Focus: The Science of Stress: What are the Origins of Chronic Back Pain of “Obscure Origins”? Turning Toward Family and Workplace Social Contexts

Chronic back pain (CBP) is a common symptom throughout the world, and those undergoing it often experience a profound degradation of life. Despite extensive research, it remains an elusive symptom. In most cases, CBP is “non-specific,” since bio-mechanisms examined in the clinic do not account for it; another way of saying this is that it is “of obscure origins.” This paper re-directs attention towards origins that are distal and usually out of sight from the vantage point of the clinic. CBP as considered here is non-specific, persists ≥ 3 months, and, additionally, interferes with activities of daily life, such as family interaction or work. A theory proposed in the paper draws upon Durkheim’s Suicide to explain why exposures in the distal social contexts of family and workplace are fundamentally implicated in CBP. The theory is formed out of previously published studies on family and workplace social contexts of CBP and, in effect, provides a theoretical framework with which to review them. After treatment of CBP in the clinic, patients return to family and workplace contexts. Unless exposures in these contexts are addressed, they serve as continually renewing sources of CBP that remain unabated regardless of mechanism-based treatment in the clinic.     

Re-Examination of Globally Flat Space-Time

In the following, we offer a novel approach to modeling the observed effects currently attributed to the theoretical concepts of “dark energy,” “dark matter,” and “dark flow.” Instead of assuming the existence of these theoretical concepts, we take an alternative route and choose to redefine what we consider to be inertial motion as well as what constitutes an inertial frame of reference in flat space-time. We adopt none of the features of our current cosmological models except for the requirement that special and general relativity be local approximations within our revised definition of inertial systems. Implicit in our ideas is the assumption that at “large enough” scales one can treat objects within these inertial systems as point-particles having an insignificant effect on the curvature of space-time. We then proceed under the assumption that time and space are fundamentally intertwined such that time- and spatial-translational invariance are not inherent symmetries of flat space-time (i.e., observable clock rates depend upon both relative velocity and spatial position within these inertial systems) and take the geodesics of this theory in the radial Rindler chart as the proper characterization of inertial motion. With this commitment, we are able to model solely with inertial motion the observed effects expected to be the result of “dark energy,” “dark matter,” and “dark flow.” In addition, we examine the potential observable implications of our theory in a gravitational system located within a confined region of an inertial reference frame, subsequently interpreting the Pioneer anomaly as support for our redefinition of inertial motion. As well, we extend our analysis into quantum mechanics by quantizing for a real scalar field and find a possible explanation for the asymmetry between matter and antimatter within the framework of these redefined inertial systems.     

An Imputation Approach for Oligonucleotide Microarrays

Oligonucleotide microarrays are commonly adopted for detecting and qualifying the abundance of molecules in biological samples. Analysis of microarray data starts with recording and interpreting hybridization signals from CEL images. However, many CEL images may be blemished by noises from various sources, observed as “bright spots”, “dark clouds”, and “shadowy circles”, etc. It is crucial that these image defects are correctly identified and properly processed. Existing approaches mainly focus on detecting defect areas and removing affected intensities. In this article, we propose to use a mixed effect model for imputing the affected intensities. The proposed imputation procedure is a single-array-based approach which does not require any biological replicate or between-array normalization. We further examine its performance by using Affymetrix high-density SNP arrays. The results show that this imputation procedure significantly reduces genotyping error rates. We also discuss the necessary adjustments for its potential extension to other oligonucleotide microarrays, such as gene expression profiling. The R source code for the implementation of approach is freely available upon request.     

