifop-butyl, the active ingredient of FUSILADE, a selective herbicide, was administered orally to three male volunteers at a dose level of 0.07 mg kg-1 body weight. Over a period of 6 d between 80 and 93% of the dose was excreted in urine as the metabolite fluazifop, the majority within the first 24 h. Peak plasma concentrations of fluazifop occurred 1-2.5 h after administration. 2. The elimination of fluazifop from plasma and urine can be described by a one-compartment pharmacokinetic model and the elimination half-life was estimated from blood and urine data to be within the range 9-37 h. Fluazifop was found to bind to serum proteins. 3. The study indicates that the amount of fluazifop-butyl absorbed in exposed persons can be assessed by measuring fluazifop concentrations in urine.

Effects of combined exposure to aluminium and ethanol on aluminium body burden and some neuronal, hepatic and haematopoietic biochemical variables in the rat. The effects of the daily administration of aluminium (25 mg kg-1, orally), ethanol (10% v/v, in drinking water) or both to adult rats, for 6 weeks, on the amount of aluminium present in the tissues and the functioning of brain biogenic amines, hepatic and serum transaminases and some haematopoietic variables were investigated. Ethanol alone was seen to inhibit the activity of delta-aminolevulinic acid dehydratase (ALAD), while aluminium alone elevated the activity of blood ALAD. However, aluminium and ethanol combined produced a more pronounced inhibition of blood ALAD and hepatic glutamic pyruvic transaminase (GPT) than either aluminium or ethanol alone. Simultaneous exposure to aluminium and ethanol also produced a significant elevation in urinary delta-aminolevulinic acid (ALA) blood zinc protoporphyrin (ZPP), serum glutamic oxaloacetic transaminase (GOT) and brain homovanillic acid (HVA), and a depletion in brain dopamine (DA) and 5-hydroxytryptamine (5-HT) levels, when compared to rats given aluminium alone. The concentration of aluminium in the blood and liver was significantly higher in rats exposed to both aluminium and ethanol than in those exposed to aluminium alone. Thus the consumption of alcohol may increase the rat's susceptibility to certain effects of aluminium.

Studies on the mutagenicity of a zinc oxide-hexachloroethane smoke. 1. A suitable method has been developed for generating atmospheres of zinc oxide/hexachloroethane smoke (ZnHCE). 2. The smoke was investigated using the Ames test and the micronucleus assay. 3. It was weakly mutagenic to the bacteria, but in the bone marrow no increases in micronuclei were detected up to toxic levels of the smoke. 4. The method used here could be applied to other pyrotechnic mixtures which give rise to complex mixtures of products.

Life-threatening ventricular arrhythmia (torsades de pointes) after haloperidol overdose. A 48-year-old woman developed QT prolongation and episodes of life-threatening ventricular tachycardia (torsades de pointes) after intentional overdose of haloperidol and orphenadrine. The arrhythmia did not respond to conventional anti-arrhythmic therapy but was suppressed by atrial overdrive pacing. A literature review identified haloperidol as the most likely cause of the torsades de pointes.

Lactation inhibition by the dopamine agonist CV 205-502. In an open pilot study with a parallel group design 30 bottle feeding women were randomly assigned in a two to one ratio to receive either the new dopamine agonist CV 205-502 or bromocriptine for lactation inhibition. Ten women who intended to breast feed served as normal controls. All treated women reached prepregnant prolactin levels within 72 h with once-daily 0.075 mg of CV 205-502 or twice-daily 2.5 mg of bromocriptine, at starting doses of 0.05 mg and 2.5 mg respectively. Fifteen of the 20 women treated with CV 205-502 reported breast symptoms, 50% occurring on days 3 and 4 of treatment. Three of the 10 women treated with bromocriptine had breast symptoms between days 2 and 28. Overall efficacy and tolerance in the two groups was very good. Side effects did not differ between the groups, with the exception of pulse rate in the standing position, which was significantly higher in the bromocriptine treated group than in either the CV 205-502 group (P = 0.02) or the breast feeding group (P less than 0.01). The coagulation tests (fibrinogen, AT III, PTT and APTT) showed no significant differences between the three groups.

Fetal liver dysfunction in Rh alloimmunization. The liver enzymes, aspartate transaminase (AST), alanine transaminase (ALT), gamma glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP), were measured in the blood of 25 fetuses with severe Rh alloimmunization at the time of their first, second and third intravascular transfusions and in 17 comparison fetuses. In the comparison group, GGT increased with advancing gestation (r = 0.7; P = 0.002), whereas ALP, AST and ALT did not correlate with gestational age. Rh hydropic fetuses (n = 8) had higher blood ALT levels than the comparison fetuses (P = 0.008) had significantly increased transaminases when compared with non hydropic fetuses (n = 17). In hydropic fetuses, AST correlated with the nucleated red cell count before transfusion (r = 0.94; P = less than 0.0001). Fetal transaminases were no longer increased in hydropic fetuses by the second (AST) or third (ALT) transfusion. In both hydropic and non hydropic fetuses, GGT increased by the second transfusion (median percentage change +85%, range -83% to +596%; P = 0.003). The rise in fetal GGT was transitory and correlated with the increase in fetal haematocrit at the first transfusion (r = 0.58; P = 0.006). This study reports liver dysfunction secondary to extramedullary erythropoiesis in Rh alloimmunization and implicates portal hypertension for the rise in fetal GGT with transfusion.

Anesthetic and hemodynamic effects of dexmedetomidine during isoflurane anesthesia in a canine model. Dexmedetomidine, an alpha 2-adrenergic agonist, was administered during isoflurane anesthesia to investigate its anesthetic sparing and hemodynamic effects in the canine model. Eleven healthy dogs were anesthetized with isoflurane, intubated, and allowed to breathe spontaneously. The animals were instrumented in order to measure or calculate mean arterial blood pressure (MABP), heart rate (HR), left ventricular end diastolic pressure (LVEDP), cardiac output (CO), and systemic vascular resistance (SVR). Isoflurane minimum alveolar concentration (MAC), baseline hemodynamic measurements, and plasma catecholamine levels were determined. A 20 micrograms/kg bolus of dexmedetomidine was injected intravenously (IV) and MAC and hemodynamic values were redetermined. When isoflurane requirements were 33% of baseline, isoflurane was returned to 90% MAC and the alpha 2-antagonist, atipamezole, was administered. All dogs were treated with 40 micrograms/kg glycopyrrolate throughout the experiment to prevent any bradycardic response. Dexmedetomidine reduced isoflurane MAC by 86%. SVR, MABP, and LVEDP were significantly increased while CO and catechloamine levels were reduced. Atipamezole fully reversed the reduction in anesthetic requirements. MABP and catecholamine levels returned to baseline. SVR and LVEDP increased while CO decreased. The dogs exhibited a profound reduction in anesthetic requirement, reduced catecholamine levels, and changes in hemodynamic parameters with dexmedetomidine administration. The anesthetic sparing effect appears to be mediated by the alpha 2-receptor, since atipamezole reversed the reduction in MAC. Hemodynamic changes may be species or dose related, or due to differences in existing sympathetic tone. The role of dexmedetomidine warrants further study as an adjunct anesthetic agent.

Unexplained CD4-positive T-cell deficiency in non-HIV patients presenting as a Pneumocystis carinii pneumonia. Three cases of Pneumocystis carinii pneumonia occurring in adults with unexplained T-cell defects are reported. No HIV markers were found during the follow up, and neither was any immunosuppressive disease. The authors emphasize the possibility that Pneumocystis pneumonia may occur and may be treated successfully in previously healthy subjects.

Inhibition by erythroid differentiation factor (activin A) of P-glycoprotein expression in multidrug-resistant human K562 erythroleukemia cells. The K562/VCR cell line, exhibiting acquired multidrug resistance (MDR) with increased expression of a cell surface glycoprotein (P-glycoprotein), was isolated from human erythroleukemia K562 cells. Various compounds that induced erythroid differentiation of K562 cells were tested for their effects on growth and differentiation of these K562/VCR cells. Sodium butyrate, hemin, 1-beta-D-arabinofuranosylcytosine, and erythroid differentiation factor (EDF) induced erythroid differentiation of K562/VCR cells as well as K562 cells. The MDR of K562/VCR cells was partly overcome by treatment with EDF but not with the other inducers. Expression of P-glycoprotein by K562/VCR cells was measured by radioimmunoassay using MRK16 monoclonal antibody. Results showed that EDF caused down-regulation of P-glycoprotein in K562/VCR cells, whereas the other inducers did not cause its down-regulation. Thus, in addition to inducing erythroid differentiation, EDF enhanced the sensitivity of K562/VCR cells to multidrugs and suppressed expression of P-glycoprotein. These results suggest that differentiation inducers may be useful in chemotherapy of leukemic MDR cells.

An antigen immunologically related to the external domain of gp185 is shed from nude mouse tumors overexpressing the c-erbB-2 (HER-2/neu) oncogene. An antigen, immunologically related to the external domain of the c-erbB-2 (HER-2/neu) protein, was found shed into the serum of nude mice bearing tumors that overexpress the c-erbB-2 protein (gp185). Utilizing paired combinations from a panel of monoclonal antibodies (TAbs 250-265), with specificity for extracellular epitopes of gp185, an immunoradiometric assay was developed to quantitate this shed antigen. The immunoradiometric assay detected membrane-bound and soluble gp185 as well as a soluble derivative corresponding in sequence to the extracellular domain of gp185 (designated gp75). This recombinantly expressed gp75 was immunoaffinity purified and used to generate a standard curve from which serum samples were quantitated. Increases in antigen levels measured in the sera of tumor-bearing nude mice correlated with both overexpression of the c-erbB-2 protein and increased tumor volume. Positive sera were obtained from mice given implants of NIH3T3 cells transfected with c-erbB-2 complementary DNA (NIH3T3t), or ovarian (SK-OV-3) or breast (MDA-MB-361) tumor cell lines overexpressing the c-erbB-2 protein. In mice bearing NIH3T3t tumors, increases in tumor volume from 80 to 9000 mm3 resulted in levels of shed antigen from 8 to greater than 1000 ng/ml gp75 equivalents. Sera from mice with c-erbB-2-negative tumors or tumors overexpressing the epidermal growth factor receptor were negative in the assay. This assay, and the quantitation of shed antigen levels, may have diagnostic or monitoring utility in cancers, such as breast and ovarian, in which the c-erbB-2 protein is overexpressed.

