Neurite outgrowth on muscle cell surfaces involves extracellular matrix receptors as well as Ca2+-dependent and -independent cell adhesion molecules.

To identify the molecules on the neuronal surface that mediate axonal growth on myotubes, we have examined neurite formation by ciliary neurons grown on myotubes in the absence or presence of specific antibodies. Dramatic inhibition of neurite outgrowth was seen only when antibodies blocked simultaneously the functions of two cell adhesion molecules--neural cell adhesion molecule (N-CAM) and neural Ca2+-dependent CAM (N-Cal-CAM)--and the neuronal receptors for several extracellular matrix (ECM) proteins. Although the antibody used to block ECM receptors (JG22) has been shown to eliminate almost all neurite growth on ECMs, it had only small effects on neurite growth on myotubes, reducing somewhat the length of neurites. Similarly, antibodies to the two CAMs, when used alone, had no detectable effects on neurite length and, when used together, had only small inhibitory effects on neurite growth. Combination of anti-ECM receptor (JG22) with antibodies to either CAM, however, greatly shortened the length of neurites. These results imply that ECM receptors and the CAMs N-CAM and N-Cal-CAM are major macromolecules used by neuronal growth cones for interactions with myotubes. Each provides a distinct mechanism for regulating growth cone motility.     

Vasoactive intestinal polypeptide and alpha 2-adrenoceptor agonists regulate adenosine 3',5'-monophosphate accumulation and melatonin release in chick pineal cell cultures

Vasoactive intestinal polypeptide (VIP) has been shown to stimulate melatonin synthesis in mammalian pineal; however, a regulatory role for VIP in the avian pineal has not been explored. Immunocytochemical and physiological response experiments were performed to investigate whether 1) immunoreactive VIP fibers innervated the avian pineal gland; 2) VIP had a specific effect on melatonin release that was mediated by cAMP stimulation; and 3) alpha 2-adrenergic signal transduction was associated with a reduction in cAMP levels. Immunocytochemical experiments demonstrated the presence of both tyrosine hydroxylase- and VIP-immunoreactive fibers in the avian pineal gland. Treatment of dispersed chick pineal cell cultures with VIP stimulated melatonin release (maximum 6-fold increase; EC50 = 1.8 nM) when administered during the 12-h light period of a 12-h light, 12-h dark cycle. Of the other four peptides tested [porcine VIP-(10-28), porcine peptide histidine isoleucine, porcine secretin, and human glucagon), only peptide histidine isoleucine stimulated melatonin release (EC50 = 30 nM). The effect of VIP was mediated by a time- and dose-dependent increase in cAMP accumulation (maximum 4-fold increase). The specific alpha 2-agonist UK-14,304 reduced cAMP accumulation (maximum 43% reduction) and inhibited melatonin release (EC50 = 19 nM) in the presence of 3 X 10(-8) M VIP. Norepinephrine-induced inhibition of nocturnal melatonin release was blocked by the elevation of cAMP achieved through the administration of forskolin (EC50 = 0.2 microM), isobutylmethylxanthine (EC50 = 112 microM), or 8-bromo-cAMP (EC50 = 166 microM). Collectively, these results demonstrate the presence and functional significance of VIP in the avian pineal gland, and the interaction of VIP and norepinephrine at the level of cAMP in the regulation of melatonin biosynthesis.     

Complex ventricular arrhythmias associated with the mitral valve prolapse syndrome. Effectiveness of moricizine (Ethmozine) in patients resistant to conventional antiarrhythmics

On the basis of epidemiologic studies, more than 10 million Americans have echocardiographic evidence of mitral valve prolapse. Although ventricular arrhythmias occur frequently (over 50 percent of patients with mitral valve prolapse), they rarely result in sustained ventricular tachycardia or sudden cardiac death. However, a common problem in clinical practice is a patient with mitral valve prolapse and symptomatic complex ventricular arrhythmias refractory or intolerant to both beta blockers and conventional type I antiarrhythmics. These drugs are known to have frequent side effects, toxicity, and proarrhythmic effects. In 17 patients with mitral valve prolapse who presented with symptomatic complex ventricular arrhythmias and who were unresponsive to an average of the three conventional agents, moricizine (Ethmozine) was effective in suppressing 90 percent of ventricular premature depolarizations, 99 percent of nonsustained runs of ventricular tachycardia, as well as all sustained runs of ventricular tachycardia, resulting in abolition of palpitations, dizziness, and syncopal episodes. Its efficacy as well as its low frequency of minor side effects makes it ideal for future consideration in the population with mitral valve prolapse, who are frequently young and may therefore require therapy for many years.     

