Kinase-dependent regulation of the secretion of thyrotrophin and luteinizing hormone by glucocorticoids and annexin 1 peptides

Our previous studies have identified a role for annexin 1 (ANXA1), a protein produced by the pituitary folliculostellate cells, as a paracrine/juxtacrine mediator of the acute regulatory effects of glucocorticoids on the release of adrenocorticotropic hormone and other pituitary hormones. In the present study, we focused on the secretion of thyroid stimulating hormone (TSH) and luteinizing hormone (LH) and used a battery of ANXA1-derived peptides to identify the key domains in the ANXA1 molecule that are critical to the inhibition of peptide release. In addition, as ANXA1 is a substrate for protein kinase C (PKC) and tyrosine kinase, we examined the roles of these kinases in the manifestation of the ANXA1-dependent inhibitory actions of dexamethasone on TSH and LH release. Dexamethasone suppressed the forskolin-induced release of TSH and LH from rat anterior pituitary tissue in vitro. Its effects were mimicked by human recombinant ANXA1 (hrANXA1) and a truncated protein, ANXA1(1-188). ANXA1(Ac2-26), also suppressed stimulated peptide release but it lacked both the potency and the efficacy of the parent protein. Shorter N-terminal ANXA1 sequences were without effect. The PKC inhibitor PKC(19-36) abolished the inhibitory actions of dexamethasone on the forskolin-evoked release of TSH and LH; it also attenuated the inhibitory actions of ANXA1(Ac2-26). Similar effects were produced by annexin 5 (ANXA5) which sequesters PKC in other systems. By contrast, the tyrosine kinase inhibitors, p60v-src (137-157) and genistein, had no effect on the secretion of TSH or LH alone or in the presence of forskolin and/or dexamethasone. Dexamethasone caused the translocation of a tyrosine-phosphorylated species of ANXA1 to the surface of pituitary cells. The total amount of ANXA1 exported from the cells in response to the steroid was unaffected by tyrosine kinase blockade. However, the degree of tyrosine-phosphorylation of the exported protein was markedly reduced by genistein. These results suggest that (i) the ANXA1-dependent inhibitory actions of dexamethasone on the release of TSH and LH require PKC and sequences in the N-terminal domain of ANXA1, but are independent of tyrosine kinase, and (ii) while dexamethasone induces the cellular exportation of a tyrosine-phosphorylated species of ANXA1, tyrosine phosphorylation per se is not critical to the steroid-induced passage of ANXA1 across the membrane.     

Peripubertal changes in the nature of the GnRH response to alpha-adrenoceptor stimulation in vitro and their modulation by testosterone

Adrenergic mechanisms have been widely implicated in the regulation of GnRH secretion in adult rats but their role in young animals, in which the activity of the GnRH neurones is minimal, is unclear. These experiments were done to examine the effects of alpha-adrenoceptor stimulation on the secretion in vitro of GnRH by hypothalami from immature and adult male rats. The alpha 1-adrenoceptor agonist, phenylephrine (10(-9) - 10(-7) M), stimulated release of GnRH from hypothalami from adult (200 g) and peripubertal (150 g) rats but inhibited markedly the secretion of the releasing factor from the limited stores available in hypothalami from immature (50 or 100 g) rats. The stimulatory and inhibitory responses to phenylephrine, evident in adult and younger rats respectively, were concentration-dependent and antagonized readily by the selective alpha 1-adrenoceptor antagonist, alfuzosin (10(-6) M), but not by the beta-adrenoceptor antagonist, propranolol (10(-6) M). Hypothalami from 14-day castrated adult rats, in which the serum LH was elevated and hypothalamic GnRH content reduced, responded to alpha 1-adrenoceptor stimulation in vitro, like those from immature rats, with a marked reduction in GnRH release. In contrast, hypothalami from corresponding castrates bearing testosterone implants, which maintained the hypothalamic GnRH content and serum LH and testosterone concentrations at levels similar to those of intact controls, exhibited the normal 'adult' response to phenylephrine. Studies utilizing 3H-prazosin indicated that the number (Bmax) of hypothalamic alpha 1-adrenoceptor binding sites increases at puberty but that receptor affinity (KD) is unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neurogenic Stuttering: Its Reticular Modulation

Emerging neurologic evidence has suggested that developmental and acquired stuttering may have a cerebral base. Investigations have revealed compensatory activation in the right cortical motor areas and deactivation in the left perisylvian region in subjects with persistent developmental stuttering. The evidence has also implicated limbic (cingulate)-basal ganglia regions. Increased speech fluency with treatment in such subjects eliminated compensatory brain activity and shifted activation back to the left hemisphere. We assess the neurology of stuttering and then present our own observations of deep brain stimulation of the thalamus with some ameliorating effect on the encompassing syndrome with speech dysfluency.     

