Ultrastructural observations on the establishment of neuromuscular junctions following prevention of embryonic death of motoneurons

Blockage of embryonic neuromuscular transmission prevents the death of duck trochlear motoneurons which occurs during the course of normal development. This electron microscopic study was undertaken to examine the establishment of the neuromuscular junctions (NMJs) in the superior oblique muscle after paralysis with α-bungarotoxin (α-BTX) to ascertain the mechanism of the prevention of embryonic cell death. Because NMJs were observed in all paralyzed muscles, it appears that nerve-evoked muscle activity is not essential for formation of the basic elements of the NMJs. NMJs in the paralyzed muscles, however, had significantly higher numbers of axon terminals compared with the saline controls. This increase in the number of axon terminals is interpreted as being due primarily to an increase in the number of motoneurons projecting into the paralyzed muscle, rather than to axonal sprouting. The increase in the number of axon terminals at NMJs occurred as soon as synapses were formed and persisted throughout development. When embryos were allowed to recover from the effects of paralysis, a decrease in the number of axon terminals at NMJs occurred. These observations suggest that the nerve-evoked muscle activity or something triggered by it may play an important role in regulating the number of nerve terminals at the NMJs during the course of embryonic development.     

alpha-Adrenoceptors in the ventricular myocardium: clonidine, naphazoline and methoxamine as partial alpha-agonists exerting a competitive dualism in action to phenylephrine.

Tha alpha-sympathomimetic agonists, clonidine, naphazoline, methoxamine, oxymetazoline and phenylephrine were used to further characterize the alpha-adrenoceptors mediating the positive inotropic effect in the isolated papillary muscle of the rabbit heart. The maximal inotropic effects of these amines were compared with the effect of isoprenaline and it was examined whether or not these amines compete for alpha-adrenoceptors. On the papillary muscle stimulated at 0.5 Hz, phenylephrine showed a high affinity (pD2 value=6.13) and produced the most pronounced intrinsic activity of the alpha-sympathomimetic amines. Therefore, the intrinsic activity of phenylephrine, in the presence of prindolol (3 X 10(-8) M), was used for comparison with those of the other alpha-agonists. Clonidine caused a positive inotropic effect: the intrinsic activity amounted to 0.32 of that of phenylephrine; the affinity was the highest among the amines tested (pD2 value=6.46); its effect was inhibited by 10(-6) M phentolamine. The affinity and the intrinsic activity of naphazoline were slightly lower than those of clonidine. Methoxamine showed a relatively high intrinsic activity (0.56) but the lowest affinity (4.68). Oxymetazoline did not cause any positive inotropic effect. Clonidine, naphazoline and oxymetazoline antagonized the positive inotropic effect of phenylephrine, mediated via the alpha-adrenocaptors in the presence of 3 X 10(-8) M prindolol, in a competitive manner. This observation suggests that these alpha-sympathomimetic amines compete with phenylephrine for the same receptor site. Thus the present results provide additional evidence for alpha-adrenoceptors mediating the positive inotropic actions of sympathomimetic amines in the rabbit papillary muscle.     

Effect of thymoxamine on the human pupil

The specificity of thymoxamine, an alpha-adrenoceptor antagonist was determined from in vitro organ bath studies using isolated preparations of canine saphenous and portal mesenteric veins. It was found that thymoxamine interacts mainly with postjunctional alpha-adrenoceptors. The miotic effects of topical thymoxamine hydrochloride were measured in normal human eyes using infrared pupillography. The effects of five different concentrations of thymoxamine were measured over time. Time-response and concentration-response relationships were calculated. The maximal pupillary response occurs at 60 min after instillation of the drug and has a half-life of 10 hr. The minimum effective concentration of thymoxamine is 0.01%, and the maximum effective concentration is 1.3%. Thymoxamine's properties could make it a clinically useful drug to diagnose angle-closure glaucoma, and also to reverse drug-induced mydriasis.     

Systematically applied chemicals that damage lung tissue

A large, and increasing number of drugs and chemicals have been found which are toxic to lung following systemic administration. These agents damage lung tissue specifically, or in addition to damage to other tissues. Mechanisms explaining the pulmonary damage produced by some lung toxins have been uncovered. These include concentration of the agent within lung, the absence of adequate pulmonary detoxication systems, and bioactivation to a toxic species within specific lung cells or at distant sites followed by transport to the lung. The basic biochemical lesions underlying lung damage, responses of individual lung cells and pulmonary repair processes to the toxic agent, and species and age differences in susceptibility to lung damage have not, however, been well defined for most lung toxins. This review describes the information available on pulmonary biochemical and pathological changes associated with some of these lung-toxic agents. In addition, mechanisms proposed to explain the lung damage are discussed. The agents covered include: paraquat, the thioureas, butylated hydroxytoluene, the trialkylphosphorothioates, various lung-toxic furans and antineoplastic agents, the pyrrolizidine alkaloids, metals and organometallic compounds, amphiphilic agents, hydrocarbons, oleic acid, 3-methylindole, and diabetogenic agents. Detailed reviews on the overall toxicity of many of these agents have been published elsewhere. This review concentrates on their pulmonary toxicity. Information is presented as an overview to illustrate both the extensive literature that is available and the important questions that remain to be answered about systemic chemicals that damage lung tissue.     

