Temperature-controlled masking/unmasking of cell-adhesive cues with poly(ethylene glycol) methacrylate based brushes.
Thin, thermoresponsive polymer coatings that allow to reversibly modulate cell adhesion and detachment are attractive substrates for cell sheet engineering. Usually, this is accomplished by applying thin poly(N-isopropylacrylamide) (PNIPAM) coatings, which allow cell adhesion via nonspecific interactions above the collapse temperature (T(T)) of the surface-attached polymer and cell detachment upon cooling below T(T). This Article presents an alternative, thermoresponsive polymer platform that is based on 2-(2-methoxyethoxy)ethyl methacrylate (MEO2MA) containing copolymer brushes prepared via surface-initiated atom transfer radical polymerization (SI-ATRP). These brushes are interesting as they gradually collapse and dehydrate upon increasing the temperature from 10 to 40 °C, yet resist nonspecific adhesion of cells over this entire temperature window. The MEO2MA based brushes presented here were modified via a two-step postpolymerization modification protocol to introduce cell-adhesive RGD containing peptide ligands. The possibility to reversibly control the swelling and collapse of these brush films by varying temperature allows to modulate the effectively available surface concentration of these cell-adhesive cues and thus provides a way to mask/unmask their biological activity. As a first proof of concept, this Article demonstrates that these MEO2MA brush copolymer films enable integrin-mediated adhesion of 3T3 fibroblasts at 37 °C and allow release of these cells by cooling to 23 °C. The use of cell-adhesive ligands, which can be thermoreversibly masked/unmasked, is attractive as it enables the use of serum-free cell culture conditions. This is advantageous since it avoids possible concerns regarding eventual toxicity and immunological side effects of serum proteins and also provides opportunities to select for particular cell types and for enhanced control over cell stimulation and differentiation.


T1 adenocarcinoma of the rectum: transanal excision or radical surgery?
Recent studies suggest local excision may be acceptable treatment of T1 adenocarcinoma of the rectum, but there is little comparative data with radical surgery to assess outcomes and quantify risk. We performed a retrospective evaluation of patients with T1 rectal cancers treated by either transanal excision or radical resection at our institution to assess patient selection, cancer recurrence, and survival. All patients who underwent surgery for T1 adenocarcinomas of the rectum (0-15 cm from anal verge) by either transanal excision (TAE) or radical resection (RAD) between January 1987 and January 2004 were identified from a prospective database. Data were analyzed using Fisher exact test, Kaplan-Meier method, and log-rank test. Three hundred nineteen consecutive patients with T1 lesions were treated by transanal excision (n = 151) or radical surgery (n = 168) over the 17-year period. RAD surgery was associated with higher tumor location in the rectum, slightly larger tumor size, a similar rate of adverse histology, and a lymph node metastasis rate of 18%. Despite these features, patients who underwent RAD surgery had fewer local recurrences, fewer distant recurrences, and significantly better recurrence-free survival (P = 0.0001). Overall and disease-specific survival was similar for RAD and TAE groups. Despite a similar risk profile in the 2 surgical groups, patients with T1 rectal cancer treated by local excision were observed to have a 3- to 5-fold higher risk of tumor recurrence compared with patients treated by radical surgery. Local excision should be reserved for low-risk cancers in patients who will accept an increased risk of tumor recurrence, prolonged surveillance, and possible need for aggressive salvage surgery. Radical resection is the more definitive surgical treatment of T1 rectal cancers.


Diffuse reflectance spectroscopy of human adenomatous colon polyps in vivo.
Diffuse reflectance spectra were collected from adenomatous colon polyps (cancer precursors) and normal colonic mucosa of patients undergoing colonoscopy. We analyzed the data by using an analytical light diffusion model, which was tested and validated on a physical tissue model composed of polystyrene beads and hemoglobin. Four parameters were obtained: hemoglobin concentration, hemoglobin oxygen saturation, effective scatterer density, and effective scatterer size. Normal and adenomatous tissue sites exhibited differences in hemoglobin concentration and, on average, in effective scatterer size, which were in general agreement with other studies that employ standard methods. These results suggest that diffuse reflectance can be used to obtain tissue information about tissue structure and composition in vivo.


Developing multiplexed assays for troponin I and interleukin-33 in plasma by peptide immunoaffinity enrichment and targeted mass spectrometry.
Protein biomarker candidates from discovery proteomics must be quantitatively verified in patient samples before they can progress to clinical validation. Here we demonstrate that peptide immunoaffinity enrichment coupled with stable isotope dilution mass spectrometry (SISCAPA-MRM) can be used to configure assays with performance suitable for candidate biomarker verification. As proof of principle, we configured SISCAPA assays for troponin I (cTnI), an established biomarker of cardiac injury, and interleukin 33 (IL-33), an emerging immunological and cardiovascular marker for which robust immunoassays are currently not available. We configured individual and multiplexed assays in which peptides were enriched from digested human plasma using antipeptide antibodies. Assay performance was established using response curves for peptides and proteins spiked into normal plasma. We quantified proteins using labeled peptides as internal standards, and we measured levels of cTnI in patients who underwent a planned myocardial infarction for hypertrophic obstructive cardiomyopathy. Measurement of cTnI and IL-33 proteins from trypsin-digested plasma was linear from 1.5 to 5000 microg/L, with imprecision <13% for both proteins, processed individually or multiplexed. Results correlated well (R = 0.89) with a commercial immunoassay. We used an established biomarker of cardiac injury and an emerging biomarker to demonstrate how SISCAPA can detect and quantify changes in concentration of proteins present at 1-10 microg/L in plasma. Our results demonstrate that these assays can be multiplexed and retain the necessary precision, reproducibility, and sensitivity to be applied to new and uncharacterized candidate biomarkers for verification of low-abundance proteins in blood.


Rotating orthogonal polarization imaging.
Surface reflections often present a problem in the polarization difference imaging of tissue. The technique described involves illumination in a single polarization state and detection in the orthogonal polarization state. Synchronously rotating both the illumination and orthogonal detection states provides an image free from surface reflections that is sensitive to the polarization properties of the underlying tissue. Results on tissue phantoms demonstrate that polarization sensitive measurements of a test target can be made up to a depth of 12 mean free paths within a scattering medium. Preliminary images of bovine tendon are also demonstrated.


Left ventricular wall stress and systolic function in untreated primary hypertension.
A noninvasive investigation was undertaken in four blood pressure (BP) groups of untreated 49-year-old men derived by screening a random population sample: normotensive men (n = 20) and subjects with borderline (n = 30), mild (n = 45), or moderate BP elevation (n = 24). We here report the findings regarding left ventricular (LV) wall stress, LV wall thickness, and LV systolic function. Although there was an increase in LV wall thickness with hypertension, the raised BP was not compensated for by a sufficient degree of LV wall thickening to keep wall stress within normal limits in the hypertensive groups. Among a subset of individuals with pronounced increase in wall thickness peak systolic wall stress approached the normal range, but end-systolic wall stress was still high. In spite of high wall stress LV systolic function was normal or supranormal in the hypertensive men. The LV ejection phase indices showed a close inverse correlation with end-systolic wall stress (r = -0.67 to -0.84) in all four BP groups, but no correlation or only a weak correlation with peak systolic wall stress (r = 0.18 to -0.40). As judged from the relationship between end-systolic wall stress and ejection phase indices of LV function in the normotensive controls, all hypertensive groups had higher than expected values for LV ejection phase indices, which indicates an increased myocardial contractility secondary to adrenergic stimulation or to a more efficient contractile machinery in the myocardial cells.


A central master driver of psychosocial stress responses in the rat.
The mechanism by which psychological stress elicits various physiological responses is unknown. We discovered a central master neural pathway in rats that drives autonomic and behavioral stress responses by connecting the corticolimbic stress circuits to the hypothalamus. Psychosocial stress signals from emotion-related forebrain regions activated a VGLUT1-positive glutamatergic pathway from the dorsal peduncular cortex and dorsal tenia tecta (DP/DTT), an unexplored prefrontal cortical area, to the dorsomedial hypothalamus (DMH), a hypothalamic autonomic center. Genetic ablation and optogenetics revealed that the DP/DTT→DMH pathway drives thermogenic, hyperthermic, and cardiovascular sympathetic responses to psychosocial stress without contributing to basal homeostasis. This pathway also mediates avoidance behavior from psychosocial stressors. Given the variety of stress responses driven by the DP/DTT→DMH pathway, the DP/DTT can be a potential target for treating psychosomatic disorders.


Self-empowerment of life through RNA networks, cells and viruses.
Our understanding of the key players in evolution and of the development of all organisms in all domains of life has been aided by current knowledge about RNA stem-loop groups, their proposed interaction motifs in an early RNA world and their regulative roles in all steps and substeps of nearly all cellular processes, such as replication, transcription, translation, repair, immunity and epigenetic marking. Cooperative evolution was enabled by promiscuous interactions between single-stranded regions in the loops of naturally forming stem-loop structures in RNAs. It was also shown that cooperative RNA stem-loops outcompete selfish ones and provide foundational self-constructive groups (ribosome, editosome, spliceosome, etc.). Self-empowerment from abiotic matter to biological behavior does not just occur at the beginning of biological evolution; it is also essential for all levels of socially interacting RNAs, cells and viruses.


Environment and obesity in the National Children's Study.
In this review we describe the approach taken by the National Children's Study (NCS), a 21-year prospective study of 100,000 American children, to understanding the role of environmental factors in the development of obesity. We review the literature with regard to the two core hypotheses in the NCS that relate to environmental origins of obesity and describe strategies that will be used to test each hypothesis. Although it is clear that obesity in an individual results from an imbalance between energy intake and expenditure, control of the obesity epidemic will require understanding of factors in the modern built environment and chemical exposures that may have the capacity to disrupt the link between energy intake and expenditure. The NCS is the largest prospective birth cohort study ever undertaken in the United States that is explicitly designed to seek information on the environmental causes of pediatric disease. Through its embrace of the life-course approach to epidemiology, the NCS will be able to study the origins of obesity from preconception through late adolescence, including factors ranging from genetic inheritance to individual behaviors to the social, built, and natural environment and chemical exposures. It will have sufficient statistical power to examine interactions among these multiple influences, including gene-environment and gene-obesity interactions. A major secondary benefit will derive from the banking of specimens for future analysis.


