Extremely High Prevalence of Metronidazole-Resistant Helicobacter pylori Strains in Mountain People (Karen and Hmong) in Thailand.
This study aimed to survey the prevalence, patterns of antibiotic resistance, and clinical factors associated with antibiotic resistance in Helicobacter pylori among the Karen and Hmong mountain people of Thailand. We recruited dyspeptic patients in the Maesod district, Tak Province, Thailand. All subjects underwent upper gastrointestinal endoscopy, and three antral gastric biopsies were obtained for rapid urease tests and culture. An epsilometer was used to determine the minimum inhibitory concentrations of amoxicillin (AMX), clarithromycin (CLR), metronidazole (MNZ), levofloxacin (LVX), ciprofloxacin (CIP), and tetracycline (TET). A total of 291 subjects were enrolled; 149 (51.2%) were infected with H. pylori. Helicobacter pylori infection was present in 47.1% of Thai, 51.7% of Karen, and 58.7% of Hmong subjects. Antibiotic resistance was present in 75.8% including AMX (0.8%), TET (0%), CLR (5.6%), MNZ (71.8%), CIP (19.4%), LVX (19.4%), and multidrug resistance in 21.8%. Karen subjects had the highest prevalence of MNZ resistance (84.6%), and Hmong subjects had the highest prevalence of fluoroquinolone (27.3%) and multidrug (34.1%) resistance. MNZ plus fluoroquinolone (14.5%) was the most common multidrug resistance. There was no association between clinical factors and antibiotic resistance. MNZ resistance was prevalent, whereas fluoroquinolone- and multidrug-resistant H. pylori infections are important problems in mountain people of Thailand.


The Importance of Parental Connectedness and Relationships With Healthcare Professionals in End-of-Life Care in the PICU.
Support from healthcare professionals in a PICU is highly valuable for parents of dying children. The way they care for the patients and their families affects the parents' initial mourning process. This study explores what interaction with hospital staff is meaningful to parents in existential distress when their child is dying in the PICU. Qualitative interview study. Level 3 PICU in the Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, and the Netherlands. Thirty-six parents of 20 children who had died in this unit 5 years previously. Parents participated in audio-recorded interviews in their own homes. The interviews were transcribed and analyzed using qualitative methods. Parents' narratives of their child's end-of-life stage in the PICU bespeak experiences of estrangement, emotional distancing, and loneliness. Significant moments shared with hospital staff that remained valuable even after 5 years primarily involved personal connectedness, reflected in frequent informational updates, personal commitment of professionals, and interpersonal contact with doctors and nurses. Parents whose children died in the PICU value personal connectedness to doctors and nurses when coping with existential distress. Medical and nursing training programs should raise awareness of parents' need for contact in all interactions but especially in times of crisis and apprehension.


Pharmacoeconomic impact of different regimens to prevent cytomegalovirus infection in renal transplant recipients.
The aim of this study was to determine the cost impact of four different strategies for prevention of cytomegalovirus (CMV) disease after renal transplantation. Hospitalization data and medical resource utilization data were prospectively collected alongside two randomized trials. In the first trial, the patients were randomized to 3-month prophylaxis with either oral ganciclovir (1 g t.i.d., n = 36) or valacyclovir (2 g q.i.d., n = 35), and to the control group (n = 12) managed by deferred therapy. In the second trial, the patients were randomly assigned to 3-month valacyclovir prophylaxis (n = 34) or preemptive therapy with valganciclovir (900 mg b.i.d. for a minimum of 14 days, n = 36) for significant CMV DNAemia. The cost analysis involved all real costs directly related to CMV during the first year after renal transplantation. The mean CMV-associated costs per patient were EUR 4,581, 2,577, 4,968, and 8,050 in patients in the ganciclovir, valacyclovir, preemptive, and deferred therapy groups, respectively (p < 0.001). Valacyclovir prophylaxis was significantly less expensive than any other regimen. The cost of one episode of CMV disease was EUR 7,510 per patient. Due to excessive incidence of CMV disease, deferred therapy was the most expensive strategy (p < 0.001). Valacyclovir prophylaxis is less expensive strategy compared with any other regimen.


Citrus Responses to Xylella fastidiosa Infection.
The xylem-limited bacterium Xylella fastidosa causes the widely disseminated citrus variegated chlorosis disease (CVC). In Brazil, CVC has been known for more than 20 years and affects only sweet orange. Lime and mandarin have remained free of symptoms despite the high inoculum pressure. Knowing the mechanisms underlying this apparent resistance is important to devise new disease control strategies. The reaction of commercial sweet orange ('Caipira', 'Natal', 'Pêra', and 'Valencia'), lime (Mexican and Persian), mandarin ('Cleopatra', 'Cravo', 'Ponkan', and 'Sunki'), and the acid citrus species Rangpur to X. fastidiosa was compared in artificially inoculated seedlings, which were assessed for symptom expression, pathogen isolation, and the amount of apparently occluded xylem vessels in cross-sectioned leaf petioles. Only the sweet orange expressed typical CVC symptoms, varying from 53.8% in Valencia to 63.0% in Caipira. Average percentages of positive isolations (pi) and occluded vessels (ov) were higher in sweet orange (pi= 59.2 to 75.0; ov = 10.7 to 25.8) than mandarin (pi = 2.3 to 16.3; ov = 1.4 to 4.0), lime (pi = 0 to 5.4; ov = 0 to 2.1), or Rangpur (pi = 1,9; ov = 1.1). There were no obvious differences in xylem anatomy among all citrus varieties, suggesting that the mechanisms of resistance to CVC are not related to any physical variation in xylem structure.


