The nutritive function of glia is regulated by signals released by neurons

The idea of a metabolic coupling between neurons and astrocytes in the brain has been entertained for about 100 years. The use recently of simple and well-compartmentalized nervous systems, such as the honeybee retina or purified preparations of neurons and glia, provided strong support for a nutritive function of glial cells: glial cells transform glucose to a fuel substrate taken up and used by neurons. Particularly, in the honeybee retina, photoreceptor-neurons consume alanine supplied by glial cells and exogenous proline. NH₄⁺ and glutamate are transported into glia by functional plasma membrane transport systems. During increased activity a transient rise in the intraglial concentration of NH₄⁺ or of glutamate causes a net increase in the level of reduced nicotinamide adenine dinucleotides [NAD(P)H]. Quantitative biochemistry showed that this is due to activation of glycolysis in glial cells by the direct action of NH₄⁺ and of glutamate, probably on the enzymatic reactions controlled by phosphofructokinase alanine aminotransferase and glutamate dehydrogenase. This activation leads to a massive increase in the production and release of alanine by glia. This constitutes an intracellular signal and it depends upon the rate of conversion of NH₄⁺ and of glutamate to alanine and α-ketoglutarate, respectively, in the glial cells. Alanine and α-ketoglutarate are released extracellularly and then taken up by neurons where they contribute to the maintenance of the mitochondrial redox potential. This signaling raises the novel hypothesis of a tight regulation of the nutritive function of glia. GLIA 21:84–91, 1997. © 1997 Wiley-Liss, Inc.     

Different genetic pathways to proximal and distal colorectal cancer influenced by sex-related factors

Mutations in the k-ras and TP53 genes, as well as microsatellite instability (MIN), are frequent genetic alterations in colorectal carcinomas and represent 3 different mechanisms in the carcinogenic process. Both the incidence of colorectal cancer and the frequency of genetic alterations in such tumours have been related to different clinico-pathological variables, including age and gender of the patient and location of the tumour. A number of studies have also reported associations between different types of genetic alterations. We therefore wanted to explore the relationship between these genetic and clinico-pathological variables using multivariate analysis on material from 282 colorectal carcinomas. Three logistic regression models were constructed: 1) the presence of K-ras mutations was dependent on MIN and age and gender of patient, with an especially low frequency among younger males and in tumours with MIN (overall p = 0.0003); 2) the presence of TP53 mutations was only dependent on tumour location, with a positive association to cancers occurring distally (p = 0.002); and 3) the presence of MIN was dependent on age, gender and K-ras and TP53 mutations, as well as on tumour location. MIN was most frequent among younger male and older female patients, was rare in tumours with K-ras or TP53 mutations and was found almost exclusively in the proximal colon (overall p < 0.0001). Our data confirm that different genetic pathways to colorectal cancer dominate in the proximal and distal segments of the bowel and suggest that the K-ras- and MIN-dependent pathways are influenced by different sex-related factors. Int. J. Cancer 74:664–669, 1997.© 1997 Wiley-Liss, Inc.     

Microsatellite instability in cervical and endometrial carcinomas

Microsatellite instability has been found preferentially in tumours associated with the hereditary non-polyposis-colorectal-cancer (HNPCC) syndrome. This phenotype, manifested as new alleles at microsatellite loci, and often the result of a defective mismatch-repair gene, is seen as allelic mobility shifts during electrophoretic runs. We examined possible alterations at 8 dinucleotide loci mapping to 6 different chromosomes in endometrial cancers (n = 20) and cervical cancers (n = 82). Overall instability was found in 30% of the endometrial cancers and in 6% of the cervical cancers, including 3 (15%) and 2 (2%) tumours, respectively, unstable at more than one locus. In contrast to the endometrial cancer sub-group, the affected cervical cancers were characterized by one or two new alleles at one or few loci. By DNA ploidy measurements 5 diploid endometrial cancers were microsatellite-unstable vs. one diploid of 6 unaltered cases (p = 0.015; Fisher's exact test). Our data confirm that a sub-set of diploid sporadic endometrial cancers are characterized by a mutator phenotype similar to that found in colorectal cancer. In contrast, among cervical cancers, not characterized by the HNPCC-tumour spectrum, this mutator phenotype is seen infrequently, and positive cases appear to display only minor alterations. Int. J. Cancer 70:499–501. © 1997 Wiley-Liss Inc.     