Critical evaluation of models for self-assembly of short and medium chain-length surfactants in aqueous solutions.
During numerous visits to our Laboratory professor Johannes (Hans) Lyklema emphasized the importance of a holistic view on thermodynamics. In order to fulfill this aim he assembled the monumental Fundamentals of Interface and Colloid Science series. The basic state functions (internal energy, enthalpy and free energies) are interrelated by Gibbs and Helmholtz relationships. First-order phase transitions are characterized by first-order state variables (temperature, pressure, entropy, volume). Interactions are, however best expressed by second-order partial derivatives (compressibility, heat capacity and expansivity). They are related to the first-order state variables by relaxation contributions quantifying the degree of cooperativity of self-assembly processes leading to phase separation. In particular they exhibit the limit when phase transitions are changed to second-order processes. This was the focus of my first review dedicated to the memory of professor Lyklema, "Characterization of van der Waals type bimodal,- lambda,- meta- and spinodal phase transitions in liquid mixtures, solid suspensions and thin films" (ACIS 253 (2018) 66). In the present review the attention is placed on short and medium chain-length surfactant self-assembly in aqueous solutions without additives (salts or solubilizates). The dependence of state functions described above on concentration, temperature and pressure is compared to corresponding dynamic molecular processes occurring on different time, frequency and length scales including structure analysis. It is convincingly shown that Hartley-Tanford space filled spherical anhydrous micelle core - polar shell model designed for long chain-length surfactants (cmc < 0.01 mol/dm3, N > 50) cannot be enforced on short and medium chain-length surfactant non-sperical micelles (cmc close to unity, N < 20). Moreover, it is shown that a proper validity evaluation of proposed models for micelle formation is seriously undermined by their application to only a narrow concentration range near critical micelle concentration (cmc). When successful each model should characterize all self-assembly processes occurring (also at limiting association concentration, lac, at second critical concentration, 2cc and at third critical concen-tration, 3cc) within the entire concentration range of thermodynamically stable surfactant solutions. All other self-assembly processes except micelle formation are rarely considered. The pre-micelle formation at lac is, for example omitted as deviations from presented models. The reviewed reports are therefore selected on the basis of maximum investigated concentration range and of largest possible number of homologues.


Provitamin A carotenoids are independently associated with matrix metalloproteinase-9 in plasma samples from a general population.
Carotenoids in plasma are inversely associated with cardiovascular risk. Low levels can be explained by low dietary intake but also by a number of other factors including inflammatory activity. Given that matrix metalloproteinase (MMP)-9 has an important role in inflammation and cardiovascular disease, we hypothesized that circulating MMP-9 levels would be inversely related to total or single carotenoids in a general population cohort. A well-characterized population-based cohort of 285 Swedish men and women (45-69 years) was used for the present study. The intake of carotenoid-rich fruits and vegetables was estimated from a food frequency questionnaire. Levels of MMP-9, C-reactive protein (CRP), interleukin (IL)-6 and six major carotenoids [β-cryptoxanthine, α-carotene, β-carotene, lutein (+zeaxanthin) and lycopene] were determined in plasma. Lower plasma levels of total and single carotenoids were associated with lower dietary intake of carotenoids, older age, male sex, lower physical activity, higher alcohol consumption, higher body mass index (BMI), higher systolic and diastolic blood pressures, lower levels of total cholesterol and HDL cholesterol and higher levels of CRP, IL-6 and MMP-9. After multivariate adjustments, plasma levels of total carotenoids and provitamin A carotenoids (β-cryptoxanthine, α-carotene and β-carotene) remained independently associated with sex, dietary intake of carotenoids, BMI, HDL cholesterol and MMP-9, whilst associations with CRP and IL-6 were not maintained. Neither dietary intake of carotenoid-rich fruits and vegetables, nor vitamin supplement use was associated with MMP-9, CRP or IL-6 levels. Plasma carotenoids were associated with a variety of factors including age, sex, dietary intake and metabolic variables. A new finding was the independent relationship in plasma between low provitamin A carotenoids and high MMP-9, suggesting a link between these carotenoids, matrix turnover and arterial remodelling.


Phosphodiesterase beta is the master regulator of cAMP signalling during malaria parasite invasion.
Cyclic nucleotide signalling is a major regulator of malaria parasite differentiation. Phosphodiesterase (PDE) enzymes are known to control cyclic GMP (cGMP) levels in the parasite, but the mechanisms by which cyclic AMP (cAMP) is regulated remain enigmatic. Here, we demonstrate that Plasmodium falciparum phosphodiesterase β (PDEβ) hydrolyses both cAMP and cGMP and is essential for blood stage viability. Conditional gene disruption causes a profound reduction in invasion of erythrocytes and rapid death of those merozoites that invade. We show that this dual phenotype results from elevated cAMP levels and hyperactivation of the cAMP-dependent protein kinase (PKA). Phosphoproteomic analysis of PDEβ-null parasites reveals a >2-fold increase in phosphorylation at over 200 phosphosites, more than half of which conform to a PKA substrate consensus sequence. We conclude that PDEβ plays a critical role in governing correct temporal activation of PKA required for erythrocyte invasion, whilst suppressing untimely PKA activation during early intra-erythrocytic development.


Longitudinal trends in malaria testing rates in the face of elimination in eastern Myanmar: a 7-year observational study.
Providing at-risk communities with uninterrupted access to early diagnosis and treatment is a key component in reducing malaria transmission and achieving elimination. As programmes approach malaria elimination targets it is critical that each case is tested and treated early, which may present a challenge when the burden of malaria is reduced. In this paper we investigate whether malaria testing rates decline over time and assess the impacts of integrating malaria and non-malaria services on testing rates in the malaria elimination task force (METF) programme in the Kayin state of Myanmar. A retrospective analysis was conducted using weekly collected data on testing rates from a network of more than 1200 malaria posts during the period from 2014 to 2020. To determine whether monthly testing rates changed over the years of programme operations, and whether integrating malaria and non-malaria services impacted these testing rates, we fitted negative binomial mixed-effects regression models to aggregate monthly data, accounting for malaria seasonal variation. In the first year of malaria post operation, testing rates declined, correlating with a decline in attendance by people from outside the malaria post catchment area, but then remained fairly constant (the Rate Ratio (RR) for 2nd versus 1st year open ranged from 0.68 to 0.84 across the four townships included in the analysis, the RR for 3rd to 6th year versus 1st year open were similar, ranging from 0.59-0.78). The implementation of a training programme, which was intended to expand the role of the malaria post workers, had minimal impact on testing rates up to 24 months after training was delivered (RR for integrated versus malaria-only services ranged from 1.00 to 1.07 across METF townships). Despite the decline in malaria incidence from 2014 to 2020, there has been no decline in the malaria testing rate in the METF programme after the establishment of the complete malaria post network in 2016. While the integration of malaria posts with other health services provides benefits to the population, our evaluation questions the necessity of integrated services in maintaining malaria testing rates in areas approaching elimination of malaria.


Accumulation of differentiating intestinal stem cell progenies drives tumorigenesis.
Stem cell self-renewal and differentiation are coordinated to maintain tissue homeostasis and prevent cancer. Mutations causing stem cell proliferation are traditionally the focus of cancer studies. However, the contribution of the differentiating stem cell progenies in tumorigenesis is poorly characterized. Here we report that loss of the SOX transcription factor, Sox21a, blocks the differentiation programme of enteroblast (EB), the intestinal stem cell progeny in the adult Drosophila midgut. This results in EB accumulation and formation of tumours. Sox21a tumour initiation and growth involve stem cell proliferation induced by the unpaired 2 mitogen released from accumulating EBs generating a feed-forward loop. EBs found in the tumours are heterogeneous and grow towards the intestinal lumen. Sox21a tumours modulate their environment by secreting matrix metalloproteinase and reactive oxygen species. Enterocytes surrounding the tumours are eliminated through delamination allowing tumour progression, a process requiring JNK activation. Our data highlight the tumorigenic properties of transit differentiating cells.


Restriction fragment length polymorphism mapping of quantitative trait loci for malaria parasite susceptibility in the mosquito Aedes aegypti.
Susceptibility of the mosquito Aedes aegypti to the malarial parasite Plasmodium gallinaceum was investigated as a quantitative trait using restriction fragment length polymorphisms (RFLP). Two F2 populations of mosquitoes were independently prepared from pairwise matings between a highly susceptible and a refractory strain of A. aegypti. RFLP were tested for association with oocyst development on the mosquito midgut. Two putative quantitative trait loci (QTL) were identified that significantly affect susceptibility. One QTL, pgs[2,LF98], is located on chromosome 2 and accounted for 65 and 49% of the observed phenotypic variance in the two populations, respectively. A second QTL, pgs[3,MalI], is located on chromosome 3 and accounted for 14 and 10% of the observed phenotypic variance in the two populations, respectively. Both QTL exhibit a partial dominance effect on susceptibility, wherein the dominance effect is derived from the refractory parent. No indication of epistasis between these QTL was detected. Evidence suggests that either a tightly linked cluster of independent genes or a single locus affecting susceptibility to various mosquito-borne parasites and pathogens has evolved near the LF98 locus; in addition to P. gallinaceum susceptibility, this general genome region has previously been implicated in susceptibility to the filarial nematode Brugia malayi and the yellow fever virus.


The malaria PTEX component PTEX88 interacts most closely with HSP101 at the host-parasite interface.
The pathogenic nature of malaria infections is due in part to the export of hundreds of effector proteins that actively remodel the host erythrocyte. The Plasmodium translocon of exported proteins (PTEX) has been shown to facilitate the trafficking of proteins into the host cell, a process that is essential for the survival of the parasite. The role of the auxiliary PTEX component PTEX88 remains unclear, as previous attempts to elucidate its function through reverse genetic approaches showed that in contrast to the core components PTEX150 and HSP101, knockdown of PTEX88 did not give rise to an export phenotype. Here, we have used biochemical approaches to understand how PTEX88 assembles within the translocation machinery. Proteomic analysis of the PTEX88 interactome showed that PTEX88 interacts closely with HSP101 but has a weaker affinity with the other core constituents of PTEX. PTEX88 was also found to associate with other PV-resident proteins, including chaperones and members of the exported protein-interacting complex that interacts with the major virulence factor PfEMP1, the latter contributing to cytoadherence and parasite virulence. Despite being expressed for the duration of the blood-stage life cycle, PTEX88 was only discretely observed at the parasitophorous vacuole membrane during ring stages and could not always be detected in the major high molecular weight complex that contains the other core components of PTEX, suggesting that its interaction with the PTEX complex may be dynamic. Together, these data have enabled the generation of an updated model of PTEX that now includes how PTEX88 assembles within the complex.


