Longitudinal risk factors for developing depressive symptoms in Parkinson's disease

BACKGROUND: Despite the established importance of identifying depression in Parkinson's disease, our understanding of the factors which place the Parkinson's disease patient at future risk of depression is limited. METHODS: Our sample consisted of 874 patients from two longitudinal cohorts, PPMI and PDBP, with median follow-up durations of 7 and 3 years respectively. Risk factors for depressive symptoms at baseline were determined using logistic regression. A Cox regression model was then used to identify baseline factors that predisposed the non-depressed patient to develop depressive symptoms that were sustained for at least one year, while adjusting for antidepressant use and cognitive impairment. Common predictors between the two cohorts were identified with a random-effects meta-analysis. RESULTS: We found in our analyses that the majority of baseline non-depressed patients would develop sustained depressive symptoms at least once during the course of the study. Probable REM sleep behavior disorder (pRBD), age, duration of diagnosis, impairment in daily activities, mild constipation, and antidepressant use were among the baseline risk factors for depression in either cohort. Our Cox regression model indicated that pRBD, impairment in daily activities, hyposmia, and mild constipation could serve as longitudinal predictors of sustained depressive symptoms. CONCLUSIONS: We identified several potential risk factors to aid physicians in the early detection of depression in Parkinson's disease patients. Our findings also underline the importance of adjusting for multiple covariates when analyzing risk factors for depression

A quantitative approach for measuring the reservoir of latent HIV-1 proviruses.

A stable latent reservoir for HIV-1 in resting CD4+ T cells is the principal barrier to a cure1-3. Curative strategies that target the reservoir are being tested4,5 and require accurate, scalable reservoir assays. The reservoir was defined with quantitative viral outgrowth assays for cells that release infectious virus after one round of T cell activation1. However, these quantitative outgrowth assays and newer assays for cells that produce viral RNA after activation6 may underestimate the reservoir size because one round of activation does not induce all proviruses7. Many studies rely on simple assays based on polymerase chain reaction to detect proviral DNA regardless of transcriptional status, but the clinical relevance of these assays is unclear, as the vast majority of proviruses are defective7-9. Here we describe a more accurate method of measuring the HIV-1 reservoir that separately quantifies intact and defective proviruses. We show that the dynamics of cells that carry intact and defective proviruses are different in vitro and in vivo. These findings have implications for targeting the intact proviruses that are a barrier to curing HIV infection

Limbic Epileptogenesis in a Mouse Model of Fragile X Syndrome

Fragile X syndrome (FXS), caused by silencing of the Fmr1 gene, is the most common form of inherited mental retardation. Epilepsy is reported to occur in 20–25% of individuals with FXS. However, no overall increased excitability has been reported in Fmr1 knockout (KO) mice, except for increased sensitivity to auditory stimulation. Here, we report that kindling increased the expressions of Fmr1 mRNA and protein in the forebrain of wild-type (WT) mice. Kindling development was dramatically accelerated in Fmr1 KO mice, and Fmr1 KO mice also displayed prolonged electrographic seizures during kindling and more severe mossy fiber sprouting after kindling. The accelerated rate of kindling was partially repressed by inhibiting N-methyl-D-aspartic acid receptor (NMDAR) with MK-801 or mGluR5 receptor with 2-methyl-6-(phenylethynyl)-pyridine (MPEP). The rate of kindling development in WT was not effected by MPEP, however, suggesting that FMRP normally suppresses epileptogenic signaling downstream of metabolic glutamate receptors. Our findings reveal that FMRP plays a critical role in suppressing limbic epileptogenesis and predict that the enhanced susceptibility of patients with FXS to epilepsy is a direct consequence of the loss of an important homeostatic factor that mitigates vulnerability to excessive neuronal excitation

Analysis of the TGFβ functional pathway in epithelial ovarian carcinoma

Epithelial ovarian carcinoma is often diagnosed at an advanced stage of disease and is the leading cause of death from gynaecological neoplasia. The genetic changes that occur during the development of this carcinoma are poorly understood. It has been proposed that IGFIIR, TGFβ1 and TGFβRII act as a functional unit in the TGFβ growth inhibitory pathway, and that somatic loss-of-function mutations in any one of these genes could lead to disruption of the pathway and subsequent loss of cell cycle control. We have examined these 3 genes in 25 epithelial ovarian carcinomas using single-stranded conformational polymorphism analysis and DNA sequence analysis. A total of 3 somatic missense mutations were found in the TGFβRII gene, but none in IGFRII or TGFβ1. An association was found between TGFβRII mutations and histology, with 2 out of 3 clear cell carcinomas having TGFβRII mutations. This data supports other evidence from mutational analysis of the PTEN and β-catenin genes that there are distinct developmental pathways responsible for the progression of different epithelial ovarian cancer histologic subtypes. © 2001 Cancer Research Campaign http://www.bjcancer.co

