Association between essential tremor and blood lead concentration

Lead is a ubiquitous toxicant that causes tremor and cerebellar damage. Essential tremor (ET) is a highly prevalent neurologic disease associated with cerebellar involvement. Although environmental toxicants may play a role in ET etiology and their identification is a critical step in disease prevention, these toxicants have received little attention. Our objective was to test the hypothesis that ET is associated with lead exposure. Therefore, blood lead (BPb) concentrations were measured and a lifetime occupational history was assessed in ET patients and in controls. We frequency matched 100 ET patients and 143 controls on age, sex, and ethnicity. BPb concentrations were analyzed using graphite furnace atomic absorption spectrophotometry. A lifetime occupational history was reviewed by an industrial hygienist. BPb concentrations were higher in ET patients than in controls (mean ± SD, 3.3 ± 2.4 and 2.6 ± 1.6 µg/dL, respectively; median, 2.7 and 2.3 µg/dL; p = 0.038). In a logistic regression model, BPb concentration was associated with diagnosis [control vs. ET patient, odds ratio (OR) per unit increase = 1.21; 95% confidence interval (CI), 1.05-1.39; p = 0.007]. BPb concentration was associated with diagnosis (OR per unit increase = 1.19; 95% CI, 1.03-1.37; p = 0.02) after adjusting for potential confounders. Prevalence of lifetime occupational lead exposure was similar in ET patients and controls. We report an association between BPb concentration and ET. Determining whether this association is due to increased exposure to lead or a difference in lead kinetics in ET patients requires further investigation

Fluoxetine reverses the memory impairment and reduction in proliferation and survival of hippocampal cells caused by methotrexate chemotherapy

RATIONALE: Adjuvant cancer chemotherapy can cause long-lasting, cognitive deficits. It is postulated that these impairments are due to these drugs targeting neural precursors within the adult hippocampus, the loss of which has been associated with memory impairment. OBJECTIVES: The present study investigates the effects of the chemotherapy, methotrexate (MTX) on spatial working memory and the proliferation and survival of the neural precursors involved in hippocampal neurogenesis, and the possible neuroprotective properties of the antidepressant fluoxetine. METHODS: Male Lister hooded rats were administered MTX (75 mg/kg, two i.v. doses a week apart) followed by leucovorin rescue (i.p. 18 h after MTX at 6 mg/kg and at 26, 42 and 50 h at 3 mg/kg) and/or fluoxetine (10 mg/kg/day in drinking water for 40 days). Memory was tested using the novel location recognition (NLR) test. Using markers, cell proliferation (Ki67) and survival (bromodeoxyuridine/BrdU), in the dentate gyrus were quantified. RESULTS: MTX-treated rats showed a cognitive deficit in the NLR task compared with the vehicle and fluoxetine-treated groups. Cognitive ability was restored in the group receiving both MTX and fluoxetine. MTX reduced both the number of proliferating cells in the SGZ and their survival. This was prevented by the co-administration of fluoxetine, which alone increased cell numbers. CONCLUSIONS: These results demonstrate that MTX induces an impairment in spatial working memory and has a negative long-term effect on hippocampal neurogenesis, which is counteracted by the co-administration of fluoxetine. If translatable to patients, this finding has the potential to prevent the chemotherapy-induced cognitive deficits experienced by many cancer survivors

Ribosomal S6 Kinase 2 (RSK2) Maintains Genomic Stability by Activating the Atm/p53-Dependent DNA Damage Pathway

10.1371/journal.pone.0074334PLoS ONE89-POLN

NADPH oxidase-mediated redox signal contributes to lipoteichoic acid-induced MMP-9 upregulation in brain astrocytes