Combination of High-Resolution Multistage Ion Mobility and Tandem MS with High Energy of Activation to Resolve the Structure of Complex Chemoenzymatically Synthesized Glycans.
Carbohydrates, in particular microbial glycans, are highly structurally diverse biomolecules, the recognition of which governs numerous biological processes. Of special interest, glycans of known monosaccharide composition feature multiple possible isomers, differentiated by the anomerism and position of their glycosidic linkages. Robust analytical tools able to circumvent this extreme structural complexity are increasing in demand to ensure not only the correct determination of naturally occurring glycans but also to support the rapid development of enzymatic and chemoenzymatic glycan synthesis. In support to the later, we report the use of complementary strategies based on mass spectrometry (MS) to evaluate the ability of 14 engineered mutants of sucrose-utilizing α-transglucosylases to produce type/group-specific Shigella flexneri pentasaccharide bricks from a single lightly protected non-natural tetrasaccharide acceptor substrate. A first analysis of the reaction media by UHPLC coupled to high-accuracy MS led to detect six reaction products of enzymatic glucosylation out of the eight possible ones. A seventh structure was evidenced by an additional step of ion mobility at a resolving power (Rp) of approximately 100. Finally, a Rp of about 250 in ion mobility made it possible to detect the eighth and last of the expected structures. Complementary to these measurements, tandem MS with high activation energy charge transfer dissociation (CTD) allowed us to unambiguously characterize seven regioisomers out of the eight possible products of enzymatic glucosylation. This work illustrates the potential of the recently described powerful IMS and CTD-MS methods for the precise structural characterization of complex glycans.


Hypertension and diabetes among Siberian Yupik Eskimos of St. Lawrence Island, Alaska.
CHANGING DIETS AND LIFESTYLES contribute to an increase in the prevalence of cardiovascular disease and diabetes in Alaska Natives. To examine the problem in detail, we have begun a systematic screening of various ethnic groups by carrying out a pilot study of Siberian Yupik Eskimos ages 39 and over. Mean LDL and HDL levels were 157 mg/dl and 63 mg/dl. Mean fasting insulin was 7.0 microunits/ml; and mean BMI, 27.1. Fasting insulin level was significantly related to both diastolic blood pressure and fasting triglyceride levels, but not to systolic blood pressure, total cholesterol, LDL cholesterol, or HDL cholesterol levels. Of the 66 people screened, 27% had evidence of hypertension.


A model of ionic transport and osmotic volume control in cochlear outer hair cells.
A computational model of the outer hair cell (OHC) of the mammalian cochlea is presented. It addresses the way in which movement of ions controls the cell shape and regulates pH. The model takes into account the possible chloride-bicarbonate exchange function of prestin, a protein highly expressed in the plasma membrane of OHCs. A model of intracellular pH transients following the imposition of a rapid acid load upon the cell has been adapted from the squid axon literature and further extended in order to investigate the effects of ion transport upon the osmotic flux of water into the cell. The model predicts the slow length changes of OHCs reported in the literature a feature which may control the contribution of OHCs to cochlear amplification.


Aphasia and acquired reading impairments: What are the high-tech alternatives to compensate for reading deficits?
People with aphasia (PWA) frequently present impairments in reading comprehension. Such impairments can be particularly debilitating due to the limitations and constraints they impose on everyday life. Recent technological advancements in the field of information and communication technologies offer many compensative tools for PWA. However, most technological tools are designed for patients with speech production impairments. Instruments addressing reading impairments associated with aphasia remain scarce and underrepresented in the scientific literature. To conduct a state-of-the-art review of the technologies currently available to PWA and acquired reading impairments. In particular, this review covers (1) research on technologies explicitly developed to compensate for reading difficulties associated with aphasia; and (2) research into which accessibility features included in mainstream high-tech systems are helpful for PWA when trying to access written material. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) international standard, the authors conducted a systematic review from 2009 to 2019. The databases inspected were Scopus, Web of Science, PubMed, the Cochrane collection, IEEE Xplore, ScienceDirect and SpringerLink. Other research papers were included after checking the references of the selected papers. The review reveals that research on compensative devices for reading impairments largely neglects tools for individuals with aphasia and acquired reading difficulties. Most of the studies in this field are qualitative investigations of how patients with literacy difficulties tackle everyday tasks with the help of mainstream technology (e.g., smartphone applications). Therefore, this paper highlights the scarce high-tech alternatives that support text comprehension in PWA and acquired reading impairments, and suggests further work on the development of customized software for smartphones and personal computers. High-tech reading tools may help PWA to regain reading autonomy. PWA and acquired reading impairments employ a wide array of devices to overcome reading difficulties, which underlines the importance of reading in everyday life. However, the supports currently available are not yet flexible and accurate enough to answer their day-to-day needs. Thus, further work is necessary to enhance the compensative devices available to them. For instance, existing new technologies in the area of natural language processing (such as automatic text simplification) could potentially be used in compensative devices. What this paper adds What is already known on the subject Most research on high-tech compensative reading tools is focused on investigating how patients with aphasia and acquired reading impairments cope with their reading difficulties in everyday life by resorting to different types of technology. Yet, we still lack specific research on compensative reading technology for PWA. What this paper adds to existing knowledge This review shows that PWA with acquired reading impairments are offered limited options for accessing written content easily and autonomously-and those few resources that are available are not specifically designed for PWA. What are the potential or actual clinical implications of this work? Both aphasia and acquired reading impairments can vary in terms of both their severity and the associated typology of cognitive impairments. Therefore, it might be interesting to investigate flexible and highly adaptable reading support designed for them-and innovations in the field of information and communication technology might prove particularly fruitful.


Development of a wireless displacement measurement system using acceleration responses.
Displacement measurements are useful information for various engineering applications such as structural health monitoring (SHM), earthquake engineering and system identification. Most existing displacement measurement methods are costly, labor-intensive, and have difficulties particularly when applying to full-scale civil structures because the methods require stationary reference points. Indirect estimation methods converting acceleration to displacement can be a good alternative as acceleration transducers are generally cost-effective, easy to install, and have low noise. However, the application of acceleration-based methods to full-scale civil structures such as long span bridges is challenging due to the need to install cables to connect the sensors to a base station. This article proposes a low-cost wireless displacement measurement system using acceleration. Developed with smart sensors that are low-cost, wireless, and capable of on-board computation, the wireless displacement measurement system has significant potential to impact many applications that need displacement information at multiple locations of a structure. The system implements an FIR-filter type displacement estimation algorithm that can remove low frequency drifts typically caused by numerical integration of discrete acceleration signals. To verify the accuracy and feasibility of the proposed system, laboratory tests are carried out using a shaking table and on a three storey shear building model, experimentally confirming the effectiveness of the proposed system.


Occupational lymphohematopoietic cancer in Korea.
The purpose of this study was to review the existing studies on lymphohematopoietic (LHP) cancer in Korea, estimate the prevalence of workers exposed to carcinogens, and determine the population attributable fraction (PAF) of leukemia. Two case series and 4 case reports were reviewed. Using official statistics, the prevalence of benzene exposure and ionizing radiation exposure was estimated. Based on the prevalence of exposure and the relative risk, The PAF of leukemia was calculated. Between 1996 and 2005, 51 cases of LHP cancer were reported from the compensation system. Greater than 50% of occupational LHP cancer was leukemia, and the most important cause was benzene. In a cohort study, the standardized incidence ratio was 2.71 (95% CI, 0.56-7.91). The prevalence of exposure was 2.5% and 2.2% in 1995 and 2000, respectively. Using the 1995 prevalence, 3.6-4.8% and 0.1% of cases with leukemia were attributable to benzene and ionizing radiation exposure, respectively, which resulted in 39.7-51.4 cases per year. Benzene is the most important cause of occupational leukemia in Korea. Considering the estimated PAF in this study, the annual number of occupational LHP cancer (51 cases during 10-yr period), might be underreported within the compensation system.


In vivo electrophysiological evidence for the regulatory role of autoreceptors on serotonergic terminals.
The present in vivo studies were undertaken to evaluate electrophysiologically the modulatory role of the terminal 5-HT autoreceptor on 5-HT neurotransmission. In a first series of experiments, the effect of the electrical activation of the ascending 5-HT pathway on the firing activity of CA3 hippocampal pyramidal neurons was measured before and after the intravenous administration of methiothepin, a terminal 5-HT autoreceptor antagonist. Methiothepin significantly increased the duration of the suppression of firing activity of these neurons by the electrical stimulation of the 5-HT pathway, without modifying their responsiveness to microiontophoretically applied 5-HT. This suggests that endogenously released 5-HT activates the 5-HT terminal autoreceptor and that methiothepin enhances the efficacy of 5-HT synaptic transmission by blocking this activation. In a second series of experiments, further evidence for the activation of terminal 5-HT autoreceptors by 5-HT released by the electrical stimulation was sought by assessing the effectiveness of 2 series of stimulations of the ascending 5-HT pathway delivered at different frequencies while recording the same postsynaptic neuron. Increasing the frequency of stimulation (from 0.8 to 5 Hz) significantly reduced the duration of suppression of firing activity of the postsynaptic neurons. This difference between the 0.8 and 5 Hz stimulations was decreased by intravenous methiothepin, suggesting that the reduced effectiveness of the stimulations delivered at the higher frequency is attributable to a greater activation of the terminal 5-HT autoreceptor. These results provide direct electrophysiological evidence for the modulatory role of the 5-HT terminal autoreceptor on 5-HT neurotransmission.