Correlations between caregiver psychiatric symptoms and offspring psychopathology in a low-resource setting.
Associations between parental/caregiver depression and adverse child outcomes are well established and have been described through one or more mechanisms: child psychopathology following exposure to a depressed caregiver, child psychopathology exacerbating a caregiver's depression, and caregiver and offspring depression sharing the same etiology. Data from low and middle-income countries is scarce. We examined correlations between common symptoms of mental disorders in caregivers and their offspring's psychopathology in a Brazilian sample. In this cross-sectional study, adult caregivers were screened for depression during routine home visits by community health workers as part of the Brazilian Family Health Strategy. Caregivers with suspected depression were assessed using the Zung Self-Rating Depression Scale and the Self-Reporting Questionnaire (SRQ-20). Children's symptoms were evaluated using the Strengths and Difficulties Questionnaire (SDQ). The sample included 68 primary caregivers and 110 children aged 6 to 15 years. Higher caregiver scores on the SRQ-20 correlated significantly with psychiatric symptoms in offspring. These results substantiate our hypothesis that child psychopathology correlates with caregivers' psychiatric symptoms. This paper adds to the growing literature on community mental health assessment and can help guide future strategies for reducing the burden of common mental disorders in caregivers and children alike in low and middle-income countries.


ERS technical standard on bronchial challenge testing: pathophysiology and methodology of indirect airway challenge testing.
Recently, this international task force reported the general considerations for bronchial challenge testing and the performance of the methacholine challenge test, a "direct" airway challenge test. Here, the task force provides an updated description of the pathophysiology and the methods to conduct indirect challenge tests. Because indirect challenge tests trigger airway narrowing through the activation of endogenous pathways that are involved in asthma, indirect challenge tests tend to be specific for asthma and reveal much about the biology of asthma, but may be less sensitive than direct tests for the detection of airway hyperresponsiveness. We provide recommendations for the conduct and interpretation of hyperpnoea challenge tests such as dry air exercise challenge and eucapnic voluntary hyperpnoea that provide a single strong stimulus for airway narrowing. This technical standard expands the recommendations to additional indirect tests such as hypertonic saline, mannitol and adenosine challenge that are incremental tests, but still retain characteristics of other indirect challenges. Assessment of airway hyperresponsiveness, with direct and indirect tests, are valuable tools to understand and to monitor airway function and to characterise the underlying asthma phenotype to guide therapy. The tests should be interpreted within the context of the clinical features of asthma.


The Critical Need to Promote Research of Aging and Aging-related Diseases to Improve Health and Longevity of the Elderly Population.
Due to the aging of the global population and the derivative increase in aging-related non-communicable diseases and their economic burden, there is an urgent need to promote research on aging and aging-related diseases as a way to improve healthy and productive longevity for the elderly population. To accomplish this goal, we advocate the following policies: 1) Increasing funding for research and development specifically directed to ameliorate degenerative aging processes and to extend healthy and productive lifespan for the population; 2) Providing a set of incentives for commercial, academic, public and governmental organizations to foster engagement in such research and development; and 3) Establishing and expanding coordination and consultation structures, programs and institutions involved in aging-related research, development and education in academia, industry, public policy agencies and at governmental and supra-governmental levels.


A process evaluation of how the routine vaccination programme is implemented at GP practices in England.
In recent years, the incidence of several pathogens of public health importance (measles, mumps, pertussis and rubella) has increased in Europe, leading to outbreaks. This has included England, where GP practices implement the vaccination programme based on government guidance. However, there has been no study of how implementation takes place, which makes it difficult to identify organisational variation and thus limits the ability to recommend interventions to improve coverage. The aim of this study is to undertake a comparative process evaluation of the implementation of the routine vaccination programme at GP practices in England. We recruited a sample of geographically and demographically diverse GP practices through a national research network and collected quantitative and qualitative data as part of a Time-Driven Activity-Based Costing analysis between May 2017 and February 2018. We conducted semi-structured interviews with practice staff involved in vaccination, who then completed an activity log for 2 weeks. Interviews were transcribed and coded using a framework method. Nine practices completed data collection from diverse geographic and socio-economic contexts, and 52 clinical and non-clinical staff participated in 26 interviews. Information relating to 372 vaccination appointments (233 childhood and 139 adult appointments) was captured using activity logs. We have defined a 14-stage care delivery value chain and detailed process map for vaccination. Areas of greatest variation include the method of reminder and recall activities, structure of vaccination appointments and task allocation between staff groups. For childhood vaccination, mean appointment length was 15.9 min (range 9.0-22.0 min) and 10.9 min for adults (range 6.8-14.1 min). Non-clinical administrative activities comprised 59.7% total activity (range 48.4-67.0%). Appointment length and total time were not related to coverage, whereas capacity in terms of appointments per eligible patient may improve coverage. Administrative tasks had lower fidelity of implementation. There is variation in how GP practices in England implement the delivery of the routine vaccination programme. Further work is required to evaluate capacity factors in a wider range of practices, alongside other contextual factors, including the working culture within practices.