Correlation of Electrical and Permeability Properties of Ion-Selective Membranes

The linear phenomenological equations giving particle and practical fluxes of a single electrolyte across an ion-selective membrane are stated and interrelated. It is shown that the experimental measurements commonly made in biological and synthetic membrane studies may be used, with minor modification, to obtain the phenomenological transport coefficients and their concentration dependences. It is demonstrated that the electrical properties of a homogeneous membrane may be obtained as functions of the bathing solution concentration by combining fluxes measured under open and short circuit. Attention is paid to the use of radiotracers when measuring ionic fluxes. To obtain all the phenomenological coefficients at least one measurement must be made under a pressure gradient. The experimental difficulties in such measurements are discussed and the merits and demerits of various experiments considered. The problems of measuring potentials and concentrations at the low pressure face of a supported membrane make several mathematically simple approaches experimentally unattractive. The best methods appear to be either the measurement of a succession of “apparent osmotic pressures” under concentration differences sufficiently small that the membrane does not require support or the study of “reverse osmosis”. Sets of equations are given which enable the phenomenological coefficients to be evaluated from convenient experiments. With a stable homogeneous membrane nine coefficients may be obtained thus enabling either the applicability of the reciprocal relations or the applicability of linear theory under the conditions of the experiments to be tested. For a discontinuous system the six independent coefficients may be obtained from experiments in a single membrane cell.     

Genetic Distinctions among Clinical and Environmental Strains of Vibrio vulnificus

Vibrio vulnificus causes rare but frequently fatal septicemia associated with raw oyster consumption by persons with underlying hepatic or immune system dysfunction. The virulence potential of environmental reservoirs appears widely distributed, because most strains are virulent in animal models; however, several investigations recently demonstrated genetic divergence among strains from clinical versus environmental origin at independent genetic loci. The present study used PCR to screen DNA polymorphisms in strains from environmental (n = 35) or clinical (n = 33) sources, and genomic relationships were determined by repetitive extragenic palindromic DNA PCR (rep-PCR) typing. Significant (P < 0.01) association was observed for typical “clinical” or “environmental” polymorphism profiles based on strain origin. Most oyster isolates (88%), including all of those with the “environmental” profile, also formed a single rep-PCR genogroup. Clinical isolates within this group did not have the typical “clinical” profile. On the other hand, clinical isolates with the typical polymorphism profile were distributed among multiple rep-PCR genogroups, demonstrating greater genetic diversity than was evident by profiling genetic polymorphisms. Wound isolates were genetically distinct from typical blood isolates by all assays. Strains from an outbreak of wound infections in Israel (biotype 3) were closely related to several U.S. strains by rep-PCR, indicating potential reservoirs of emerging disease. Strains genetically related to blood isolates appeared to be relatively rare in oysters, as only one had the “clinical” polymorphism profile or clustered by rep-PCR. However, this study was not an extensive survey, and more sampling using rep-PCR for sensitive genetic discrimination is needed to determine the virulence potential of environmental reservoirs.     

Fecal Contamination of Drinking-Water in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis

Background

Access to safe drinking-water is a fundamental requirement for good health and is also a human right. Global access to safe drinking-water is monitored by WHO and UNICEF using as an indicator “use of an improved source,” which does not account for water quality measurements. Our objectives were to determine whether water from “improved” sources is less likely to contain fecal contamination than “unimproved” sources and to assess the extent to which contamination varies by source type and setting.

Methods and Findings

Studies in Chinese, English, French, Portuguese, and Spanish were identified from online databases, including PubMed and Web of Science, and grey literature. Studies in low- and middle-income countries published between 1990 and August 2013 that assessed drinking-water for the presence of Escherichia coli or thermotolerant coliforms (TTC) were included provided they associated results with a particular source type. In total 319 studies were included, reporting on 96,737 water samples. The odds of contamination within a given study were considerably lower for “improved” sources than “unimproved” sources (odds ratio [OR] = 0.15 [0.10–0.21], I² = 80.3% [72.9–85.6]). However over a quarter of samples from improved sources contained fecal contamination in 38% of 191 studies. Water sources in low-income countries (OR = 2.37 [1.52–3.71]; p<0.001) and rural areas (OR = 2.37 [1.47–3.81] p<0.001) were more likely to be contaminated. Studies rarely reported stored water quality or sanitary risks and few achieved robust random selection. Safety may be overestimated due to infrequent water sampling and deterioration in quality prior to consumption.