Acceptability and Feasibility of Implementing Accelorometry-Based Activity Monitors and a Linked Web Portal in an Exercise Referral Scheme: Feasibility Randomized Controlled Trial.
Exercise referral schemes (ERSs) are recommended for patients with health conditions or risk factors. Evidence points to the initial effectiveness and cost-effectiveness of such schemes for increasing physical activity, but effects often diminish over time. Techniques such as goal setting, self-monitoring, and personalized feedback may support motivation for physical activity and maintenance of effects. Wearable technologies could provide an opportunity to integrate motivational techniques into exercise schemes. However, little is known about acceptability to exercise referral populations or implementation feasibility within exercise referral services. To determine the feasibility and acceptability of implementing an activity-monitoring device within the Welsh National ERS to inform a decision on whether and how to proceed to an effectiveness trial. We conducted a feasability randomized controlled trial with embedded mixed-methods process evaluation and an exploratory economic analysis. Adults (N=156) were randomized to intervention (plus usual practice; n=88) or usual practice only (n=68). Usual practice was a 16-week structured exercise program. The intervention group additionally received an accelerometry-based activity monitor (MyWellnessKey) and associated Web platform (MyWellnessCloud). The primary outcomes were predefined progression criteria assessing acceptability and feasibility of the intervention and proposed evaluation. Postal questionnaires were completed at baseline (time 0:T0), 16 weeks (T1), and 12 months after T0 (T2). Routine data were accessed at the same time-points. A subsample of intervention participants and scheme staff were interviewed following the initiation of intervention delivery and at T2. Participants were on average aged 56.6 (SD 16.3) years and mostly female (101/156, 64.7%) and white (150/156, 96.2%). Only 2 of 5 progression criteria were met; recruitment and randomization methods were acceptable to participants, and contamination was low. However, recruitment and retention rates (11.3% and 67.3%, respectively) fell substantially short of target criteria (20% and 80%, respectively), and disproportionally recruited from the least deprived quintile. Only 57.4% of intervention participants reported receipt of the intervention (below the 80% progression threshold). Less than half reported the intervention to be acceptable at T2. Participant and staff interviews revealed barriers to intervention delivery and engagement related to the device design as well as context-specific technological challenges, all of which made it difficult to integrate the technology into the service. Routinely collected health economic measures had substantial missing data, suggesting that other methods for collecting these should be used in future. To our knowledge, this is the first study to evaluate short- and long-term feasibility and acceptability of integrating wearable technologies into community-based ERSs. The findings highlight device- and context-specific barriers to doing this in routine practice, with typical exercise referral populations. Key criteria for progression to a full-scale evaluation were not met. ISRCTN Registry ISRCTN85785652; http://www.isrctn.com/ISRCTN85785652.


Imaging gold nanorods in excised human breast carcinoma by spectroscopic optical coherence tomography.
Plasmon-resonant gold nanorods (GNRs) can serve as imaging agents for spectroscopic optical coherence tomography (SOCT). The aspect ratio of the GNRs are adjusted for maximum absorption in the far red to create a partial spectral overlap with the low-wavelength edge of the near-infrared SOCT imaging band. The spectroscopic absorption profile of the GNRs is incorporated into a depth-resolved algorithm for mapping the relative GNR density within OCT images. This technique enables us to image GNR distributions in excised human breast carcinomas, demonstrating their potential as OCT contrast agents in heteregeneous, highly scattering tissues.


Heart Failure With Reduced Ejection Fraction: A Review.
Worldwide, the burden of heart failure has increased to an estimated 23 million people, and approximately 50% of cases are HF with reduced ejection fraction (HFrEF). Heart failure is a clinical syndrome characterized by dyspnea or exertional limitation due to impairment of ventricular filling or ejection of blood or both. HFrEF occurs when the left ventricular ejection fraction (LVEF) is 40% or less and is accompanied by progressive left ventricular dilatation and adverse cardiac remodeling. Assessment for heart failure begins with obtaining a medical history and physical examination. Also central to diagnosis are elevated natriuretic peptides above age- and context-specific thresholds and identification of left ventricular systolic dysfunction with LVEF of 40% or less as measured by echocardiography. Treatment strategies include the use of diuretics to relieve symptoms and application of an expanding armamentarium of disease-modifying drug and device therapies. Unless there are specific contraindications, patients with HFrEF should be treated with a β-blocker and one of an angiotensin receptor-neprilysin inhibitor, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker as foundational therapy, with addition of a mineralocorticoid receptor antagonist in patients with persistent symptoms. Ivabradine and hydralazine/isosorbide dinitrate also have a role in the care of certain patients with HFrEF. More recently, sodium-glucose cotransporter 2 (SGLT2) inhibitors have further improved disease outcomes, significantly reducing cardiovascular and all-cause mortality irrespective of diabetes status, and vericiguat, a soluble guanylate cyclase stimulator, reduces heart failure hospitalization in high-risk patients with HFrEF. Device therapies may be beneficial in specific subpopulations, such as cardiac resynchronization therapy in patients with interventricular dyssynchrony, transcatheter mitral valve repair in patients with severe secondary mitral regurgitation, and implantable cardiac defibrillators in patients with more severe left ventricular dysfunction particularly of ischemic etiology. HFrEF is a major public health concern with substantial morbidity and mortality. The management of HFrEF has seen significant scientific breakthrough in recent decades, and the ability to alter the natural history of the disease has never been better. Recent developments include SGLT2 inhibitors, vericiguat, and transcatheter mitral valve repair, all of which incrementally improve prognosis beyond foundational neurohormonal therapies. Disease morbidity and mortality remain high, with a 5-year survival rate of 25% after hospitalization for HFrEF.


An integrated model of social environment and social context for pediatric rehabilitation.
This article considers the conceptualization and operationalization of "social environment" and "social context" with implications for research and practice with children and youth with impairments. We first discuss social environment and social context as constructs important for understanding interaction between external environmental qualities and the individual's experience. The article considers existing conceptualizations within psychological and sociological bodies of literature, research using these concepts, current developmental theories and issues in the understanding of environment and participation within rehabilitation science. We then describe a model that integrates a person-focused perspective with an environment-focused perspective and that outlines the mechanisms through which children/youth and social environment interact and transact. Finally, we consider the implications of the proposed model for research and clinical practice. This conceptual model directs researchers and practitioners toward interventions that will address the mechanisms of child-environment interaction and that will build capacity within both children and their social environments, including families, peers groups and communities. Health is created and lived by people within the settings of their everyday life; where they learn, work, play, and love [p.2]. Understanding how social environment and personal factors interact over time to affect the development of children/youth can influence the design of services for children and youth with impairments. The model described integrates the individual-focused and environment-focused perspectives and outlines the mechanisms of the ongoing reciprocal interaction between children/youth and their social environments: provision of opportunities, resources and supports and contextual processes of choice, active engagement and collaboration. Addressing these mechanisms could contribute to creating healthier environments in which all children, including children with impairments, have experiences that lead to positive developmental benefits.


A randomized control trial of phototherapy and 20% albumin versus phototherapy and saline in Kilifi, Kenya.
The study evaluated the efficacy of phototherapy and 20% albumin infusion to reduce total serum bilirubin (TSB) in neonates with severe hyperbilirubinemia. The primary outcome was a reduction of TSB at the end of treatment. The secondary outcomes were the need for exchange transfusion, inpatient mortality, neurological outcomes at discharge, and development outcomes at 12-months follow-up. One hundred and eighteen neonates were randomly assigned to phototherapy and 20% albumin (n = 59) and phototherapy and saline (n = 69). The median age at admission was 5 (interquartile range (IQR) 3-6) days, and the median gestation was 36 (IQR 36-38) weeks. No significant differences were found in the change in TSB (Mann-Whitney U =609, p = 0.98) and rate of change in TSB per hour after treatment (Mann-Whitney U = 540, p = 0.39) between the two groups. There were no significant differences between the two groups in the proportion of participants who required exchange transfusion (χ2 (2) = 0.36, p = 0.546); repeat phototherapy (χ2 (2) = 2.37, p = 0.123); and those who died (χ2 (2) = 0.92, p = 0.337). Trial registration The trial was registered in the International Standardized Randomized Controlled Trial Number (ISRCTN); trial registration number ISRCTN89732754.


Severe Sweet's Syndrome with Elevated Cutaneous Interleukin-1β after Azathioprine Exposure: Case Report and Review of the Literature.
Sweet's syndrome (SS) is a dermatosis with systemic symptoms characterized by tender, red nodules or papules, occasionally covered with vesicles, pustules or bullae, usually affecting the upper limbs, face and neck. SS is frequently observed in patients with leukemia or connective tissue diseases, while it is rather seldom in patients with inflammatory bowel disease. The exact pathogenesis of SS is only partially understood. We report the case of a 50-year-old patient with indeterminate colitis, presenting with a febrile diffuse papulopustular and necrotizing skin eruption that healed with significant scarring and appeared 14 days after onset of treatment with azathioprine. Histological examination revealed the presence of features typical of SS, gene expression analysis very high levels of interleukin-1β (IL-1β) mRNA in lesional skin, and immunohistochemistry high levels of IL-1β at the protein level. SS associated with azathioprine is being increasingly reported and is reviewed herein.


Constructing a man-made c-type cytochrome maquette in vivo: electron transfer, oxygen transport and conversion to a photoactive light harvesting maquette.
The successful use of man-made proteins to advance synthetic biology requires both the fabrication of functional artificial proteins in a living environment, and the ability of these proteins to interact productively with other proteins and substrates in that environment. Proteins made by the maquette method integrate sophisticated oxidoreductase function into evolutionarily naive, non-computationally designed protein constructs with sequences that are entirely unrelated to any natural protein. Nevertheless, we show here that we can efficiently interface with the natural cellular machinery that covalently incorporates heme into natural cytochromes c to produce in vivo an artificial c-type cytochrome maquette. Furthermore, this c-type cytochrome maquette is designed with a displaceable histidine heme ligand that opens to allow functional oxygen binding, the primary event in more sophisticated functions ranging from oxygen storage and transport to catalytic hydroxylation. To exploit the range of functions that comes from the freedom to bind a variety of redox cofactors within a single maquette framework, this c-type cytochrome maquette is designed with a second, non-heme C, tetrapyrrole binding site, enabling the construction of an elementary electron transport chain, and when the heme C iron is replaced with zinc to create a Zn porphyrin, a light-activatable artificial redox protein. The work we describe here represents a major advance in de novo protein design, offering a robust platform for new c-type heme based oxidoreductase designs and an equally important proof-of-principle that cofactor-equipped man-made proteins can be expressed in living cells, paving the way for constructing functionally useful man-made proteins in vivo.