Interaction between bcl-2 and p21 (WAF1/CIP1) in breast carcinomas with wild-type p53

The bcl-2 protein is found to be over-expressed in many types of human tumours and is a potent inhibitor of apoptosis. The exact mechanism by which bcl-2 prevents apoptosis and exercises its oncogenic effect is still unclear. Other studies on cell lines have reported that bcl-2 over-expression is related to suppression of p21 (WAF1/CIP). We have investigated the relationship between bcl-2 protein over-expression and expression of the p21 protein in a series of human breast carcinomas. Selected tumour samples from 100 breast-cancer patients (38 with abnormal p53 status, scored as protein accumulation and/or mutation, and 62 without detectable p53 alterations), were immunostained for bcl-2 protein, the p21 protein and the oestrogen-receptor (ER) protein. A highly significant association was found between reduced p21-protein expression and over-expression of bcl-2 in tumours with no detectable p53 alterations (p < 0.001). A significant association was seen between ER immunoreactivity and expression of the bcl-2 protein, as well as between bcl-2 protein expression and tumours of the higher differentiation grade (grade-2 tumours). No association was seen between bcl-2 over-expression and the presence of metastases. Our findings indicate that down-regulation of p21 may be a result of up-regulation of bcl-2 independent of p53. Int. J. Cancer 73:38–41, 1997. © 1997 Wiley-Liss, Inc.     

EFFECT OF VESTIBULAR REHABILITATION ON CHANGE IN HEALTH-RELATED QUALITY OF LIFE IN PATIENTS WITH DIZZINESS AND BALANCE PROBLEMS AFTER TRAUMATIC BRAIN INJURY: A RANDOMIZED CONTROLLED TRIAL

ObjectiveSecondary analysis, testing the effect on change in health-related quality of life of group-based vestibular rehabilitation in patients with mild-moderate traumatic brain injury, dizziness and balance problems.DesignA single-blind randomized controlled trial.SubjectsA total of 65 patients aged 16–60 years with a Rivermead Post-concussion Symptoms Questionnaire dizziness score ≥2, and DizzinessHandicap Inventory score >15 points. Data collection was performed at baseline 3.5 (standard deviation (SD) 2.1) months post-injury, end of intervention, and 4.4 (SD 1.0) months after baseline.MethodsQuality of Life after Brain Injury was the main outcome. Independent variables were demographic and injury variables, Hospital Anxiety and Depression Scale, changes on the Rivermead Post-concussion Symptoms Questionnaire (RPQ3 physical and RPQ13 psychological/cognitive), and Vertigo Symptom Scale-Short Form.ResultsMean age of participants was 39.4 years (SD 13.0); 70.3% women. Predictors of change inthe Quality of Life after Brain Injury were receiving the vestibular rehabilitation (p =0.049), baseline psychological distress (p =0.020), and changein RPQ3 physical (p =0.047) and RPQ13 psychological/cognitive (p =0.047). Adjusted R2 was 0.399,F=6.13, p < 0.001.ConclusionThere was an effect in favour of the intervention group in improvement in health-related quality of life. Changes on the Rivermead Post-concussion Symptoms Questionnaire were also associated with change on the Quality of Life after Brain Injury.LAY ABSTRACTThis paper is the first to present results of a vestibular rehabilitation intervention study on changes in health-related quality of life in patients with dizziness and balance problems after mild-to-moderate traumatic brain injury. The intervention group received exercises and guidance aimed at self-efficacy and how to cope with their dizziness and balance problems. In addition, both the intervention and control groups received treatment as usual, comprising multidisciplinary rehabilitation at a university hospital. The main result was measured as change on the Quality of Life after Brain Injury questionnaire. Post-concussion symptoms, vertigo and psychological distress were also measured. The study showed that the group receiving the vestibular rehabilitation intervention underwent more improvement in health-related quality of life than the group receiving usual treatment alone. Other factors that influenced the improvement in quality of life were psychological distress at the start of the study and fewer post-concussion symptoms.Key words: quality of life, traumatic brain injury, dizziness, randomized controlled trial, psychological distress, patientreported outcome measure