Electrophysiology of Ethmozine (moricizine HCl) for ventricular tachycardia

Moricizine HCl, an antiarrhythmic phenothiazine drug, was investigated for its efficacy against ventricular tachycardia (VT) in a group of 60 patients from 8 institutions using electrophysiologic testing before and after oral administration. Moricizine HCl significantly prolonged PR, QRS, AH and HV intervals and cycle length for atrioventricular nodal block, but had minimal or no effect on repolarization or cardiac refractory periods. Induction of sustained VT (in 33 patients) and nonsustained VT (in 14 patients) occurred at baseline. During moricizine HCl therapy, sustained VT was induced in 31 patients and nonsustained VT in 7 patients. In individual patients, suppression of VT induction was obtained in 18% of patients with sustained VT and in 27% of patients with nonsustained VT. Cycle length of induced VT was significantly prolonged by moricizine HCl therapy. During prospective follow-up of 37 patients, electrophysiologic study predicted recurrence of nonrecurrence of VT with a sensitivity value of 82% and specificity of 65%.     

Alcohol and the Woman of Childbearing Age – A Public Health Problem

Recent work has established on a rational basis what has been understood instinctively throughout recorded history – that excessive maternal consumption of alcohol is harmful to the baby developing in utero. From conception onwards, the risk of anomalies of development (mostly minor) and retardation of intrauterine growth increases more or less in proportion to the level of alcohol consumption. Since much of the damage occurs early in pregnancy before most women realise that they are pregnant, the problem of prevention becomes one for the public health field. All professional workers concerned with women of child-bearing age should be aware, therefore, of what the facts are and how to help the woman who may become pregnant to reduce her alcohol intake. They have a dual role to play – detection of those at risk and effective counselling of the patients after their identification.     

Loneliness and its Association with Health Behaviors in People with a Lived Experience of a Serious Mental Illness

To explore the association between loneliness and efficacy to engage in health behaviors that are known to reduce the risk of early mortality in people with serious mental illness (SMI). This secondary data analysis was based on a cross-sectional study of 113 participants with SMI residing in New Hampshire. Ordinary Least Squares regressions were used to examine bivariate relationships between variables of interest. Participants had a primary mental health diagnosis of major depressive disorder (37.2%), schizophrenia spectrum disorder (28.3%), bipolar disorder (29.2%), or posttraumatic stress disorder (5.3%). High levels of loneliness were associated with low levels of self-efficacy to manage chronic diseases (p =?0.0001), as well as low levels of self-efficacy to manage psychological well-being (R² =?.31; F =?9.49, p =?0.0001; RMSE =?1.66). Loneliness may serve as a barrier to healthy behaviors, and thus, contribute to early mortality among people with SMI. The growing body of literature that demonstrates the importance of addressing loneliness in people with SMI should stimulate policymakers and researchers to target loneliness as a mechanism to address early mortality in people with SMI.

     

Targeted Endodontic Microsurgery: Implications of the Greater Palatine Artery

IntroductionTargeted Endodontic Microsurgery (TEMS) combines trephine burs and 3D-printed guides to make flapless maxillary palatal root-end surgery possible. This study assessed the location of the greater palatine artery (GPA), the relationship of the GPA to maxillary molar root ends, and the feasibility of flapless palatal-approach TEMS.MethodsThree endodontists analyzed 250 cone-beam computed tomographic images of maxillary molars for (1) transition morphology between the hard palate and the alveolar process adjacent to first and second molars as an indication of the most likely location of the GPA, (2) the superior-inferior relationship between the GPA and root ends, and (3) the feasibility of palatal-approach TEMS.ResultsPalatal transition morphology included 20% Spine, 72% Bridge, and 8% Smooth. GPA position as related to palatal root ends was classified as 34% superior, 40% adjacent, and 21% inferior. Five percent of classifications were undefined. TEMS was deemed feasible for 47% of maxillary first molars and 52% of second molars, and was significantly more feasible with GPAs superior to palatal root ends. Reasons for infeasibility included GPA proximity and unfavorable resection angle or level. Maxillary first molar palatal roots were 11.13 ± 2.68 mm from the greater palatine foramen (GPF) and 2.37 ± 1.46 mm from the GPA. Second molar palatal roots were 4.94 ± 2.55 mm from the GPF and 2.53 ± 1.77 mm from the GPA.ConclusionsPalatal transition morphology and GPA position adjacent to maxillary molars, as manifested in cone-beam computed tomographic coronal views, suggested maxillary palatal root TEMS could be accomplished with a 2-mm safety margin in 47% of first molars and 52% of second molars. Historical paradigms that do not consider flapless palatal surgical approaches may need to be revised.     

Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury

Ischemia and reperfusion represent major mechanisms of tissue injury and organ failure. The timing of administration and the duration of action limit current treatment approaches using pharmacological agents. In this study, we have successfully developed a preemptive strategy for tissue protection using an adenoassociated vector system containing erythropoietin hypoxia response elements for ischemia-regulated expression of the therapeutic gene human heme-oxygenase-1 (hHO-1). We demonstrate that a single administration of this vector several weeks in advance of ischemia/reperfusion injury to multiple tissues such as heart, liver, and skeletal muscle yields rapid and timely induction of hHO-1 during ischemia that resulted in dramatic reduction in tissue damage. In addition, overexpression of therapeutic transgene prevented long-term pathological tissue remodeling and normalized tissue function. Application of this regulatable system using an endogenous physiological stimulus for expression of a therapeutic gene may be a feasible strategy for protecting tissues at risk of ischemia/reperfusion injury.