Differential localization of prostaglandin E synthase isoforms in human placental cell types.
Increased prostaglandin E(2)(PGE(2)) synthesis involves multiple enzymes and two isoforms of the terminal enzyme of this biosynthetic pathway, PGE synthase (PGES), were recently identified. Cytosolic PGES (cPGES) is identical to the Hsp90 chaperone, p23, and is reportedly functionally coupled to constitutive PG endoperoxide H synthase-1 (PGHS-1). Microsomal PGES (mPGES), on the other hand, is inducible by proinflammatory cytokines such as IL-1beta. We have studied the cellular localization of both enzyme isoforms in human placenta at term and early gestation (10 weeks). Cytosolic PGES was immunolocalized to the fibroblasts and macrophages in villous stroma, whereas mPGES was localized in the extravillous trophoblasts (EVTs) as well as macrophages in both term and early gestation tissues. Microsomal PGES was also observed in cytotrophoblasts (CTs), but not in syncytiotrophoblasts (STs), in early gestation. Apoptotic early gestational STs were heavily stained with cPGES. We also investigated the cellular localization of cPLA(2)and PGHS-2 in early gestation and at term. Cytosolic PLA(2)was immunolocalized to the stroma and STs at term, but was only observed in CTs in early gestation. PGHS-2, on the other hand, was immunolocalized to both extravillous and STs in early gestation and at term. Our results suggest that mPGES could play a role in trophoblast invasion via its association with EVTs in the basal plate, whereas cPGES could be involved in apoptosis or repair mechanisms.


Radiosurgery and stereotactic radiotherapy for intracranial meningiomas.
The authors report the evolution of linear accelerator (LINAC)-based radiosurgery in the treatment of patients with intracranial meningiomas. They describe the technical aspects as well as clinical and radiological outcomes. The authors performed a retrospective review of 161 patients harboring 194 intracranial meningiomas treated with various types of stereotactic irradiation at their institution between May 1991 and July 2002. Clinical and radiological follow-up data (mean follow-up period 32.5 months, range 6-125 months) were obtained in 128 patients (79.5%) with 156 meningiomas (80.4%). There were 88 women and 40 men whose mean age was 57.2 years (range 18-87 years). Stereotactic irradiation was the primary treatment in 44 patients, and 84 patients underwent resection prior to radiosurgery. Stereotactic radiosurgery (SRS) was used to treat 79 lesions and fractionated stereotactic radiotherapy (SRT) was used to treat 77. The mean dose for SRS was 1567 cGy (range 1200-2285 cGy) prescribed to a mean isodose line of 66.6% (range 50-90%). Stereotactic radiotherapy was delivered using a mean dose of 4839 cGy (range 2380-5400 cGy), prescribed to a mean isodose line of 89% (range 50-90%). The mean follow-up periods were 40 and 24 months in SRS- and SRT-treated patients, respectively. Tumor control was achieved in 58 SRT-treated benign meningiomas (90%) and in 70 SRT-treated lesions (97.2%). In patients with atypical meningiomas a considerably poorer prognosis was seen. Clinical improvement or stabilization of symptoms was observed in the majority of patients. Symptomatic complications were limited to four patients (5%) treated with SRS and four (5.2%) treated with SRT. Stereotactic irradiation techniques have changed the neurosurgical approach to intracranial meningiomas. Either SRS or SRT delivered as a primary treatment in selected cases of skull base lesions or as an adjuvant after conservative resection has improved the management of these complex intracranial tumors.


Binge-Eating Disorder in Adults: A Systematic Review and Meta-analysis.
The best treatment options for binge-eating disorder are unclear. To summarize evidence about the benefits and harms of psychological and pharmacologic therapies for adults with binge-eating disorder. English-language publications in EMBASE, the Cochrane Library, Academic OneFile, CINAHL, and ClinicalTrials.gov through 18 November 2015, and in MEDLINE through 12 May 2016. 9 waitlist-controlled psychological trials and 25 placebo-controlled trials that evaluated pharmacologic (n = 19) or combination (n = 6) treatment. All were randomized trials with low or medium risk of bias. 2 reviewers independently extracted trial data, assessed risk of bias, and graded strength of evidence. Therapist-led cognitive behavioral therapy, lisdexamfetamine, and second-generation antidepressants (SGAs) decreased binge-eating frequency and increased binge-eating abstinence (relative risk, 4.95 [95% CI, 3.06 to 8.00], 2.61 [CI, 2.04 to 3.33], and 1.67 [CI, 1.24 to 2.26], respectively). Lisdexamfetamine (mean difference [MD], -6.50 [CI, -8.82 to -4.18]) and SGAs (MD, -3.84 [CI, -6.55 to -1.13]) reduced binge-eating-related obsessions and compulsions, and SGAs reduced symptoms of depression (MD, -1.97 [CI, -3.67 to -0.28]). Headache, gastrointestinal upset, sleep disturbance, and sympathetic nervous system arousal occurred more frequently with lisdexamfetamine than placebo (relative risk range, 1.63 to 4.28). Other forms of cognitive behavioral therapy and topiramate also increased abstinence and reduced binge-eating frequency and related psychopathology. Topiramate reduced weight and increased sympathetic nervous system arousal, and lisdexamfetamine reduced weight and appetite. Most study participants were overweight or obese white women aged 20 to 40 years. Many treatments were examined only in single studies. Outcomes were measured inconsistently across trials and rarely assessed beyond end of treatment. Cognitive behavioral therapy, lisdexamfetamine, SGAs, and topiramate reduced binge eating and related psychopathology, and lisdexamfetamine and topiramate reduced weight in adults with binge-eating disorder. Agency for Healthcare Research and Quality.


Genomic structure and transcript analysis of the Rapid Alkalinization Factor (RALF) gene family during host-pathogen crosstalk in Fragaria vesca and Fragaria x ananassa strawberry.
Rapid Alkalinization Factors (RALFs) are cysteine-rich peptides ubiquitous within plant kingdom. They play multiple roles as hormonal signals in diverse processes, including root elongation, cell growth, pollen tube development, and fertilization. Their involvement in host-pathogen crosstalk as negative regulators of immunity in Arabidopsis has also been recognized. In addition, peptides homologous to RALF are secreted by different fungal pathogens as effectors during early stages of infection. Previous studies have identified nine RALF genes in the diploid strawberry (Fragaria vesca) genome. This work describes the genomic organization of the RALF gene families in commercial octoploid strawberry (Fragaria × ananassa) and the re-annotated genome of F. vesca, and then compares findings with orthologs in Arabidopsis thaliana. We reveal the presence of 15 RALF genes in F. vesca genotype Hawaii 4 and 50 in Fragaria x ananassa cv. Camarosa, showing a non-homogenous localization of genes among the different Fragaria x ananassa subgenomes. Expression analysis of Fragaria x ananassa RALF genes upon infection with Colletotrichum acutatum or Botrytis cinerea showed that FanRALF3-1 was the only fruit RALF gene upregulated after fungal infection. In silico analysis was used to identify distinct pathogen inducible elements upstream of the FanRALF3-1 gene. Agroinfiltration of strawberry fruit with deletion constructs of the FanRALF3-1 promoter identified a 5' region required for FanRALF3-1 expression in fruit, but failed to identify a region responsible for fungal induced expression.


Collective Activity of Many Bistable Assemblies Reproduces Characteristic Dynamics of Multistable Perception.
The timing of perceptual decisions depends on both deterministic and stochastic factors, as the gradual accumulation of sensory evidence (deterministic) is contaminated by sensory and/or internal noise (stochastic). When human observers view multistable visual displays, successive episodes of stochastic accumulation culminate in repeated reversals of visual appearance. Treating reversal timing as a "first-passage time" problem, we ask how the observed timing densities constrain the underlying stochastic accumulation. Importantly, mean reversal times (i.e., deterministic factors) differ enormously between displays/observers/stimulation levels, whereas the variance and skewness of reversal times (i.e., stochastic factors) keep characteristic proportions of the mean. What sort of stochastic process could reproduce this highly consistent "scaling property?" Here we show that the collective activity of a finite population of bistable units (i.e., a generalized Ehrenfest process) quantitatively reproduces all aspects of the scaling property of multistable phenomena, in contrast to other processes under consideration (Poisson, Wiener, or Ornstein-Uhlenbeck process). The postulated units express the spontaneous dynamics of attractor assemblies transitioning between distinct activity states. Plausible candidates are cortical columns, or clusters of columns, as they are preferentially connected and spontaneously explore a restricted repertoire of activity states. Our findings suggests that perceptual representations are granular, probabilistic, and operate far from equilibrium, thereby offering a suitable substrate for statistical inference. Spontaneous reversals of high-level perception, so-called multistable perception, conform to highly consistent and characteristic statistics, constraining plausible neural representations. We show that the observed perceptual dynamics would be reproduced quantitatively by a finite population of distinct neural assemblies, each with locally bistable activity, operating far from the collective equilibrium (generalized Ehrenfest process). Such a representation would be consistent with the intrinsic stochastic dynamics of neocortical activity, which is dominated by preferentially connected assemblies, such as cortical columns or clusters of columns. We predict that local neuron assemblies will express bistable dynamics, with spontaneous active-inactive transitions, whenever they contribute to high-level perception.


Double effect, all over again: the case of Sister Margaret McBride.
As media reports have made widely known, in November 2009, the ethics committee of St. Joseph's Hospital in Phoenix, Arizona, permitted the abortion of an eleven-week-old fetus in order to save the life of its mother. This woman was suffering from acute pulmonary hypertension, which her doctors judged would prove fatal for both her and her previable child. The ethics committee believed abortion to be permitted in this case under the so-called principle of double effect, but Thomas J. Olmsted, the bishop of Phoenix, disagreed with the committee and pronounced its chair, Sister Margaret McBride, excommunicated latae sententiae, "by the very commission of the act." In this article, I take the much discussed Phoenix case as an occasion to subject the principle of double effect to another round of philosophical scrutiny. In particular, I examine the third condition of the principle in its textbook formulation, namely, that the evil effect in question may not be the means to the good effect. My argument, in brief, is that the textbook formulation of the principle does not withstand philosophical scrutiny. Nevertheless, in the end, I do not claim that we should then "do away" with the principle altogether. Instead, we do well to understand it within the context of casuistry, the tradition of moral reasoning from which it issued.


