Clinical and functional investigation of 10 missense mutations and a novel frameshift insertion mutation of the gene for copper-zinc superoxide dismutase in UK families with amyotrophic lateral sclerosis

Mutations of the gene SOD-1, which encodes the enzyme copper-zinc superoxide dismutase, occur in patients with a familial form of amyotrophic lateral sclerosis (ALS). We investigated 71 families with more than one individual affected by ALS for clinical features and SOD-1 mutations. Mutations were identified in 14 families, indicating the presence of SOD-1 mutations in around 20% of this population. There were 10 different heterozygote missense point mutations in eight different codons, and a novel two-base frameshift insertion (132insTT), which leads to substitution of aspartic acid for glutamic acid at codon 132, and a premature stop codon at 133, with predicted truncation of the protein. SOD enzyme activity was reduced to around 50% of normal in individuals with SOD-1 mutations, and may be a useful predictor for the presence of these mutations. A predilection for disease onset in the lower limbs appears to be a distinguishing feature of familial ALS with SOD-1 mutations, and accords with findings in transgenic mouse models. In general, the finding of an SOD-1 mutation does not accurately predict a prognosis or disease severity.     

Effects of sleep on wake-induced c-fos expression

We investigated the effects of sleep on wake-induced c-fos expression in the cerebral cortex of rats and c-fos-lacZ transgenic mice. In the cortex of rats, the levels of c-Fos, detected both by immunocytochemistry and Western blot, remained high during 6 or 12 hr of enforced wakefulness but declined rapidly (within 1 hr) with increasing time of recovery sleep. Similarly, in the transgenic mice in which lacZ expression is driven from the c-fos promoter, beta-galactosidase activity was high after enforced wakefulness and declined with increasing amounts of sleep. These results suggest that the decrease in c-Fos protein in cortical neurons during sleep may be attributable to cessation of c-fos expression, activation of a process that degrades the wake-induced c-Fos, or both.     

Misoprostol in the treatment of chronic refractory constipation: results of a long-term open label trial

BACKGROUND: Misoprostol is known to be effective in stimulating intestinal transit both in healthy individuals and in patients with chronic constipation when evaluated in short-term trials. The aim of this study was to determine the utility of misoprostol in the long-term management of patients with chronic refractory constipation. METHODS: Eighteen patients were offered misoprostol (600-2400 microg/day) as adjunctive therapy in an open-ended, non-blinded trial. All patients were encouraged to continue the drug for a minimum of 4 weeks, after which time the effect on bowel movement patterns was evaluated and continued use of misoprostol was offered to those patients who demonstrated a clinical benefit. RESULTS: Six patients withdrew prior to 4 weeks because of side-effects. In the 12 patients who continued the treatment and were evaluated at 4 weeks, the mean interval between bowel movement frequency had decreased from a baseline of 11.25 to 4.8 days (P = 0.0004). Eight patients continued the long-term treatment, with sustained response seen in six. In a subset of patients (n = 4) the effect of single-dose misoprostol (400 microg) was evaluated compared to healthy controls (n = 5) on post-prandial segmental colonic motility. Misoprostol augmented the colonic motility response to a meal throughout the colon, and this was significantly greater in the left versus right colonic segments (P < 0.05). CONCLUSIONS: Misoprostol can be effective as part of the long-term medical treatment of patients with chronic refractory constipation, but side-effects are observed at higher doses and can be a limiting factor. Part of misoprostol's action may be mediated through the augmentation of colonic motility, particularly of the left colon.     

Diagnosis and treatment of pustular disorders in the neonate

The analytical result of a laboratory examination is a scientific fact and has no medical meaning as such. It must be interpreted to become a medical finding. To explain the very complex cognitive procedure of the interpretation a three-level model is used. In an environment of cost containment in health care systems the quality of medical laboratory findings is very important. Analytical results are monitored by quality control procedures. For measuring the performance of medical findings the concept of the 'validity' of a laboratory test is used. Validity means the 'degree of achieving the objective'. Accordingly, a valid laboratory finding is one which correctly answers the question which the physician at the sick-bed directs to the laboratory. Quantitative measures for the validity of interpretation can be developed by an analysis of the underlying classification processes. Characteristic indices describing the validity quantitatively in terms of conditional probabilities can be derived from decision tables. Examples of 'validity indices' are diagnostic (or prognostic) 'sensitivity' and 'specificity'. These indices are powerful tools for developing strategies for the clinical use of laboratory examinations in diagnosis, prognosis and therapy management. Moreover, validity indices are appropriate output quantities for the estimation of effectiveness and efficiency of a diagnostic or prognostic examination.     

Ocular fixation control as a function of age and exposure duration.

[Correction Notice: An erratum for this article was reported in Vol 3(1) of Psychology and Aging (see record 2008-10694-001). In the aforementioned article, the following corrections should be made: 1. The title of Table 1 should be changed to Mean Bivariate Areas (min-arc2) and Mean Horizontal and Vertical Standard Deviations (min-arc) of Fixations of Older and Younger Groups. 2. The equation on page 304 should have used the natural log rather than the log base 10. The corrected equation is provided in the erratum.] In previous work we reported that fixation stability did not deteriorate in older adults over relatively long viewing durations. In the present study we reanalyzed the data to examine potential aging effects on fixational control for viewing durations typically used in psychological experimentation. Monocular eye movements were recorded in 12 older and 12 younger observers using a dual Purkinje image technique, while observers fixated a stationary target. The two-dimensional scatter of eye positions was measured during nine viewing durations ranging from 100 ms to 12.8 s. Fixational control of the two groups was comparable at all of the viewing durations. Both younger and older observers were able to maintain fixation within an area several times smaller than the size of the fovea. Implications for aging studies that use briefly presented visual stimuli are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Distinct ontogeny of glucocorticoid and mineralocorticoid receptor and 11beta-hydroxysteroid dehydrogenase types I and II mRNAs in the fetal rat brain suggest a complex control of glucocorticoid actions

Glucocorticoids (GCs) act via intracellular mineralocorticoid (MR) and glucocorticoid receptors (GR). However, it has recently been recognized that GC access to receptors is determined by the presence of tissue-specific 11beta-hydroxysteroid dehydrogenases (11beta-HSDs) that catalyze the interconversion of active corticosterone and inert 11-dehydrocorticosterone. 11beta-HSD type 1 (11beta-HSD1) is a bidirectional enzyme in vitro that acts predominantly as a reductase (regenerating corticosterone) in intact neurons. In contrast, 11beta-HSD type 2 (11beta-HSD2) is a higher affinity exclusive dehydrogenase that excludes GCs from MR in the kidney, producing aldosterone-selectivity in vivo. We have examined the ontogeny of 11beta-HSD mRNAs and enzyme activity during prenatal brain development and correlated this with GR and MR mRNA development. These data reveal that (1) 11beta-HSD2 mRNA is highly expressed in all CNS regions during midgestation, but expression is dramatically reduced during the third trimester except in the thalamus and cerebellum; (2) 11beta-HSD2-like activity parallels closely the pattern of mRNA expression; (3) 11beta-HSD1 mRNA is absent from the CNS until the the third trimester, and activity is low or undectectable; and (4) GR mRNA is highly expressed throughout the brain from midgestation, but MR gene expression is absent until the last few days of gestation. High 11beta-HSD2 at midgestation may protect the developing brain from activation of GR by GCs. Late in gestation, repression of 11beta-HSD2 gene expression may allow increasing GC activation of GR and MR, permitting key GC-dependent neuronal and glial maturational events.