Conclusion

Access to an “improved source” provides a measure of sanitary protection but does not ensure water is free of fecal contamination nor is it consistent between source types or settings. International estimates therefore greatly overstate use of safe drinking-water and do not fully reflect disparities in access. An enhanced monitoring strategy would combine indicators of sanitary protection with measures of water quality. Please see later in the article for the Editors'' Summary     

Dogs (Canis familiaris) Evaluate Humans on the Basis of Direct Experiences Only

Reputation formation is a key component in the social interactions of many animal species. An evaluation of reputation is drawn from two principal sources: direct experience of an individual and indirect experience from observing that individual interacting with a third party. In the current study we investigated whether dogs use direct and/or indirect experience to choose between two human interactants. In the first experiment, subjects had direct interaction either with a “nice” human (who played with, talked to and stroked the dog) or with an “ignoring” experimenter who ignored the dog completely. Results showed that the dogs stayed longer close to the “nice” human. In a second experiment the dogs observed a “nice” or “ignoring” human interacting with another dog. This indirect experience, however, did not lead to a preference between the two humans. These results suggest that the dogs in our study evaluated humans solely on the basis of direct experience.     

Could Public Restrooms Be an Environment for Bacterial Resistomes?

Antibiotic resistance in bacteria remains a major problem and environments that help to maintain such resistance, represent a significant problem to infection control in the community. Restrooms have always been regarded as potential sources of infectious diseases and we suggest they have the potential to sustain bacterial “resistomes”. Recent studies have demonstrated the wide range of different bacterial phyla that can be found in non-healthcare restrooms. In our study we focused on the Staphylococci. These species are often skin contaminants on man and have been reported as common restroom isolates in recent molecular studies. We collected samples from 18 toilets sited in 4 different public buildings. Using MALDI-TOF-MS and other techniques, we identified a wide range of antibiotic resistant Staphylococci and other bacteria from our samples. We identified 19 different Staphylococcal species within our isolates and 37.8% of the isolates were drug resistant. We also identified different Staphylococcal species with the same antibiograms inhabiting the same restrooms. Bacterial “resistomes” are communities of bacteria often localised in specific areas and within these environments drug resistance determinants may be freely transferred. Our study shows that non-healthcare restrooms are a source of antibiotic resistant bacteria where a collection of antibiotic resistance genes in pathogenic and non-pathogenic bacteria could form a resistome containing a “nexus of genetic diversity”     

Elemental Fingerprinting of Mussel Shells to Predict Population Sources and Redistribution Potential in the Gulf of Maine

As the climate warms, species that cannot tolerate changing conditions will only persist if they undergo range shifts. Redistribution ability may be particularly variable for benthic marine species that disperse as pelagic larvae in ocean currents. The blue mussel, Mytilus edulis, has recently experienced a warming-related range contraction in the southeastern USA and may face limitations to northward range shifts within the Gulf of Maine where dominant coastal currents flow southward. Thus, blue mussels might be especially vulnerable to warming, and understanding dispersal patterns is crucial given the species'' relatively long planktonic larval period (>1 month). To determine whether trace elemental “fingerprints” incorporated in mussel shells could be used to identify population sources (i.e. collection locations), we assessed the geographic variation in shell chemistry of blue mussels collected from seven populations between Cape Cod, Massachusetts and northern Maine. Across this ∼500 km of coastline, we were able to successfully predict population sources for over two-thirds of juvenile individuals, with almost 80% of juveniles classified within one site of their collection location and 97% correctly classified to region. These results indicate that significant differences in elemental signatures of mussel shells exist between open-coast sites separated by ∼50 km throughout the Gulf of Maine. Our findings suggest that elemental “fingerprinting” is a promising approach for predicting redistribution potential of the blue mussel, an ecologically and economically important species in the region.     

