Contributions of central and systemic inflammation to the pathophysiology of Parkinson's disease

Idiopathic Parkinson’s disease (PD) represents a complex interaction between the inherent vulnerability of the nigrostriatal dopaminergic system, a possible genetic predisposition, and exposure to environmental toxins including inflammatory triggers. Evidence now suggests that chronic neuroinflammation is consistently associated with the pathophysiology of PD. Activation of microglia and increased levels of pro-inflammatory mediators such as TNF-alpha,IL-1beta and IL-6, reactive oxygen species and eicosanoids has been reported after post mortem analysis of the substantia nigra from PD patients and in animal models of PD. It is hypothesised that chronically activated microglia secrete high levels of pro-inflammatory mediators which damage neurons and further activate microglia, resulting in a feed forward cycle promoting further inflammation and neurodegeneration. Moreover, nigrostriatal dopaminergic neurons are more vulnerable to pro-inflammatory and oxidative mediators than other cell types because of their low intracellular glutathione concentration. Systemic inflammation has also been suggested to contribute to neurodegeneration in PD, as lymphocyte infiltration has been observed in brains of PD patients and in animal models of PD, substantiating the current theory of a fundamental role of inflammation in neurodegeneration. We will examine the current evidence in the literature which offers insight into the premise that both central and systemic inflammation may contribute to neurodegeneration in PD. We will discuss the emerging possibility of the use of diagnostic tools such as imaging technologies for PD patients. Finally, we will present the immunomodulatory therapeutic strategies that are now under investigation and in clinical trials as potential neuroprotective drugs for PD

Proteomic analysis of the cerebrospinal fluid of patients with restless legs syndrome/Willis-Ekbom disease

BACKGROUND: Restless Legs Syndrome/Willis-Ekbom Disease (RLS/WED) is a sensorimotor disorder that causes patients to experience overwhelming and distressing sensations in the legs compelling the patient to move their legs to provide relief. The purpose of this study was to determine if biomarkers in the cerebrospinal fluid can distinguish RLS/WED patients from neurological controls. METHODS: We obtained CSF samples by lumbar puncture from 5 early-onset RLS/WED patients and 5 controls. We performed 2-dimensional difference in-gel electrophoresis (2D-DIGE). Proteins that were significantly altered were identified by Student’s t-test. Protein spots that were differentially expressed (p ≤ 0.05, Av. Ratio ≥ 2.0) between RLS/WED and control CSF samples were identified using MALDI-TOF-MS. Statistical analyses of the validation immunoblot assays were performed using Student’s t-test. RESULTS: In this discovery study we identified 6 candidate CSF protein markers for early-onset RLS/WED. Four proteins (Cystatin C, Lipocalin-type Prostaglandin D2 Synthase, Vitamin D binding Protein, and β-Hemoglobin) were increased and 2 proteins (Apolipoprotein A1 and α-1-acid Glycoprotein) were decreased in RLS/WED patients. CONCLUSIONS: Our results reveal a protein profile in the RLS/WED CSF that is consistent with clinical findings of disruptive sleep, cardiovascular dysfunction and painful symptoms. Moreover, protein profiles are consistent with neuropathological findings of activation of hypoxia inducible factor (HIF) pathways and alterations in dopaminergic systems. These data indicate the CSF of RLS/WED patients may provide information relevant to biological basis for RLS/WED, treatment strategies and potential new treatment targets