Positive memory training for the treatment of depression in schizophrenia: A randomised controlled trial.
Around half of people diagnosed with schizophrenia suffer from co-morbid depression, yet there are no evidence-based psychological treatments to target this presentation. Participants were aged 18-65 years old, had a clinical diagnosis of schizophrenia or schizoaffective disorder and at least a mild level of depression. Participants were randomly assigned (1:1) to receive PoMeT or treatment as usual. PoMeT was delivered in up to 12 individual sessions within 3 months. We stratified randomisation by site and by severity of depression using randomised-permuted blocks. Assessments were carried out at baseline, 3-month, 6-month and 9-month by assessors who were blind to treatment allocation. The primary outcome was reduction in the symptoms of depression at 3-month, 6-month and 9-month as measured by the BDI-II. Analysis was by intention-to-treat with linear mixed-effects models. The trial was registered with the ISRCTN registry number 99485756. One hundred participants were randomly assigned to either PoMeT (n = 49) or treatment as usual (n = 51). The reduction in BDI-II total score at 3 months was significantly greater for PoMeT than for treatment as usual (mean difference = 4.33, SE = 2.00, 95% CI 0.38 to 8.23; p = 0.03). To our knowledge this is, to date, the largest powered randomised controlled trial focused on the psychological treatment of depression in people diagnosed with schizophrenia. Results indicate that a brief targeted intervention can reduce the symptoms of depression in the group. The main limitation of the study is the lack of an active control group which may contribute to an inflated treatment effect.


SH3BGRL3 Protein as a Potential Prognostic Biomarker for Urothelial Carcinoma: A Novel Binding Partner of Epidermal Growth Factor Receptor.
Mass spectrometry-based biomarker discovery has clinical benefit. To identify novel biomarkers for urothelial carcinoma, we performed quantitative proteomics on pooled urine pairs from patients with and without urothelial carcinoma. Shot-gun proteomics using liquid chromatography-tandem mass spectrometry and stable isotope dimethyl labeling identified 219 candidate proteins. The potential implication of SH3 domain binding glutamic acid-rich protein like 3 (SH3BGRL3) was examined by immunoblotting of the urine (n = 13) and urothelial tumors (n = 32). Additional immunohistochemistry was performed on bladder cancer array (n = 1145) and correlated with tumor aggressiveness. Then, biologic functions and signaling pathways of SH3BGRL3 were explored using stable cell lines. The detectable urine SH3BGRL3 in patients with urothelial carcinoma was positively associated with higher histologic grading and muscle invasiveness of urothelial carcinoma. SH3BGRL3 is expressed in 13.9% (159/1145) of bladder cancer cohort and is positively associated with muscle invasion (P = 0.0028). SH3BGRL3 expression is associated with increased risk of progression in patients with nonmuscle-invasive bladder cancer (P = 0.032). SH3BGRL3 expression is significantly associated with a high level of epidermal growth factor receptor (EGFR) in bladder cancer (P < 0.0001). SH3BGRL3 promotes the epithelial-mesenchymal transition, cell migration, and proliferation of urothelial carcinoma in vitro. SH3BGRL3 interacts with phosphor-EGFR at Y1068, Y1086, and Y1173 through Grb2 by its proline-rich motif, and activates the Akt-associated signaling pathway. Evaluation of SH3BGRL3 expression status or urine content may identify a subset of patients with bladder cancer who may require more intensive treatment. SH3BGRL3 deserves further investigation as a cotargeting candidate for designing EGFR-based cancer therapies. Clin Cancer Res; 21(24); 5601-11. ©2015 AACR.


Identifying the photoreceptive inputs to the mammalian circadian system using transgenic and retinally degenerate mice.
The endogenous circadian clock of mammals retains synchrony with the external light:dark cycle through ocular photoreceptors. To date the identity of the photoreceptors responsible for mediating this response is unknown. This review outlines attempts using transgenic mouse models to address this deficit. Mice bearing specific inherited lesions of both rod and cone photoreceptors retain circadian photosensitivity as assessed by photoentrainment of behavioural rhythms and the light-induced suppression of pineal melatonin. These findings indicate that as yet unidentified non-rod, non-cone ocular photoreceptors are capable of contributing to circadian light responses. Nevertheless, the possibility that circadian photosensitivity is the responsibility of multiple photoreceptor classes including both rod/cone and novel photopigments remains. There is some indirect evidence in favour of this hypothesis. A definitive resolution of this issue is likely to employ comparisons of circadian action spectra in wild type and retinally degenerate mice.