Association between stressful life events and exacerbation in multiple sclerosis: a meta-analysis

Objective To quantify the association between stressful life events and exacerbations of multiple sclerosis.Data sources PubMed, PsychInfo, and Psychological Abstracts searched for empirical papers from 1965 to February 2003 with terms “stress”, “trauma”, and “multiple sclerosis”.Review methods Three investigators independently reviewed papers for inclusion/exclusion criteria and extracted the relevant data, including methods, sample statistics, and outcomes.Results Of 20 studies identified, 14 were included. The meta-analysis showed a significant increase in risk of exacerbation in multiple sclerosis after stressful life events, with a weighted average effect size of d = 0.53 (95% confidence interval 0.40 to 0.65), P < 0.0001. The studies were homogenous, Q = 16.62, P = 0.22, I² = 21.8%. Neither sampling nor study methods had any effect on study outcomes.Conclusions There is a consistent association between stressful life events and subsequent exacerbation in multiple sclerosis. However these data do not allow the linking of specific stressors to exacerbations nor should they be used to infer that patients are responsible for their exacerbations. Investigation of the psychological, neuroendocrine, and immune mediators of stressful life events on exacerbation may lead to new behavioural and pharmacological strategies targeting potential links between stress and exacerbation.     

Experiences of Community-Living Older Adults Receiving Integrated Care Based on the Chronic Care Model: A Qualitative Study

BackgroundIntegrated care models aim to solve the problem of fragmented and poorly coordinated care in current healthcare systems. These models aim to be patient-centered by providing continuous and coordinated care and by considering the needs and preferences of patients. The objective of this study was to evaluate the opinions and experiences of community-living older adults with regard to integrated care and support, along with the extent to which it meets their health and social needs.MethodsSemi-structured interviews were conducted with 23 older adults receiving integrated care and support through “Embrace,” an integrated care model for community-living older adults that is based on the Chronic Care Model and a population health management model. Embrace is currently fully operational in the northern region of the Netherlands. Data analysis was based on the grounded theory approach.ResultsResponses of participants concerned two focus areas: 1) Experiences with aging, with the themes “Struggling with health,” “Increasing dependency,” “Decreasing social interaction,” “Loss of control,” and “Fears;” and 2) Experiences with Embrace, with the themes “Relationship with the case manager,” “Interactions,” and “Feeling in control, safe, and secure”. The prospect of becoming dependent and losing control was a key concept in the lives of the older adults interviewed. Embrace reinforced the participants’ ability to stay in control, even if they were dependent on others. Furthermore, participants felt safe and secure, in contrast to the fears of increasing dependency within the standard care system.ConclusionThe results indicate that integrated care and support provided through Embrace met the health and social needs of older adults, who were coping with the consequences of aging.     

Characterization of Chlorinated Aliphatic Hydrocarbons and Environmental Variables in a Shallow Groundwater in Shanghai Using Kriging Interpolation and Multifactorial Analysis

CAHs, as a cleaning solvent, widely contaminated shallow groundwater with the development of manufacturing in China''s Yangtze River Delta. This study focused on the distribution of CAHs, and correlations between CAHs and environmental variables in a shallow groundwater in Shanghai, using kriging interpolation and multifactorial analysis. The results showed that the overall CAHs plume area (above DIV) was approximately 9,000 m² and located in the 2–4 m underground, DNAPL was accumulated at an area of approximately 1,400 m² and located in the 6-8m sandy silt layer on the top of the muddy silty clay. Heatmap of PPC for CAHs and environmental variables showed that the correlation between “Fe²⁺” and most CAHs such as “1,1,1-TCA”, “1,1-DCA”, “1,1-DCE” and “%TCA” were significantly positive (p<0.001), but “%CA” and/or “%VC” was not, and “Cl^-” was significantly positive correlated with “1,1-DCA” and “1,1-DCE” (p<0.001). The PCA demonstrated that the relative proportions of CAHs in groundwater were mostly controlled by the sources and the natural attenuation. In conclusion, the combination of geographical and chemometrics was helpful to establishing an aerial perspective of CAHs and identifying reasons for the accumulation of toxic dechlorination intermediates, and could become a useful tool for characterizing contaminated sites in general.     

