Methyl iodide poisoning presenting as a mimic of acute stroke: a case report

<p>Abstract</p> <p>Introduction</p> <p>Stroke mimics are usually non-vascular disease processes. These raise the possibility of a stroke and are common in clinical practice. It is necessary to distinguish these mimics in order to provide early and appropriate management, as well as reduce possible harm on our patient.</p> <p>Case presentation</p> <p>We report the case of a 50-year-old Caucasian man who developed symptoms suggestive of posterior circulation stroke after he was exposed to methyl iodide at his workplace. Results of stroke investigations of our patient were negative, and a detailed occupational history clinched the diagnosis. Acute presentation with a stroke-like picture is rare in cases of methyl iodide poisoning. We have attempted to discuss the differential diagnosis of stroke mimics through a review of literature.</p> <p>Conclusion</p> <p>Stroke mimics are difficult to diagnose in an emergency room situation and may be initially treated as stroke. This case report underlines the importance of history taking, especially occupational history, in the differential diagnosis of stroke. We also stress the need to recognize mimics at presentation in order to arrive at an early and appropriate management of patients.</p

Evolution favors protein mutational robustness in sufficiently large populations

BACKGROUND: An important question is whether evolution favors properties such as mutational robustness or evolvability that do not directly benefit any individual, but can influence the course of future evolution. Functionally similar proteins can differ substantially in their robustness to mutations and capacity to evolve new functions, but it has remained unclear whether any of these differences might be due to evolutionary selection for these properties. RESULTS: Here we use laboratory experiments to demonstrate that evolution favors protein mutational robustness if the evolving population is sufficiently large. We neutrally evolve cytochrome P450 proteins under identical selection pressures and mutation rates in populations of different sizes, and show that proteins from the larger and thus more polymorphic population tend towards higher mutational robustness. Proteins from the larger population also evolve greater stability, a biophysical property that is known to enhance both mutational robustness and evolvability. The excess mutational robustness and stability is well described by existing mathematical theories, and can be quantitatively related to the way that the proteins occupy their neutral network. CONCLUSIONS: Our work is the first experimental demonstration of the general tendency of evolution to favor mutational robustness and protein stability in highly polymorphic populations. We suggest that this phenomenon may contribute to the mutational robustness and evolvability of viruses and bacteria that exist in large populations

CD4 T Cell Immunity Is Critical for the Control of Simian Varicella Virus Infection in a Nonhuman Primate Model of VZV Infection

Primary infection with varicella zoster virus (VZV) results in varicella (more commonly known as chickenpox) after which VZV establishes latency in sensory ganglia. VZV can reactivate to cause herpes zoster (shingles), a debilitating disease that affects one million individuals in the US alone annually. Current vaccines against varicella (Varivax) and herpes zoster (Zostavax) are not 100% efficacious. Specifically, studies have shown that 1 dose of varivax can lead to breakthrough varicella, albeit rarely, in children and a 2-dose regimen is now recommended. Similarly, although Zostavax results in a 50% reduction in HZ cases, a significant number of recipients remain at risk. To design more efficacious vaccines, we need a better understanding of the immune response to VZV. Clinical observations suggest that T cell immunity plays a more critical role in the protection against VZV primary infection and reactivation. However, no studies to date have directly tested this hypothesis due to the scarcity of animal models that recapitulate the immune response to VZV. We have recently shown that SVV infection of rhesus macaques models the hallmarks of primary VZV infection in children. In this study, we used this model to experimentally determine the role of CD4, CD8 and B cell responses in the resolution of primary SVV infection in unvaccinated animals. Data presented in this manuscript show that while CD20 depletion leads to a significant delay and decrease in the antibody response to SVV, loss of B cells does not alter the severity of varicella or the kinetics/magnitude of the T cell response. Loss of CD8 T cells resulted in slightly higher viral loads and prolonged viremia. In contrast, CD4 depletion led to higher viral loads, prolonged viremia and disseminated varicella. CD4 depleted animals also had delayed and reduced antibody and CD8 T cell responses. These results are similar to clinical observations that children with agammaglobulinemia have uncomplicated varicella whereas children with T cell deficiencies are at increased risk of progressive varicella with significant complications. Moreover, our studies indicate that CD4 T cell responses to SVV play a more critical role than antibody or CD8 T cell responses in the control of primary SVV infection and suggest that one potential mechanism for enhancing the efficacy of VZV vaccines is by eliciting robust CD4 T cell responses

Somatic Mutagenesis with a Sleeping Beauty Transposon System Leads to Solid Tumor Formation in Zebrafish