Sustaining a traumatic brain injury (TBI) affects patients’ functioning and health-related quality of life (HRQL) (1). TBI is defined as an alteration in brain function, or other evidence of brain pathology, caused by an external force (2). Research shows that HRQL is often reduced after a TBI, independent of the severity of the injury (3). Problems in cognitive, emotional, or physical functioning are associated with HRQL after TBI (4). Systematic reviews emphasize the multifactorial aetiology of post-concussion syndrome/symptoms (PCS), and that pre- and post-injury mental health are predictors of post-injury functioning after mild TBI (5, 6). Furthermore, both psychological and physical post-concussion symptoms, including dizziness, show significant correlation with the physical and mental aspects of HRQL (7).Dizziness is a subjective experience that is often described as vertigo and balance problems, or lightheadedness and disorientation (8). The aetiology of dizziness after a TBI can be caused by injuries in the vestibular system (9, 10), or have a non-vestibular origin (10). Zeldovich et al. found that 46% of patients with mild or moderate TBI and persistent PCS experienced dizziness post-injury and, at 6 months post-injury, dizziness was reported by approximately 30% of patients with complicated mild TBI (4). After 1 year, dizziness was reported in 25% of patients (11). Challenges caused by dizziness may hamper return to physical activities and work and increase the patients’ perception of post-concussion symptom pressure (12). There is, however, a lack of intervention studies on dizziness and balance problems after TBI (13). We have shown previously that self-reported dizzinessrelated disability, measured by the Dizziness Handicap Inventory (DHI), is associated with vertigo symptoms, balance problems, and psychological distress (14). These findings showed that a group-based adjusted programme for vestibular rehabilitation (VR) had an immediate, but not long-term, effect on dizzinessrelated disability (15). However, to our knowledge, there are no studies into how HRQL is affected in the subgroup of the TBI population having dizziness and balance problems.The current study reports results for HRQL from a randomized controlled trial (RCT) that tested the efficacy of an individually modified, group-based VR intervention designed specifically for reducing dizziness and balance problems after TBI (15, 16). It is not known how HRQL change was in this subgroup of patients with TBI, and whether injury-related factors and changes in post-injury functioning had an effect on change in HRQL reported on a TBI-specific outcome measure. Hence, the main objectives of this secondary analysis of a RCT was to test the effect on changes in HRQL of a group-based VR programme in addition to routine multidisciplinary rehabilitation on patients with mild-to-moderate TBI and dizziness and balance problems. Secondarily, the current study aimed to describe the HRQL over time. It was hypothesized that mental health at baseline, improved persistent PCS and functioning, and reduced dizziness would have significant positive effects on changes in HRQL, and that the intervention group would show significantly more improvement in HRQL than the control group.     

Evaluation of 12 Commercial Tests for Detection of Epstein-Barr Virus-Specific and Heterophile Antibodies