Cardiovascular effects of intrahypothalamic injections of alpha-melanocyte stimulating hormone

Injection of alpha-melanocyte stimulating hormone (alpha-MSH, 0.6-1.2 nmol in 100-300 nl) into the rostral dorsomedial hypothalamic nucleus of the halothane anesthetized rat resulted in a 12% increase in heart rate (41 +/- 4 bpm) which was accompanied by a slight increase in blood pressure (5 +/- 1 mm Hg). The response was characterized by a gradual onset, with a peak increase at 7 +/- 1 min and a duration of 51 +/- 6 min. Tachyphylaxis to the response was apparent for at least 180 min following initial exposure to the peptide. In contrast to the increase in heart rate observed following alpha-MSH injection into the dorsomedial nucleus, injections into the medial preoptic, anterior, paraventricular or posterior hypothalamic nuclei had no significant effects on blood pressure and heart rate. These data suggest a possible role for brain alpha-MSH in the central control of heart rate at a site within the dorsomedial nucleus of the hypothalamus.     

The effect of α-naphthylisothiocyanate on bile secretion prior to and during the onset of cholestasis in the rat

The effect of α-naphthylisothiocyanate (ANIT) on bile flow, erythritol clearance, bile acid excretion and bilirubin excretion was studied in rats. The median time-to-effect (Et50) for the appearance of cholestasis was about 15 h. ANIT failed to exert a gradual effect on bile flow or erythritol clearance before the onset of cholestasis. However, 3 h before complete cessation of bile flow, a rapid decline in bile flow and bile acid excretion was observed. Bile acid-independent flow was markedly reduced. However, the bile acid-dependent component was also affected.     

Uptake and release of [3H]dopamine by the median eminence: evidence for presynaptic dopaminergic receptors and for dopaminergic feedback inhibition

The accumulation and release of [3H]dopamine by the median eminence in vitro was studied after treatments with different pharmacological agents, to determine whether such a procedure would be useful for measuring neuronal activity in the tuberoinfundibular dopaminergic system. The accumulation of [3H]dopamine was temperature, time, and sodium dependent, and reduced by unlabelled dopamine and by a potent dopamine uptake blocker, nomifensine. The outflow of tritium was studied after blocking the oxidative deamination of dopamine by nialamide. The outflow of tritium was elicited consistently by biphasic square wave electrical pulses and by high molarity potassium ions. The response to electrical stimulation was dependent largely on calcium and partially on sodium. The response to high molarity potassium ions was reduced in the absence of calcium ions. The response to electrical stimulation was increased by nomifensine and by a dopaminergic antagonist, haloperidol, and was reduced by dopamine and by a dopaminergic agonist, piribedil. The inhibitory action of dopamine was antagonized by haloperidol. These results indicate the existence of uptake and release mechanisms in the tuberoinfundibular dopamine neurons, and suggest that dopamine may inhibit its own release via dopaminergic receptors. This in vitro method may be useful for measuring dopamine uptake and release by tuberoinfundibular dopaminergic neurons.     

Abnormal production of tumor necrosis factor (TNF) -- alpha and clinical efficacy of the TNF inhibitor etanercept in a patient with PAPA syndrome [corrected

We report a family with pyogenic sterile arthritis, pyoderna and acne syndrome (PAPA). The proband presented several episodes of sterile pyogenic arthritis and became unresponsive to glucocorticoids. After treatment with the tumor necrosis factor inhibitor etanercept, the disease underwent rapid and sustained clinical remission. Production of tumor necrosis factor-alpha by mononuclear cells of the proband and of the affected relatives was abnormally elevated.     

Peripheral inflammatory and fibrinolytic markers in adolescents with growth hormone deficiency: relation to postprandial dyslipidemia

OBJECTIVE: To determine whether peripheral inflammatory and fibrinolytic markers are elevated in growth hormone-deficient (GHD) adolescents and associated with increased postprandial lipoproteins. STUDY DESIGN: Fifteen GHD children on GH treatment with a chronologic age of 12.7 +/- 2.5 years and 10 untreated GHD adolescents with a chronologic age of 13.0 +/- 2.6 years were studied. Triglycerides (TG), C-reactive protein (CRP), fibrinogen, interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) were measured in the fasting state and 4 hours after ingesting a high-fat meal; 15 healthy adolescents served as controls. RESULTS: Fasting and postprandial TG of untreated GHD children were higher than those in treated subjects and healthy controls. Fasting TNF-alpha, CRP, and fibrinogen concentrations of untreated GHD adolescents were higher than those in healthy controls, but similar to those of GH-treated GHD adolescents. Although fibrinogen levels increased after a high-fat meal in GHD adolescents, CRP, TNF-alpha, and IL-6 concentrations did not increase further. Fasting and postprandial TG of untreated GHD adolescents were positively associated with fasting and postprandial CRP, and with postprandial TNF-alpha and IL-6 concentrations. Fasting TG also correlated positively with fasting fibrinogen concentrations in untreated and treated GHD adolescents. CONCLUSIONS: The pronounced inflammatory response seen in GHD adolescents seems to be associated with the presence of elevated levels of fasting and postprandial TG, which may result in an increased susceptibility for premature atherosclerosis.