Large-scale sequencing of human cancer genomes and mouse transposon-induced tumors has identified a vast number of genes mutated in different cancers. One of the outstanding challenges in this field is to determine which genes, when mutated, contribute to cellular transformation and tumor progression. To identify new and conserved genes that drive tumorigenesis we have developed a novel cancer model in a distantly related vertebrate species, the zebrafish, Danio rerio. The Sleeping Beauty (SB) T2/Onc transposon system was adapted for somatic mutagenesis in zebrafish. The carp ß-actin promoter was cloned into T2/Onc to create T2/OncZ. Two transgenic zebrafish lines that contain large concatemers of T2/OncZ were isolated by injection of linear DNA into the zebrafish embryo. The T2/OncZ transposons were mobilized throughout the zebrafish genome from the transgene array by injecting SB11 transposase RNA at the 1-cell stage. Alternatively, the T2/OncZ zebrafish were crossed to a transgenic line that constitutively expresses SB11 transposase. T2/OncZ transposon integration sites were cloned by ligation-mediated PCR and sequenced on a Genome Analyzer II. Between 700–6800 unique integration events in individual fish were mapped to the zebrafish genome. The data show that introduction of transposase by transgene expression or RNA injection results in an even distribution of transposon re-integration events across the zebrafish genome. SB11 mRNA injection resulted in neoplasms in 10% of adult fish at ∼10 months of age. T2/OncZ-induced zebrafish tumors contain many mutated genes in common with human and mouse cancer genes. These analyses validate our mutagenesis approach and provide additional support for the involvement of these genes in human cancers. The zebrafish T2/OncZ cancer model will be useful for identifying novel and conserved genetic drivers of human cancers

How to juggle priorities? An interactive tool to provide quantitative support for strategic patient-mix decisions: an ophthalmology case

An interactive tool was developed for the ophthalmology department of the Academic Medical Center to quantitatively support management with strategic patient-mix decisions. The tool enables management to alter the number of patients in various patient groups and to see the consequences in terms of key performance indicators. In our case study, we focused on the bottleneck: the operating room. First, we performed a literature review to identify all factors that influence an operating room's utilization rate. Next, we decided which factors were relevant to our study. For these relevant factors, two quantitative methods were applied to quantify the impact of an individual factor: regression analysis and computer simulation. Finally, the average duration of an operation, the number of cancellations due to overrun of previous surgeries, and the waiting time target for elective patients all turned out to have significant impact. Accordingly, for the case study, the interactive tool was shown to offer management quantitative decision support to act proactively to expected alterations in patient-mix. Hence, management can anticipate the future situation, and either alter the expected patient-mix or expand capacity to ensure that the key performance indicators will be met in the future

Urinary Proteomics to Support Diagnosis of Stroke

Accurate diagnosis in suspected ischaemic stroke can be difficult. We explored the urinary proteome in patients with stroke (n = 69), compared to controls (n = 33), and developed a biomarker model for the diagnosis of stroke. We performed capillary electrophoresis online coupled to micro-time-of-flight mass spectrometry. Potentially disease-specific peptides were identified and a classifier based on these was generated using support vector machine-based software. Candidate biomarkers were sequenced by liquid chromatography-tandem mass spectrometry. We developed two biomarker-based classifiers, employing 14 biomarkers (nominal p-value <0.004) or 35 biomarkers (nominal p-value <0.01). When tested on a blinded test set of 47 independent samples, the classification factor was significantly different between groups; for the 35 biomarker model, median value of the classifier was 0.49 (−0.30 to 1.25) in cases compared to −1.04 (IQR −1.86 to −0.09) in controls, p<0.001. The 35 biomarker classifier gave sensitivity of 56%, specificity was 93% and the AUC on ROC analysis was 0.86. This study supports the potential for urinary proteomic biomarker models to assist with the diagnosis of acute stroke in those with mild symptoms. We now plan to refine further and explore the clinical utility of such a test in large prospective clinical trials

Individual working memory capacity is uniquely correlated with feature-based attention when combined with spatial attention

A growing literature suggests that working memory and attention are closely related constructs. Both involve the selection of task-relevant information, and both are characterized by capacity limits. Furthermore, studies using a variety of methodological approaches have demonstrated convergent working memory and attention-related processing at the individual, neural and behavioral level. Given the varieties of both constructs, the specific kinds of attention and WM must be considered. We find that individuals’ working memory capacity (WMC) uniquely interacts with feature-based attention when combined with spatial attention in a cuing paradigm (Posner, 1980). Our findings suggest a positive correlation between WM and feature-based attention only within the spotlight of spatial attention. This finding lends support to the controlled attention view of working memory by demonstrating that integrated feature-based expectancies are uniquely correlated with individual performance on a working memory task

Microsecond Time-Resolved Absorption Spectroscopy Used to Study CO Compounds of Cytochrome bd from Escherichia coli