Exchange Properties of Isolated Cell Walls of Lemna minor L

From our theoretical treatment which is an extension of the classical Donnan theory, we have estimated the rational selectivity coefficients of the carboxylic groups of the walls during exchanges of divalent ions against monovalent ones (i.e. calcium and potassium or calcium and sodium ions). These coefficients express the interactions between the different ions, those between the counter-ions and the ionized groups of the wall, and the influence of water. These quantitative values are consistent with the great affinity of the carboxylic groups for the calcium ions. They vary with the experimental conditions, showing a purely physicochemical mechanism of “regulation” of the exchanges in the cells walls of Lemna minor L.     

The Potential Regulatory Mechanisms of miR-196a in Huntington’s Disease through Bioinformatic Analyses

High throughput screening is a powerful tool to identify the potential candidate molecules involved during disease progression. However, analysis of complicated data is one of the most challenging steps on the way to obtaining useful results from this approach. Previously, we showed that a specific miRNA, miR-196a, could ameliorate the pathological phenotypes of Huntington’s disease (HD) in different models, and performed high throughput screening by using the striatum of transgenic mice. In this study, we further tried to identify the potential regulatory mechanisms using different bioinformatic tools, including Database for Annotation, Visualization and Integrated Discovery (DAVID), Molecular Signatures Database (MSigDB), TargetScan and MetaCore. The results showed that miR-196a dominantly altered “ABC transporters”, “RIG-I-like receptor signaling pathway”, immune system”, “adaptive immune system”,“tissue remodeling and wound repair” and “cytoskeleton remodeling”. In addition, miR-196a also changed the expression of several well-defined pathways of HD, such as apoptosis and cell adhesion. Since these analyses showed the regulatory pathways are highly related to the modification of the cytoskeleton, we further confirmed that miR-196a could enhance the neurite outgrowth in neuroblastoma cells, suggesting miR-196a might provide beneficial functions through the alteration of cytoskeleton structures. Since impairment of the cytoskeleton has been reported in several neuronal diseases, this study will provide not only the potential working mechanisms of miR-196a but also insights for therapeutic strategies for use with different neuronal diseases.     

Patent and Exclusivity Status of Essential Medicines for Non-Communicable Disease

Objective

The threat of non-communicable diseases (“NCDs”) is increasingly becoming a global health crisis and are pervasive in high, middle, and low-income populations resulting in an estimated 36 million deaths per year. There is a need to assess intellectual property rights (“IPRs”) that may impede generic production and availability and affordability to essential NCD medicines.

Methods

Using the data sources listed below, the study design systematically eliminated NCD drugs that had no patent/exclusivity provisions on API, dosage, or administration route. The first step identified essential medicines that treat certain high disease burden NCDs. A second step examined the patent and exclusivity status of active ingredient, dosage and listed route of administration using exclusion criteria outlined in this study.

Materials

We examined the patent and exclusivity status of medicines listed in the World Health Organization’s (“WHO”) Model List of Essential Drugs (Medicines) (“MLEM”) and other WHO sources for drugs treating certain NCDs. i.e., cardiovascular and respiratory disease, cancers, and diabetes. We utilized the USA Food and Drug Administration Orange Book and the USA Patent and Trademark Office databases as references given the predominant number of medicines registered in the USA.

Results

Of the 359 MLEM medicines identified, 22% (79/359) address targeted NCDs. Of these 79, only eight required in-depth patent or exclusivity assessment. Upon further review, no NCD MLEM medicines had study patent or exclusivity protection for reviewed criteria.

Conclusions

We find that ensuring availability and affordability of potential generic formulations of NCD MLEM medicines appears to be more complex than the presence of IPRs with API, dosage, or administration patent or exclusivity protection. Hence, more sophisticated analysis of NCD barriers to generic availability and affordability should be conducted in order to ensure equitable access to global populations for these essential medicines.     