Characterization of the human MDR3 P-glycoprotein and its recognition by P-glycoprotein-specific monoclonal antibodies. We have cloned a human MDR3 complementary DNA, coding for a P-glycoprotein, into a mammalian expression vector and cotransfected it with a selectable marker into drug-sensitive human BRO melanoma cells. With low frequency we obtained stable, MDR3-expressing clones. Immunocytochemical and immunoblotting analysis of these clones using the monoclonal antibody C219 indicated that human MDR3 P-glycoprotein, like human MDR1 P-glycoprotein, was mainly localized in the plasma membrane and probably glycosylated. Although a significant fraction of the cells (5-10%) in one of the MDR3-expressing clones expressed as much P-glycoprotein as a clearly drug-resistant MDR1-transfected clone, we found no resistance against a range of drugs affected by multidrug resistance. The drugs tested included vincristine, colchicine, VP16-213, daunorubicin, doxorubicin, actinomycin D, and gramicidin D. We did not detect enhanced daunorubicin efflux either in any of the MDR3-expressing cells by fluorescence microscopy. Direct selection with vincristine, actinomycin D, gramicidin D, or daunorubicin of BRO cells transfected with expression constructs containing the regular MDR3 complementary DNA, or a complementary DNA representing a major MDR3 splice variant (C(-141)), likewise failed to yield resistant clones. Thus, although human MDR3 P-glycoprotein is highly similar to human MDR1 P-glycoprotein, we found no indications that it can transport drugs. We investigated the cross-reactivity of the monoclonal antibodies C219, C494, JSB-1, HYB-241, and MRK16, recognizing human MDR1 P-glycoprotein, with human MDR3 P-glycoprotein using immunocytochemistry and immunoblotting. Apart from monoclonal antibody C219, none of the monoclonal antibodies showed detectable cross-reactivity with human MDR3 P-glycoprotein. In our hands, monoclonal antibodies MRK16 and HYB-241 were most suitable for sensitive and specific cytochemical detection of human MDR1 P-glycoprotein.

Relationship of the expression of the multidrug resistance gene product (P-glycoprotein) in human colon carcinoma to local tumor aggressiveness and lymph node metastasis. P-glycoprotein mediates classic multidrug resistance by functioning as an efflux pump that excretes lipophilic chemotherapeutic drugs from cancer cells. We now report an association of P-glycoprotein in colon carcinomas with another tumor property, i.e., enhancement of local tumor aggressiveness. P-glycoprotein was detected with monoclonal antibody immunohistochemistry in 65 of 95 primary colon adenocarcinomas, which were stage B1 or greater. In all but 1 of the 95 cases, solitary invading carcinoma cells were present at the leading edge of the tumor. This subpopulation of invasive carcinoma cells expressed P-glycoprotein (P-Gp+) in 47 of the 95 surgically resected colon specimens. Cases were grouped on the basis of the presence (Group 1, 47 cases) or absence (Group 2, 48 cases) of P-Gp+ invasive carcinoma cells. There was a significantly greater incidence of vessel invasion (P less than 0.001) and lymph node metastases (P less than 0.01) in Group 1 cases. Groups 1 and 2 did not differ with respect to tumor size, depth of invasion of the bowel wall, histological grade, maximum tumor size, mitotic index, mucin production, or presence of perineural invasion (P greater than 0.1). Our findings indicate that P-Gp+ invasive colon cancer cells may have an increased potential for dissemination, suggesting that P-glycoprotein may influence cell behavior.

Thymocyte maturation following interaction with thymus-derived macrophages. Murine C57BL/6 thymocytes were cultivated together with syngeneic thymus-derived macrophages (TDM phi) for up to 96 hr to determine whether TDM phi participate in thymocyte maturation. The expression level of H-2b and Thy-1.2 antigens served as thymocyte differentiation surface markers as analyzed by flow cytometry. Indirect immunofluorescent staining profiles of the thymocytes demonstrate a dramatic increase in H-2b expression and a profound decrease in Thy-1.2 expression during cultivation with TDM phi. A similar phenomenon was observed when enriched populations of immature thymocytes were cocultivated with TDM phi. These changes were not observed when thymocytes were cultivated alone or with trypsin-treated TDM phi; neither were they observed when cortisone-resistant thymocytes manifesting mature characteristics were cultivated together with TDM phi. These findings suggest that interaction of thymocytes with TDM phi, involving binding and engulfment, results in the appearance of mature thymocyte subsets.

Granulomas in murine schistosomiasis mansoni contain vasoactive intestinal peptide-responsive lymphocytes. Granulomas develop around schistosome ova in murine Schistosoma mansoni. These granulomas have eosinophils that produce VIP. It is possible that VIP participates in immunoregulation. VIP-mediated effects usually operate through a cAMP-dependent mechanism. To identify VIP-responsive inflammatory cells in murine schistosomiasis, inflammatory cells were exposed to VIP and assessed for adenylate cyclase activation and VIP binding. VIP increased adenylate cyclase activity in splenic lymphocytes from both normal and infected mice. In each case, the half-maximal stimulation was at about 5 x 10(-8) M. [125I]VIP bound to splenic lymphocytes specifically, with a Kd of 10(-8) M. This suggested that maximal adenylate cyclase activation requires full receptor occupancy. The receptor was highly specific for VIP. Hormone analogs, that are VIP receptor antagonists in some tissues, were only weak agonists of the lymphocyte VIP receptor. Granuloma cells also bound VIP and responded with adenylate cyclase activation in a manner similar to that of spleen cells. Both splenic T and B lymphocytes responded to VIP. Deletion experiments, using anti-Thy 1.2, suggested that most of the responsive granuloma cells were T lymphocytes. Thus, VIP alters cAMP metabolism in granuloma T cells through a receptor-coupled mechanism similar to that observed for spleen cells. Binding studies on mouse intestinal epithelial cells suggested that their VIP receptor is functionally and possibly structurally different from the VIP receptor on mouse lymphocytes. Additional experiments suggested that VIP and other neuropeptides are unlikely to alter the granulomatous response through a primary interaction with the granuloma macrophages.

Assessment of residual curarization using low-current stimulation. The present study employed train-of-four (TOF) stimulation at a current of 20 mA to assess the incidence and degree of residual neuromuscular blockade in 64 randomly selected Post Anesthesia Care Unit (PACU) patients. Group C (Control, n = 10) had received anaesthesia without nondepolarizing muscle relaxant; Group V (n = 25) had received vecuronium; and Group P (n = 29) had received pancuronium. At the end of surgery, each patient had been considered by his anaesthetist to have adequate neuromuscular function on the basis of clinical signs and tactile or visual evaluation of responses to TOF stimulation. However, upon testing in the PACU 15 min later, 45% (13 of 29) of Group P patients and 8% (2 of 25) of Group V patients had a TOF ration less than 0.70. This study indicates that residual curarization may be commonly encountered following long-acting relaxants despite qualitative intraoperative TOF monitoring. The present incidence, detected at a current of 20 mA, is consistent with previous reports which employed supramaximal TOF stimulation. We conclude that despite intraoperative monitoring, residual curarization following long-acting nondepolarizing agents is common and that it may be detected with TOF at a low stimulating current (20 mA).

Continuous vecuronium infusion for prolonged muscle relaxation in children. Facilitation of mechanical ventilation of the lungs using an infusion of vecuronium in 11 infants and children and four neonates in an intensive care unit is described. A loading dose of vecuronium of 0.1 mg.kg-1 was followed by an infusion at an initial rate of 0.1 mg.kg-1.hr-1. The infusion rate was adjusted to maintain a neuromuscular block of approximately 90% as assessed by the presence of one response to a train-of-four stimulation. The duration of the infusions varied from 9.5 to 179 hr. The mean dose of vecuronium administered was 0.14 mg.kg-1.hr-1 (+/- 0.05, SD) in the children and 0.11 mg.kg-1.hr-1 (+/- 0.05) in the neonates. Mean recovery times from the time of stopping the infusion until absence of apparent fade in response to tetanic stimulation were 51.7 (+/- 17.6) and 46.8 (+/- 16.5) min for the children and neonates respectively. No adverse cardiovascular or toxic effects were noted. This technique of vecuronium infusion to facilitate mechanical ventilation of the lungs is feasible and satisfactory in clinical use.

Comparison of two esmolol bolus doses on the haemodynamic response and seizure duration during electroconvulsive therapy. Twelve ASA physical status I-III patients were enrolled in a double-blind, prospective, randomized, three-way, within-patient crossover study designed to determine the effect of two standard esmolol bolus doses (100 and 200 mg) on the haemodynamic response and seizure duration during electro-convulsive therapy (ECT). Esmolol or placebo was administered one minute prior to induction of anaesthesia and exactly two minutes before ECT. Both the 100 and 200 mg bolus doses significantly blunted the maximum increase in heart rate (HR) and mean arterial pressure (MAP) following ECT in comparison with placebo. Compared with placebo, esmolol 100 mg decreased maximum HR by 23 +/- 3%, maximum MAP by 17 +/- 7% and maximum rate-pressure product (RPP) by 40 +/- 9%. Esmolol 200 mg decreased maximum HR by 25 +/- 3%, maximum MAP by 19 +/- 3% and maximum RPP by 42 +/- 5%. No significant difference was found between the two esmolol doses at corresponding measurement points before and after ECT. Treatment with esmolol 200 mg resulted in a significantly shorter mean seizure duration than with placebo. As the 200 mg dose caused a shorter seizure duration and the haemodynamic effects of 100 mg and 200 mg doses were similar, it was concluded that the 100 mg esmolol bolus dose was the better dose for ECT.

Echocardiographic detection of coronary artery disease during dobutamine infusion. Two-dimensional echocardiography performed during dobutamine infusion has been proposed as a potentially useful method for detecting coronary artery disease. However, the safety and diagnostic value of dobutamine stress echocardiography has not been established. In this study, echocardiograms were recorded during step-wise infusion of dobutamine to a maximum dose of 30 micrograms/kg/min in 103 patients who also underwent quantitative coronary angiography. The echocardiograms were digitally stored and displayed in a format that allowed simultaneous analysis of rest and stress images. Development of a new abnormality in regional function was used as an early end point for the dobutamine infusion. No patient had a symptomatic arrhythmia or complications from stress-induced ischemia. Significant coronary artery disease (greater than or equal to 50% diameter stenosis) was present in 35 of 55 patients who had normal echocardiograms at rest. The sensitivity and specificity of dobutamine-induced wall motion abnormalities for coronary artery disease was 89% (31 of 35) and 85% (17 of 20), respectively. The sensitivity was 81% (17 of 21) in those with one-vessel disease and 100% (14 of 14) in those with multivessel or left main disease. Forty-one of 48 patients with abnormal echocardiograms at baseline had localized rest wall motion abnormalities. Fifteen had coronary artery disease confined to regions that had abnormal rest wall motion, and 26 had disease remote from these regions. Thirteen of 15 patients (87%) without remote disease did not develop remote stress-induced abnormalities, and 21 of 26 (81%) who had remote disease developed corresponding abnormalities. Echocardiography combined with dobutamine infusion is a safe and accurate method for detecting coronary artery disease and for predicting the extent of disease in those who have localized rest wall motion abnormalities.

Neurohumoral regulation of collateral perfusion. Mature coronary collaterals, which develop during chronic coronary occlusion, are not simply passive conduits but are capable of active vasomotion. Collateral perfusion must traverse not only these vessels but also proximal and distal coronary vessels. This series of resistances significantly modulates perfusion to collateral-dependent and potentially ischemic myocardium. The collateral vessels themselves possess unique vasomotor characteristics, particularly markedly augmented constriction to vasopressin. The recipient coronary microcirculation develops endothelial dysfunction during collateral development, a phenomenon that may markedly alter neurohumoral regulation of perfusion to collateral-dependent myocardium. Finally, the resistances proximal to the origin of the collateral vasculature, which are negligible at rest, become significant when flow to nonischemic regions (non-collateral-dependent) is increased, predisposing to the collateral steal phenomenon. Although collateral vessels play a crucial role in preventing myocardial infarction and often restore both resting and exercise perfusion to normal, the need to use these vessels is associated with important alterations of regulatory mechanisms in the coronary circulation.