Model-free decision making is prioritized when learning to avoid harming others.
Moral behavior requires learning how our actions help or harm others. Theoretical accounts of learning propose a key division between "model-free" algorithms that cache outcome values in actions and "model-based" algorithms that map actions to outcomes. Here, we tested the engagement of these mechanisms and their neural basis as participants learned to avoid painful electric shocks for themselves and a stranger. We found that model-free decision making was prioritized when learning to avoid harming others compared to oneself. Model-free prediction errors for others relative to self were tracked in the thalamus/caudate. At the time of choice, neural activity consistent with model-free moral learning was observed in subgenual anterior cingulate cortex (sgACC), and switching after harming others was associated with stronger connectivity between sgACC and dorsolateral prefrontal cortex. Finally, model-free moral learning varied with individual differences in moral judgment. Our findings suggest moral learning favors efficiency over flexibility and is underpinned by specific neural mechanisms.


Understanding rare adverse sequelae of breast implants: anaplastic large-cell lymphoma, late seromas, and double capsules.
Breast implant-associated anaplastic large cell lymphoma (BI-ALCL) is a distinct type of T-cell lymphoma arising around breast implants. The United States FDA recently updated the 2011 safety communication, warning that women with breast implants may have a very low risk of developing ALCL adjacent to a breast implant. According to the World Health Organization, BI-LCL is not a breast cancer or cancer of the breast tissue; it is a lymphoma, a cancer of immune cells. BI-ALCL is highly curable in the majority of patients. Informed consent should include the risk of BI-ALCL with breast implant patients. Women with breast implants are encouraged to contact their plastic surgeon if they notice swelling, fluid collections, or unexpected changes in breast shape. Physicians are encouraged to send suspicious peri-prosthetic fluid for CD30 immunohistochemistry, cell block cytology, and culture in symptomatic patients. An observation from reported cases indicates a predominance of textured device involvement. More information is needed to fully understand risk factors and etiology. The association of bacteria and biofilm with ALCL is currently being investigated and one theory is that biofilm may play a role in this disease process stressing the importance of best practice techniques intraoperatively. Recent studies have reported clinical presentation, prognosis, and treatment outcomes with long term followup demonstrating the critical role for surgical management.


Measuring the effective area and charge density of platinum electrodes for bionic devices.
Neural stimulation is usually performed with fairly large platinum electrodes. Smaller electrodes increase the applied charge density, potentially damaging the electrode. Greater understanding of the charge injection mechanism is required for safe neural stimulation. The charge injection mechanism and charge injection capacity were measured by cyclic voltammetry. Electrodes were cleaned mechanically or by potential cycling in acidic solutions. The effective electrode area was measured by hydrogen adsorption or reduction of [Formula: see text]. The water window and safe potential window were affected by changes to electrolyte, electrode size, polishing method and oxygen concentration. Capacitance and Faradaic current contribute to the charge injection capacity. Varying voltammetric scan rate (measurement time), electrode size, polishing method, potential window, electrolyte and oxygen concentration affected the charge injection capacity and ratio of oxidation to reduction charge. Hydrogen adsorption in acidic solutions provided an inaccurate effective electrode area. Reduction of a solution phase redox species with a linear or radial diffusion profile could provide an effective electrode area. The charge density (charge injection capacity divided by electrode area) of a platinum electrode is dependent on the charge injection capacity and electrode area measurement technique. By varying cyclic voltammetric conditions, the charge density of platinum ranged from 0.15 to 5.57 mC cm-2. The safe potential window, charge injection mechanism, charge injection capacity and charge density of platinum depends on electrolyte, size of the electrode, oxygen concentration and differences in electrode polishing method. The oxidation and reduction charge injection capacities are not equal. Careful control of a platinum electrodes surface may allow larger charge densities and safe use of smaller electrodes. New electrode materials and geometries should be tested in a consistent manner to allow comparison of potential suitability for neural stimulation.


Investigating the Protein Signature of Adamantinomatous Craniopharyngioma Pediatric Brain Tumor Tissue: Towards the Comprehension of Its Aggressive Behavior.
Although histologically benign, adamantinomatous craniopharyngioma (AC) pediatric brain tumor is a locally aggressive disease that frequently determines symptoms and hormonal dysfunctions related to the mass effect on the surrounding structures. Another typical feature of this benign neoplasm is the presence of voluminous liquid cysts frequently associated with the solid component. Even if studies have been devoted to the proteomic characterization of the tumor intracystic fluid, poor explorations have been performed on its solid part, principally investigated by transcriptomics technologies. In the present study, seven specimens of AC whole tumor tissue have been analyzed by LC-MS for a preliminary assessment of the proteomic profile by a top-down/bottom-up integrated approach. Thymosin beta 4, ubiquitin, calmodulin, S100 proteins, prothymosin α isoform 2, alpha-defensins 1-4, and fragments largely belonging to vimentin, hemoglobin, and glial fibrillary acidic protein characterized the intact proteome. The identification of alpha-defensins, formerly characterized in AC intracystic fluid, reinforces the hypothesis of a role for inflammation in tumor pathogenesis. A total number of 1798 unique elements were identified by a bottom-up approach with a special focus on the 433 proteins commonly characterized in the 85.7% of the samples analyzed. Their gene ontology classification evidenced the involvement of the adherence system, intermediate filaments, and actin cytoskeleton in tumor pathogenesis and of elements part of the Wnt, FGF, and EGFR signaling pathways. In addition, proteins involved in calcium modulation, innate immunity, inflammation, CCKR and integrin signaling, and gonadotropin-releasing hormone receptor pathways were also outlined. Further than confirming proteomic data previously obtained on AC intracystic fluid, these results offer a preliminary overview of the AC whole tissue protein phenotype, adding new hints towards the comprehension of this still obscure pediatric brain tumor.


