Distribution and retention in bone of /sup 226/Ra and comparison with the ICRP 20 model

Analyses are presented of the ratios of /sup 226/Ra to calcium in over 650 samples of compact and cancellous bone from 66 female and 26 male subjects who had died from less than one to 60 years after first exposure to radium. The /sup 226/Ra/Ca ratios were normalized to the terminal /sup 226/Ra skeletal content. The /sup 226/Ra/Ca ratios for vertebrae were essentialy identical to those for other cancellous bone for a given subject. Comparisons of the data with predictions of the ICRP model of alkaline earth metabolism show that for female cancellous bone the normalized /sup 226/Ra/Ca ratios tended to be greater than predicted, while those for female cortical bone (femoral and tibial shaft) tended to be less. The data for males were fitted better by the model. A modification of the model to reduce the amount of radium deposited in soft tissue fitted the data better in some respects. A straight line linear least squares fit to the data appeared to fit as well as, or better than, the models. A radiation effect was suggested in that the normalized /sup 226/Ra/Ca ratio for vertebrae relative to the ratio expected increased with skeletal absorbed dose for vertebra. However, no such effect was apparent for compact bone or for the cancellous bone as a whole

Neurogranin as a Cerebrospinal Fluid Biomarker for Synaptic Loss in Symptomatic Alzheimer Disease

IMPORTANCE: Neurogranin (NGRN) seems to be a promising novel cerebrospinal fluid (CSF) biomarker for synaptic loss; however, clinical, and especially longitudinal, data are sparse. OBJECTIVE: To examine the utility of NGRN, with repeated CSF sampling, for diagnosis, prognosis, and monitoring of Alzheimer disease (AD). DESIGN, SETTING, AND PARTICIPANTS: Longitudinal study of consecutive patients who underwent 2 lumbar punctures between the beginning of 1995 and the end of 2010 within the memory clinic–based Amsterdam Dementia Cohort. The study included 163 patients: 37 cognitively normal participants (mean [SE] age, 64 [2] years; 38% female; and mean [SE] Mini-Mental State Examination [MMSE] score, 28 [0.3]), 61 patients with mild cognitive impairment (MCI) (mean [SE] age, 68 [1] years; 38% female; and mean [SE] MMSE score, 27 [0.3]), and 65 patients with AD (mean [SE] age, 65 [1] years; 45% female; and mean [SE] MMSE score, 22 [0.7]). The mean (SE) interval between lumbar punctures was 2.0 (0.1) years, and the mean (SE) duration of cognitive follow-up was 3.8 (0.2) years. Measurements of CSF NGRN levels were obtained in January and February 2014. MAIN OUTCOME AND MEASURE: Levels of NGRN in CSF samples. RESULTS: Baseline CSF levels of NGRN in patients with AD (median level, 2381 pg/mL [interquartile range, 1651-3416 pg/mL]) were higher than in cognitively normal participants (median level, 1712 pg/mL [interquartile range, 1206-2724 pg/mL]) (P = .04). Baseline NGRN levels were highly correlated with total tau and tau phosphorylated at threonine 181 in all patient groups (all P < .001), but not with Aβ42. Baseline CSF levels of NGRN were also higher in patients with MCI who progressed to AD (median level, 2842 pg/mL [interquartile range, 1882-3950 pg/mL]) compared with those with stable MCI (median level, 1752 pg/mL [interquartile range, 1024-2438 pg/mL]) (P = .004), and they were predictive of progression from MCI to AD (hazard ratio, 1.8 [95% CI, 1.1-2.9]; stratified by tertiles). Linear mixed-model analyses demonstrated that within-person levels of NGRN increased over time in cognitively normal participants (mean [SE] level, 90 [45] pg/mL per year; P < .05) but not in patients with MCI or AD. CONCLUSIONS AND RELEVANCE: Neurogranin is a promising biomarker for AD because levels were elevated in patients with AD compared with cognitively normal participants and predicted progression from MCI to AD. Within-person levels of NGRN increased in cognitively normal participants but not in patients with later stage MCI or AD, which suggests that NGRN may reflect presymptomatic synaptic dysfunction or loss

Clinical, Genetic, And Structural Basis Of Congenital Adrenal Hyperplasia Due To 11Β-Hydroxylase Deficiency