DIII-D Studies of Massive Gas Injection Fast Shutdowns for Disruption Mitigation

Injection of massive quantities of gas is a promising technique for fast shutdown of ITER for the purpose of avoiding divertor and first wall damage from disruptions. Previous experiments using massive gas injection (MGI) to terminate discharges in the DIII-D tokamak have demonstrated rapid shutdown with reduced wall heating and halo currents (relative to natural disruptions) and with very small runaway electron (RE) generation [1]. Figure 1 shows time traces which give an overview of shutdown time scales. Typically, of order 5 x 10{sup 22} Ar neutrals are fired over a pulse of 25 ms duration into stationary (non-disrupting) discharges. The observed results are consistent with the following scenario: within several ms of the jet trigger, sufficient Ar neutrals are delivered to the plasma to cause the edge temperature to collapse, initiating the inward propagation of a cold front. The exit flow of the jet [Fig. 1(a)] has a {approx} 9 ms rise time; so the quantity of neutrals which initiates the edge collapse is small (<10{sup 20}). When the cold front reaches q {approx} 2 surface, global magnetohydrodynamic (MHD) modes are destabilized [2], mixing hot core plasma with edge impurities. Here, q is the safety factor. Most (>90%) of the plasma thermal energy is lost via impurity radiation during this thermal quench (TQ) phase. Conducted heat loads to the wall are low because of the cold edge temperature. After the TQ, the plasma is very cold (of order several eV), so conducted wall (halo) currents are low, even if the current channel contacts the wall. The plasma current profile broadens and begins decaying resistively. The decaying current generates a toroidal electric field which can accelerate REs; however, RE beam formation appears to be limited in MGI shutdowns. Presently, it is thought that the conducted heat flux and halo current mitigation qualities of the MGI shutdown technique will scale well to a reactor-sized tokamak. However, because of the larger RE gain from avalanching and the presence of a RE seed population due to Compton-scattered fast electrons, it is possible that a RE beam can be formed well into the CQ, after the flux surfaces initially destroyed by the TQ MHD have had time to heal. Crucial MGI issues to be studied in present devices are therefore the formation, amplification, and transport of RE and the transport of impurities into the core plasma (important because the presence of impurities can, via collisional drag, help suppress RE amplification). In the study of impurity transport, both neutral delivery (directly driven into the core by the jet pressure) and ion delivery (mixed into the core by MHD) are of interest, as both contribute to RE drag. Here, three new results relevant to RE suppression from MGI are presented: (1) evidence is presented that neutral jet propagation is stopped by toroidal magnetic field pressure, (2) MGI appears to cause the CQ to begin before sufficient impurities have been injected for complete collisional suppression of RE, and (3) flux surface destruction over the region q {le} 2 occurs during the TQ. The first result suggests that neutrals cannot be delivered to the core of large tokamak discharges by MGI, even during the CQ. The second result indicates that (at least for argon MGI in DIII-D), insufficient impurities (either neutral or ion) are delivered for collisional suppression of RE at the start of the CQ. The last result suggests that the destruction of good field lines resulting from MGI is quite extensive and should be sufficient to prevent RE formation, at least at the start of the CQ

Glutamate Induces the Elongation of Early Dendritic Protrusions via mGluRs in Wild Type Mice, but Not in Fragile X Mice

Fragile X syndrome (FXS), the most common inherited from of autism and mental impairment, is caused by transcriptional silencing of the Fmr1 gene, resulting in the loss of the RNA-binding protein FMRP. Dendritic spines of cortical pyramidal neurons in affected individuals are abnormally immature and in Fmr1 knockout (KO) mice they are also abnormally unstable. This could result in defects in synaptogenesis, because spine dynamics are critical for synapse formation. We have previously shown that the earliest dendritic protrusions, which are highly dynamic and might serve an exploratory role to reach out for axons, elongate in response to glutamate. Here, we tested the hypothesis that this process is mediated by metabotropic glutamate receptors (mGluRs) and that it is defective in Fmr1 KO mice. Using time-lapse imaging with two-photon microscopy in acute brain slices from early postnatal mice, we find that early dendritic protrusions in layer 2/3 neurons become longer in response to application of glutamate or DHPG, a Group 1 mGluR agonist. Blockade of mGluR5 signaling, which reverses some adult phenotypes of KO mice, prevented the glutamate-mediated elongation of early protrusions. In contrast, dendritic protrusions from KO mice failed to respond to glutamate. Thus, absence of FMRP may impair the ability of cortical pyramidal neurons to respond to glutamate released from nearby pre-synaptic terminals, which may be a critical step to initiate synaptogenesis and stabilize spines