Intrinsic Mechanisms Regulating Neuronal Migration in the Postnatal Brain.
Neuronal migration is a fundamental brain development process that allows cells to move from their birthplaces to their sites of integration. Although neuronal migration largely ceases during embryonic and early postnatal development, neuroblasts continue to be produced and to migrate to a few regions of the adult brain such as the dentate gyrus and the subventricular zone (SVZ). In the SVZ, a large number of neuroblasts migrate into the olfactory bulb (OB) along the rostral migratory stream (RMS). Neuroblasts migrate in chains in a tightly organized micro-environment composed of astrocytes that ensheath the chains of neuroblasts and regulate their migration; the blood vessels that are used by neuroblasts as a physical scaffold and a source of molecular factors; and axons that modulate neuronal migration. In addition to diverse sets of extrinsic micro-environmental cues, long-distance neuronal migration involves a number of intrinsic mechanisms, including membrane and cytoskeleton remodeling, Ca2+ signaling, mitochondria dynamics, energy consumption, and autophagy. All these mechanisms are required to cope with the different micro-environment signals and maintain cellular homeostasis in order to sustain the proper dynamics of migrating neuroblasts and their faithful arrival in the target regions. Neuroblasts in the postnatal brain not only migrate into the OB but may also deviate from their normal path to migrate to a site of injury induced by a stroke or by certain neurodegenerative disorders. In this review, we will focus on the intrinsic mechanisms that regulate long-distance neuroblast migration in the adult brain and on how these pathways may be modulated to control the recruitment of neuroblasts to damaged/diseased brain areas.


Early events in kidney donation: progression of endothelial activation, oxidative stress and tubular injury after brain death.
Cerebral injury leading to brain death (BD) causes major physiologic derangements in potential organ donors, which may result in vascular-endothelial activation and affect posttransplant graft function. We investigated the kinetic of pro-coagulatory and pro-inflammatory endothelial activation and the subsequent oxidative stress and renal tubular injury, early after BD declaration. BD was induced by slowly inflating a balloon-catheter inserted in the extradural space over a period of 30 min. Rats (n = 30) were sacrificed 0.5, 1, 2 or 4 h after BD-induction and compared with sham-controls. This study demonstrates immediate pro-coagulatory and pro-inflammatory activation of vascular endothelium after BD in kidney donor rats, proportional with the duration of BD. E- and P-Selectins, Aalpha/Bbeta-fibrinogen mRNA were abruptly and progressively up-regulated from 0.5 h BD onwards; P-Selectin membrane protein expression was increased; fibrinogen was primarily visualized in the peritubular capillaries. Plasma von Willebrand factor was significantly higher after 2 h and 4 h BD. Urine heart-fatty-acid-binding-protein and N-acetyl-glucosaminidase, used as new specific and sensitive markers of proximal and distal tubular damage, were found significantly increased after 0.5 h, with a maximum at 4 h. Unexpectedly, oxidative stress was detectable only late, after the installation of tubular injury, suggesting only a secondary role for hypoxia in triggering these injuries.


Trigger Point Dry Needling.
Increasingly, physical therapists in the United States and throughout the world are using dry needling to treat musculoskeletal pain, even though this treatment has been a controversial addition to practice. To better generalize to physical therapy practice the findings about dry needling thus far, the authors of a study published in the March 2017 issue of JOSPT identified the need for a systematic review examining the effectiveness of dry needling performed by physical therapists on people with musculoskeletal pain. Their review offers a meta-analysis of data from several included studies and assesses the evidence for risks of bias. J Orthop Sports Phys Ther 2017;47(3):150. doi:10.2519/jospt.2017.0502.


High-throughput and Comprehensive Drug Surveillance Using Multisegment Injection-capillary Electrophoresis Mass Spectrometry.
New analytical methods are urgently needed to enable high-throughput, yet comprehensive drug screening, given an alarming opioid and prescription drug crisis in public health. Conventional urine drug testing based on a two-tier immunoassay screen followed by a gas chromatography-tandem mass spectrometry (GC-MS/MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS) method are expensive and prone to bias while being limited to targeted panels of known drugs of abuse (DoA). Herein, we outline an improved method for drug surveillance that allows for the resolution and detection of an expanded panel of DoA and their metabolites when using multisegment injection-capillary electrophoresis-mass spectrometry (MSI-CE-MS). Multiplexed separations of ten urine samples with a quality control by CE (< 3 min/sample) in conjunction with full-scan data acquisition using a time-of-flight mass spectrometer (TOF-MS) under positive ion mode detection allows for the identification and quantification of DoA above recommended cut-off levels. An excellent resolution of drug isomers and isobars, including background interferences, are achieved when using MSI-CE-MS with an electrokinetic spacer between sample segments, where accurate mass/molecular formula together with the comigration of a matching deuterated internal standard and the detection of one or more bio-transformed metabolites facilitate DoA identification over a wider detection window. Additionally, urine samples can be analyzed directly without enzyme deconjugation for the rapid screening without complicated sample workup. MSI-CE-MS enables the surveillance of a broad spectrum of DoA that is required for the treatment monitoring of high-risk patients, including confirming prescribed drug adherence, revealing illicit drug use/substitution, and evaluating optimal dosage regimes as required for new advances in precision medicine.