High permanent plasma adrenaline levels: a marker of adrenal medullary disease in medullary thyroid carcinoma. Increases in urinary, plasma and tumour adrenaline have been previously observed in MEN II patients with phaeochromocytoma. However, the sensitivity of adrenaline for early detection of adrenal medullary disease has not been accurately evaluated. Twenty-five patients with medullary thyroid carcinoma (MTC) histologically confirmed but without clinical or biological evidence of phaeochromocytoma have been studied. Medullary adrenal status was evaluated by adrenal CT-scan. MIBG scintigraphy, determination of urinary VMA, metanephrines and total catecholamine levels, measurement of nyctohemeral plasma adrenaline or noradrenaline concentrations (every 2 h during 24 h) and clonidine suppression test. Four of the 25 patients had evidence of adrenal medullary disease in view of the coexistence of CT-scan, MIBG scintigraphy and plasma adrenaline abnormalities. Moderate adrenal enlargement (unilateral, n = 3; bilateral, n = 1) was observed on scans together with a high adrenal MIBG uptake (bilateral, n = 4). Among the urinary parameters studied, a minor MN increase was observed in only one of the four patients. Plasma adrenaline levels were significantly (P less than 0.01) different from those of the other 21 patients (mean + SD 115 + 110 pmol/l). This plasma adrenaline increase is reproducible and not suppressed by clonidine. Unilateral adrenalectomy performed in one patient confirmed a phaeochromocytoma and induced normalization of plasma adrenaline levels. In contrast, the plasma noradrenaline levels of the four patients were not statistically different from those of the other 21 patients. These data suggest that persistent high plasma adrenaline levels may be selectively increased in MTC patients together with a moderate adrenal CT-scan enlargement and a high adrenal MIBG uptake, despite a normal urinary excretion of total catecholamines and catecholamines metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

Factors determining the acute pressor response to alcohol. The pressor response to acute alcohol loading is variable and the factors influencing it are unknown. Data from 34 standardized alcohol loading studies were analysed to try to identify any factor(s) that might predict the pressor response to oral alcohol. The maximum blood pressure rise following an acute alcohol load was assessed for each subject over a 4 hour period. Age, weight, recent alcohol intake, baseline blood pressure, pulse rate and serum gamma glutamyl transferase levels were entered, as the independent variables, into a multiple linear regression analysis with the maximum blood pressure response as the dependent variable. Alcohol consumption in the week prior to the study predicted the systolic blood pressure pressor response to acute alcohol loading. None of the independent variables entered had any predictive value for diastolic or mean arterial blood pressure response.

There are few catecholamine- or neuropeptide Y-containing synapses in the intermediolateral cell column of rat thoracic spinal cord. 1. A quantitative electron microscopic immunocytochemical technique was used to assess the number of synapses immunoreactive for tyrosine hydroxylase (TH), phenylethanolamine N-methyl-transferase (PNMT) and neuropeptide Y (NPY) in the intermediolateral cell column in segments T2 and T3 of rat thoracic spinal cord. 2. TH synapses comprised about 5%; PNMT synapses 1-2%; and NPY synapses 1-2% of the total number of synapses in the intermediolateral cell column. All three types of synapses were predominantly or exclusively on dendrites. 3. Our results suggest that catecholamine/NPY neurons may not provide a major synaptic input to sympathetic preganglionic neurons in rat upper thoracic spinal cord.

Long-term maintenance treatment of reflux esophagitis with omeprazole. Prospective study in patients with H2-blocker-resistant esophagitis. Thirty-four patients with H2-blocker-resistant reflux esophagitis subsequently healed by 40 mg omeprazole daily entered a maintenance study with 20 mg omeprazole. In 31 evaluable cases the observation period was at least 12 months (mean 24 months). Esophagitis remained in remission in two thirds of patients despite dose reduction. Relapses of esophagitis occurred in 10 cases within six months, which rapidly healed by increasing the omeprazole dose to 40 mg. No further recurrence with 20 mg omeprazole was found later than six months. Peptic strictures primarily requiring repeated dilatation in six patients during healing with omeprazole did not reappear while on omeprazole maintenance. Major side effects that could be attributed to omeprazole were not observed. Gastrin levels remained within or slightly above the normal range in the vast majority. It is concluded that omeprazole maintenance treatment in severe reflux esophagitis is an effective and safe therapy.

Peroxisomal oxidases in various tissues of diabetic rats. The effect of diabetes mellitus induced by streptozotocin on the activities of peroxisomal oxidases and H2O2-metabolizing enzymes, and lipid peroxidation in various rat tissues were investigated. Peroxisomal acyl-CoA oxidase, D-amino acid oxidase and L-alpha-hydroxyacid oxidase were measured by a sensitive spectrophotometric method using dichlorofluorescein/peroxidase as the detector of H2O2. Acyl-CoA oxidase activity was increased most markedly in the heart of diabetic rats, less markedly in the liver, and tended to be increased in the kidneys. The activities of other peroxisomal oxidases were much lower than that of acyl-CoA oxidase in the liver and kidneys, and were undetectable in the heart. Catalase activity was decreased in the liver and kidneys of diabetics, and was increased in the heart. Glutathione peroxidase activity was increased more markedly in the kidneys of the diabetics, and less markedly in the heart than in the liver. Lipid peroxide level was higher in the kidneys of the diabetics than in the controls, unchanged in the heart, and was lower in the liver of the diabetics than in the controls. Thus, peroxisomal beta-oxidation and the H2O2 production coupled with that, were activated in various tissues of diabetic rats, presumably as a part of the overall increase in lipid oxidation. However, they did not appear to contribute to the enhanced oxidative stress induced by diabetes mellitus.

Bicuculline-induced epileptogenesis in the human neocortex maintained in vitro. Intracellular and extracellular recordings were made from human neocortical slices of the temporal lobe maintained in vitro. The slices were treated with bicuculline methiodide to reduce synaptic inhibition mediated by tha gamma-aminobutyric acid A (GABAA) receptor. Spontaneously occurring epileptiform activity was never observed in over 60 slices examined. All epileptiform discharges were elicited by single-shock stimuli delivered in the underlying white matter or within the cortical layers. Intracellularly, the stimulus-induced epileptiform discharge resembled the paroxysmal depolarization shift (PDS). This potential was observed in neurons located between 200 and 2200 microns from the pia. It was characterized by a 100-1800 ms long depolarization which triggered burst firing of action potentials, and was at times followed by an afterdischarge. Simultaneous intracellular and extracellular recordings showed that each PDS was reflected by the synchronous discharge of a neuronal aggregate. The voltage behaviour of the PDS and its preceding EPSP was analyzed in cells that were injected with the lidocaine derivative QX-314. The amplitudes of the PDS depolarizing envelope measured at its peak and during its falling phase both behaved as a monotonic function of the membrane potential by increasing in amplitude during hyperpolarization. In addition, the PDS peak amplitude showed a much greater rate of increase than the early EPSP peak amplitude, thus suggesting that the synaptic conductance underlying the PDS was much greater. Perfusion of the neocortical slices with the N-Methyl-D-aspartate (NMDA) receptor antagonist DL-2-amino-phosphonovaleric acid (APV) reduced both the duration and the amplitude of the paroxysmal field discharge in a dose related fashion. The effects of APV were reflected intracellularly by an attenuation of the PDS's late phase and a blockade of the afterdischarge. Similar findings were also obtained by using the NMDA receptor antagonist 3-((+-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid. These data indicate that reduction or blockade of the GABAA receptor is sufficient to elicit epileptiform discharges in the human neocortex maintained in vitro. Mechanisms dependent upon the NMDA receptor contribute to this type of epileptiform response mainly by prolonging the stimulus-induced depolarizing potential and the associated burst of firing.

Morphofunctional study of the effects of fetal exposure to cyproterone acetate on the hypothalamo-pituitary-gonadal axis of adult rats. Fetal exposure to cyproterone acetate (CPA), while allowing, normal sexual morphogenesis, has previously been shown to lead to functional endocrine abnormalities in adult rats of both sexes. Because of this, we examined morphologically and morphometrically the hypothalamic nuclei involved in sexual dimorphism as well as the pituitary lactotropes of rats exposed in utero from day 15 to 20 of gestation to CPA. Male and female offspring was studied at the age of 70-80 days. In both sexes the brain weight was lower (p less than 0.05) in CPA-treated than in control rats. Morphometrical investigations showed that the surface density (Sv) and the volume density (Vv) of the ventromedial nucleus were higher (p less than 0.05) in CPA-treated male than in control rats. By comparing sexes the Sv and Vv of the ventromedial nucleus were higher (p less than 0.01) in CPA-treated male than in corresponding female rats. Also the nuclear surface of the tyrosine hydroxylase-immunoreactive neurons of the arcuate nucleus was higher (p less than 0.05) in CPA-treated male than in female rats. In lactotropes of the pituitary gland the immunoreactive prolactin (PRL) was densitometrically increased (p less than 0.05) in CPA-treated female compared with control rats. By electron microscopy, PRL granules and autophagocytosis appeared to be more abundant in CPA-treated rats of both sexes. These data show that fetal exposure to CPA results in long-term anatomical and physiological alterations of hypothalamic and preoptic nuclei as well as of the pituitary lactotropes. These permanent changes support the functional endocrine abnormalities observed in adult rats.

Tyrosine hydroxylase immunoreactive neurons in organotypic slice cultures of the rat striatum and neocortex. Organotypic slice cultures of striatum and neocortex were prepared from newborn to seven day old rats and cultured for three to 60 days. When processed for tyrosine hydroxylase (TH) immunocytochemistry medium-sized, aspiny TH immunoreactive (TH-i) neurons with a similar morphology were revealed in the striatum and the neocortex. The neurons had a very similar morphology in both tissues and were present both when the two tissues were grown separately as single cultures and when grown together either en bloc as part of the same tissue slices or as co-cultures. In order to examine whether innervation by dopaminergic fibers would affect the expression of TH-i neurons in the striatal slice cultures, co-cultures of ventral mesencephalon (VM) and striatum were prepared, but the ingrowth of TH-i fibers from the VM did not alter the expression of TH immunoreactivity by a subpopulation of striatal neurons.

Regulation of rat insulin-receptor kinase by glucose in vivo. The effects of acute and chronic hyperglycemia on the kinase activity of insulin receptors in vivo were studied in the rat. Skeletal muscle-derived insulin receptors were isolated, with preservation of the in vivo phosphorylation state, from nondiabetic rats subjected to hyperinsulinemic clamps at either euglycemia (mean 5.2 mM) or hyperglycemia (14.4 mM) or from streptozocin-induced diabetic rats at euglycemia (5.1 mM) or hyperglycemia (14.2 mM). Kinase activity toward histone of insulin receptors from nondiabetic animals rendered hyperglycemic for 80-90 min was 50% higher than that of receptors from rats clamped at euglycemia (mean +/- SE 4.5 +/- 0.4 vs. 3.0 +/- 0.3 fmol of phosphate into histone, respectively, P less than 0.02), although kinase activity of receptors isolated from animals rendered diabetic for 10-14 days before hyperglycemic or euglycemic clamps showed no such effect. These results suggest that acute hyperglycemia may increase insulin-receptor kinase activity in vivo, possibly augmenting glucose disposal thereby, whereas the chronic hyperglycemia of diabetes mellitus results in metabolic derangements that nullify this effect.

