Manganese toxicity with ephedrone abuse manifesting as parkinsonism: a case report

Introduction: Neurologic consequences of manganese toxicity have been recognized since 1837. A new form of presumed manganese poisoning has been reported in drug addicted persons from Eastern Europe and the Baltic states who have intravenously injected self-prepared methcathinone hydrochloride (ephedrone), which is synthesized from pseudoephedrine hydrochloride using potassium permanganate as a potent oxidant. This clinical syndrome is under-recognized in Western Europe and there are no reported cases in the literature from Ireland. Case presentation: We report a 30-year-old Eastern European man who presented with a two-year history of gait disturbance. A neurological assessment revealed features of parkinsonism which included hypophonia, hypomimia, mild bradykinesia and rigidity with no resting tremor. He held his arms slightly abducted from his sides when walking, with a reduction in arm swing. Magnetic resonance imaging of his brain showed a high signal on T1 in the globus pallidus and serum manganese levels were raised. He had no response to levodopa. Conclusion: Manganism secondary to ephedrone abuse causing parkinsonism has emerged in Western Europe in recent years due to mass immigration and often remains unrecognized. This paper highlights the various features of this rare cause of parkinsonism and aids in its recognition and subsequent diagnosis. Neurologists in Western Europe will increasingly encounter such patients

Efficient Utilization of Rare Variants for Detection of Disease-Related Genomic Regions

When testing association between rare variants and diseases, an efficient analytical approach involves considering a set of variants in a genomic region as the unit of analysis. One factor complicating this approach is that the vast majority of rare variants in practical applications are believed to represent background neutral variation. As a result, analyzing a single set with all variants may not represent a powerful approach. Here, we propose two alternative strategies. In the first, we analyze the subsets of rare variants exhaustively. In the second, we categorize variants selectively into two subsets: one in which variants are overrepresented in cases, and the other in which variants are overrepresented in controls. When the proportion of neutral variants is moderate to large we show, by simulations, that the both proposed strategies improve the statistical power over methods analyzing a single set with total variants. When applied to a real sequencing association study, the proposed methods consistently produce smaller p-values than their competitors. When applied to another real sequencing dataset to study the difference of rare allele distributions between ethnic populations, the proposed methods detect the overrepresentation of variants between the CHB (Chinese Han in Beijing) and YRI (Yoruba people of Ibadan) populations with small p-values. Additional analyses suggest that there is no difference between the CHB and CHD (Chinese Han in Denver) datasets, as expected. Finally, when applied to the CHB and JPT (Japanese people in Tokyo) populations, existing methods fail to detect any difference, while it is detected by the proposed methods in several regions

Cdk1 Targets Srs2 to Complete Synthesis-Dependent Strand Annealing and to Promote Recombinational Repair

Cdk1 kinase phosphorylates budding yeast Srs2, a member of UvrD protein family, displays both DNA translocation and DNA unwinding activities in vitro. Srs2 prevents homologous recombination by dismantling Rad51 filaments and is also required for double-strand break (DSB) repair. Here we examine the biological significance of Cdk1-dependent phosphorylation of Srs2, using mutants that constitutively express the phosphorylated or unphosphorylated protein isoforms. We found that Cdk1 targets Srs2 to repair DSB and, in particular, to complete synthesis-dependent strand annealing, likely controlling the disassembly of a D-loop intermediate. Cdk1-dependent phosphorylation controls turnover of Srs2 at the invading strand; and, in absence of this modification, the turnover of Rad51 is not affected. Further analysis of the recombination phenotypes of the srs2 phospho-mutants showed that Srs2 phosphorylation is not required for the removal of toxic Rad51 nucleofilaments, although it is essential for cell survival, when DNA breaks are channeled into homologous recombinational repair. Cdk1-targeted Srs2 displays a PCNA–independent role and appears to have an attenuated ability to inhibit recombination. Finally, the recombination defects of unphosphorylatable Srs2 are primarily due to unscheduled accumulation of the Srs2 protein in a sumoylated form. Thus, the Srs2 anti-recombination function in removing toxic Rad51 filaments is genetically separable from its role in promoting recombinational repair, which depends exclusively on Cdk1-dependent phosphorylation. We suggest that Cdk1 kinase counteracts unscheduled sumoylation of Srs2 and targets Srs2 to dismantle specific DNA structures, such as the D-loops, in a helicase-dependent manner during homologous recombinational repair

The Cysteine Rich Necrotrophic Effector SnTox1 Produced by Stagonospora nodorum Triggers Susceptibility of Wheat Lines Harboring Snn1

The wheat pathogen Stagonospora nodorum produces multiple necrotrophic effectors (also called host-selective toxins) that promote disease by interacting with corresponding host sensitivity gene products. SnTox1 was the first necrotrophic effector identified in S. nodorum, and was shown to induce necrosis on wheat lines carrying Snn1. Here, we report the molecular cloning and validation of SnTox1 as well as the preliminary characterization of the mechanism underlying the SnTox1-Snn1 interaction which leads to susceptibility. SnTox1 was identified using bioinformatics tools and verified by heterologous expression in Pichia pastoris. SnTox1 encodes a 117 amino acid protein with the first 17 amino acids predicted as a signal peptide, and strikingly, the mature protein contains 16 cysteine residues, a common feature for some avirulence effectors. The transformation of SnTox1 into an avirulent S. nodorum isolate was sufficient to make the strain pathogenic. Additionally, the deletion of SnTox1 in virulent isolates rendered the SnTox1 mutated strains avirulent on the Snn1 differential wheat line. SnTox1 was present in 85% of a global collection of S. nodorum isolates. We identified a total of 11 protein isoforms and found evidence for strong diversifying selection operating on SnTox1. The SnTox1-Snn1 interaction results in an oxidative burst, DNA laddering, and pathogenesis related (PR) gene expression, all hallmarks of a defense response. In the absence of light, the development of SnTox1-induced necrosis and disease symptoms were completely blocked. By comparing the infection processes of a GFP-tagged avirulent isolate and the same isolate transformed with SnTox1, we conclude that SnTox1 may play a critical role during fungal penetration. This research further demonstrates that necrotrophic fungal pathogens utilize small effector proteins to exploit plant resistance pathways for their colonization, which provides important insights into the molecular basis of the wheat-S. nodorum interaction, an emerging model for necrotrophic pathosystems