<p>Abstract</p> <p>Background</p> <p>Lipoteichoic acid (LTA) is a component of gram-positive bacterial cell walls and may be elevated in the cerebrospinal fluid of patients suffering from meningitis. Among matrix metalloproteinases (MMPs), MMP-9 has been observed in patients with brain inflammatory diseases and may contribute to the pathology of brain diseases. Moreover, several studies have suggested that increased oxidative stress is implicated in the pathogenesis of brain inflammation and injury. However, the molecular mechanisms underlying LTA-induced redox signal and MMP-9 expression in brain astrocytes remain unclear.</p> <p>Objective</p> <p>Herein we explored whether LTA-induced MMP-9 expression was mediated through redox signals in rat brain astrocytes (RBA-1 cells).</p> <p>Methods</p> <p>Upregulation of MMP-9 by LTA was evaluated by zymographic and RT-PCR analyses. Next, the MMP-9 regulatory pathways were investigated by pretreatment with pharmacological inhibitors or transfection with small interfering RNAs (siRNAs), Western blotting, and chromatin immunoprecipitation (ChIP)-PCR and promoter activity reporter assays. Moreover, we determined the cell functional changes by migration assay.</p> <p>Results</p> <p>These results showed that LTA induced MMP-9 expression via a PKC(α)-dependent pathway. We further demonstrated that PKCα stimulated p47^phox/NADPH oxidase 2 (Nox2)-dependent reactive oxygen species (ROS) generation and then activated the ATF2/AP-1 signals. The activated-ATF2 bound to the AP-1-binding site of MMP-9 promoter, and thereby turned on MMP-9 gene transcription. Additionally, the co-activator p300 also contributed to these responses. Functionally, LTA-induced MMP-9 expression enhanced astrocytic migration.</p> <p>Conclusion</p> <p>These results demonstrated that in RBA-1 cells, activation of ATF2/AP-1 by the PKC(α)-mediated Nox(2)/ROS signals is essential for upregulation of MMP-9 and cell migration enhanced by LTA.</p

Justify your alpha

Benjamin et al. proposed changing the conventional “statistical significance” threshold (i.e.,the alpha level) from p ≤ .05 to p ≤ .005 for all novel claims with relatively low prior odds. They provided two arguments for why lowering the significance threshold would “immediately improve the reproducibility of scientific research.” First, a p-value near .05provides weak evidence for the alternative hypothesis. Second, under certain assumptions, an alpha of .05 leads to high false positive report probabilities (FPRP2 ; the probability that a significant finding is a false positive

Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study

BACKGROUND: This study undertakes a systematic and comprehensive analysis of brain gene expression profiles of immune/inflammation-related genes in aging and Alzheimer’s disease (AD). METHODS: In a well-powered microarray study of young (20 to 59 years), aged (60 to 99 years), and AD (74 to 95 years) cases, gene responses were assessed in the hippocampus, entorhinal cortex, superior frontal gyrus, and post-central gyrus. RESULTS: Several novel concepts emerge. First, immune/inflammation-related genes showed major changes in gene expression over the course of cognitively normal aging, with the extent of gene response far greater in aging than in AD. Of the 759 immune-related probesets interrogated on the microarray, approximately 40% were significantly altered in the SFG, PCG and HC with increasing age, with the majority upregulated (64 to 86%). In contrast, far fewer immune/inflammation genes were significantly changed in the transition to AD (approximately 6% of immune-related probesets), with gene responses primarily restricted to the SFG and HC. Second, relatively few significant changes in immune/inflammation genes were detected in the EC either in aging or AD, although many genes in the EC showed similar trends in responses as in the other brain regions. Third, immune/inflammation genes undergo gender-specific patterns of response in aging and AD, with the most pronounced differences emerging in aging. Finally, there was widespread upregulation of genes reflecting activation of microglia and perivascular macrophages in the aging brain, coupled with a downregulation of select factors (TOLLIP, fractalkine) that when present curtail microglial/macrophage activation. Notably, essentially all pathways of the innate immune system were upregulated in aging, including numerous complement components, genes involved in toll-like receptor signaling and inflammasome signaling, as well as genes coding for immunoglobulin (Fc) receptors and human leukocyte antigens I and II. CONCLUSIONS: Unexpectedly, the extent of innate immune gene upregulation in AD was modest relative to the robust response apparent in the aged brain, consistent with the emerging idea of a critical involvement of inflammation in the earliest stages, perhaps even in the preclinical stage, of AD. Ultimately, our data suggest that an important strategy to maintain cognitive health and resilience involves reducing chronic innate immune activation that should be initiated in late midlife