Scopu

Novel Proteins Linking the Actin Cytoskeleton to the Endocytic Machinery in Saccharomyces cerevisiae

The importance of coupling the process of endocytosis to factors regulating actin dynamics has been clearly demonstrated in yeast, and many proteins involved in these mechanisms have been identified and characterized. Here we demonstrate the importance of two additional cortical components, Ysc84p and Lsb5p, which together are essential for the organization of the actin cytoskeleton and for fluid phase endocytosis. Both Ysc84p and Lsb5p were identified through two-hybrid screens with different domains of the adaptor protein Sla1p. Ysc84p colocalizes with cortical actin and requires the presence of an intact actin cytoskeleton for its cortical localization. Ycl034w/Lsb5p localizes to the cell cortex but does not colocalize with actin. The Lsb5 protein contains putative VHS and GAT domains as well as an NPF motif, which are all domains characteristic of proteins involved in membrane trafficking. Deletion of either gene alone does not confer any dramatic phenotype on cells. However, deletion of both genes is lethal at elevated temperatures. Furthermore, at all temperatures this double mutant has depolarized actin and an almost undetectable level of fluid phase endocytosis. Our data demonstrate that Ysc84p and Lsb5p are important components of complexes involved in overlapping pathways coupling endocytosis with the actin cytoskeleton in yeast

Tropospheric ozone: respiratory effects and Australian air quality goals.

OBJECTIVE--To review the health effects of tropospheric ozone and discuss the implications for public health policy. DESIGN--Literature review and consultation with scientists in Australia and overseas. Papers in English or with English language abstracts were identified by Medline search from the international peer reviewed published reports. Those from the period 1980-93 were read systematically but selected earlier papers were also considered. Reports on ozone exposures were obtained from environmental agencies in the region. RESULTS--Exposure to ozone at concentrations below the current Australian air quality goal (0.12 ppm averaged over one hour) may cause impaired respiratory function. Inflammatory changes in the small airways and respiratory symptoms result from moderate to heavy exercise in the presence of ozone at levels of 0.08-0.12 ppm. The changes in respiratory function due to ozone are short lived, vary with the duration of exposure, may be modified by levels of other pollutants (such as sulphur dioxide and particulates), and differ appreciably between individuals. Bronchial lavage studies indicate that inflammation and other pathological changes may occur in the airways before reductions in air flow are detectable, and persist after respiratory function has returned to normal. It is not known whether exposures to ozone at low levels (0.08-0.12 ppm) cause lasting damage to the lung or, if such damage does occur, whether it is functionally significant. At present, it is not possible to identify confidently population subgroups with heightened susceptibility to ozone. People with asthma may be more susceptible to the effects of ozone than the general population but the evidence is not consistent. Recent reports suggest that ozone increases airway reactivity on subsequent challenge with allergens and other irritants. Animal studies are consistent with the findings in human populations. CONCLUSION--A new one hour air quality ozone goal of 0.08 ppm for Australia, and the introduction of a four hour goal of 0.06 ppm are recommended on health grounds

The involvement of aβ in the neuroinflammatory response

In the same year as Alzheimer described the case of Auguste D. as a peculiar disease of the cerebral cortex, Fischer published his classic paper about miliary plaque formation in a large number of brains from patients with senile dementia [1]. In this paper and a following one from 1910, Fischer stated that plaque formation is the result of the deposition of a peculiar foreign substance in the cortex that induces a regenerative response of the surrounding nerve fibers [2]. He described spindle-shaped thickening of nerve fibers terminating with club forms in the corona of plaques (Fig. 4.1). These altered nerve fibers were considered as axonal sprouting, and the terminal club forms showed a strong similarity with the clubshaped buddings of axons found in developing nerve fibers and after transections of peripheral nerves as described by Cajal some years earlier. According to Fischer, the crucial step of the plaque formation is the deposition of a foreign substance that provokes a local inflammatory response step followed by a regenerative response of the surrounding nerve fibers. However, Fischer could not find morphological characteristics of an inflammatory process around the plaques after extensive histopathological observations including complement binding studies. The only tissue reaction appeared to be an overgrowth of club-formed neurites