Neurotransmitter glutamate: its clinical importance

Excitatory amino acid glutamate has several important functions in the mammalian central nervous system (CNS). This review focuses on the transmitter role of glutamate and discusses anatomical and pharmacological data of clinical neurological relevance. Experimental and clinical conditions which have been associated with altered content, uptake, membrane binding or release of glutamate in the CNS are discussed. Such conditions include, epilepsy, disorders of the basal ganglia, cerebral ischemia, hypoxia, hypoglycemia, metabolic encephalopathies, olivopontocerebellar atrophy and cerebellar ataxias, amino acidopathies, mental and other neurological disorders. With the exception of a few fibre systems, it is very difficult to differentiate between glutamate and aspartate as CNS transmitters. The term glutamate is, thus, used in the sense glutamate and/or aspartate unless specifically stated.     

Analysis of two inbred strains of mice derived from the SENCAR stock with different susceptibility to skin tumor progression

The SENCAR stock of mice has proved to be a useful model in dissecting out the multistage nature as well as the critical mechanisms involved in skin tumorigenesis. This outbred stock was selectively bred to be susceptible to initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). In order to obtain mice more suitable for genetic analyses of tumor susceptibility and tissue transplantation studies, several inbred lines of mice were derived from the SENCAR stock. One of these lines, the SSIN mice, has a higher susceptibility to tumor promotion compared to the SENCAR stock but is very resistant to tumor progression. On the other hand, the SENCAR B/Pt mice, derived also from the outbred stock, not only have a tumor promotion susceptibility almost identical to the SSIN mice, but they also have a high susceptibility to tumor progression. In order to understand the nature of the phenotypic differences between these two inbred lines we have characterized them using several parameters and markers that are associated with the progression of papillomas to squamous cell carcinoma (SCC). In this sense we analysed the tumor multiplicity and SCC incidence, and the expression of markers of progression and cell cycle related proteins in papillomas derived from both strains. Our results showed that while both strains have a similar papilloma multiplicity and incidence the SENCAR B/Pt mice have 67% incidence of SCC, compared to 0% in the SSIN. SENCAR B/Pt papillomas at 30 weeks of promotion have a higher and aberrant expression of K13, and loss of connexin 26. TGF-beta1 was found to be over-expressed in the suprabasal and superficial cells in the SENCAR B/Pt papillomas, while it was only expressed in the superficial cell layer in those derived from SSIN. The SENCAR B/Pt papillomas also showed an enlarged proliferative compartment with overexpression of cyclin D1 and PCNA as seen by immunohistochemistry and Western blot.      

Prognostic factors of status epilepticus in adults

Aim. Status epilepticus (SE) can lead to sequelae or even death. Identifying characteristics associated with poor outcome is crucial in guiding patient treatment. Based on our retrospective patient cohorts, potential prognostic factors were analysed. Methods. Patients consecutively treated for refractory convulsive status epilepticus (CSE) between 2001 and 2010 and non‐convulsive status epilepticus (NCSE) between 2004 and 2009 were studied. Outcome was compared to prognostic variables. Index SE episodes were used for the statistical analyses. Crosstabs and independent samples t‐test were applied. Due to sample size, logistic regression was performed for the combined groups. Results. In total, 50% (9/18) of index refractory CSE and 42% (16/38) of index NCSE episodes led to sequelae. Refractory CSE requiring narcosis for >20 hours was associated with poor outcome (p=0.05). De novo presentation (p=0.0001), long‐lasting SE (>2 hours) (p=0.014), age >65 years (p=0.002), and refractory SE (p=0.047) were predictors of poor outcome following NCSE. Based on logistic regression for combined refractory CSE and NCSE, de novo presentation was identified as the strongest predictor of sequelae. Conclusions. Older age and de novo SE are predictors of sequelae following NCSE. Prolonged SE is a risk factor for poor outcome, both for refractory CSE and NCSE. Aggressive initial treatment to terminate seizures during the early phase is therefore essential.     