A conditional mutant of the fatty acid synthase unveils unexpected cross talks in mycobacterial lipid metabolism.
Unlike most bacteria, mycobacteria rely on the multi-domain enzyme eukaryote-like fatty acid synthase I (FAS I) to make fatty acids de novo. These metabolites are precursors of the biosynthesis of most of the lipids present both in the complex mycobacteria cell wall and in the storage lipids inside the cell. In order to study the role of the type I FAS system in Mycobacterium lipid metabolism in vivo, we constructed a conditional mutant in the fas-acpS operon of Mycobacterium smegmatis and analysed in detail the impact of reduced de novo fatty acid biosynthesis on the global architecture of the cell envelope. As expected, the mutant exhibited growth defect in the non-permissive condition that correlated well with the lower expression of fas-acpS and the concomitant reduction of FAS I, confirming that FAS I is essential for survival. The reduction observed in FAS I provoked an accumulation of its substrates, acetyl-CoA and malonyl-CoA, and a strong reduction of C12 to C18 acyl-CoAs, but not of long-chain acyl-CoAs (C19 to C24). The most intriguing result was the ability of the mutant to keep synthesizing mycolic acids when fatty acid biosynthesis was impaired. A detailed comparative lipidomic analysis showed that although reduced FAS I levels had a strong impact on fatty acid and phospholipid biosynthesis, mycolic acids were still being synthesized in the mutant, although with a different relative species distribution. However, when triacylglycerol degradation was inhibited, mycolic acid biosynthesis was significantly reduced, suggesting that storage lipids could be an intracellular reservoir of fatty acids for the biosynthesis of complex lipids in mycobacteria. Understanding the interaction between FAS I and the metabolic pathways that rely on FAS I products is a key step to better understand how lipid homeostasis is regulated in this microorganism and how this regulation could play a role during infection in pathogenic mycobacteria.


Disturbed local auxin homeostasis enhances cellular anisotropy and reveals alternative wiring of auxin-ethylene crosstalk in Brachypodium distachyon seminal roots.
Observations gained from model organisms are essential, yet it remains unclear to which degree they are applicable to distant relatives. For example, in the dicotyledon Arabidopsis thaliana (Arabidopsis), auxin biosynthesis via indole-3-pyruvic acid (IPA) is essential for root development and requires redundant TRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS 1 (TAA1) and TAA1-RELATED (TAR) genes. A promoter T-DNA insertion in the monocotyledon Brachypodium distachyon (Brachypodium) TAR2-LIKE gene (BdTAR2L) severely down-regulates expression, suggesting reduced tryptophan aminotransferase activity in this mutant, which thus represents a hypomorphic Bdtar2l allele (Bdtar2l(hypo) ). Counterintuitive however, Bdtar2l(hypo) mutants display dramatically elongated seminal roots because of enhanced cell elongation. This phenotype is also observed in another, stronger Bdtar2l allele and can be mimicked by treating wild type with L-kynerunine, a specific TAA1/TAR inhibitor. Surprisingly, L-kynerunine-treated as well as Bdtar2l roots display elevated rather than reduced auxin levels. This does not appear to result from compensation by alternative auxin biosynthesis pathways. Rather, expression of YUCCA genes, which are rate-limiting for conversion of IPA to auxin, is increased in Bdtar2l mutants. Consistent with suppression of Bdtar2l(hypo) root phenotypes upon application of the ethylene precursor 1-aminocyclopropane-1-carboxylic-acid (ACC), BdYUCCA genes are down-regulated upon ACC treatment. Moreover, they are up-regulated in a downstream ethylene-signaling component homolog mutant, Bd ethylene insensitive 2-like 1, which also displays a Bdtar2l root phenotype. In summary, Bdtar2l phenotypes contrast with gradually reduced root growth and auxin levels described for Arabidopsis taa1/tar mutants. This could be explained if in Brachypodium, ethylene inhibits the rate-limiting step of auxin biosynthesis in an IPA-dependent manner to confer auxin levels that are sub-optimal for root cell elongation, as suggested by our observations. Thus, our results reveal a delicate homeostasis of local auxin and ethylene activity to control cell elongation in Brachypodium roots and suggest alternative wiring of auxin-ethylene crosstalk as compared to Arabidopsis.


