Abolition of flow-dependent EDRF release before that evoked by agonists in hypercholesterolaemic rabbits.

1. We have used a pulsatile cascade bioassay system to investigate the effects of dietary-induced hypercholesterolaemia on EDRF release evoked by acetylcholine and by the oscillatory and time-averaged components of flow, in isolated segments of rabbit abdominal aorta. 2. Flow pulsatility (frequency range 0.1-10 Hz) was studied with constant flow (9 ml min-1) at a pulse pressure amplitude of 2 mmHg. Frequency-related EDRF release, maximal at 6 Hz, was slightly attenuated after 4 weeks and abolished after 8 weeks of cholesterol feeding. 3. Time-averaged shear stress was manipulated with dextran (1-4% w/v, 80000 mol. wt.), to increase perfusate viscosity. EDRF release induced by increased perfusate viscosity was unaffected after 4 weeks but abolished after 8 weeks of cholesterol feeding. 4. Endothelium-dependent relaxations to acetylcholine (0.1-10 microM) were not influenced after 4 weeks and only partially attenuated (by 60% of the maximal response, EC50 unchanged at 6.45 +/- 0.04 vs. 6.4 +/- 0.1 microM) after 8 weeks of cholesterol feeding. 5. Blood cholesterol levels were significantly (P < 0.001) increased after 4 weeks (26 +/- 3.6 vs 2.6 +/- 0.6 mmol l-1) and 8 weeks (56.2 +/- 3.8 vs 1.3 +/- 0.1 mmol l-1) of cholesterol feeding but after 8 weeks plasma L-arginine levels were not significantly different from the age-matched controls (0.2 +/- 0.05 vs. 0.19 +/- 0.04 mmol l-1). 6. We conclude that hypercholesterolaemia impairs flow-related (pulsatile- and time-averaged shear-induced) EDRF release earlier than acetylcholine-induced relaxation in rabbit aorta.(ABSTRACT TRUNCATED AT 250 WORDS)     

Developmental cellular electrophysiologic effects of propafenone on the rabbit atrioventricular node.

Transmembrane recordings and surface electrograms were used to evaluate the influence of propafenone on the cellular electrophysiology of isolated neonatal and adult rabbit atrioventricular node (AVN) preparations. An automatic interval of 863 +/- 82 ms (mean +/- SEM, n = 14) in neonates was found to be significantly shorter than the 1510- +/- 205-ms (n = 12) automatic interval observed in adults. Propafenone in a concentration of 5 x 10(-6) M significantly increased the automatic interval of neonatal pacemakers but not that of the adult preparations. These changes in automaticity produced by propafenone were not dependent on the adrenergic receptor-blocking action of the drug. The pacemaker escape time after overdrive pacing was also shorter in the neonate than in the adult. Propafenone prolonged the escape time of the neonatal tissues but not those of the adult. AVN refractory period, A-H interval, and antegrade Wenckebach rate were comparably increased in a concentration-dependent manner in both age groups. The maximum diastolic potential was decreased by propafenone in the neonatal atrionodal tissue but not in other regions of the AVN and not in any region of the adult AVN. Action-potential duration was increased in all regions of the AVN in both age groups. Action-potential amplitude and maximum upstroke velocity were decreased by propafenone in both age groups. Unlike other excitable tissues of the heart, the action-potential duration of AVN nodal cells increased with decreasing pacing intervals as the pacing interval approached the Wenckebach interval.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of pindolol on endocrine and temperature responses to buspirone in healthy volunteers

Ten healthy subjects received buspirone (30 mg orally) with and without pre-treatment with the 5-HT1A receptor antagonist, pindolol (80 mg over 3 days). Following pindolol treatment the growth hormone and hypothermic responses to buspirone were significantly decreased. There was also a delay in the onset of the prolactin response to buspirone but the total amount of prolactin secretion, calculated as area under the curve, was not significantly reduced. The data suggest that the growth hormone and hypothermic responses to buspirone in humans are mediated by 5-HT1A receptors, but an explanation founded on pharmacokinetic factors cannot presently be excluded. Both this latter possibility and the lack of selectivity of pindolol for 5-HT receptors indicate the need for the further neuroendocrine studies of the mode of action of buspirone, preferably with more selective 5-HT1A receptor antagonists.     