Two-stage activated nano-truck enhanced specific aggregation and deep delivery for synergistic tumor ablation.
Although nanomedicines have shown high performance in tumor theranostics, their anticancer activity is still limited by the drug delivery capacity, especially lack of targeting capability, poor tumor accumulation, and insufficient tumor deep-penetration. To address this challenge, a high biocompatibility nano-truck (BMP NT) with a two-stage delivery mechanism is designed and developed to achieve the precision therapeutic efficacy of cancer. In view of the enhanced permeability retention (EPR) effect, the surface cleavable layer of BMP NTs can be selectively removed by the overexpressed MMP-2 in a tumor-microenvironment to expose the hydrophobic segments for an induced "braking effect" strategy, resulting in a significant increase in tumor accumulation. Once internalized into cancer cells with the overproduced glutathione (GSH) and H2O2, the BMP NTs undergo the second-stage "unloading process" to release Mn2+ ions and ultrasmall Bi2S3@BSA nanoparticles, and the obtained Mn2+ ions can act as a Fenton-like catalyst for continuously catalyzing the endogenous H2O2 into highly toxic hydroxyl radicals (˙OH) for CDT. The GSH depletion will in turn improve the Mn2+-H2O2 reaction, further enhancing CDT efficiency. Meanwhile, the ultrasmall Bi2S3@BSA endows BMP NTs with excellent photothermal conversion ability to generate local hyperthermia and accelerate the intratumoral Fenton process, thus leading to an effective tumor therapeutic outcome in the synergistic function of CDT/photothermal therapy (PTT). Moreover, the BMP NTs can be used for in situ self-generation magnetic resonance imaging (MRI) and photoacoustic (PA) imaging to guide precision cancer therapy.


Worklessness and regional differences in the social gradient in general health: Evidence from the 2001 English census.
There has been much focus on separating contextual and compositional influences on social inequalities in health. However, there has been less focus on the important role of place in shaping the distribution of risk factors. Spatial variations in worklessness are one such factor. In this paper, then we examine the extent to which between and within regional differences in the social gradient in self-rated general health are associated with differences in rates of worklessness. Data were obtained for men and women of working age (25-59) who had ever worked from the Sample of Anonymised Records (Individual SAR)-a 3% representative sample of the 2001 English Census (349,699 women and 349,181 men). Generalised linear models were used to calculate region and age adjusted prevalence difference for not good health by education (as an indicator of socio-economic status) and employment status. The slope index of an inequality was also calculated for each region. For both men and women, educational inequalities in worklessness and not good health are largest in those regions with the highest overall levels of worklessness. Adjusting for worklessness considerably attenuated the educational health gradient within all English regions (by over 60%) and virtually eliminated between region differences. Macroeconomic policies, which influence the demand for labour, may have an important role in creating inequalities in general health of the working age population both within and between regions. Employment policy may therefore be one important approach to tackling spatial and socio-economic health inequalities.


Extent of heterogeneity in mitochondrial DNA of European populations.
Variation in the mitochondrial DNA (mtDNA) control region as detected by sequence-specific oligonucleotide (SSO) probes is described for 595 individuals from six European or European-derived populations. Estimates of diversity for mtDNA types exceed 0.91 in all populations, while 50% of the 158 types which were observed occur only once. Of 68 shared types, most occur rarely (< 3% of the total population); only one type occurs at a frequency greater than 10%, and it is present at comparable frequencies in all six populations (18-29%). An analysis of molecular variance (AMOVA) incorporating genetic distances between types shows that 100% of the variation present in the total sample is attributable to within-population diversity, while there are essentially no between-population differences. Another AMOVA was performed for the first hypervariable region SSO sites only, which included this sample plus an additional 537 SSO types from mine more European populations that were inferred from published mtDNA control region sequence data. Similar results were obtained, with over 99% of the variation overall attributable to within-population differences, and less than 1% of the variation attributable to between-population differences. The Saami were the most different from other populations, which had been observed in an earlier study of nucleotide sequence data. Overall, there is no statistically significant heterogeneity for European populations (p > 0.001), and these groups are virtually indistinguishable with respect to mtDNA SSO types. These results demonstrate the utility of mtDNA typing for forensic investigations.


De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
The Mediator is an evolutionarily conserved, multi-subunit complex that regulates multiple steps of transcription. Mediator activity is regulated by the reversible association of a four-subunit module comprising CDK8 or CDK19 kinases, together with cyclin C, MED12 or MED12L, and MED13 or MED13L. Mutations in MED12, MED13, and MED13L were previously identified in syndromic developmental disorders with overlapping phenotypes. Here, we report CDK8 mutations (located at 13q12.13) that cause a phenotypically related disorder. Using whole-exome or whole-genome sequencing, and by international collaboration, we identified eight different heterozygous missense CDK8 substitutions, including 10 shown to have arisen de novo, in 12 unrelated subjects; a recurrent mutation, c.185C>T (p.Ser62Leu), was present in five individuals. All predicted substitutions localize to the ATP-binding pocket of the kinase domain. Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism. Congenital heart disease occurred in six subjects; additional features present in multiple individuals included agenesis of the corpus callosum, ano-rectal malformations, seizures, and hearing or visual impairments. To evaluate the functional impact of the mutations, we measured phosphorylation at STAT1-Ser727, a known CDK8 substrate, in a CDK8 and CDK19 CRISPR double-knockout cell line transfected with wild-type (WT) or mutant CDK8 constructs. These experiments demonstrated a reduction in STAT1 phosphorylation by all mutants, in most cases to a similar extent as in a kinase-dead control. We conclude that missense mutations in CDK8 cause a developmental disorder that has phenotypic similarity to syndromes associated with mutations in other subunits of the Mediator kinase module, indicating probable overlap in pathogenic mechanisms.


Direct response to Notch activation: signaling crosstalk and incoherent logic.
Notch is the receptor in one of a small group of conserved signaling pathways that are essential at multiple stages in development. Although the mechanism of transduction impinges directly on the nucleus to regulate transcription through the CSL [CBF-1/Su(H)/LAG-1] [corrected] DNA binding protein, there are few known direct target genes. Thus, relatively little is known about the immediate cellular consequences of Notch activation. We therefore set out to determine the genome-wide response to Notch activation by analyzing the changes in messenger RNA (mRNA) expression and the sites of CSL occupancy within 30 minutes of activating Notch in Drosophila cells. Through combining these data, we identify high-confidence direct targets of Notch that are implicated in the maintenance of adult muscle progenitors in vivo. These targets are enriched in cell morphogenesis genes and in components of other cell signaling pathways, especially the epidermal growth factor receptor (EGFR) pathway. Also evident are examples of incoherent network logic, where Notch stimulates the expression of both a gene and the repressor of that gene, which may result in a transient window of competence after Notch activation. Furthermore, because targets comprise both positive and negative regulators, cells become poised for both outcomes, suggesting one mechanism through which Notch activation can lead to opposite effects in different contexts.


Refractive error at birth and its relation to gestational age.
The refractive status of premature infants is not well studied. This study was done to find the norms of refractive error in newborns at different gestational ages. One thousand two hundred three (1203) eyes were examined for refractive error by streak retinoscopy within the first week of life between June 2001 and September 2002. Tropicamide eye drops (0.8%) with phenylephrine 0.5% were used to achieve cycloplegia and mydriasis. The refractive error was measured in the vertical and horizontal meridia in both eyes and was recorded to the nearest dioptre (D). The neonates were grouped in five gestational age groups ranging from 24 weeks to 43 weeks. Extremely preterm babies were found to be myopic with a mean MSE (mean spherical equivalent) of -4.86 D. The MSE was found to progressively decrease (become less myopic) with increasing gestation and was +2.4 D at term. Astigmatism of more than 1 D spherical equivalent was seen in 67.8% of the eyes examined. Among newborns with > 1 D of astigmatism, the astigmatism was with-the-rule (vertical meridian having greater refractive power than horizontal) in 85% and against-the-rule in 15%. Anisometropia of more than 1 D spherical equivalent was seen in 31% babies. Term babies are known to be hypermetropic, and preterm babies with retinopathy of prematurity (ROP) are known to have myopia. This study provides data on the mean spherical equivalent, the degree of astigmatism, and incidence of anisometropia at different gestational ages. This is the largest study in world literature looking at refractive errors at birth against gestational age. It should help understand the norms of refractive errors in preterm babies.


Inhibition of spinal microglia and astrocytes contributes to the anti-allodynic effect of electroacupuncture in neuropathic pain induced by spinal nerve ligation.
Besides neurons, activated microglia and astrocytes in the spinal cord dorsal horn (SCDH) contribute to the pathogenesis of chronic pain. Electroacupuncture (EA) has been used widely to treat various chronic pain diseases, however, the underlying mechanisms of EA are still not fully understood. Male Sprague-Dawley rats were randomly divided into four groups, including an untreated healthy Control group (n=14), a True-spinal nerve ligation (SNL) group that underwent SNL and remained untreated (n=25), a True-SNL+EA group that underwent SNL followed by EA treatment (n=25), and a Sham-SNL group that underwent sham surgery and remained untreated (n=15). SNL was performed unilaterally at L5 and EA was applied to ST36 and BL60 bilaterally once per day. Paw withdrawal thresholds (PWTs) were measured ipsilaterally at baseline and 1, 3, 7, and 14 days after ligation. Activation of microglia and astrocytes in the SCDH were examined bilaterally by immunofluorescence staining, and concentrations of interleukin-1β (IL-1β) and interleukin (IL-6) were measured in the ipsilateral SCDH by ELISA. SNL significantly decreased PWTs and activated glial cells in the superficial laminae of the ipsilateral SCDH. In rats with SNL, glial fibrillary acidic protein (GFAP) immunoreactivity peaked at 7 days and was maintained until 14 days post-ligation, while anti-integrin alphaM (OX-42) immunoreactivity peaked at 3 days and declined gradually. EA significantly alleviated SNL-induced mechanical allodynia. Furthermore, EA reduced microglial activation (OX-42 positive ratios) in the lumbar SCDH at 3 days post-ligation and suppressed astrocyte activation (GFAP positive ratios) at all time points observed. EA stimulation alleviates SNL-induced neuropathic pain, at least in part through inhibition of spinal glial activation. Moreover, inhibition of spinal microglia and astrocyte activation may contribute to the immediate effects and maintenance of EA analgesia, respectively.