Inactivation of the transforming growth factor β type II receptor in human small cell lung cancer cell lines

Transforming growth factor β (TGF-β) exerts a growth inhibitory effect on many cell types through binding to two types of receptors, the type I and II receptors. Resistance to TGF-β due to lack of type II receptor (RII) has been described in some cancer types including small cell lung cancer (SCLC). The purpose of this study was to examine the cause of absent RII expression in SCLC cell lines. Northern blot analysis showed that RII RNA expression was very weak in 16 of 21 cell lines. To investigate if the absence of RII transcript was due to mutations, we screened the poly-A tract for mutations, but no mutations were detected. Additional screening for mutations of the RII gene revealed a GG to TT base substitution in one cell line, which did not express RII. This mutation generates a stop codon resulting in predicted synthesis of a truncated RII of 219 amino acids. The nature of the mutation, which has not previously been observed in RII, has been linked to exposure to benzo[a]-pyrene, a component of cigarette smoke. Since RII has been mapped to chromosome 3p22 and nearby loci are often hypermethylated in SCLC, it was examined whether the lack of RII expression was due to hypermethylation. Southern blot analysis of the RII promoter did not show altered methylation patterns. The restriction endonuclease pattern of the RII gene was altered in two SCLC cell lines when digested with Sma 1. However, treatment with 5-aza-2′-deoxycytidine did not induce expression of RII mRNA. Our results indicate that in SCLC lack of RII mRNA is not commonly due to mutations and inactivation of RII transcription was not due to hypermethylation of the RII promoter or gene. Thus, these data show that in most cases of the SCLC cell lines, the RII gene and promoter is intact in spite of absent RII expression. However, the nature of the mutation found could suggest that it was caused by cigarette smoking. © 1999 Cancer Research Campaig

Ablations of Ghrelin and Ghrelin Receptor Exhibit Differential Metabolic Phenotypes and Thermogenic Capacity during Aging

mice are adaptive. mice.Our data therefore suggest that GHS-R ablation activates adaptive thermogenic function(s) in BAT and increases EE, thereby enabling the retention of a lean phenotype. This is the first direct evidence that the ghrelin signaling pathway regulates fat-burning BAT to affect energy balance during aging. This regulation is likely mediated through an as-yet-unidentified new ligand of GHS-R

Plasma Performance Improvements with Liquid Lithium Limiters in CDX-U

The use of flowing liquid lithium as a first wall for a reactor has potentially attractive physics and engineering features. The Current Drive experiment-Upgrade (CDX-U) at the Princeton Plasma Physics Laboratory has begun experiments with a fully toroidal liquid lithium limiter. CDX-U is a compact [R = 34 cm, a = 22 cm, Btoroidal = 2 kG, IP =100 kA, T(subscript)e(0) {approx} 100 eV, n(subscript)e(0) {approx} 5 x 10{sup 19} m-3] short-pulse (<25 msec) spherical tokamak with extensive diagnostics. The limiter, which consists of a shallow circular stainless steel tray of radius 34 cm and width 10 cm, can be filled with lithium to a depth of a few millimeters, and forms the lower limiting surface for the discharge. Heating elements beneath the tray are used to liquefy the lithium prior to the experiment. The total area of the tray is approximately 2000 cm{sup 2}. The tokamak edge plasma, when operated in contact with the lithium-filled tray, shows evidence of reduced impurities and recycling. The reduction in re cycling and impurities is largest when the lithium is liquefied by heating to 250 degrees Celsius. Discharges which are limited by the liquid lithium tray show evidence of performance enhancement. Radiated power is reduced and there is spectroscopic evidence for increases in the core electron temperature. Furthermore, the use of a liquid lithium limiter reduces the need for conditioning discharges prior to high current operation. The future development path for liquid lithium limiter systems in CDX-U is also discussed