Potential antitumor agents XIX [1]. Synthesis and antitumor activity of tricyclic compounds related to lotifazole.

The synthesis of phenothiazine and anthraquinone derivatives, bearing at least one fragment present in lotifazole, is reported. Some of the new compounds showed antitumor activity in vitro (P388 leukemia cells) and in vivo (Ehrlich ascites tumor cells in mice).     

Testicular microlithiasis: sonographic and clinical features.

Eleven cases of bilateral diffuse microlithiasis of the testes were evaluated sonographically. The presence of testicular microlithiasis was coincidental to the presence of testicular neoplasms (n = 2), nontesticular malignant lesion in the abdomen or chest (n = 2), subfertility (n = 2), varicocele (n = 1), epididymitis (n = 1), testicular maldescent (n = 1), scrotal trauma (n = 1), and transient scrotal pain (n = 1). Clinical follow-up suggested that testicular microlithiasis is an asymptomatic nonprogressive condition. Sonographic examination of testicular microlithiasis shows diffuse hyperechoic nonshadowing foci measuring 1-2 mm in diameter throughout both testes. The diagnosis of testicular microlithiasis was pathologically proved in five cases. In six cases, the diagnosis was made on the basis of the sonographic appearance (n = 6), clinical information and follow-up (n = 6), and radiologic demonstration of testicular microcalcifications (n = 3). The sonographic appearance of testicular microlithiasis is specific, and we believe that biopsy or orchiectomy in these cases is unnecessary.     

The effects of training, immobilization and remobilization on musculoskeletal tissue

Compared with the knowledge on immobilization, the effects of remobilization on musculoskeletal tissues have not been well established. What is sure is that remobilization and rehabilitation of any component of the musculoskeletal tissues require much more time than the time needed to cause the immobilization atrophy. With intensive rehabilitation, the functional properties of skeletal muscles can be improved significantly even years after the injury and following immobilization, but no study has shown whether full recovery is possible and whether these rehabilitated muscles are able to respond normally to further training. Experimental studies have given evidence that slow-twitch muscle fibres have better capacity for recovery than fast-twitch fibres, most likely due to better circulation and higher protein turnover. Also evidence has been given that fibre regeneration is possible through satellite cell activation and myotube formation. Very little is known, however, about the effects of age, gender or the level of preimmobilization muscle performance on the restoration capacity. Also the fate of the marked structural changes (for example, connective tissue accumulation) induced by immobilization is unknown. Tendon and ligament tissues are likely to respond appropriately to remobilization, resulting in acceleration of collagen synthesis and fibril neoformation. However, there is a strong suspicion that remobilized tendons and ligaments will not achieve all the biochemical and biomechanical properties of their healthy counterparts. Specifically, the amount of weak type III collagen has been shown to be overrepresented in these tissues instead of mature, strong type I collagen. It is not known whether this is an important risk factor for ruptures during later activity. The effects of remobilization on muscle-tendon junction and proprioceptive organs are not known. It would not be surprising if the serious structural changes induced by immobilization were unrestorable. In the literature dealing with immobilization and remobilization, cartilage degeneration is always a major concern, because not only too strenuous training or immobilization, but also unskilful remobilization may activate this process leading finally to osteoarthrosis. Bone may be one of the best components of musculoskeletal tissues to respond to remobilization, probably because the immobilization atrophy of bone is largely quantitative (osteoporosis) only. The prerequisites for bony recovery are that the follow-up time is long enough (months) and that immobilization has not exceeded about 6 months, the time limit between active and inactive (irreversible) osteoporosis. Prevention of the atrophying effects of immobilization can be very successful if performed properly. According to present knowledge, there are many methods for the purpose, including preimmobilization training early, controlled mobilization; optimal positioning of the immobilized joint; muscular training during immobilization; early weightbearing; exercise with the nonimmobilized extremity; and electrical stimulation. Lots of education and information will be needed, however, before these methods are deeply rooted in the daily routines of the attending physicians, physical therapists, athletic trainers and other persons involved in the treatment of musculoskeletal problems.     