LanCLs add glutathione to dehydroamino acids generated at phosphorylated sites in the proteome.
Enzyme-mediated damage repair or mitigation, while common for nucleic acids, is rare for proteins. Examples of protein damage are elimination of phosphorylated Ser/Thr to dehydroalanine/dehydrobutyrine (Dha/Dhb) in pathogenesis and aging. Bacterial LanC enzymes use Dha/Dhb to form carbon-sulfur linkages in antimicrobial peptides, but the functions of eukaryotic LanC-like (LanCL) counterparts are unknown. We show that LanCLs catalyze the addition of glutathione to Dha/Dhb in proteins, driving irreversible C-glutathionylation. Chemo-enzymatic methods were developed to site-selectively incorporate Dha/Dhb at phospho-regulated sites in kinases. In human MAPK-MEK1, such "elimination damage" generated aberrantly activated kinases, which were deactivated by LanCL-mediated C-glutathionylation. Surveys of endogenous proteins bearing damage from elimination (the eliminylome) also suggest it is a source of electrophilic reactivity. LanCLs thus remove these reactive electrophiles and their potentially dysregulatory effects from the proteome. As knockout of LanCL in mice can result in premature death, repair of this kind of protein damage appears important physiologically.


Agriculture and nutrition in India: mapping evidence to pathways.
In India, progress against undernutrition has been slow. Given its importance for income generation, improving diets, care practices, and maternal health, the agriculture sector is widely regarded as playing an important role in accelerating the reduction in undernutrition. This paper comprehensively maps existing evidence along agriculture-nutrition pathways in India and assesses both the quality and coverage of the existing literature. We present a conceptual framework delineating six key pathways between agriculture and nutrition. Three pathways pertain to the nutritional impacts of farm production, farm incomes, and food prices. The other three pertain to agriculture-gender linkages. After an extensive search, we found 78 research papers that provided evidence to populate these pathways. The literature suggests that Indian agriculture has a range of important influences on nutrition. Agriculture seems to influence diets even when controlling for income, and relative food prices could partly explain observed dietary changes in recent decades. The evidence on agriculture-gender linkages to nutrition is relatively weak. Sizeable knowledge gaps remain. The root causes of these gaps include an interdisciplinary disconnect between nutrition and economics/agriculture, a related problem of inadequate survey data, and limited policy-driven experimentation. Closing these gaps is essential to strengthening the agriculture sector's contribution to reducing undernutrition.


One year B and D vitamins supplementation improves metabolic bone markers.
Vitamin D and vitamin B deficiency are common in elderly subjects and are important risk factors for osteoporosis and age-related diseases. Supplementation with these vitamins is a promising preventative strategy. The objective of this study was to evaluate the effects of vitamins D3 and B supplementation on bone turnover and metabolism in elderly people. Healthy subjects (n=93; >54 years) were randomly assigned to receive either daily vitamin D3 (1200 IU), folic acid (0.5 mg), vitamin B12 (0.5 mg), vitamin B6 (50 mg), and calcium carbonate (456 mg) (group A) or only vitamin D3 plus calcium carbonate (group B) in a double blind trial. We measured at baseline and after 6 and 12 months of supplementation vitamins, metabolites, and bone turnover markers. At baseline mean plasma 25-hydroxy vitamin D [25(OH)D] was low (40 or 30 nmol/L) and parathormone was high (63.7 or 77.9 pg/mL). 25(OH)D and parathormone correlated inversely. S-Adenosyl homocysteine and S-adenosyl methionine correlated with bone alkaline phosphatase, sclerostin, and parathormone. One year vitamin D3 or D3 and B supplementation increased plasma 25(OH)D by median 87.6% (group A) and 133.3% (group B). Parathormone was lowered by median 28.3% (A) and 41.2% (B), bone alkaline phosphatase decreased by 2.8% (A) and 16.2% (B), osteocalin by 37.5% (A) and 49.4% (B), and tartrate-resistant-acid-phosphatase 5b by 6.1% (A) and 36.0% (B). Median total homocysteine (tHcy) was high at baseline (group A: 12.6, group B: 12.3 µmol/L) and decreased by B vitamins (group A) to 8.9 µmol/L (29.4%). tHcy lowering had no additional effect on bone turnover. One year vitamin D3 supplementation with or without B vitamins decreased the bone turnover significantly. Vitamin D3 lowered parathormone. The additional application of B vitamins did not further improve bone turnover. The marked tHcy lowering by B vitamins may modulate the osteoporotic risk.


The carbon footprint of a renal service in the United Kingdom.
Anthropogenic climate change presents a major global health threat. However, the very provision of healthcare itself is associated with a significant environmental impact. Carbon footprinting techniques are increasingly used outside of the healthcare sector to assess greenhouse gas emissions and inform strategies to reduce them. This study represents the first assessment of the carbon footprint of an individual specialty service to include both direct and indirect emissions. This was a component analysis study. Activity data were collected for building energy use, travel and procurement. Established emissions factors were applied to reconcile this data to carbon dioxide equivalents (CO(2)eq) per year. The Dorset Renal Service has a carbon footprint of 3006 tonnes CO(2)eq per annum, of which 381 tonnes CO(2)eq (13% of overall emissions) result from building energy use, 462 tonnes CO(2)eq from travel (15%) and 2163 tonnes CO(2)eq (72%) from procurement. The contributions of the major subsectors within procurement are: pharmaceuticals, 1043 tonnes CO(2)eq (35% of overall emissions); medical equipment, 753 tonnes CO(2)eq (25%). The emissions associated with healthcare episodes were estimated at 161 kg CO(2)eq per bed day for an inpatient admission and 22 kg CO(2)eq for an outpatient appointment. These results suggest that carbon-reduction strategies focusing upon supply chain emissions are likely to yield the greatest benefits. Sustainable waste management and strategies to reduce emissions associated with building energy use and travel will also be important. A transformation in the way that clinical care is delivered is required, such that lower carbon clinical pathways, treatments and technologies are embraced. The estimations of greenhouse gas emissions associated with outpatient appointments and inpatient stays calculated here may facilitate modelling of the emissions of alternative pathways of care.


Peripheral Neuropathy Phenotyping in Rat Models of Type 2 Diabetes Mellitus: Evaluating Uptake of the Neurodiab Guidelines and Identifying Future Directions.
Diabetic peripheral neuropathy (DPN) affects over half of type 2 diabetes mellitus (T2DM) patients, with an urgent need for effective pharmacotherapies. While many rat and mouse models of T2DM exist, the phenotyping of DPN has been challenging with inconsistencies across laboratories. To better characterize DPN in rodents, a consensus guideline was published in 2014 to accelerate the translation of preclinical findings. Here we review DPN phenotyping in rat models of T2DM against the 'Neurodiab' criteria to identify uptake of the guidelines and discuss how DPN phenotypes differ between models and according to diabetes duration and sex. A search of PubMed, Scopus and Web of Science databases identified 125 studies, categorised as either diet and/or chemically induced models or transgenic/spontaneous models of T2DM. The use of diet and chemically induced T2DM models has exceeded that of transgenic models in recent years, and the introduction of the Neurodiab guidelines has not appreciably increased the number of studies assessing all key DPN endpoints. Combined high-fat diet and low dose streptozotocin rat models are the most frequently used and well characterised. Overall, we recommend adherence to Neurodiab guidelines for creating better animal models of DPN to accelerate translation and drug development.


Chemo-mechanical coupling in kerogen gas adsorption/desorption.
Kerogen plays a central role in hydrocarbon generation in an oil/gas reservoir. In a subsurface environment, kerogen is constantly subjected to stress confinement or relaxation. The interplay between mechanical deformation and gas adsorption of the materials could be an important process for shale gas production but unfortunately is poorly understood. Using a hybrid Monte Carlo/molecular dynamics simulation, we show here that a strong chemo-mechanical coupling may exist between gas adsorption and mechanical strain of a kerogen matrix. The results indicate that the kerogen volume can expand by up to 5.4% and 11% upon CH4 and CO2 adsorption at 192 atm, respectively. The kerogen volume increases with gas pressure and eventually approaches a plateau as the kerogen becomes saturated. The volume expansion appears to quadratically increase with the amount of gas adsorbed, indicating a critical role of the surface layer of gas adsorbed in the bulk strain of the material. Furthermore, gas uptake is greatly enhanced by kerogen swelling. Swelling also increases the surface area, porosity, and pore size of kerogen. Our results illustrate the dynamic nature of kerogen, thus questioning the validity of the current assumption of a rigid kerogen molecular structure in the estimation of gas-in-place for a shale gas reservoir or gas storage capacity for subsurface carbon sequestration. The coupling between gas adsorption and kerogen matrix deformation should be taken into consideration.


Endosomal chloride-proton exchange rather than chloride conductance is crucial for renal endocytosis.
Loss of the endosomal anion transport protein ClC-5 impairs renal endocytosis and underlies human Dent's disease. ClC-5 is thought to promote endocytosis by facilitating endosomal acidification through the neutralization of proton pump currents. However, ClC-5 is a 2 chloride (Cl-)/proton (H+) exchanger rather than a Cl- channel. We generated mice that carry the uncoupling E211A (unc) mutation that converts ClC-5 into a pure Cl- conductor. Adenosine triphosphate (ATP)-dependent acidification of renal endosomes was reduced in mice in which ClC-5 was knocked out, but normal in Clcn5(unc) mice. However, their proximal tubular endocytosis was also impaired. Thus, endosomal chloride concentration, which is raised by ClC-5 in exchange for protons accumulated by the H+-ATPase, may play a role in endocytosis.