X-Ray Solution Scattering of Squid Heavy Meromyosin: Strengthening the Evidence for an Ancient Compact off State

The overall conformations of regulated myosins or heavy meromyosins from chicken/turkey, scallop, tarantula, limulus, and scorpion sources have been studied by a number of techniques, including electron microscopy, sedimentation, and pulsed electron paramagnetic resonance. These studies have indicated that the binding of regulatory ions changes the conformation of the molecule from a compact shape found in the “off” state of the muscle to extended relationships between the tail and independently mobile heads that predominate in the “on” state. Here we strengthen the argument for the generality of this conformational change by using small angle X-ray scattering on heavy meromyosin from squid. Small angle X-ray scattering allows the protein to be visualized in solution under mild and relatively physiological conditions, and squid differs from the other species studied by at least 500 million years of evolution. Analysis of the data indicates that upon addition of Ca²⁺ the radius of gyration increases. Differences in the squid “on” and “off” states are clearly distinguishable as bimodal and unimodal pair distance distribution functions respectively. These observations are consistent with a Ca²⁺-free squid heavy meromyosin that is compact, but which becomes extended when Ca²⁺ is bound. Further, the scattering profile derived from the current model of tarantula heavy meromyosin in the “off” state is in excellent agreement with the measured “off” state scattering profile for squid heavy meromyosin. The previous and current studies together provide significant evidence that regulated myosin''s compact off-state conformation is an ancient trait, inherited from a common ancestor during divergent evolution.     

Bayesian Analysis of Congruence of Core Genes in Prochlorococcus and Synechococcus and Implications on Horizontal Gene Transfer

It is often suggested that horizontal gene transfer is so ubiquitous in microbes that the concept of a phylogenetic tree representing the pattern of vertical inheritance is oversimplified or even positively misleading. “Universal proteins” have been used to infer the organismal phylogeny, but have been criticized as being only the “tree of one percent.” Currently, few options exist for those wishing to rigorously assess how well a universal protein phylogeny, based on a relative handful of well-conserved genes, represents the phylogenetic histories of hundreds of genes. Here, we address this problem by proposing a visualization method and a statistical test within a Bayesian framework. We use the genomes of marine cyanobacteria, a group thought to exhibit substantial amounts of HGT, as a test case. We take 379 orthologous gene families from 28 cyanobacteria genomes and estimate the Bayesian posterior distributions of trees – a “treecloud” – for each, as well as for a concatenated dataset based on putative “universal proteins.” We then calculate the average distance between trees within and between all treeclouds on various metrics and visualize this high-dimensional space with non-metric multidimensional scaling (NMMDS). We show that the tree space is strongly clustered and that the universal protein treecloud is statistically significantly closer to the center of this tree space than any individual gene treecloud. We apply several commonly-used tests for incongruence/HGT and show that they agree HGT is rare in this dataset, but make different choices about which genes were subject to HGT. Our results show that the question of the representativeness of the “tree of one percent” is a quantitative empirical question, and that the phylogenetic central tendency is a meaningful observation even if many individual genes disagree due to the various sources of incongruence.     

Tuberculosis Prevention in South Africa

Background

South Africa has one of the highest per capita rates of tuberculosis (TB) incidence in the world. In 2012, the South African government produced a National Strategic Plan (NSP) to control the spread of TB with the ambitious aim of zero new TB infections and deaths by 2032, and a halving of the 2012 rates by 2016.

Methods

We used a transmission model to investigate whether the NSP targets could be reached if immediate scale up of control methods had happened in 2014. We explored the potential impact of four intervention portfolios; 1) “NSP” represents the NSP strategy, 2) “WHO” investigates increasing antiretroviral therapy eligibility, 3) “Novel Strategies” considers new isoniazid preventive therapy strategies and HIV “Universal Test and Treat” and 4) “Optimised” contains the most effective interventions.

Findings

We find that even with this scale-up, the NSP targets are unlikely to be achieved. The portfolio that achieved the greatest impact was “Optimised”, followed closely by “NSP”. The “WHO” and “Novel Strategies” had little impact on TB incidence by 2050. Of the individual interventions explored, the most effective were active case finding and reductions in pre-treatment loss to follow up which would have a large impact on TB burden.

Conclusion

Use of existing control strategies has the potential to have a large impact on TB disease burden in South Africa. However, our results suggest that the South African TB targets are unlikely to be reached without new technologies. Despite this, TB incidence could be dramatically reduced by finding and starting more TB cases on treatment.