Ten microbiological departments in Norway have participated in a multicenter evaluation of the following commercial tests for detection of Epstein-Barr virus (EBV)-specific and heterophile antibodies: CAPTIA Select viral capsid antigen (VCA)-M/G/EBNA (Centocor Inc.), Enzygnost anti-EBV/immunoglobulin M (IgM) and IgG (Dade Behring), Vironostika EBV VCA IgM/IgG/EBNA enzyme-linked immunosorbent assay (ELISA) (Organon Teknika), SEROFLUOR immunofluorescence assay and EBV Combi-Test (Institute Virion Ltd.), anti-EBV recombinant IgM- and IgG-early antigen/EBNA IgG ELISA (Biotest Diagnostics), EBV IgM/IgG/EBNA ELISA (Gull Laboratories), Paul-Bunnell-Davidsohn test (Sanofi Diagnostics Pasteur), Monosticon Dri-Dot (Organon Teknika), Avitex-IM (Omega Diagnostics Ltd.), Alexon Serascan infectious mononucleosis test (Alexon Biomedical Inc.), Clearview IM (Unipath Ltd.), and Cards±OS Mono (Pacific Biotech, Inc.). The test panel included sera from patients with primary EBV infection, immunocompromised patients with recent cytomegalovirus infection, healthy persons (blood donors), and EBV-seronegative persons. Among the tests for EBV-specific antibodies the sensitivity was good, with only small differences between the different assays. However, there was a greater variation in specificity, which varied between 100% (Enzygnost) and 86% (Biotest). Tests for detection of heterophile antibodies based on purified or selected antigen (Avitex, Alexon, Clearview IM, and Cards±OS Mono) were more sensitive than the Paul-Bunnell-Davidsohn and Monosticon tests.     

Invasive Ability of an Escherichia coli Strain Isolated from the Ileal Mucosa of a Patient with Crohn’s Disease

Crohn's disease (CD) is an inflammatory bowel disease in which Escherichia coli strains have been suspected of being involved. We demonstrated previously that ileal lesions of CD are colonized by E. coli strains able to adhere to intestinal Caco-2 cells but devoid of the virulence genes so far described in the pathogenic E. coli strains involved in gastrointestinal infections. In the present study we compared the invasive ability of one of these strains isolated from an ileal biopsy of a patient with CD, strain LF82, with that of reference enteroinvasive (EIEC), enteropathogenic (EPEC), enterotoxigenic (ETEC), enteraggregative (EAggEC), enterohemorrhagic (EHEC), and diffusely adhering (DAEC) E. coli strains. Gentamicin protection assays showed that E. coli LF82 was able to efficiently invade HEp-2 cells. Its invasive level was not significantly different from that of EIEC and EPEC strains (P > 0.5) but significantly higher than that of ETEC (P < 0.03), EHEC (P < 0. 005), EAggEC (P < 0.004) and DAEC (P < 0.02) strains. Strain LF82 also demonstrated efficient ability to invade intestinal epithelial cultured Caco-2, Intestine-407, and HCT-8 cells. Electron microscopy examination of infected HEp-2 cells revealed the presence of numerous intracellular bacteria located in vacuoles or free in the host cell cytoplasm. In addition, the interaction of strain LF82 with epithelial cells was associated with the elongation of microvillar extensions that extruded from the host cell membranes and engulfed the bacteria. This internalization mechanism strongly resembles Salmonella- or Shigella-induced macropinocytosis. The use of cytochalasin D and colchicine showed that the uptake of strain LF82 by HEp-2 cells was mediated by both an actin microfilament-dependent mechanism and microtubule involvement. In addition, strain LF82 survived for at least 24 h in HEp-2 and Intestine-407 cells and efficiently replicated intracellularly in HEp-2 cells. PCR and hybridization experiments did not reveal the presence of any of the genetic determinants encoding EIEC, EPEC, or ETEC proteins involved in bacterial invasion. Thus, these findings show that LF82, which colonized the ileal mucosa of a patient with CD, is a true invasive E. coli strain and suggest the existence of a new potentially pathogenic group of E. coli, which we propose be designated adherent-invasive E. coli.     

Small Animal Inhalation Chambers and the Significance of Dust Ingestion from the Contaminated Coat when Exposing Rats to Zinc Chromate

Abstract The relative significance of dust ingestion during and after short-term inhalation exposure to a zinc chromate aerosol has been studied. Two groups of rats were exposed in the same dust cloud, one in open wire cages and the other in fiber glass tubes. The chromium excretion during the following 2¹/₂ days was 8.4 times higher in faeces and 5.5 times higher in urine in the animals exposed in cages, compared with those exposed in tubes.