Sequence of fimbrial subunit-encoding genes from virulent and benign isolates of Dichelobacter (Bacteroides) nodosus. Both virulent and benign isolates of the ovine pathogen Dichelobacter (Bacteroides) nodosus produce polar fimbriae which have been implicated in twitching motility. The fimbrial subunit-encoding genes from two virulent and two benign serogroup-B isolates of D. nodosus were cloned and sequenced. Analysis of the deduced amino acid (aa) sequences of these subunits indicated the presence of substitutions that appeared to correlate with the virulence phenotype. However, these aa substitutions were located in variable regions of the protein where they are unlikely to alter the functional properties of the fimbriae. The aa sequences of the serogroup-B subunits had a very high level (91-95%) of similarity, particularly at the N terminus, where the conserved region extended up to aa 61. Specific aa substitutions within the subunit of one isolate may reflect its serotypic variation from the other serogroup-B subunits studied.

Dietary n-3 (omega-3) polyunsaturated fatty acid effects on animal tumorigenesis. Environmental variables influence the incidence and expression of disease. Dietary fat is one environmental variable that has been associated experimentally and epidemiologically with alterations in certain types of tumorigenesis. Recently, detailed biochemical analyses have shown that not all fatty acid families possess the same tumor-promoting potential. In general, diets containing high levels of the n-6 polyunsaturated fatty acids have routinely enhanced tumorigenesis in lipid sensitive carcinogen-induced and tumor transplant tumor models, whereas diets with equivalent levels of n-3 polyunsaturated fatty acids have diminished tumorigenesis. At present, there is no definitive biochemical mechanism that fully explains these observations, but several possibilities have been proposed. One of the most attractive of these hypotheses is that each polyunsaturated fatty acid family has an individual effect on eicosanoid metabolism which determines its tumor-promoting potential. Regardless of current uncertainties about mechanisms of action, however, results of numerous animal models affirm the importance of qualitative, as well as quantitative, dietary lipid differences on tumorigenesis. This knowledge strengthens the probability that further advances in our understanding of lipid-tumor interrelationships will have important preventive and therapeutic medical benefits.

Synthesis of the nonconserved dihydroorotase domain of the multifunctional hamster CAD protein in Escherichia coli. CAD is the multifunctional protein of higher eukaryotes which catalyzes the first three steps of pyrimidine biosynthesis. Its enzymatic activities exist as independent domains in the order: N terminus-carbamylphosphate synthetase II(CPSase)-dihydroorotase(DHOase)-aspartate transcarbamylase(ATCase)-C terminus. To functionally define the minimum hamster cDNA region required to encode an active DHOase, expression constructs were generated. Many such constructs complement Escherichia coli mutants defective not only in DHOase but also in ATCase. Constructs deleted for most of the sequence encoding the ATCase domain continue to complement E. coli mutants defective in DHOase. All of these smaller constructs also lack the region encoding CPSase. Therefore, a 'genetic cassette', containing information for neither the CPSase nor the ATCase domain, can direct the synthesis of a polypeptide with DHOase activity. Interestingly, inclusion of a portion of the DHOase-ATCase interdomain bridge appears to be required for optimum activity.

Genetic polymorphism of the murine myogenic gene Myo-D1. Polymorphism of the myogenic gene, Myo-D1, has been sought to examine genetic mechanisms which control skeletal muscle development. By Southern analysis, three restriction-fragment length polymorphisms (RFLPs) have been found in various mouse strains using the TaqI, SacI and BglII restriction endonucleases and a full-length cDNA Myo-D1 probe. Reference to the distribution of RFLPs in different mouse strains derived from Mus mus (M.m.) domesticus and M.m. musculus subspecies suggests that Myo-D1 rearrangements are subject to nonrandom association. The biological significance of RFLP of the Myo-D1 gene is yet to be determined.

Two patients with insulin resistance due to decreased levels of insulin-receptor mRNA. Mutations have been identified in the insulin-receptor gene in insulin-resistant patients. We studied two patients with acanthosis nigricans and insulin resistance caused by a decrease in the number of cell surface insulin receptors. Patient 1 was an 11-yr-old boy with a fasting insulin level of 2130 pM; patient 2 was a 14-yr-old girl with hyperandrogenism and a fasting insulin level of 580-740 pM. Based on Southern-blotting studies, the structure of both alleles of the insulin-receptor gene in both patients appeared to be grossly normal. There was no evidence of insertions, deletions, or major rearrangements. Moreover, the nucleotide sequences of all 22 exons of the gene were normal in both patients. Thus, the predicted amino acid sequences of both patients' insulin receptors were normal. In Epstein-Barr virus-transformed lymphoblasts from patient 1, insulin-receptor mRNA levels were so low they could not be detected with an RNase A protection assay, whereas mRNA levels from patient 2 were in the lower half of the normal range. By use of a more sensitive assay based on the polymerase chain reaction, insulin-receptor mRNA could be detected in Epstein-Barr virus-transformed lymphoblasts from both patients. Moreover, because of the existence of silent polymorphisms in the nucleotide sequences, it was possible to differentiate the two alleles of the insulin-receptor gene in both patients. In patient 2, the two alleles were expressed asymmetrically, with 90% of the mRNA molecules having been transcribed from one allele but only 10% transcribed from the second allele. This suggests that there is an unidentified mutation in the underexpressed allele that acts in a cis-dominant fashion to decrease insulin-receptor mRNA levels. However, in patient 1, both alleles were expressed symmetrically in similarly low levels. Although not proven, it seems likely that the mutations that decrease insulin-receptor mRNA levels in patient 1 also map to the insulin-receptor locus.

Expression of an immunogenic region of HIV by a filamentous bacteriophage vector. Vectors derived from the Escherichia coli filamentous phage, fd-tet, expressing parts of the human immunodeficiency virus (HIV) gag genes were constructed and analyzed. The immunoreactive domain of HIV Gag antigens was produced in the form of a fusion protein, with a phage minor coat protein, called protein III, playing an important role in phage infectivity. A micropanning procedure, utilizing the strong affinity of biotinylated antibody to streptavidin, was applied for the selection of clones. A simple preparation procedure consisting of polyethyleneglycol precipitation of the recombinant phage from the E. coli supernatant allowed us to detect HIV antigens by enzyme-linked immunosorbent assay (ELISA). Cloned FUSE-gag, as isolated using anti-Gag RL4.72.1 monoclonal antibody (mAb), contained a nucleotide sequence coding for 91 amino acids of HIV Gag p24. It specifically reacted with the mAb in the ELISA. Construction of the mAb-selectable phages permitted localization of epitopes for mAb. Infectivity of the phage clone was specifically neutralized by the anti-HIV mAb. Immunoelectroblotting analysis of recombinant phages revealed the presence of an about 65-kDa band reacting with anti-HIV mAb. This Mr corresponded to the size of the fused form of the FUSE 1 protein III. Human sera from HIV-infected and uninfected individuals reacted with recombinant protein III, as well as the original form of protein III.

In vivo benzodiazepine receptor occupancy by CL 218,872 visualized by positron emission tomography in the brain of the living baboon: modulation by GABAergic transmission and relation with anticonvulsant activity. In vivo benzodiazepine receptor occupancy by increasing doses of CL 218,872 has been evaluated in the baboon Papio papio, using (11C) RO 15-1788 as specific radioligand and positron emission tomography as external detection system. Although BZR heterogeneity has been previously demonstrated in the brain of the living baboon using PET, we did not observe in our studies that CL 218,872 interacts preferentially with one of the BZR subtypes. The monophasic pattern of the dose dependent CL 218,872 displacement curve and the corresponding "in vivo Hill coefficient" near unity suggest that CL 218,872 binds in cerebral baboon cortex with a similar affinity with BZ1 as well as BZ2 subtypes. The anticonvulsant properties of CL 218,872 against bicuculline and allylglycine-induced seizures were correlated with benzodiazepine receptor occupancy by assessment of electroencephalographic activity during positron emission tomography studies. Our data confirmed in vivo the hypothesis of a partial agonist anticonvulsant activity of CL 218,872. At the same time, the use of a GABA-antagonist (bicuculline) or an inhibitor of the GABA synthesis (allylglycine) suggested the existence of an allosteric interaction between benzodiazepine receptors and GABA receptors.

Development of environmentally compatible controlled release formulations of a mosquito larvicide. A new controlled release system of a mosquito larvicide, fenthion has been developed by the chemical modification of sodium carboxymethylcellulose into a hydrophobic gel of copper carboxymethylcellulose. Four formulations having a slab geometry were developed with two concentrations of the larvicide and two extents of cross-linking. The release profile of the larvicide from the formulations was studied under laboratory conditions. The formulation with a cross-linking period for 48 h and a 20 per cent larvicide concentration with respect to the dry weight of the formulation has been found to be stable with a sustained release of the active ingredient for a period of 25 wk. The release profile of the formulation followed zero order release kinetics after three weeks in water. The concentration of fenthion ranged between 0.07 and 0.21 mg/l at the application rate of one slab per five litres of water with an average release rate of 6.38 mg/wk during the period of study.

Somatostatin cells in rat antral mucosa: qualitative and quantitative ultrastructural analyses in different states of gastric acid secretion. In the gastrointestinal tract somatostatin is localized in endocrine cells and in neurons. The antral somatostatin (D-) cell shares features of both cell types. The activity of the antral D-cell is regulated by intragastric pH. Therefore different states of gastric acidity were induced experimentally in order to study D-cell morphology at the electron microscopical level. The morphological findings were related to measurements of plasma and tissue concentrations of the peptide. The D-cell is characterized by extensive membrane interdigitations with neighbouring cells. Changes in the activity of antral D-cells are reflected by an increase in cytoplasmic secretory granule density and a shift of secretory granules towards basal cell processes. Direct endocrine cell contacts at the level of the perikarya were rarely observed. The intracellular distribution of secretory granules suggests that cell communication is more likely to take place at the level of the strongly immunoreactive cytoplasmic processes. No evidence for endocrine or exocrine (luminar) secretion was observed morphologically. This is in agreement with the concept of paracrine secretion of the antral D-cell.

DARPP-32 like protein in specific snail (Helix aspersa) neurones. Monoclonal antibodies to DARPP-32 recognise an antigen which is present in specific neurones in the snail (Helix aspersa). Consecutive sections 10-microns-thick processed for the localisation of DARPP-32 and tyrosine-hydroxylase immunoreactivity did not show a coexistence in any neuronal structures. DARPP-32 positive cells were, however, often morphologically closely associated with tyrosine-hydroxylase positive cells, implying a functional relationship consistent with the proposed role of DARPP-32. Immunochemical analysis of the DARPP-32 immunoreactive material in the snail nervous system shows that the substance has a molecular weight of 28 kDa and therefore different from the DARPP-32 protein found in the rat brain.