Mitochondrial DNA toxicity in forebrain neurons causes apoptosis, neurodegeneration, and impaired behavior.
Mitochondrial dysfunction underlying changes in neurodegenerative diseases is often associated with apoptosis and a progressive loss of neurons, and damage to the mitochondrial genome is proposed to be involved in such pathologies. In the present study we designed a mouse model that allows us to specifically induce mitochondrial DNA toxicity in the forebrain neurons of adult mice. This is achieved by CaMKIIalpha-regulated inducible expression of a mutated version of the mitochondrial UNG DNA repair enzyme (mutUNG1). This enzyme is capable of removing thymine from the mitochondrial genome. We demonstrate that a continual generation of apyrimidinic sites causes apoptosis and neuronal death. These defects are associated with behavioral alterations characterized by increased locomotor activity, impaired cognitive abilities, and lack of anxietylike responses. In summary, whereas mitochondrial base substitution and deletions previously have been shown to correlate with premature and natural aging, respectively, we show that a high level of apyrimidinic sites lead to mitochondrial DNA cytotoxicity, which causes apoptosis, followed by neurodegeneration.


A microRNA signature associated with early recurrence in breast cancer.
Recurrent breast cancer occurring after the initial treatment is associated with poor outcome. A bimodal relapse pattern after surgery for primary tumor has been described with peaks of early and late recurrence occurring at about 2 and 5 years, respectively. Although several clinical and pathological features have been used to discriminate between low- and high-risk patients, the identification of molecular biomarkers with prognostic value remains an unmet need in the current management of breast cancer. Using microarray-based technology, we have performed a microRNA expression analysis in 71 primary breast tumors from patients that either remained disease-free at 5 years post-surgery (group A) or developed early (group B) or late (group C) recurrence. Unsupervised hierarchical clustering of microRNA expression data segregated tumors in two groups, mainly corresponding to patients with early recurrence and those with no recurrence. Microarray data analysis and RT-qPCR validation led to the identification of a set of 5 microRNAs (the 5-miRNA signature) differentially expressed between these two groups: miR-149, miR-10a, miR-20b, miR-30a-3p and miR-342-5p. All five microRNAs were down-regulated in tumors from patients with early recurrence. We show here that the 5-miRNA signature defines a high-risk group of patients with shorter relapse-free survival and has predictive value to discriminate non-relapsing versus early-relapsing patients (AUC = 0.993, p-value<0.05). Network analysis based on miRNA-target interactions curated by public databases suggests that down-regulation of the 5-miRNA signature in the subset of early-relapsing tumors would result in an overall increased proliferative and angiogenic capacity. In summary, we have identified a set of recurrence-related microRNAs with potential prognostic value to identify patients who will likely develop metastasis early after primary breast surgery.


On the manifestations of memory in visual search.
Evidence is presented supporting the thesis that performance in visual search tasks is affected by the contribution of memory processes. Three levels of analysis, corresponding to the various time scales present in a typical search experiment, are discussed. Perceptual learning involves the task and stimulus specific improvement seen across blocks of training. Trial-to-trial priming has an influence which extends over 5-8 trials and lasts on the order of 30 s. Within-trial tagging prevents the re-inspection of already attended (or fixated) items. Also at the within-trial level of analysis, parallel accumulation of evidence for target presence/absence or target location inherently involves memory mechanisms. Organizing the various phenomena in this way makes it apparent that the various mechanisms may interact in a causal way. Within-trial tagging may contribute to priming which may contribute to perceptual learning. Recent proposals that visual search is memoryless (amnesic) are discussed and dismissed.


G-proteins modulate cumulative inactivation of N-type (Cav2.2) calcium channels.
Precise regulation of N-type (Ca(V)2.2) voltage-gated calcium channels (Ca-channels) controls many cellular functions including neurotransmitter and hormone release. One important mechanism that inhibits Ca2+ entry involves binding of G-protein betagamma subunits (Gbetagamma) to the Ca-channels. This shifts the Ca-channels from "willing" to "reluctant" gating states and slows activation. Voltage-dependent reversal of the inhibition (facilitation) is thought to reflect transient dissociation of Gbetagamma from the Ca-channels and can occur during high-frequency bursts of action potential-like waveforms (APW). Inactivation of Ca-channels will also limit Ca2+ entry, but it remains unclear whether G-proteins can modulate inactivation. In part this is because of the complex nature of inactivation, and because facilitation of Ca-channel currents (I(Ca)) masks the extent and kinetics of inactivation during typical stimulation protocols. We used low-frequency trains of APW to activate I(Ca). This more closely mimics physiological stimuli and circumvents the problem of facilitation which does not occur at < or = 5 Hz. Activation of endogenous G-proteins reduced both Ca2+-dependent, and voltage-dependent inactivation of recombinant I(Ca) in human embryonic kidney 293 cells. This was mimicked by expression of wild-type Gbetagamma, but not by a point mutant of Gbetagamma with reduced affinity for Ca-channels. A similar decrease in the inactivation of I(Ca) was produced by P2Y receptors in adrenal chromaffin cells. Overall, our data identify and characterize a novel effect of G-proteins on I(Ca), and could have important implications for understanding how G-protein-coupled receptors control Ca2+ entry and Ca2+-dependent events such as neurotransmitter and hormone release.