Seroprevalence of Zika virus in wild African green monkeys and baboons

ABSTRACT Zika virus (ZIKV) has recently spread through the Americas and has been associated with a range of health effects, including birth defects in children born to women infected during pregnancy. Although the natural reservoir of ZIKV remains poorly defined, the virus was first identified in a captive “sentinel” macaque monkey in Africa in 1947. However, the virus has not been reported in humans or nonhuman primates (NHPs) in Africa outside Gabon in over a decade. Here, we examine ZIKV infection in 239 wild baboons and African green monkeys from South Africa, the Gambia, Tanzania, and Zambia using combinations of unbiased deep sequencing, quantitative reverse transcription-PCR (qRT-PCR), and an antibody capture assay that we optimized using serum collected from captive macaque monkeys exposed to ZIKV, dengue virus, and yellow fever virus. While we did not find evidence of active ZIKV infection in wild NHPs in Africa, we found variable ZIKV seropositivity of up to 16% in some of the NHP populations sampled. We anticipate that these results and the methodology described within will help in continued efforts to determine the prevalence, natural reservoir, and transmission dynamics of ZIKV in Africa and elsewhere. IMPORTANCE Zika virus (ZIKV) is a mosquito-borne virus originally discovered in a captive monkey living in the Zika Forest of Uganda, Africa, in 1947. Recently, an outbreak in South America has shown that ZIKV infection can cause myriad health effects, including birth defects in the children of women infected during pregnancy. Here, we sought to investigate ZIKV infection in wild African primates to better understand its emergence and spread, looking for evidence of active or prior infection. Our results suggest that up to 16% of some populations of nonhuman primate were, at some point, exposed to ZIKV. We anticipate that this study will be useful for future studies that examine the spread of infections from wild animals to humans in general and those studying ZIKV in primates in particular. Podcast: A podcast concerning this article is available

Semiclassical quantization of the hydrogen atom in crossed electric and magnetic fields

The S-matrix theory formulation of closed-orbit theory recently proposed by Granger and Greene is extended to atoms in crossed electric and magnetic fields. We then present a semiclassical quantization of the hydrogen atom in crossed fields, which succeeds in resolving individual lines in the spectrum, but is restricted to the strongest lines of each n-manifold. By means of a detailed semiclassical analysis of the quantum spectrum, we demonstrate that it is the abundance of bifurcations of closed orbits that precludes the resolution of finer details. They necessitate the inclusion of uniform semiclassical approximations into the quantization process. Uniform approximations for the generic types of closed-orbit bifurcation are derived, and a general method for including them in a high-resolution semiclassical quantization is devised

High-resolution Spectroscopic Reconnaissance of a Temperate Sub-Neptune

The study of temperate sub-Neptunes is the new frontier in exoplanetary science. A major development in the past year has been the first detection of carbon-bearing molecules in the atmosphere of a temperate sub-Neptune, K2-18 b, a possible Hycean world, with the James Webb Space Telescope (JWST). The JWST is poised to characterise the atmospheres of several other such planets with important implications for planetary processes in the temperate regime. Meanwhile, ground-based high-resolution spectroscopy has been highly successful in detecting chemical signatures of giant exoplanets, though low-mass planets have remained elusive. In the present work, we report the atmospheric reconnaissance of a temperate sub-Neptune using ground-based high-resolution transmission spectroscopy. The long orbital period and the low systemic velocity results in a low planetary radial velocity during transit, making this system a valuable testbed for high-resolution spectroscopy of temperate sub-Neptunes. We observe high-resolution time-series spectroscopy in the H- and K-bands during the planetary transit with the IGRINS instrument (R$\sim$45,000) on Gemini-South. Using observations from a single transit we find marginal evidence (2.2$\sigma$) for the presence of methane (CH$_4$) in the atmosphere and no evidence for ammonia (NH$_3$) despite its strong detectability for a cloud-free H$_2$-rich atmosphere. We assess our findings using injection tests with different atmospheric scenarios, and find them to be consistent with a high CH$_4$/NH$_3$ ratio and/or the presence of high-altitude clouds. Our results demonstrate the capability of Gemini-S/IGRINS for atmospheric characterization of temperate sub-Neptunes, and the complementarity between space- and ground-based facilities in this planetary regime.Comment: Accepted for publication in ApJ Letter

Candidate gene analysis of femoral neck trabecular and cortical volumetric bone mineral density in older men.