Linkage disequilibrium between the HLA-DQA2 alleles and the HLA/DR/DQ complex. A statistically significant association was observed between alleles of the HLA-DQA2 and of the DR/DQ complex in a DNA-restriction fragment length polymorphism study of 219 members from 21 multiplex families of patients with hyperthyroid Graves' disease and 773 unrelated individuals selected for homozygosity of the HLA-DQA2 alleles. This data provides evidence for linkage disequilibrium rather than for a hot spot of recombination within the HLA-DQ subregion.

Diversity among DRw13 DQw7 haplotypes as revealed by serology Dw typing and restriction fragment length polymorphism. HLA-DRw13 is in linkage disequilibrium with DQw6; an unusual association, DRw13 DQw7, is found in 2% of our Caucasoid population. Investigation of genotyped individuals and of families by two allosera and by Dw typing revealed two subtypes: one recognized by homozygous typing cell HAG and by two allosera, the other subtype remained unreactive with both reagents. Analysis of DNA fragments with DNA probes indicated that the HAG-negative subset had DNA fragments in common with DRw6 while the HAG-positive subset shared DNA fragments with DR5. However, all DRw13 DQw7 cells are Dw24 as seen by hybridization with DRB probe.

Effects of nitric oxide on platelet-activating factor- and alpha-adrenergic-stimulated vasoconstriction and glycogenolysis in the perfused rat liver. Effects of nitric oxide (NO) on hemodynamic and glycogenolytic responses to platelet-activating factor (PAF) and phenylephrine were investigated in perfused livers derived from fed rats. Infusion of NO (34 microM) into perfused livers inhibited PAF (0.22 nM)-induced increases in hepatic glucose output and portal pressure approximately 90 and 85%, respectively, and abolished effects of PAF on hepatic oxygen consumption. NO attenuated PAF-stimulated increases in glucose output and portal pressure, the latter indicative of hepatic vasoconstriction, with a similar dose dependence with an IC50 of approximately 8 microM. In contrast to its effects on PAF-induced responses in the perfused liver, NO inhibited increases in hepatic portal pressure in response to phenylephrine (10 microM) approximately 75% without altering phenylephrine-stimulated glucose output and oxygen consumption. Similarly, infusion of NO into perfused livers significantly inhibited increases in hepatic portal pressure but not in glucose output in response to a submaximal concentration of phenylephrine (0.4 microM). Like NO, sodium nitroprusside (83 microM) significantly inhibited hemodynamic but not glycogenolytic responses to phenylephrine in perfused livers. However, PAF (0.22 nM)-stimulated alterations in hepatic portal pressure, glucose output, and oxygen consumption were unaffected by infusion of sodium nitroprusside (83 microM) into perfused livers. These results provide the first evidence for regulatory effects of NO in the perfused liver and support the contention that PAF, unlike phenylephrine, stimulates glycogenolysis by mechanisms secondary to hepatic vasoconstriction. These observations raise the intriguing possibility that NO may act in liver to regulate hemodynamic responses to vasoactive mediators.

Characterization of the functional domains of the natriuretic peptide receptor/guanylate cyclase by radiation inactivation. Radiation inactivation has been used to evaluate the molecular size of domains responsible for atrial natriuretic peptide (ANP)-binding and cyclase functions of the ANP receptor/guanylate cyclase. Two types of inactivation curves were observed for cyclase function in both adrenal cortex and aortic smooth muscle cells: 1) biphasic with enhanced guanylate cyclase activity after exposure to low radiation doses and 2) linear after preincubation of membrane proteins with 0.5 microM ANP or solubilization with Triton X-100. The existence of an inhibitory component was the simplest model that best explained the types of radiation curves obtained. Activation of guanylate cyclase by ANP or Triton X-100 could occur via the dissociation of this inhibitory component from the catalytic domain. On the other hand, the loss of ANP-binding activity was linear with increasing radiation exposures under basal, ANP treatment, and Triton X-100 solubilization conditions. Radiation inactivation sizes of about 30 kDa for cyclase function, 20 kDa for ANP-binding function, and 90 kDa for inhibitory function were calculated. These studies suggest that the ANP receptor/guanylate cyclase behaves as a multidomain protein. The results obtained by radiation inactivation of the various biological functions of this receptor are compatible with the hypothesis of an intramolecular inhibitory domain repressing the guanylate cyclase catalytic domain within its membrane environment.

Biosynthetic thiolase from Zoogloea ramigera. Evidence for a mechanism involving Cys-378 as the active site base. Biosynthetic thiolase from Zoogloea ramigera was inactivated with a mechanism-based inactivator, 3-pentynoyl-S-pantetheine-11-pivalate (3-pentynoyl-SPP) where K1 = 1.25 mM and kinact = 0.26 min-1, 2,3-pentadienoyl-SPP obtained from nonenzymatic rearrangement of 3-pentynoyl-SPP where K1 = 1.54 mM and kinact = 1.9 min-1 and an affinity labeling reagent, acryl-SPP. The results obtained with the alkynoyl and allenoyl inactivators are taken as evidence that thiolase from Z. ramigera is able to catalyze proton abstraction uncoupled from carbon-carbon bond formation. The inactivator, 3-pentynoyl-SPP and the affinity labeling reagent, acryl-SPP, trap the same active site cysteine residue, Cys-378. To assess if Cys-378 is the active site residue involved in deprotonation of the second molecule of acetyl-CoA, a Gly-378 mutant enzyme was studied. In the thiolysis direction the Gly-378 mutant was more than 50,000-fold slower than wild type and over 100,000-fold slower in the condensation direction. However, the mutant enzyme was still capable of forming the acetyl-enzyme intermediate and incorporated 0.81 equivalents of 14C-label after incubation with [14C]Ac-CoA for 60 min. The reversible exchange of 32P-label from [32P]CoASH into Ac-CoA, catalyzed by the Gly-378 mutant enzyme, proceeded with a Vmax (exchange) 8,000-fold less than the wild type enzyme but at least 10-fold faster than the overall condensation reaction. These data provide evidence that Cys-378 is the active site base.

Purification and tissue level of the beta-amyloid peptide precursor of rat brain. The beta-amyloid peptide precursor (beta-APP) exists in brain tissue as a membrane-associated protein extractable with 1% Triton X-100. beta-APP has been purified to near homogeneity by the following procedure: 1) anion exchange chromatography, 2) affinity chromatography on heparin agarose, and 3) immunoaffinity adsorption on matrix-bound antibodies directed to a synthetic peptide corresponding to the last 24 amino acids of the cDNA derived amino acid sequence of beta-APP. Conditions were chosen to minimize denaturation of the protein. The identity of the protein was confirmed by its immunoreactivity with antisera directed to five subsequences derived from the cDNA sequence. The amino-terminal sequence of beta-APP was found to be Leu-Glu-Val-Pro-Thr-Asp-Gly-Asn-Ala-Gly-Leu-Leu-Ala-Glu-Pro, which commences at residue 18 of the cDNA-derived primary structure. The procedure resulted in a 2000-fold purification of beta-APP. The purified protein migrated on polyacrylamide gels as a doublet of apparent molecular mass 100-120 kDa, although the predicted molecular mass of its constituent amino acids is 76 kDa. beta-APP clearly behaves anomalously in gel electrophoresis. The beta-APP content of rat brain amounted to 46 micrograms/g tissue. The half-life of the protein was calculated to be about 10 h, which is 30 times as long as that observed by others in transfected PC-12 cells. We conclude that transfected cell systems may not be adequate models for beta-APP processing.

Gene characterization and promoter analysis of the human 5-lipoxygenase-activating protein (FLAP). The human gene for the recently identified 5-lipoxy-genase-activating protein (FLAP) has been cloned. The gene was isolated from two different genomic libraries and is contained within four overlapping bacteriophage clones. The gene spans greater than 31 kilobases and consists of five small exons and four large introns. Southern blot analysis of human genomic DNA suggests the presence of a single FLAP gene per haploid genome. A restriction site polymorphism was identified in intron II of the gene. This restriction fragment length polymorphism appears to be present in the normal population at a fairly high frequency. The transcription initiation site was located, at an adenine residue, 74 base pairs upstream of the ATG initiation codon. Examination of the sequence of the gene 5' to the mRNA start site revealed the presence of a possible TATA box (TGTAAT) 22 base pairs upstream and potential AP-2 and glucocorticoid receptor binding sites. Functional analysis of the FLAP gene promoter was assayed by transient transfection of mouse P388D1 cells (macrophage) and human HepG2 cells (hepatoma) with 5'-flanking sequences of the FLAP gene fused upstream of the chloramphenicol acetyltransferase reporter gene. Expression in the mouse macrophage cell line of the various FLAP gene promoter constructs revealed both tissue specificity and enhancer-like activities whereas in the hepatoma cell line only a minimum level of activity was obtained.

Purification and identification of photoreceptor guanylate cyclase. Photoreceptor guanylate cyclase was solubilized and purified from bovine rod outer segments with 50-150-fold increase in specific activity using the nonionic detergent n-dodecyl-beta-D-maltoside. Guanylate cyclase activities correlated with the enrichment of a protein with an apparent Mr = 112,000. The purified enzyme showed specific activities of 100-700 nmol of cGMP produced/min/mg protein and exhibited positive cooperativity with respect to MnGTP (Hill coefficient n = 1.6 +/- 0.1). The apparent Km was 274 +/- 67 microM, and the turnover number was determined to be 0.2-1.3 cGMP produced/s. The molar ratio of the 112-kDa protein to rhodopsin corresponds to 1:104. This indicates that the amount of guanylate cyclase in rod photoreceptors is nearly equimolar to the amount of the phosphodiesterase.

The efficacy and tolerability of CV 205-502 (a nonergot dopaminergic drug) in macroprolactinoma patients and in prolactinoma patients intolerant to bromocriptine. We studied the effect of CV 205-502 in 12 patients with macroprolactinomas and 8 patients with PRL-secreting tumors, who were selected because of previous repeatedly shown intolerance to bromocriptine in even small doses. We also investigated serum insulin-like growth factor-I (IGF-I) levels before and during CV 205-502 therapy. In 12 macroprolactinoma patients followed for 1 yr, 0.075-0.450 mg CV 205-502 lowered PRL levels by 91.2 +/- 5.4%. Only 3 of the patients had transient side-effects of nausea, dizziness, or fatigue. In eight patients with PRL-secreting tumors who were bromocriptine intolerant, CV 205-502 (0.075-0.300 mg daily) lowered PRL levels by 80.2 +/- 6.3%. Four of these patients showed transient side-effects (nausea, fatigue, and/or tachycardia). None of the patients discontinued therapy. There was a close correlation between pretreatment circulating PRL levels and tumor size, expressed in cubic millimeters. The decrease in pituitary tumor size after 52 weeks of CV 205-502 therapy (-74 +/- 6%) was also correlated with the decrease in PRL levels (P less than 0.01). In four patients with hypopituitarism, lowered IGF-I levels did not change during CV 205-502 therapy. However, in seven previously untreated patients with macroprolactinoma and normal CV 205-502 is a potent dopaminergic drug, which effectively controls PRL secretion and induces tumor shrinkage. At the doses used in our study, it causes only mild and transient side-effects in a minority of patients and can also be used to treat hyperprolactinemic patients who have shown intolerance to bromocriptine therapy.

