Autophagy induced by Alexander disease-mutant GFAP accumulation is regulated by p38/MAPK and mTOR signaling pathways

Glial fibrillary acidic protein (GFAP) is the principle intermediate filament (IF) protein in astrocytes. Mutations in the GFAP gene lead to Alexander disease (AxD), a rare, fatal neurological disorder characterized by the presence of abnormal astrocytes that contain GFAP protein aggregates, termed Rosenthal fibers (RFs), and the loss of myelin. All GFAP mutations cause the same histopathological defect, i.e. RFs, though little is known how the mutations affect protein accumulation as well as astrocyte function. In this study, we found that GFAP accumulation induces macroautophagy, a key clearance mechanism for prevention of aggregated proteins. This autophagic response is negatively regulated by mammalian target of rapamycin (mTOR). The activation of p38 MAPK by GFAP accumulation is in part responsible for the down-regulation of phosphorylated-mTOR and the subsequent activation of autophagy. Our study suggests that AxD mutant GFAP accumulation stimulates autophagy, in a manner regulated by p38 MAPK and mTOR signaling pathways. Autophagy, in turn, serves as a mechanism to reduce GFAP levels.     

Diminished concentrations of insulin-like growth factor I in cystic fibrosis

Cystic fibrosis is frequently accompanied by a catabolic condition with low body mass index caused by a number of disease complications. Insulin-like growth factor-I (IGF-I) is an anabolic hormone and an important marker of nutritional status, liver function, and linear growth. Available data on IGF-I in cystic fibrosis are sparse and conflicting. From 1990-3, 235 of our 240 patients (114 males, 121 females, median age 16.2 years, ranged 0.1-44.0 years) had IGF-I measured once by radioimmunoassay. IGF-I was significantly reduced compared with a healthy Scandinavian control population: mean (-2 SD to +2 SD) IGF-I SD score was -0.97 (-3.7 to 1.7) in males and -0.67 (-3.2 to 1.9) in females. Height SD score was -0.95 (-3.3 to 1.4) in males and -0.81 (-3.2 to 1.6) in females. In patients who were still in the growth period a significant correlation of IGF-I SD score to height SD score (r = 0.28, p < 0.001) was found. The low IGF-I concentrations may reflect the catabolic state of many patients with cystic fibrosis and play a part in their abnormal growth pattern.     

Timing hormonal therapy in prostate cancer

The history of the use of hormonal therapy to treat prostrate cancer is outlined, focusing on such treatments and disease scenarios as diethylstilboestrol therapy, androgen ablation alone or in conjunction with radiation, and the treatment of minimal disease burdens. Studies have pointed to the benefits of initiating androgen ablation therapy earlier in the treatment of prostate cancer; the greatest benefits of anti-androgen therapy may be gained when only tiny amounts of prostate cancer are present.     

Gene expression of a gene family in maize based on noncollinear haplotypes

Genomic regions of nearly every species diverged into different haplotypes, mostly based on point mutations, small deletions, and insertions that do not affect the collinearity of genes within a species. However, the same genomic interval containing the z1C gene cluster of two inbred lines of Zea mays significantly lost their gene collinearity and also differed in the regulation of each remaining gene set. Furthermore, when inbreds were reciprocally crossed, hybrids exhibited an unexpected shift of expression patterns so that "overdominance" instead of "dominance complementation" of allelic and nonallelic gene expression occurred. The same interval also differed in length (360 vs. 263 kb). Segmental rearrangements led to sequence changes, which were further enhanced by the insertion of different transposable elements. Changes in gene order affected not only z1C genes but also three unrelated genes. However, the orthologous interval between two subspecies of rice (not rice cultivars) was conserved in length and gene order, whereas changes between two maize inbreds were as drastic as changes between maize and sorghum. Given that chromosomes could conceivably consist of intervals of haplotypes that are highly diverged, one could envision endless breeding opportunities because of their linear arrangement along a chromosome and their expression potential in hybrid combinations ("binary" systems). The implication of such a hypothesis for heterosis is discussed.     

Validity and Responsiveness of Generic Preference-based HRQOL Instruments in Chronic Epilepsy

Generic, preference-based instruments are recommended for assessing health-related quality of life (HRQOL) in cost-utility analyses (CUA). We aimed to determine which instrument is the most appropriate for CUA of epilepsy care, using established psychometric criteria. We compared validity and responsiveness of EQ5D (using both UK and US preferences), visual analog scale (VAS), Health Utilities Index Mark II (HUI-2) and Mark III (HUI-3) and SF6D in 165 adults evaluated for epilepsy surgery. SF6D had the strongest or next-strongest associations with seizure severity and seizure control. It was not associated with education or IQ. Only SF6D and HUI-3 discriminated between patients with and without seizures 2 years after baseline evaluation. SF6D was most or next-most responsive to being seizure-free for 2 years, in most responsiveness analyses. VAS was also responsive, but showed less evidence of validity. The QOLIE-89, an epilepsy-targeted profile instrument, had stronger evidence for validity and responsiveness than the preference instruments. SF6D has several key psychometric advantages over four other preference instruments in CUAs of epilepsy care. This may reflect better coverage of HRQOL dimensions affected by epilepsy, greater sensitivity at the upper end of the HRQOL continuum, or both. These findings may not generalize to other chronic conditions.     

Physiological anticoagulants and activated protein C resistance in childhood stroke

Immunological and functional protein S, protein C and antithrombin III levels and anticoagulant responses to activated protein C were measured in 24 patients with stroke in childhood. No hereditary deficiencies were found. The protein S levels in healthy controls of younger age did not differ from the adult levels. For optimal screening of protein S deficiency, measurements using functional as well as immunological assays are recommended. Appropriate criteria for the diagnosis of the deficiencies must be carefully applied if unnecessary anxiety and inappropriate treatment of children are to be avoided.     

Evaluation of attempted prevention of unexpected infant death in very high-risk infants by planned health care

Three hundred and ninety-six babies born in Sheffield between 1982 and 1990 identified as being at "very high risk" of unexpected infant death by means of a scoring system, received an intensive programme of health care including a case discussion between a paediatrician, the GP and the health visitor held in the family doctor's surgery, weekly visits from the health visitor and informal hospital admission. Significantly fewer sudden unexpected infant deaths occurred in this group than were expected by logistic regression anlysis or occurred in the best available control group with comparable scores ( p = 0.024). Problems in evaluation include identification of an adequate control population, ethical difficulties in introducing a controlled study when the programme is already perceived as effective, and the calculation of "expected death rates". The results of this study indicate that very energetic programmes of intervention may prevent some deaths in vulnerable infants.     

Fibromatosis of bone in children

Radiographs, computed tomograms, and radionuclide bone scans were obtained preoperatively in three children with fibromatosis involving the bones and soft tissues of the extremities. Two of the children had identical scar-like bone lesions of the proximal tibia, which, to the authors' knowledge, have not been reported before in this disease. The lesions recurred in two children.