DSYB catalyses the key step of dimethylsulfoniopropionate biosynthesis in many phytoplankton

Dimethylsulfoniopropionate (DMSP) is a globally important organosulfur molecule and the major precursor for dimethyl sulfide. These compounds are important info-chemicals, key nutrients for marine microorganisms, and are involved in global sulfur cycling, atmospheric chemistry and cloud formation1,2,3. DMSP production was thought to be confined to eukaryotes, but heterotrophic bacteria can also produce DMSP through the pathway used by most phytoplankton4, and the DsyB enzyme catalysing the key step of this pathway in bacteria was recently identified5. However, eukaryotic phytoplankton probably produce most of Earth’s DMSP, yet no DMSP biosynthesis genes have been identified in any such organisms. Here we identify functional dsyB homologues, termed DSYB, in many phytoplankton and corals. DSYB is a methylthiohydroxybutryate methyltransferase enzyme localized in the chloroplasts and mitochondria of the haptophyte Prymnesium parvum, and stable isotope tracking experiments support these organelles as sites of DMSP synthesis. DSYB transcription levels increased with DMSP concentrations in different phytoplankton and were indicative of intracellular DMSP. Identification of the eukaryotic DSYB sequences, along with bacterial dsyB, provides the first molecular tools to predict the relative contributions of eukaryotes and prokaryotes to global DMSP production. Furthermore, evolutionary analysis suggests that eukaryotic DSYB originated in bacteria and was passed to eukaryotes early in their evolution

Looking through the 'window of opportunity': is there a new paradigm of podiatry care on the horizon in early rheumatoid arthritis?

Over the past decade there have been significant advances in the clinical understanding and care of rheumatoid arthritis (RA). Major paradigm changes include earlier disease detection and introduction of therapy, and 'tight control' of follow-up driven by regular measurement of disease activity parameters. The advent of tumour necrosis factor (TNF) inhibitors and other biologic therapies have further revolutionised care. Low disease state and remission with prevention of joint damage and irreversible disability are achievable therapeutic goals. Consequently new opportunities exist for all health professionals to contribute towards these advances. For podiatrists relevant issues range from greater awareness of current concepts including early referral guidelines through to the application of specialist skills to manage localised, residual disease activity and associated functional impairments. Here we describe a new paradigm of podiatry care in early RA. This is driven by current evidence that indicates that even in low disease activity states destruction of foot joints may be progressive and associated with accumulating disability. The paradigm parallels the medical model comprising early detection, targeted therapy, a new concept of tight control of foot arthritis, and disease monitoring

Problem drug use the public health imperative: what some of the literature says

<p>Abstract</p> <p>Background</p> <p>With more than 200,000 problem drug users is contact with structured treatment services in England the public health imperative behind drug treatment is great. Problem drug use for many is a chronic and relapsing condition, where "cure" is often neither a reasonable or appropriate expectation and it can further be argued that in these circumstances problem drug use is no different from any number of chronic and enduring health conditions that are managed in the health care system and therefore should be conceptualised as such.</p> <p>Discussion</p> <p>A public health approach to drug treatment emphasises the need for drug users in or accessing treatment, to reduce their harmful drug use, reduce drug use related risks such as sepsis and overdose and stay alive for longer. However a public health perspective in relation to problem drug use isn't always either apparent or readily understood and to that end there is still a significant need to continue the arguments and debate that treatment and interventions for problem and dependent drug users need to extend beyond an individualistic approach. For the purposes of discussion in this article public and population health will be used interchangeably.</p> <p>Summary</p> <p>A recognition and acceptance that a public and population health approach to the management of problem drug users is sound public health policy also then requires a long term commitment in terms of staffing and resources where service delivery mirrors that of chronic condition management.</p

Lymphocyte recruitment and homing to the liver in primary biliary cirrhosis and primary sclerosing cholangitis

The mechanisms operating in lymphocyte recruitment and homing to liver are reviewed. A literature review was performed on primary biliary cirrhosis (PBC), progressive sclerosing cholangitis (PSC), and homing mechanisms; a total of 130 papers were selected for discussion. Available data suggest that in addition to a specific role for CCL25 in PSC, the CC chemokines CCL21 and CCL28 and the CXC chemokines CXCL9 and CXCL10 are involved in the recruitment of T lymphocytes into the portal tract in PBC and PSC. Once entering the liver, lymphocytes localize to bile duct and retain by the combinatorial or sequential action of CXCL12, CXCL16, CX3CL1, and CCL28 and possibly CXCL9 and CXCL10. The relative importance of these chemokines in the recruitment or the retention of lymphocytes around the bile ducts remains unclear. The available data remain limited but underscore the importance of recruitment and homing

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p