Investigation and characterization of receptors for pituitary adenylate cyclase-activating polypeptide in human brain by radioligand binding and chemical cross-linking. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a novel peptide of hypothalamic origin which increases adenylate cyclase activity in rat anterior pituitary cell cultures. The 38-amino acid peptide shows a close sequence homology to vasoactive intestinal peptide (VIP). Binding sites for PACAP in membranes from postmortem human brain tissue were studied using [125I]PACAP27 as the radioligand. High specific binding sites (amount of specific binding measured at 0.25 nM [125I]PACAP27 in femtomoles per mg protein +/- SEM; n = 4) were present in hypothalamus (344.5 +/- 13.0), brain stem (343.0 +/- 29.3), cerebellum (292.0 +/- 21.1), cortex (259.6 +/- 19.8), and basal ganglia (259.2 +/- 50.3). Specific binding sites in pituitary, although present, were less abundant (35.0 +/- 8.9). Binding of [125I]PACAP27 was reversible and time, pH, and temperature dependent. Despite the homology with VIP, VIP was a poor inhibitor of [125I]PACAP27 binding (IC50, greater than 1 microM) compared with PACAP27 (IC50, 0.5-1.3 nM) and PACAP38 (IC50, 0.2-1.3 nM). Scatchard plots of [125I]PACAP27 binding showed the presence of both high and lower affinity sites. Chemical cross-linking of PACAP-binding sites revealed that [125I]PACAP27 was bound to polypeptide chains of 67,000 and 48,000 mol wt. Thus, we have demonstrated the presence of PACAP-specific receptors in human brain which are not VIP receptors. This opens the possibility of PACAP functioning as a novel neurotransmitter/neuromodulator in human brain.

Interleukin 2 therapy in severe atopic dermatitis. Interleukin 2 (IL-2) at a dose of 10,000 to 20,000 U/kg/q 8 hr was given for 9-12 days to six patients with cases of severe atopic dermatitis (AD) which were refractory to conventional therapy. After IL-2 therapy, the clinical symptoms and signs of eczema including pruritus, scratching, papulovesicles, and lichenification were much improved, but all of them recurred 2-6 weeks after stopping treatment. Adverse reactions were similar to those reported previously, but all of them subsided after discontinuation of therapy. Laboratory findings showed decreased T-cell subsets, especially CD4+ cells, and increased IL-2R+ (CD25) cells, but there was no significant change in serum IL-2, serum IgE, or in vitro IgE production. Immunopathological studies of the skin biopsies showed decreased mononuclear-cell infiltration, depletion of CD4+ cells, and enhanced expression of CD25 and HLA-DR antigens. As lymphokine-activated killer (LAK)-cell activity against cultured fibroblasts was similar in patients with AD and in normals and CD1+ Langerhans cells were not decreased after IL-2 therapy, we speculate that the depletion of helper/inducer CD4+ cells and hence abrogation of the exaggerated antigen processing and cellular activation in diseased skin are the explanation for the transient efficacy of IL-2 in the treatment of atopic dermatitis.

Endothelial expression of intercellular adhesion molecule (ICAM-1) is unaffected by marrow aplasia-inducing chemotherapy. Sequential skin biopsies were obtained from five patients receiving chemotherapy for acute myelocytic leukemia. The first specimen was taken on the fourth day of initial chemotherapy and subsequent specimens were obtained at weekly intervals thereafter, until discharge. In all cases, clinically normal skin was selected as the biopsy site. A panel of monoclonal antibodies was applied to frozen tissue sections, including anti-intercellular adhesion molecule-1 (ICAM-1), anti-lymphocyte function-associated antigen-1 (LFA-1), and anti-HLA-DR. Bound antibody was detected using the avidin-biotin complex method. Endothelial cell expression of ICAM-1 and lymphocyte expression of LFA-1 were unaffected over the course of the ensuing, profound marrow aplasia. This finding suggests that this mechanism of lymphocyte trafficking in the skin remains operational despite the administration of antileukemic agents.

A controlled study of disruptive vocalizations among geriatric residents in nursing homes. This paper reports the results of a controlled study comparing geriatric residents in nursing homes who displayed disruptive vocalizations with residents in a comparison group. Two 350-bed nursing homes were surveyed, and it was found that 11% of the residents engaged in disruptive vocalizations, at least once per week, of sufficient severity to require consideration in the resident's care plan. Results show that disruptive vocalizers were more functionally impaired and were more likely to receive a diagnosis of dementia. They were also more likely to display a higher activity level and to experience sleep disturbance and to be prescribed neuroleptic medications. Descriptive data are presented on typology of disruptive vocalizations, likely situations for their occurrence, and the utilization and perceived efficacy of common interventions. Suggestions are made regarding behavioral treatments for this vexing problem.

Changes in urinary proximal tubule parameters in neonatal rats exposed to cadmium chloride during pregnancy. Pregnant Sprague-Dawley rats were injected intraperitoneally with physiological saline solution (vehicle) or cadmium chloride (CdCl2) at 2.0 or 2.5 mg kg-1 on days 8, 10, 12 and 14 of gestation. On postnatal day (PND) 3, 12 or 49, the offspring were examined for 8- or 24-h urinary excretion of beta 2-microglobulin (beta 2-m), metallothionein (MT) and urinary activity of three proximal tubular enzymes: gammaglutamyl transferase (GGT), alkaline phosphatase (ALP) and N-acetyl-beta-glucosaminidase (NAG). Treatment with CdCl2 did not affect growth or survival of offspring. Significant decreases in the urinary excretion of GGT, ALP and NAG were observed on PND 3, at both doses. Exposure to 4 x 2.5 mg kg-1 resulted in functional deficit of the proximal tubule on PND 3, as evidenced by the significant increase in beta 2-m. Except for a slight but significant increase of beta 2-m in 49-day-old males, all the other urinary parameters returned to control values on PND 12. There was no effect on MT. Results from this study show that prenatal exposure to CdCl2 can induce significant changes in the kidney biochemistry of rats in the early postnatal period.

Opioid, 5-HT1A and alpha 2 receptors localized to subsets of guinea-pig myenteric neurons. The expression of mu opioid, alpha 2 and 5-hydroxytryptamine1A (5-HT1A) receptors on guinea-pig myenteric neurons was determined using receptor selective agonists during intracellular recordings in vitro. Agonists known to hyperpolarize myenteric neurons by increasing potassium conductance were tested: noradrenaline and UK 14304 (alpha 2 agonists); 5-HT, 8-hydroxydipropylaminotetralin, 5-carboxamidotryptamine (5-HT1A agonists); normorphine, [Met5]-enkephalin and D-Ala2-Phe4, Gly-ol5 enkephalin (mu agonists). The alpha 2 agonists hyperpolarized 46/67 AH cells; mu agonists hyperpolarized 11/66 AH cells and 5-HT1A agonists inhibited 28/57 AH cells. Hyperpolarizations to both alpha 2 and mu agonists were observed in 11/59 AH cells; hyperpolarizations to both alpha 2 and 5-HT1A agonists were observed in 23/49 AH cells. Hyperpolarizations mediated at alpha 2 receptors were observed in 11/54 S neurons and mu agonists hyperpolarized 17/45 S cells. alpha 2 and mu receptors were localized together on 10/43 S cells tested with receptor selective agonists. 5-HT1A-mediated hyperpolarizations were not observed in 36 S cells. Presynaptic inhibition of fast excitatory post-synaptic potentials (fast e.p.s.p.s., S neurons) was observed in all cells tested with alpha 2 agonists (n = 32); in 14/23 cells tested with 5-HT1A agonists and in 8/22 cells tested with mu agonists. Both alpha 2 and 5-HT1A agonists inhibited fast e.p.s.p.s in 15/23 cells, while alpha 2 and mu agonists both inhibited the fast e.p.s.p. in 8/21 cells. Inhibition of fast e.p.s.p.s by mu and 5-HT1A agonists occurred together in 2/19 cells. Slow non-cholinergic e.p.s.p.s were inhibited by alpha 2 agonists in 19/19 cells and by 5-HT1A agonists in 19/21 cells. alpha 2- and 5-HT1A-mediated inhibition of slow e.p.s.p.s occurred together in 12/14 cells. These data allow AH neurons to be divided into two groups: those expressing alpha 2 and 5-HT1A receptors and those expressing alpha 2 and mu receptors. alpha 2 and mu receptors coexist on S neurons which do not express 5-HT1A receptors. Terminals that release acetylcholine express either alpha 2 and mu or alpha 2 and 5-HT1A receptors, consistent with the idea that they are provided by AH cells. Terminals that release mediators of the slow e.p.s.p. express primarily alpha 2 and 5-HT1A receptors.

Effect of guanethidine on dopamine in small intensely fluorescent cells of the superior cervical ganglion of the rat. To determine the portion of ganglionic dopamine stored in the small intensely fluorescent (SIF) cells of the superior cervical ganglion, rats were treated chronically with the neurotoxin guanethidine (50 mg/kg i.p. daily for 6, 13 or 18 days) which destroys noradrenergic neurons. The guanethidine effect was assessed in the ganglion using biochemistry of dopamine and norepinephrine and immunocytochemistry of tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH). After 18 days of treatment, the ganglionic norepinephrine content was reduced by 80%, but the dopamine content was reduced by only 20%. Morphologic analysis of ganglia stained to distinguish noradrenergic neurons (TH positive, DBH positive) and SIF cells (TH positive, DBH negative) indicated that guanethidine treatment reduced the number of noradrenergic neurons by 70%, dropping from 19413 +/- 1402 to 6515 +/- 1296 per ganglion, but increased the number of dopaminergic SIF cells by 80% from 578 +/- 150 to 1056 +/- 151 per ganglion. Based on these findings, it is concluded that a substantial portion of the dopamine in the rat superior cervical ganglion is located outside the noradrenergic neurons, i.e. in the SIF cells. Extrapolating the data obtained using guanethidine versus control rat leads to infer that although the proportion of SIF cells in the superior cervical ganglion is small (3 +/- 1% of the SIF and noradrenergic neurons combined), about 40% of the total ganglionic dopamine resides in SIF cells, with the remainder serving as precursor in noradrenergic neurons.

Opioid innervation of the caudal ventrolateral medulla is not critical for the expression of the aortic depressor nerve response in the rabbit. We investigated the influence of endogenous opioids in the caudal ventrolateral medulla (CVLM) on the expression of the baroreflex response induced by the electrical stimulation (50 Hz, 0.2 ms, 11 V, 10 s) of the aortic depressor nerve. We used microinjection of selective opioid antagonists into the functionally identified depressor area of the CVLM in chloralose-anesthetized rabbits. Injection of vehicles or the mu-antagonist beta-funaltrexamine (0.3 nmol) into the CVLM had no effects, while naloxone (20 nmol), ICI 174,864 (delta-antagonist, 0.3 nmol) or nor-binaltorphimine (kappa-antagonist, 1 nmol) abolished the depressor response, but themselves all elicited a tonic depressor effect as well. In contrast, intravenous naloxone (5 mg/kg) induced a small but significant increase in arterial pressure and did not alter the depressor response. Hypotensive hemorrhage induced a decrease in arterial pressure similar to that seen with local injection of naloxone into the CVLM, but did not change the reflex, suggesting that the reflex abolition was not due to the decrease in basal arterial pressure per se. CVLM injection of glutamate (10 nmol) or the GABA-antagonist bicuculline (0.1 nmol), non-opioid agents which activate CVLM and induce a tonic depressor effect, also abolished the depressor response suggesting that the reflex abolition was secondary to general activation or disinhibition of the CVLM. Thus, although the CVLM is tonically inhibited by endogenous opioid inputs acting via delta- and kappa-receptors, our data provide no evidence that opioid neurons which provide input to this region constitute a specific and integral component in mediating the aortic depressor response. However, the more general role that opioids play in tonically influencing the resting level of activity in the CVLM, is nevertheless very important in enabling the normal expression of this baroreflex.