In contrast to conventional dual-energy X-ray absorptiometry, quantitative computed tomography separately measures trabecular and cortical volumetric bone mineral density (vBMD). Little is known about the genetic variants associated with trabecular and cortical vBMD in humans, although both may be important for determining bone strength and osteoporotic risk. In the current analysis, we tested the hypothesis that there are genetic variants associated with trabecular and cortical vBMD at the femoral neck by genotyping 4608 tagging and potentially functional single-nucleotide polymorphisms (SNPs) in 383 bone metabolism candidate genes in 822 Caucasian men aged 65 years or older from the Osteoporotic Fractures in Men Study (MrOS). Promising SNP associations then were tested for replication in an additional 1155 men from the same study. We identified SNPs in five genes (IFNAR2, NFATC1, SMAD1, HOXA, and KLF10) that were robustly associated with cortical vBMD and SNPs in nine genes (APC, ATF2, BMP3, BMP7, FGF18, FLT1, TGFB3, THRB, and RUNX1) that were robustly associated with trabecular vBMD. There was no overlap between genes associated with cortical vBMD and trabecular vBMD. These findings identify novel genetic variants for cortical and trabecular vBMD and raise the possibility that some genetic loci may be unique for each bone compartment

Neurochemistry of Attention-Deficit/Hyperactivity Disorder (ADHD)

There are numerous books about Attention-Deficit/Hyperactivity Disorder (ADHD) on the market. These books range from being very nontechnical, geared towards elementary educators and parents, to highly technical, geared towards medical and mental health professionals. To complicate matters further, the manner in which ADHD is defined and diagnosed has recently changed with the release of the DSM-V in 2013, which makes even relatively recent texts out-of-date. This Creative Inquiry project involves research into the most recent data on the neurochemistry behind what causes ADHD and comorbid conditions, as well as the neurochemistry of how drugs used to treat these conditions work to affect patient mental health. The goal of this project is to write and publish a book that begins with simple descriptions of these processes and builds to more technical language, providing parents and teachers with the ability to become experts in ADHD without a preexisting background in science

Hyperspectral Perfusion Monitoring of Irradiated Breast Patients

Studies examining acute perfusion changes (month) in irradiated fields are limited. Hyperspectral imaging (HSI) is a novel method of scanning spectroscopy that provides direct measurement of cutaneous tissue perfusion that is non-invasive. In this clinical study, we examine the ability of HSI to assess cutaneous changes in skin perfusion during the acute period following irradiation in patients. Patients undergoing external beam breast conserving radiotherapy (n=15) or post-mastectomy radiation (n=3) were enrolled. Total treatment doses ranged between 42 Gy and 50 Gy. Baseline images were obtained before irradiation for bilateral breasts in each patient and then subsequently at each dose fraction. Skin reaction assessment was also performed on the patients. In the irradiated breast, total perfusion was found to increase prior to skin reaction formation and continued to steadily increase over the first 30 days in all patients. Skin reactions included erythema and dry desquamation starting at day 11. These findings suggest that HSI can identify early changes of tissue oxygenation and perfusion in acute radiation injury and may be able to predict the severity of such injuries. Future work will look at mitigating acute injury with topical applications and studying the perfusion changes in chronically irradiated skin

Theory of tunable pH sensitive vesicles of anionic and cationic lipids or anionic and neutral lipids

The design of vesicles which become unstable at an easily tuned value of pH is of great interest for targeted drug delivery. We present a microscopic theory for two forms of such vesicles. A model of lipids introduced by us previously is applied to a system of ionizable, anionic lipid, and permanently charged, cationic lipid. We calculate the pH at which the lamellar phase becomes unstable with respect to an inverted hexagonal one, a value which depends continuously on the system composition. Identifying this instability with that displayed by unilamellar vesicles undergoing fusion, we obtain very good agreement with the recent experimental data of Hafez et al., Biophys. J. 2000 79: 1438-1446, on the pH at which fusion occurs vs. vesicle composition. We explicate the mechanism in terms of the role of the counter ions. This understanding suggests that a system of a neutral, non lamellar forming lipid stabilized by an anionic lipid would serve equally well for preparing tunable, pH sensitive vesicles. Our calculations confirm this. Further, we show that both forms of vesicle have the desirable feature of exhibiting a regime in which the pH at instability is a rapidly varying function of the vesicle composition.Comment: five figures, to appear in Biophys.