Hyperacuity thresholds for oscillatory movement are abnormal in strabismic and anisometropic amblyopes.

The hyperacuity performance of amblyopic individuals is known to be abnormal, particularly on vernier tasks. Oscillatory movement displacement thresholds (OMDT's) a form of hyperacuity, were investigated over a range of temporal frequencies (1, 4, 7, 10, and 13 Hz) in 8 normal controls, 5 strabismic amblyopes, and 4 anisometropic amblyopes to see if this form of hyperacuity was also affected by amblyopia. OMDT's were found to be significantly raised in all of the strabismic amblyopes and three of the four anisometropes over all temporal frequencies investigated when compared to the control group. In the fourth anisometrope, OMDT's were raised at low temporal frequencies only. The findings are interpreted as evidence that magnocellular and parvocellular channels are affected in the amblyopic visual system. The functional loss in amblyopia cannot be described completely unless both temporal and spatial thresholds are investigated.     

Survival prediction in terminal cancer patients: a systematic review of the medical literature

The clinical significance of studies on survival predictors in terminal cancer patients is hindered by both methodological limitations and the difficulty of finding common predictors for all final events in cancer related deaths. To evaluate the published medical literature concerned with the survival of patients with terminal cancer and identify potential prognostic factors, major electronic databases including MEDLINE (1966-), CANCERLIT (1983-) and EMBASE (1988-) were searched up to September 1999. Studies were included in our review if published in English, were cohort studies, addressed the identification of clinical prognostic factors for survival and looked at samples with median survival of < or = 3 months. Data extracted from selected papers included: sample size, median survival, type of study, sampling frame, cohort type, type of statistical analysis (univariate or multivariate), choice of models and underlying assumptions, predictors examined and their reported level of statistical significance. A total of 24 studies were found and reviewed. On the basis of these studies, performance status and the presence of cognitive failure, weight loss, dysphagia, anorexia and dyspnoea appear to be independent survival predictors in this population. Clinical estimation of survival by the treating physician appeared independently associated with survival but the magnitude of the association generally appeared small. Clinical predictions should be considered as one of many criteria, rather than as a unique criterion by which to choose therapeutic interventions or health care programmes for terminally ill cancer patients. The use of convenient samples as opposed to more representative inception cohorts, the inclusion of different variables in the statistical analyses and inappropriate statistical methods appear to be major limitations of the reviewed literature. Methodological improvements in the design and conduction of future studies may reduce the prognostic uncertainty in this population.     

Toluene-diisocyanate induced asthma: evaluation of antibodies in the serum of affected workers against a tolyl mono-isocyanate protein conjugate

Radioallergosorbent testing was used to look for the presence of specific IgE antibody against a para-tolyl-mono-isocyanate human serum albumin conjugate in sera from five groups of subjects. The first three groups consisted of individuals exposed to toluene diisocyanate (TDI) who had been shown by bronchial provocation testing with levels of TDI below the threshold limit value of 0.02 parts/10(6), to have immediate asthmatic reactions, late asthmatic reactions or no respiratory changes at all. The two control groups consisted of atopic and non-atopic individuals who had no respiratory symptoms and no known exposure to TDI. Although RAST showed high ct/min in some of the sera from patients with proven TDI-induced respiratory disease, these levels were not significantly different from controls and appeared to reflect the presence in these sera of high levels of total IgE (greater than 100 mu ml--1). There is no evidence from this study for the presence of specific IgE antibody against a para-tolyl mono isocyanate human serum albumin conjugate in patients with TDI-induced respiratory disease. This finding may reflect absence of antibodies, or that the techniques for their detection are not always effective even when performed by experienced persons, and there is a potential source of error in the interpretation of results when sera contain large amounts of IgE.     

A pre-operative clinical scoring system to distinguish perforation risk with pediatric appendicitis

Importance

Appendicitis is a common, potentially serious pediatric disease. An important factor in determining management strategy [whether/when to perform appendectomy, duration of antibiotic therapy/hospitalization, etc.] and predicting outcome is distinguishing whether perforation is present.