Cellular, immunologic and biochemical characterization of topical retinoic acid-treated human skin. Histologic and clinical improvement of sun-exposed skin following topical treatment with retinoic acid has been reported. Daily application of retinoic acid typically results within 2-5 d in an erythematous scaling reaction, which lessens with continued usage. The cellular, immunologic, and biochemical basis of this retinoid reaction and its role in the repair of photodamaged skin are not known. To investigate the retinoid reaction in man, we have treated non-sun-exposed skin with 0.1% retinoic acid cream (Retin-A, Ortho Pharmaceutical Corporation, Raritan, NJ) under occlusion for 4 d to induce erythema and then examined changes in 1) histology, 2) expression of cell-surface molecules, 3) the enzymes and second messengers of the phospholipase C/protein kinase C signal-transduction system, 4) levels of eicosanoids, and 5) levels of interleukin-1 protein and mRNA. These parameters were chosen for measurement both because they are indicators of epidermal function and previous studies suggest they may be responsive to retinoic acid treatment. Epidermal cell growth as judged by increased epidermal thickness and mitotic figures was significantly increased in retinoic acid-treated skin compared to vehicle-treated controls. Increased numbers of CD4+ T cells accompanied by prominence of dermal dendrocytes in the papillary dermis and focal keratinocyte expression of intercellular adhesion molecule-1 were observed in retinoic acid-treated biopsies. Phosphoinositide-specific phospholipase C activity and 1,2-diacylglycerol content were also elevated in retinoic acid-treated epidermis. Protein kinase C activity was reduced by one third in both the soluble and membrane fraction, suggesting down-regulation. Surprisingly, in view of the inflammatory nature of the retinoid reaction, no increases were observed in arachidonic acid, its metabolites, interleukin-1 alpha, or interleukin-1 beta. To examine the specificity of the retinoid reaction, subjects were treated with the irritant sodium lauryl sulfate, under conditions that resulted in a reaction clinically similar to that observed with retinoic acid. The histologic alterations induced by sodium lauryl sulfate were found to be indistinguishable from those induced by retinoic acid. These data indicate that, although a wide range of cellular and molecular alterations occur in retinoic acid-treated skin, these changes may not be necessarily specific or unique for retinoic acid.

Recovery of amino acid neurotransmitters from the spinal cord during posterior epidural stimulation: a preliminary study. Continuous posterior epidural spinal cord stimulation (SCS) has been an effective method for treating spasticity. The mechanisms of SCS include activation of inhibitory segmental neuronal systems and suprasegmental structures that produce inhibitory descending control. The neurochemical correlates of the mechanism of action have not been clearly defined. Microdialysis of the spinal cord extracellular space in an in vivo preparation during continuous epidural SCS was performed. The recovery of amino acid neurotransmitters, aspartate, glutamate, gamma-aminobutyric acid (GABA), glycine, and taurine from stimulated animals was compared to non-stimulated animals. Evoked potentials from the cortex and spinal cord of the stimulated animals were recorded to insure that there had been adequate epidural stimulation and normal segmental cord function. A significant increase in the concentration of glycine was seen after 90 minutes of continuous stimulation. The levels of the other amino acids were not significantly elevated. These results suggest that amelioration of spasticity with epidural SCS may involve enhanced glycine release, the major inhibitory neurotransmitter of the spinal cord.

Cytokine-induced expression of intercellular adhesion molecule-1 (ICAM-1) in cultured human oligodendrocytes and astrocytes. We investigated the expression of intercellular adhesion molecule-1 (ICAM-1) on primary cultures of human adult oligodendrocytes and astrocytes. Under unstimulated conditions, low levels of ICAM-1 immunoreactivity were identified on both oligodendrocytes (less than 50%) and astrocytes (less than 30%). After 48 hours' exposure to immune mediators, such as culture supernatant of phytohemagglutinin (PHA)-stimulated lymphocytes, interferon gamma (IFN-gamma; 1,000 U/ml), tumor necrosis factor alpha (TNF-alpha; 2,000 U/ml), interleukin-1 alpha (IL-1 alpha; 1,000 U/ml) and lipopolysaccharide (LPS; 50 micrograms/ml), ICAM-1 expression on both cell types was markedly increased in terms of intensity and cell numbers. IFN-gamma and culture supernatant of PHA-stimulated lymphocytes were the most potent inducers of ICAM-1 among the mediators tested, while TNF-alpha, IL-alpha and LPS were less effective, although variations were observed among cultures derived from different donors. Cytokine-induced expression of ICAM-1 on glial cells may play a role in mediating lymphocyte-glial cell interactions at sites of inflammation in the central nervous system.

Molecular forms of soluble human T lymphocyte receptor for sheep erythrocytes in serum and saliva. Using a specific serum anti-soluble T lymphocytes receptor for sheep erythrocytes (E) and SDS-PAGE, we detected radioactive bands of molecular weight 58,000 in immunoprecipitates of supernatant of heated human lymphocytes (SHL), in the supernatant of PHA stimulated lymphocyte cultures (SLC), normal human serum (NHS), and serum from cancer and uremia patients, labelled with 131I. By Sephadex G-200 chromatography, in addition to this fraction, we detected molecules of molecular weight higher than 150,000 which interact with the anti-soluble receptor serum (anti-RS), in serum from cancer and uremia patients. These molecules were detected in NHS or SHL after concentration or by prolonged exposure of SDS-PAGE with some labelled and immunoprecipitated SHL samples. The soluble receptors of molecular weights 58,000 (RS1) and more than 150,000 (RS2) were fully identical when analyzed by immunodiffusion with anti-RS serum. When submitted to immunoelectrophoresis, RS1 showed electrophoretic migration similar to that of albumin, while RS2 showed a pattern close to that of alpha 2-globulin. However, RS2 did not show antigenic relationship with IgM and was not an immune complex with IgG. Even though the presence of RS in human saliva has not yet been reported, molecules that interact with anti-RS serum have been detected in human saliva and are fully identical to molecules found in supernatant of heated human T lymphocytes and NHS. The RS molecules present in human saliva have a molecular weight and electrophoretic migration similar to those of RS1 from SLC and from human serum and have no antigenic relationship with human albumin.

Subsequent testicular histology: fertility and fecundity of rats subjected to unilateral incarcerated inguinal hernia during the prepubertal period. An experimental study was designed to evaluate subsequent ipsilateral and contralateral testicular histologies, fertility, and fecundity of rats subjected to unilateral incarcerated inguinal hernia during the prepubertal period. Three study groups each containing 12 rats (28-day-old) were established. In group 1 the rats were only anesthetized. In group 2 the rats had undergone a sham operation. Left-sided incarcerated inguinal hernias were created in rats constituting group 3. After the rats had reached 4 months of age, each male rat was housed with two known fertile female rats for 3 weeks. Male rats were then castrated and the testes were evaluated histologically. Female rats were followed for 30 additional days, and the number of females impregnanted and the number of rats given birth to by each female rat were recorded. Left-sided incarcerated inguinal hernia has caused a lessened testicular/body weight ratio in the left testes, and histological deteriorations in both left and right testes that were expressed through diminished mean seminiferous tubular diameter and mean testicular biopsy scores. The fertility rate was not affected, but the number of rats produced by each male rat was lesser after having the incarcerated inguinal hernia. Unilateral incarcerated inguinal hernia during prepubertal period resulted in deteriorated ipsilateral and contralateral testicular histology and diminished the exocrine function of testes in rats.

Brain growth and cognitive improvement in children with human immunodeficiency virus-induced encephalopathy after 6 months of continuous infusion zidovudine therapy. The ventricular area at the level of the foramen of Monro was measured from axial x-ray computed tomography (CT) scans obtained prior to and 6 months after the initiation of continuous infusion of zidovudine (ZDV) in eight children with human immunodeficiency virus-induced encephalopathy. Evidence of moderate to severe central atrophy was present on initial CT scans (p less than 0.05). Ventricular area and ventricular brain area ratio (VBR) decreased after ZDV therapy in seven of eight children (mean decrease of 21.5 and 20%, respectively, p less than 0.05). The degree of decrease in VBR correlated with reductions in cerebrospinal fluid (CSF) protein concentration (r = 0.93, p less than 0.01), but not lymphocyte T4 or T8 counts. Intelligence quotients (IQs) improved in all seven children tested (mean improvement of 17.7%, p less than 0.01) and correlated significantly with reductions in CSF protein concentration (r = -0.85, p = 0.003). The magnitude of IQ changes was not significantly correlated with the magnitude of changes in ventricular area. We conclude that the cognitive improvement of HIV encephalopathy seen after 6 months of continuous infusion of ZDV is accompanied by reduction in brain atrophy and decreased CSF protein, suggesting an ameliorating effect of ZDV on the pathogenesis of AIDS encephalopathy in children.

Serum erythropoietin titers in patients with human immunodeficiency virus (HIV) infection and anemia. The pathophysiology of anemia in patients with human immunodeficiency virus (HIV) infection is multifactorial. In order to determine the role of erythropoietin (EPO) response as a cause of the anemia, serum levels were determined by direct radioimmunoassay in 110 symptomatic patients with various stages of HIV infection. Symptomatic patients (ARC and AIDS) not receiving zidovudine (ZDV) therapy demonstrated a strong inverse relationship between serum EPO and hemoglobin levels (p = 0.01 and p less than 0.001, respectively). Patients with AIDS who were anemic while receiving ZDV demonstrated serum EPO levels that ranged from normal to markedly elevated (9-3,390 mU/ml). The diversity of serum EPO levels in patients with HIV infection and anemia suggests that the etiology of anemia in these patients and their potential response to recombinant human EPO may not be uniform.

Lymphocyte immunophenotypes among anti-HTLV-I/II-positive blood donors and recipients. The Transfusion Safety Study Group. The Transfusion Safety Study retrospectively screened a repository of serum specimens collected in late 1984-early 1985 to identify blood donors with antibody to human T-cell lymphotropic virus (HTLV) at that time. They and their recipients have been traced for additional HTLV studies. Immunophenotypic analyses of peripheral blood lymphocytes from nine anti-HTLV-positive recipients, assumed to be infected during or since late 1984, showed no significant changes from healthy controls. Evaluation of the immunophenotypes of the 48 donors, however, showed significant elevations in the absolute counts of the T-cell (CD2) and natural killer (CD56) populations, the T helper/inducer and suppressor/inducer subsets (CD4+ CD29+ and CD4+ CD45RA+), and changes in T-cell activation markers. Long-term but not recent HTLV infection appears to alter the T-cell immunophenotypic pattern. Both infection with HTLV and human immunodeficiency virus type 1 are associated with a decreased CD2+ CD26+ count.