Cytochrome bd is a tri-heme (b558, b595, d) respiratory oxygen reductase that is found in many bacteria including pathogenic species. It couples the electron transfer from quinol to O2 with generation of an electrochemical proton gradient. We examined photolysis and subsequent recombination of CO with isolated cytochrome bd from Escherichia coli in oneelectron reduced (MV) and fully reduced (R) states by microsecond time-resolved absorption spectroscopy at 532-nm excitation. Both Soret and visible band regions were examined. CO photodissociation from MV enzyme possibly causes fast (t,1.5 ms) electron transfer from heme d to heme b595 in a small fraction of the protein, not reported earlier. Then the electron migrates to heme b558 (t,16 ms). It returns from the b-hemes to heme d with t,180 ms. Unlike cytochrome bd in the R state, in MV enzyme the apparent contribution of absorbance changes associated with CO dissociation from heme d is small, if any. Photodissociation of CO from heme d in MV enzyme is suggested to be accompanied by the binding of an internal ligand (L) at the opposite side of the heme. CO recombines with heme d (t,16 ms) yielding a transient hexacoordinate state (CO-Fe2+ -L). Then the ligand slowly (t,30 ms) dissociates from heme d. Recombination of CO with a reduced heme b in a fraction of the MV sample may also contribute to the 30-ms phase. In R enzyme, CO recombines to heme d (t,20 ms), some heme b558 (t,0.2–3 ms), and finally migrates from heme d to heme b595 (t,24 ms) in ,5% of the enzyme population. Data are consistent with the recent nanosecond study of Rappaport et al. conducted on the membranes at 640-nm excitation but limited to the Soret band. The additional phases were revealed due to differences in excitation and other experimental conditions

A cortical motor nucleus drives the basal ganglia-recipient thalamus in singing birds

The pallido-recipient thalamus transmits information from the basal ganglia to the cortex and is critical for motor initiation and learning. Thalamic activity is strongly inhibited by pallidal inputs from the basal ganglia, but the role of nonpallidal inputs, such as excitatory inputs from cortex, remains unclear. We simultaneously recorded from presynaptic pallidal axon terminals and postsynaptic thalamocortical neurons in a basal ganglia–recipient thalamic nucleus that is necessary for vocal variability and learning in zebra finches. We found that song-locked rate modulations in the thalamus could not be explained by pallidal inputs alone and persisted following pallidal lesion. Instead, thalamic activity was likely driven by inputs from a motor cortical nucleus that is also necessary for singing. These findings suggest a role for cortical inputs to the pallido-recipient thalamus in driving premotor signals that are important for exploratory behavior and learning.National Institutes of Health (U.S.) (Grant R01DC009183)National Institutes of Health (U.S.) (Grant K99NS067062)Damon Runyon Cancer Research Foundation (Postdoctoral Fellowship)Charles A. King Trust (Postdoctoral Fellowship

A Randomized Controlled Pilot Trial of Azithromycin or Artesunate Added to Sulfadoxine-Pyrimethamine as Treatment for Malaria in Pregnant Women

New anti-malarial regimens are urgently needed in sub-Saharan Africa because of the increase in drug resistance. We investigated the safety and efficacy of azithromycin or artesunate combined with sulfadoxine-pyrimethamine used for treatment of malaria in pregnant women in Blantyre, Malawi.This was a randomized open-label clinical trial, conducted at two rural health centers in Blantyre district, Malawi. A total of 141 pregnant women with uncomplicated Plasmodium falciparum malaria were recruited and randomly allocated to 3 treatment groups: sulfadoxine-pyrimethamine (SP; 3 tablets, 500 mg sulfadoxine and 25 mg pyrimethamine per tablet); SP plus azithromycin (1 g/dayx2 days); or SP plus artesunate (200 mg/dayx3 days). Women received two doses administered at least 4 weeks apart. Heteroduplex tracking assays were performed to distinguish recrudescence from new infections. Main outcome measures were incidence of adverse outcomes, parasite and fever clearance times and recrudescence rates. All treatment regimens were well tolerated. Two women vomited soon after ingesting azithromycin. The parasite clearance time was significantly faster in the SP-artesunate group. Recrudescent episodes of malaria were less frequent with SP-azithromycin [Hazard Ratio 0.19 (95% confidence interval 0.06 to 0.63)] and SP-artesunate [Hazard Ratio 0.25 (95% confidence interval 0.10 to 0.65)] compared with SP monotherapy. With one exception (an abortion in the SP-azithromycin group), all adverse pregnancy outcomes could be attributed to known infectious or obstetrical causes. Because of the small sample size, the effect on birth outcomes, maternal malaria or maternal anemia could not be evaluated.Both SP-artesunate and SP-azithromycin appeared to be safe, well tolerated and efficacious for the treatment of malaria during pregnancy. A larger study is needed to determine their safety and efficacy in preventing poor birth outcomes.ClinialTrials.gov NCT00287300