Atrial Inhibited Pacing in the Sick Sinus Node Syndrome: Clinical Value and the Demand for Rate Responsiveness

A consecutive series of 66 patients (males = 32; mean age +/- SD = 71 +/- 9 years) given atrial inhibited pacemakers for sick sinus nodes were followed to study the incidence of lead failures, chronic atrial tachyarrhythmias, and atrioventricular conduction disturbances. The need for rate responsive pacing was also assessed. Pre and postoperative investigation could include carotid sinus massage, Holter monitoring, exercise testing, and invasive electrophysiology. The mean follow-up time +/- SD was 32 +/- 29 months (median = 26 months). Three patients (5%) had their pacemakers replaced due to lead failures (loss of sensing = 2; exit block = 1). Two pacemakers (3%) were replaced after 5 and 22 months due to atrial fibrillation. Four patients (6%) received new pacemakers because of development of second-degree or complete atrioventricular block after 1, 6, 12, and 31 months, respectively. During exercise, most patients (76%) responded with an increase in sinus rate at least as marked as that achievable with the currently available rate responsive pacemakers. Assuming careful patient selection, atrial inhibited pacing is well suited for many patients with sinus node dysfunction and preserved atrioventricular conduction. There is a limited need for rate responsive pacemakers in these patients.     

Six-month follow-up of children with obstructive sleep apnoea

OBJECTIVES: This study examined prospectively changes in development, temperament and sleep related behaviour in children referred for obstructive sleep apnoea (OSA) and polysomnographic sleep study, some of whom had surgical intervention. METHODOLOGY: Using a prospective cohort study design, parents of 56 children referred for OSA completed sleep and temperament questionnaires and their child was assessed developmentally at the time of the polysomnographic sleep study. Forty (72%) of the children were neurologically normal. At 6 months, 42 children were reassessed using sleep and temperament questionnaires and a developmental assessment. After excluding the primary snorers, subjects were categorised as having had intervention (n = 24) or not (n = 15), and differences over the 6-month period in Griffiths scores, temperament and sleep related behaviour were examined. RESULTS: Regardless of intervention status, there was an improvement in night-time and day-time sleep behaviour for the total group, though the extent of improvement was more marked in the intervention group. For the neurologically normal children, improvement in the sleep behaviour was only significant for the intervention group (P < 0.05). Intervention did not result in any significant changes in Griffiths developmental score or temperament. CONCLUSION: Surgical intervention improves sleep behaviour in children though not temperament or development.     

Loss of GPER identifies new targets for therapy among a subgroup of ERα-positive endometrial cancer patients with poor outcome

Background:

The G protein-coupled oestrogen receptor, GPER, has been suggested as an alternative oestrogen receptor. Our purpose was to investigate the potential of GPER as a prognostic and predictive marker in endometrial carcinoma and to search for new drug candidates to improve treatment of aggressive disease.

Materials and method:

A total of 767 primary endometrial carcinomas derived from three patient series, including an external dataset, were studied for protein and mRNA expression levels to investigate and validate if GPER loss identifies poor prognosis and new targets for therapy in endometrial carcinoma. Gene expression levels, according to ERα/GPER status, were used to search the connectivity map database for small molecular inhibitors with potential for treatment of metastatic disease for receptor status subgroups.

Results:

Loss of GPER protein is significantly correlated with low GPER mRNA, high FIGO stage, non-endometrioid histology, high grade, aneuploidy and ERα loss (all P-values ⩽0.05). Loss of GPER among ERα-positive patients identifies a subgroup with poor prognosis that until now has been unrecognised, with reduced 5-year survival from 93% to 76% (P=0.003). Additional loss of GPER from primary to metastatic lesion counterparts further supports that loss of GPER is associated with disease progression.

Conclusion:

These results support that GPER status adds clinically relevant information to ERα status in endometrial carcinoma and suggest a potential for new inhibitors in the treatment of metastatic endometrial cancers with ERα expression and GPER loss.     

A comparison of three questionnaires (EAT-12, EDI,and EDE-Q) for assessment of eating problems in healthy female adolescents

On the basis of the restraint theory and the continuum hypothesis of eating disorders, the objective of this paper was twofold. First, subjects who, on the basis of items from the Eating Disorder Examination Questionnaire (EDE-Q) which are generated from DSM-III-R diagnostic criteria, fulfilled the diagnostic criteria for anorexia nervosa (AN) and bulimia nervosa (BN) were identified. Second, differences in scale scores between a case group and a non-case group were tested, and case group distribution of the two self-report questionnaires Eating Attitudes Test (EAT-12) and Eating Disorder Inventory (EDI) was compared as a means for investigating the sensitivity of the instruments in detecting eating disorder cases. In a classroom setting 224 8th-grade female students from 5 schools in western Norway completed the questionnaires. The responses to the questionnaires were analysed by case group and instrument/subscales by using the t test, Cohen's d-values, eta squared statistic, point biserial correlation, and two-way ANOVA. No BN cases and 10 AN cases were identified. AN cases scored significantly higher on all measures of eating problems than normal subjects and differed most from non-cases on the "dieting" dimension. Clinical implications are discussed in the light of screening.