A mouse dry eye model induced by topical administration of benzalkonium chloride.
To develop a dry eye model of mouse induced by topical administration of benzalkonium chloride (BAC) and investigate the possible mechanisms. BAC at concentration of 0.2% was applied to the mouse ocular surface for 7 days. Phenol red thread tear test, tear break-up time (BUT) test, corneal inflammatory index scoring, fluorescein and rose bengal test were performed to evaluate the toxic effects of BAC on the ocular surface. Global specimens were collected on day (D) 7 and labeled with a series of antibodies including cytokeratin 10 (K10) and mucin 5AC (MUC5AC). Apoptosis of ocular surface epithelium was evaluated by in situ terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Histologic analysis and transmission electron microscopy (TEM) were performed on D7. BAC at a concentration of 0.2% successfully induced a dry eye condition with decreased tear volume and BUTs, increased corneal fluorescein and rose bengal scores. The Inflammatory index was increased in accompaniment with higher tumor necrosis factor-α (TNF-α) expression and more inflammatory infiltration in the cornea. Immunolabeling revealed positive K10 expression in BAC-treated corneal epithelium and fewer MUC5AC-positive cells in the BAC-treated conjunctival fornix. TUNEL assay showed more apoptotic cells in the corneal basal epithelium. TEM showed that the size and intervals of the microvillis were both reduced in the corneal epithelium. Topical administration of 0.2% BAC in mouse induces changes resembling that of dry eye syndrome in humans, and thus, represents a novel model of dry eye.


Bromocriptine in management of large pituitary tumours.
Bromocriptine has an accepted place in the management of small pituitary tumours that secrete either prolactin or growth hormone. The treatment of large tumours with extrasellar extensions is more difficult, however: though surgery is the standard treatment, it is often unsuccessful in returning excessive hormone secretion to normal and may cause hypopituitarism. A prospective trial was undertaken to assess the frequency with which changes in pituitary function and size of large tumours occurs. Nineteen patients were studied before and during treatment with bromocriptine (7.5 to 60 ml/day) for three to 22 months, using contrast radiology and a detailed assessment of pituitary function. Eighteen patients had hyperprolactinaemia and two of these also had raised concentrations of growth hormones; one patient had an apparently non-functioning tumour. In 12 patients (63%) tumour size decreased with bromocriptine and no tumour enlarged. Nine patients had visual-field defects, which improved in seven, becoming normal in five. Pituitary function improved in nine patients (47%) becoming entirely normal in three. Bromocriptine should be the treatment of choice in patients with large pituitary tumours with extrasellar extensions, provided close supervision is maintained.


Work conditioning, work hardening and functional restoration for workers with back and neck pain.
Physical conditioning programs, variously called work conditioning, work hardening and functional restoration/exercise programs, aim to improve work status and function. Previous attempts have been made to evaluate the efficacy of work-oriented back pain management programs, but none have focused exclusively on work or functional outcomes. To compare the effectiveness of physical conditioning programs with management strategies that do not include physical conditioning programs, for workers with back and neck pain, in reducing time lost from work and increasing functional status. We searched the following databases to 31 May 2000: MEDLINE from 1966, EMBASE from 1980, CINAHL from 1982, Biomedical Collection: I (from 1993), II (from 1995), III (from 1995), IV (from 1995), PsycINFO from 1967, the Cochrane Central Register of Controlled Trials, PEDro. Randomized controlled trials (RCTs) that studied adults with work disability related to back or neck pain, who were included in physical conditioning programs. Two reviewers independently extracted data and assessed trial quality. Where data could be pooled, a meta-analysis was performed using RevMan. For continuous outcomes, we nominated a saving of 10 sick days as the smallest treatment effect that would be clinically worthwhile. For dichotomous outcomes, we considered that an intervention that affected less than one in 10 people would not be clinically worthwhile. Eighteen RCTs were identified in 20 publications. Twenty-three relevant contrasts were investigated. There is evidence that physical conditioning programs that include a cognitive-behavioural approach can reduce the number of sick days lost at 12 months follow-up by an average of 45 days, when compared to general practitioner usual care or advice, for workers with chronic back pain. For work-related outcomes, there is little evidence for or against the efficacy of specific exercises that are not accompanied by a cognitive-behavioural approach, in reducing sick days lost due to back pain, for workers with either acute or chronic back pain. Physical conditioning programs that include a cognitive-behavioural approach plus intensive physical training (specific to the job or not) that includes aerobic capacity, muscle strength and endurance, and coordination; are in some way work-related; and are given and supervised by a physiotherapist or a multidisciplinary team, seem to be effective in reducing the number of sick days for some workers with chronic back pain, when compared to usual care. However, there is no evidence of their efficacy for acute back pain.


HIV Type 1 transmission networks among men having sex with men and heterosexuals in Kenya.
We performed a molecular phylogenetic study on HIV-1 polymerase sequences of men who have sex with men (MSM) and heterosexual patient samples in Kenya to characterize any observed HIV-1 transmission networks. HIV-1 polymerase sequences were obtained from samples in Nairobi and coastal Kenya from 84 MSM, 226 other men, and 364 women from 2005 to 2010. Using Bayesian phylogenetics, we tested whether sequences clustered by sexual orientation and geographic location. In addition, we used trait diffusion analyses to identify significant epidemiological links and to quantify the number of transmissions between risk groups. Finally, we compared 84 MSM sequences with all HIV-1 sequences available online at GenBank. Significant clustering of sequences from MSM at both coastal Kenya and Nairobi was found, with evidence of HIV-1 transmission between both locations. Although a transmission pair between a coastal MSM and woman was confirmed, no significant HIV-1 transmission was evident between MSM and the comparison population for the predominant subtype A (60%). However, a weak but significant link was evident when studying all subtypes together. GenBank comparison did not reveal other important transmission links. Our data suggest infrequent intermingling of MSM and heterosexual HIV-1 epidemics in Kenya.


Gedunin and Azadiradione: Human Pancreatic Alpha-Amylase Inhibiting Limonoids from Neem (Azadirachta indica) as Anti-Diabetic Agents.
Human pancreatic α-amylase (HPA) inhibitors offer an effective strategy to lower postprandial hyperglycemia via control of starch breakdown. Limonoids from Azadirachta indica known for their therapeutic potential were screened for pancreatic α-amylase inhibition, a known anti-diabetic target. Studies were carried out to reveal their mode of action so as to justify their hypoglycemic potential. Of the nine limonoids isolated/semi-synthesized from A.indica and screened for α-amylase inhibition, azadiradione and exhibited potential inhibition with an IC50 value of 74.17 and 68.38 μM, respectively against HPA under in vitro conditions. Further screening on AR42J α-amylase secretory cell line for cytotoxicity and bioactivity revealed that azadiradione and gedunin exhibited cytotoxicity with IC50 of 11.1 and 13.4μM. Maximal secreted α-amylase inhibition of 41.8% and 53.4% was seen at 3.5 and 3.3μM, respectively. Michaelis-Menten kinetics suggested a mixed mode of inhibition with maltopentaose (Ki 42.2, 18.6 μM) and starch (Ki' 75.8, 37.4 μM) as substrate with a stiochiometry of 1:1 for both azadiradione and gedunin, respectively. The molecular docking simulation indicated plausible π-alkyl and alkyl-alkyl interactions between the aromatic amino acids and inhibitors. Fluorescence and CD confirmed the involvement of tryptophan and tyrosine in ligand binding to HPA. Thermodynamic parameters suggested that binding is enthalpically and entropically driven with ΔG° of -21.25 kJ mol-1 and -21.16 kJ mol-1 for azadiradione and gedunin, respectively. Thus, the limonoids azadiradione and gedunin could bind and inactivate HPA (anti-diabetic target) and may prove to be lead drug candidates to reduce/control post-prandial hyperglycemia.


Smoking, diabetes and cardiovascular diseases in men in the Asia Pacific region.
To assess whether there is a statistical interaction between smoking and diabetes that is related to the risk of cardiovascular disease (CVD) in men in the Asia Pacific region. An individual participant data meta-analysis was conducted on 34 cohort studies, involving 16 492 participants with diabetes (47.4% smokers) and 188 897 without (47.6% smokers). Hazard ratios (HR) and 95% confidence intervals (CI) were calculated for smoking (stratified by study and adjusted for age) for those with and without diabetes. In men with diabetes, the HR (95% CI) comparing current smokers with non-smokers was 1.42 (1.10-1.83) for coronary heart disease, 1.10 (0.88-1.37) for total stroke and 1.15 (0.98-1.35) for total CVD. The corresponding figures for men without diabetes were 1.47 (1.33-1.61), 1.27 (1.16-1.39) and 1.35 (1.27-1.44), respectively. There was no evidence of a statistical interaction between diabetes and current smoking, the number of cigarettes smoked per day or quitting smoking. Smoking cessation was associated with a 19% reduction in CVD risk, irrespective of diabetes status. The effects of cigarette smoking and smoking cessation are broadly similar in men with and without diabetes. In Asia, where there are high rates of smoking and a rapidly increasing prevalence of diabetes, strategies that encourage smokers to quit are likely to have huge benefits in terms of reducing the burden of CVD in men with diabetes.


The inhibitory receptor NKG2A determines lysis of vaccinia virus-infected autologous targets by NK cells.
Signals transduced by inhibitory receptors that recognize self-MHC class I molecules prevent NK cells from being activated by autologous healthy target cells. In order for NK cells to be activated upon contact with an infected cell, the balance between the activating and inhibitory signals that regulate NK cell function must be altered in favor of activation. By studying liver-derived NK cells, we show that only a subpopulation of NK cells expressing high levels of the inhibitory receptor NKG2A are able to lyse autologous vaccinia-infected targets, and that this is due to selective down-regulation of HLA-E. These data demonstrate that release from an inhibitory receptor:ligand interaction is one mechanism that permits NK cell recognition of a virally infected target, and that the variegated expression of inhibitory receptors in humans generates a repertoire of NK cells with different antiviral potentials.


Efficacy and cost of micronutrient treatment of childhood psychosis.
Psychosis is difficult to treat effectively with conventional pharmaceuticals, many of which have adverse long-term health consequences. In contrast, there are promising reports from several research groups of micronutrient treatment (vitamins, minerals, amino acids and essential fatty acids) of mood, anxiety and psychosis symptoms using a complex formula that appears to be safe and tolerable. We review previous studies using this formula to treat mental symptoms, and present an 11-year-old boy with a 3-year history of mental illness whose parents chose to transition him from medication to micronutrients. Symptom severity was monitored in three clusters: anxiety, obsessive compulsive disorder and psychosis. Complete remission of psychosis occurred, and severity of anxiety and obsessional symptoms decreased significantly (p<0.001); the improvements are sustained at 4-year follow-up. A cost comparison revealed that micronutrient treatment was <1% of his inpatient mental healthcare. Additional research on broad-spectrum micronutrient treatment is warranted.