Acute hemodynamic effects of intravenous bolus injection of isosorbide dinitrate in aged patients with congestive heart failure]

In order to investigate whether intravenous bolus injection of isosorbide dinitrate (ISDN) is a safe and efficient therapy in aged patients with congestive heart failure, we studied acute hemodynamic effects in 11 patients. Peak effects on preload were observed after 5 to 10 minutes of bolus injection and unloading effects continued effectively for 60 minutes. At peak effect, pulmonary systolic pressure decreased from 50.2 +/- 2.6 to 36.2 +/- 2.6 mmHg (-28.5%, p less than 0.01) and pulmonary end diastolic pressure decreased from 25.0 +/- 2.2 to 18.5 +/- 2.1 mmHg (-26.0%, p less than 0.01). Mean pulmonary artery wedge pressure decreased from 23.4 +/- 2.2 to 16.0 +/- 2.1 mmHg (-31.6%, p less than 0.01). Mean right atrial pressure decreased from 10.5 +/- 1.8 to 7.4 +/- 2.0 mmHg (-29.5%, p less than 0.01). Blood pressure, heart rate, cardiac index, systemic and pulmonary vascular resistance showed no significant changes. Thus, intravenous bolus injection of ISDN showed a potent vasodilator effects on preload, and may be a safe and useful treatment for aged patients with acute congestive heart failure.     

Eosinophilic activation in cystic fibrosis.

BACKGROUND--The neutrophil is a potent contributor to pulmonary destruction in cystic fibrosis. Since eosinophils also possess destructive potential the involvement of eosinophils in cystic fibrosis has been investigated. METHODS--Eosinophil numbers and levels of eosinophil cationic protein (ECP), a marker of eosinophil activation, were determined in the serum of 42 patients with cystic fibrosis and in the sputum of 10 of them. To determine neutrophil activation levels of myeloperoxidase (MPO) were also measured. RESULTS--In cystic fibrosis increased serum levels of ECP were detected compared with healthy non-atopic subjects. Serum ECP levels were not related to the peripheral blood eosinophil count. A strong correlation with ECP concentrations in sputum indicated that the level of ECP in serum was representative of its pulmonary level. Levels of MPO were also increased in cystic fibrosis. A strong correlation was found between MPO and pulmonary function. In addition, ECP was related to arterial oxygen and carbon dioxide tensions. Antibiotic treatment reduced neutrophil activation without effect on ECP levels. CONCLUSIONS--Until now Pseudomonas aeruginosa and neutrophils were held to be primarily responsible for progressive tissue damage in cystic fibrosis. The results of this study suggest that eosinophils might also participate in such pulmonary destruction.     

Oilseed rape and seasonal symptoms: epidemiological and environmental studies.

BACKGROUND--There is widespread concern that the cultivation of oilseed rape leads to seasonal epidemics of respiratory symptoms in populations living in the neighbourhood, and it has been suggested that the plant is a potent allergen. A study was therefore undertaken to determine the prevalence of seasonal symptoms in rural populations close to and far from areas of oilseed rape cultivation, and to measure the levels of allergen and other potentially harmful substances released by the crop. METHODS--Random samples of 1000 adults from the general practice populations of two villages surrounded by oilseed rape fields, and 1000 adults from one village far from such cultivation, were taken. The subjects completed a previously validated questionnaire on respiratory and other symptoms, including questions on symptom seasonality, occupation, and smoking habits. Pollen and fungal spore counts were made around fields of oilseed rape and in the villages. The chemicals released by oilseed rape were measured in the field. RESULTS--Overall, 86.8% of the subjects completed the questionnaires and the populations of the two samples were generally comparable. Spring and summer exacerbations of symptoms occurred equally in the two areas in approximately 25% of the population. There were small but significant excesses of cough, wheeze, and headaches in spring in the oilseed rape area (2.3% v 1.1%, 6.8% v 4.6%, and 4.8% v 2.8%, respectively), and cough, wheeze, and itchy skin were more prevalent in smokers. Counts of oilseed rape pollen were generally low except adjacent to fields, and counts of fungal spores were mostly higher in the rape than the non-rape areas. Oilseed rape was shown to give off terpenes and these were detected close to fields. CONCLUSIONS--While it is likely that a proportion of the spring symptoms occurring in people living in close proximity to oilseed rape is caused by the plant, the excess of such symptoms is small. This, together with the low levels of pollen in the area, suggests that allergy to oilseed rape pollen is uncommon. The general prevalence of seasonal symptoms in rural areas is of interest, and a proportion of these cases is likely to be caused by factors other than allergy. Release of chemicals by plants and natural rises in summer ozone levels may be contributors.