Justify your alpha

In response to recommendations to redefine statistical significance to p ≤ .005, we propose that researchers should transparently report and justify all choices they make when designing a study, including the alpha level

PCBs in phytoplankton in the Odra Estuary

Eleven PCB congeners were determined in phytoplankton samples collected from the Odra Estuary at 9 stations in 2001–2002. The PCB concentrations were related to the temperature, turbidity, salinity, oxygen and redox potential of the water as well as to the pigment content in the samples. The results indicate that phytoplankton and the detritus derived from it play a crucial role in the distribution of PCBs, their transfer from the water column to sediments and from the Estuary to the sea. The species composition of the phytoplankton occurring in this area could also be very important as regards the sorption of PCBs

Właściwości strukturalne i odporność na zużywanie ścierne stali Brinar 400 i Brinar 500

In the paper, microstructures and the examination results of abrasive-wear resistance of steel grades Brinar 400 and Brinar 500 are presented. It was found on the grounds of light and electron scanning microscopy that these steels are characterised by subtle differences in microstructures, influencing their mechanical and usable properties. In as-delivered condition, the steels have fine-grained structure with post-martensitic orientation, containing few particles of carbide phases. Such microstructures of Brinar steels and the performed chemical analyses indicate that their properties are formed during specialised operations of thermo-mechanical rolling. Generally, it can be said that the examined steels were designed according to the accepted standards of material engineering, related to low-alloy, high-strength, and abrasive-wear resistant martensitic steels. According to the above, the obtained results of structural examinations of Brinar 400 and Brinar 500 steels were referred to real abrasive-wear indices obtained by the spinning bowl method with use of various abrasive soil masses. The tests carried-out in light soil (loamy sand), medium soil (sandy loam), and in heavy soil (loam), as well as hardness measurements showed strict dependence of abrasive-wear indices on microstructures and the heattreatment condition of the examined steels. Examination results of abrasive-wear resistance of Brinar steels were compared with those of steel 38GSA in normalised conditions.W pracy przedstawiono budowę strukturalną oraz wyniki badań odporności na zużywanie ścierne stali Brinar 400 i Brinar 500. Na podstawie przeprowadzonych metodami mikroskopii świetlnej i skaningowej badań wykazano, że stale te cechują się subtelną różnicą w budowie strukturalnej rzutującą na ich charakterystyki wytrzymałościowe i użytkowe. W stanie dostarczenia rozpatrywane stale charakteryzują się drobnoziarnistą strukturą o orientacji pomartenzytycznej z nielicznymi wydzieleniami faz węglikowych. Powyższy typ budowy strukturalnej stali Brinar oraz przeprowadzone analizy spektralne składu chemicznego wskazują, iż ich właściwości kształtowane są w toku specjalistycznych zabiegów termomechanicznego walcowania. Ogólnie rzecz biorąc, można stwierdzić, że badane stale zostały zaprojektowane zgodnie z przyjętymi kanonami inżynierii materiałowej odnośnie do niskostopowych, wysokowytrzymałych stali martenzytycznych odpornych na zużywanie ścierne. Zgodnie z powyższym uzyskane wyniki badań strukturalnych stali Brinar 400 i Brinar 500 odniesiono do rzeczywistych wskaźników odporności na zużycie ścierne uzyskanych metodą „wirującej misy” z wykorzystaniem zróżnicowanych glebowych mas ściernych. Zrealizowane badania w glebie lekkiej (piasek gliniasty), glebie średniej (glina lekka) oraz glebie ciężkiej (glina zwykła), a także przeprowadzone pomiary twardości wykazały ścisłą zależność uzyskanych wskaźników odporności na zużywanie ścierne od budowy fazowej oraz od stanu obróbki cieplnej badanych stali. Wyniki badań odporności na zużywanie ścierne stali Brinar odniesiono porównawczo do stali 38GSA w stanie normalizowanym