Restriction fragment length polymorphism analysis of HLA-DR, DQ, DP and C4 alleles in Caucasians with systemic lupus erythematosus. HLA-DR, DQ, DP and C4 null alleles were determined by restriction fragment length polymorphism (RFLP) analysis in 60 Caucasian patients with systemic lupus erythematosus (SLE) and 66 controls. DR3 (DRw17) and DQw2.1 were increased in frequency in the patients with SLE associated with the presence of C4A null genes. HLA-DP alleles determined by RFLP analysis of genomic DNA as well as of PCR amplified DNA were not associated with SLE or any clinical or autoantibody subset thereof. No DR, DQ, or C4 null gene association was found with renal or neuropsychiatric involvement or nDNA antibodies (or levels thereof). These data suggest that the primary predisposition to SLE lies with HLA-DR or C4 null alleles, and not with HLA-DP.

Toxicity profiles of disease modifying antirheumatic drugs in rheumatoid arthritis. The toxicity profiles of 7 disease modifying antirheumatic drugs (DMARD) (hydroxychloroquine, intramuscular (im) gold, D-penicillamine, oral gold, methotrexate (MTX), azathioprine and cyclophosphamide) were evaluated in 2,479 patients with rheumatoid arthritis consecutively enrolled at 5 centers in the Arthritis, Rheumatism and Aging Medical Information System (ARAMIS) program. Incidence rates for side effects are reported as events/1000 patient-years. Our descriptive study revealed an individual profile of prevalent toxicities for each drug. Oral gold was characterized by substantial lower gastrointestinal (GI) toxicity (diarrhea 391 events/1000 patient-years, loose bowel movement 148, lower abdominal pain 76), MTX by hepatotoxicity (47) while D-penicillamine had the only clinically significant incidence of altered taste (40). MTX users reported the most mucosal ulcers (87), followed by oral gold (76), im gold (55) and D-penicillamine (38). Rash was frequently seen with gold compounds and D-penicillamine, while upper GI toxicity was common with immunosuppressive agents. Cyclophosphamide had 48% discontinuations within 6 months. MTX had the lowest discontinuation rate in the first 6 months, but then showed little difference from im gold. A preliminary similarity index was developed to compare the toxicity profiles of various DMARD. Close similarities were found between toxicity profiles of im gold and D-penicillamine, and between azathioprine and MTX. Oral gold had a unique toxicity pattern. Knowledge of these different toxicity patterns can enable more appropriate selection of agents for particular patients.

Response to sulfasalazine in rheumatoid arthritis: life table analysis of a 5-year followup. Eighty-six patients with rheumatoid arthritis treated with sulfasalazine were followed for 5 years, or until treatment was discontinued. At the end of 5 years, there was a 22% probability of successfully continuing treatment. Most adverse effects developed in the first 3 months of treatment. In 38 patients treatment was discontinued because of inefficacy. In 18 of these, a brief period of improvement was followed by clinical relapse. Twenty were regarded as having no useful response to sulfasalazine. The treatment continuation rate of 22% at 5 years is in marked contrast to the pessimistic longterm evaluations of second line drugs that have recently been reported.

Astemizole, an H1 antagonist, has no additional therapeutic effect in rheumatoid arthritis. Mast cells are found in increased numbers in the synovium of patients with rheumatoid arthritis (RA) and may play a role in synovitis. They produce proinflammatory substances including histamine. A double blind placebo controlled study was undertaken in 60 patients with active RA using the H1 receptor blocker, astemizole, as an adjuvant to usual therapies. After 3 months of treatment there were no significant differences in clinical and laboratory variables between the groups. We conclude that H1 antagonist treatment with astemizole has no additional therapeutic effect in RA.

Embolization of cardiac myxomas masquerading as polyarteritis nodosa. Cardiac myxomas are rare tumors which can mimic other diseases. We describe a 19-year-old man who presented clinically with polyarteritis nodosa (PAN). Muscle biopsy showed vasculitis, but corticosteroid and immunosuppressive therapy was initially effective. Cardiac myxomas were found by echocardiogram when the disease relapsed and were resected surgically. Segmental arterial aneurysms and stenoses were found on angiography after leg ischemia. We suggest that echocardiography should be performed in all cases of clinically suspected PAN.

Allele loss at the retinoblastoma locus in human ovarian cancer. To gain a broad spectrum on allelic loss of specific loci in ovarian tumors, we initially examined DNA from 23 pairs of ovarian tumors and matched peripheral blood lymphocyte samples from the same patients, using 27 polymorphic DNA markers distributed on 13 chromosomes. Significant high frequency of allelic deletion (22%-44%) at chromosome 13 loci (D13S31, D13S32, D13S33, and D13S34) at bands q12-q34 was observed in tumor tissues. These results led us to investigate the loss of heterozygosity at the retinoblastoma (RB) locus in ovarian tumors, because the RB gene is a tumor-suppressor gene located at 13q14. Analysis of the variable number of tandem repeat sequence polymorphism in intron 20 in the RB gene revealed that 6 (30%) of 20 patients with informative samples showed allelic loss at the RB locus in their tumor tissues. This loss, of relatively high frequency, suggests that the RB gene, or a closely linked gene, seems to be involved in the development of ovarian cancer.

The operational costs of spraying residual insecticides: a case-study from Nepal. Little attention has been paid to the cost implications of different insecticides for malaria control, particularly to the local (non-insecticide) costs. This study in Nepal explored the significance of operational costs in relation to insecticide cost and examined the extent to which operational costs varied for DDT, malathion and Ficam. A detailed analysis was done of costs relating to spraying, transport and safety. The study found that the operational cost differences were relatively small in comparison with the costs of the chemicals themselves and the cost of transporting them to Nepal, though DDT and Ficam had significantly lower operational costs than malathion. Operational costs were paid mainly by the Nepalese government and insecticide and external freight costs by donors.

[Effect of adrenergic beta blockers on hemodynamics, diastolic relaxation and distensibility of left-ventricular myocardium in patients with ischemic heart disease]. Altogether 32 patients were investigated by catheterization of the left ventricular cavity with volume loading of 76% solution of verographin++ administered at 0.65 ml per kg body mass. beta-blockade with preliminary i.v. administration of 5 mg obsidan or 10 mg cordanum was shown to improve myocardial diastolic function as a result of improved myocardial distensibility in CHD patients.

[Comparative effectiveness of psychotropic drugs in patients with chronic ischemic heart disease]. As many as 348 courses of psychotropic and antianginal chemotherapy were performed for coronary disease confirmed angiographically. Hypochondriac patients were resistant to the drugs, depressive states and anxiety showed the best response. Tranquilizers and neuroleptic agents proved effective in anxiety, neuroleptics in cardiophobia and hypochondria, antidepressants in depression and asthenia. The addition of psychotropic drugs to antianginal therapy produced a positive effect on cardiac pain with antidepressants benefit ranking first, neuroleptics second and tranquilizers third. Being moderate and transient, treatment-related side effects did not cause the treatment discontinuation.

Reduction of infarct size by systemic amino acid supplementation during reperfusion. The amino acids aspartate and glutamate, in combination, were evaluated as a means of reducing infarct size and improving cardiac function during reperfusion in an intact pig having an acute anteroseptal infarct. Three groups of 6 pigs each were randomly studied in a blinded manner: control (no amino acids), aspartate/glutamate 3 mmol/L, and aspartate/glutamate 13 mmol/L. The left anterior descending coronary artery was occluded distal to its first diagonal branch for 60 minutes followed by reperfusion for 6 hours. Aspartate and glutamate were administered systemically immediately before reperfusion. The following parameters were measured: infarct size and percent area at risk, global metabolic function, global and regional myocardial function, and tissue parameters of metabolic function. The results clearly showed a significant decrease in infarct size from 60% of the area at risk in control pigs to 37% in both 3 mmol/L and 13 mmol/L amino acid groups. Cardiac output, coronary blood flow, and global oxygen consumption were not significantly affected by the use of amino acids relative to the control group. Global left ventricular mechanical function was also not adversely affected by the infarct and was not altered by amino acid administration. Regional function, however, was significantly decreased by occlusion of the left anterior descending coronary artery in all groups to near 20% and only significantly recovered to 64% in the 13 mmol/L amino acid group. Adenosine triphosphate and acetyl coenzyme A measurements documented significant increases in the 13 mmol/L amino acid group relative to the control group. The conclusions of this study strongly support aspartate/glutamate supplementation for stunned, reperfused myocardium. It is apparent that the effect of amino acid supplementation on glycolysis is directly translated into improved regional function and reduced infarct size.

Randomised study of antiepileptic drug withdrawal in patients in remission. Medical Research Council Antiepileptic Drug Withdrawal Study Group. A prospective multicentre randomised study of continued antiepileptic treatment vs slow withdrawal was conducted in 1013 patients who had been free of seizures for at least 2 years. Comparison of randomised and eligible, but non-randomised, patients suggests the results should be applicable to a wider patient population. By 2 years after randomisation, 78% of patients in whom treatment was continued and 59% of those in whom it was withdrawn remained seizure free, but thereafter the differences between the two groups diminished. Non-compliance with continued treatment accounted for only a small proportion of the risk to the group continuing with treatment. The most important factors determining outcome were longer seizure-free periods (reducing the risk) and more than one antiepileptic drug and a history of tonic-clonic seizures (increasing the risk). Other factors (eg, history of neonatal seizures, specific electroencephalographic features) seemed to have smaller effects, but even in such a large study the confidence intervals for these observations were wide.

Scheduling of revaccination against hepatitis B virus. Studies have shown that to maintain protection against infection after a primary course of hepatitis B immunisation, revaccination can be scheduled on the basis of an anti-hepatitis B virus surface antigen (anti-HBs) titre obtained 1 month after the booster dose. However, schemes which require post-booster testing may present practical difficulties. We applied a random-effects regression model to data from 118 Senegalese infants given three injections of hepatitis B vaccine about 6 weeks apart and a booster injection at 13 months, and show that revaccination can be scheduled on the basis of an anti-HBs titre recorded at the time of the booster dose. We also show that titre-at-booster is no less accurate in predicting future titre than 1-month post-booster titre. In several other studies the post-booster decline in anti-HBs conforms to the same mathematical description, indicating the generality of our findings.

Identification of hepatitis A virus as a trigger for autoimmune chronic hepatitis type 1 in susceptible individuals. To identify factors contributing to the pathogenesis of autoimmune chronic active hepatitis (CAH) healthy relatives of 13 patients with the disorder were followed prospectively for 4 years. 58 relatives were monitored for various serological markers and for T-lymphocyte migration inhibitory activity every 2 months. 3 cases of subclinical acute hepatitis A occurred during the study. In 2 of the 3 subjects, before hepatitis A virus (HAV) infection, there was a defect in suppressor-inducer T lymphocytes specifically controlling immune responses to the asialoglycoprotein receptor, an antigen expressed on the hepatocyte surface. In these 2 subjects, specific helper T cells and antibodies to the asialoglycoprotein receptor persisted and increased after acute hepatitis A, and autoimmune CAH type 1 developed within 5 months. Thus, in susceptible individuals HAV is a trigger for autoimmune CAH.