Design considerations for a 3-d laser Doppler velocimeter for studying gravity waves in shallow water.
A laser velocimeter system using three frequency-modulated light beams and one detector for measurement of the instantaneous velocity vector in reversing flow is considered. An analysis of the scattering and detection processes by means of the Mie and optical mixing theories is outlined. A system proposed for gravity wave studies uses an argon-ion laser and three Bragg cells as a source and a photomultiplier detector of the light backscattered from 0.2-microm-diameter spheres, introduced into the flow in a low concentration, and can measure local velocity vectors.of magnitude between 0.1 m/sec and 3.0 m/sec, with turbulent fluctuations of 1% or greater intensity.


Severe orthostatic hypotension following weight reduction surgery.
Surgical interventions for morbid obesity are common practice in many countries, especially when other treatment options have failed or when rapid weight loss is desired. The association between weight and blood pressure is well established, especially the paradigm of obesity-related hypertension. We describe a 45-year-old obese woman with a medical history of hypertension and type 2 diabetes mellitus who lost 57 kg within a few months after a weight reduction surgery. She suffered from severe orthostatic hypotension, which probably resulted from sympathetic nervous system dysfunction. Our patient's clinical status improved with pharmacological interventions, but her symptoms resolved completely after she gained weight following a surgical reversal of the gastric partitioning owing to a local complication. Autonomic nervous system activity does change with the changes in body weight, but after evaluation of this patient, we believe that rapid weight loss may impair sympathetic function and blood pressure control. Although losing weight is a known treatment option for hypertension, exaggerated reversal of obesity-related hypertension might result in orthostatic hypotension.


Simvastatin to modify neutrophil function in older patients with septic pneumonia (SNOOPI): study protocol for a randomised placebo-controlled trial.
Community-acquired pneumonia (CAP) is considered the leading cause of death from infectious disease in developed countries, while complications of CAP - sepsis being the most common and challenging - increase the risk of mortality. During the progression of sepsis, a state of neutrophil 'paralysis' develops resulting in the impairment of neutrophil anti-microbial functions including: chemotaxis, production of reactive oxygen species, and formation of neutrophil extracellular traps (NETs). Mechanisms underlying defective neutrophil function remain elusive although NET formation has been implicated in the immunosuppression and increased rates of sepsis observed in neonates. There is, however, increasing evidence that statins are able to modulate neutrophil function in sepsis as several systematic reviews have concluded that statins have a role in improving infection-related outcomes and mortality while, in vitro, statins have also been shown to boost NET formation in healthy individuals. The 'SNOOPI' trial is a phase 4, randomised placebo-controlled trial. The aim of this study is to determine whether oral treatment with simvastatin compared to placebo optimises neutrophil anti-microbial functions in elderly patients with septic pneumonia improving patient outcomes in the elderly. The primary outcome will be NET production within 72 to 96 hours of treatment with simvastatin or placebo measured in response to a number of inflammatory mediators, including IL8, f-Met-Leu-Phe and lipopolysaccharide. Secondary outcomes include neutrophil migratory capacity; reactive oxygen species production; neutrophil phagocytic capacity; safety and tolerability of simvastatin administration within this patient group; biological markers of neutrophil activation, the inflammatory response, alveolar epithelial and endothelial injury; systemic endothelial function biomarkers and pulmonary extracellular matrix degradation. This study aims to recruit 60 patients admitted into Queen Elizabeth Hospital Birmingham NHS-Foundation Trust. This study will investigate the ability of in vivo simvastatin therapy to modulate neutrophil anti-microbial functions in CAP-associated sepsis. EudraCT number: 2012-003343-29 (Trial Registered: 26 November 2012).


Alcohol marketing and drunkenness among students in the Philippines: findings from the nationally representative Global School-based Student Health Survey.
A largely unaddressed issue in lower income countries and the Philippines, in particular, is the role of alcohol marketing and its potential link to early alcohol use among youth. This study examines the associations between exposures to alcohol marketing and Filipino youths' drinking prevalence and drunkenness. Cross-sectional analyses were used to examine the Global School-based Student Health Survey (GSHS) conducted in Philippines (2011). The self-administered questionnaires were completed by students primarily 13 to 16 years of age (N = 5,290). Three statistical models were computed to test the associations between alcohol marketing and alcohol use, while controlling for possible confounding factors. Alcohol marketing, specifically through providing free alcohol through a company representative, was associated with drunkenness (AOR: 1.84; 95% CI=1.06-3.21) among youths after controlling for demographic and psychosocial characteristics, peer environment, and risky behaviors. In addition, seeing alcohol ads in newspapers and magazines (AOR: 1.65, 95% CI=1.05-2.58) and seeing ads at sports events, concerts or fairs (AOR: 1.50, 95% CI =1.06-2.12) were significantly associated with increased reports of drunkenness. There are significant associations between alcohol marketing exposure and increased alcohol use and drunkenness among youth in the Philippines. These findings highlight the need to put policies into effect that restrict alcohol marketing practices as an important prevention strategy for reducing alcohol use and its dire consequences among vulnerable youth.


Robust nonrigid registration to capture brain shift from intraoperative MRI.
We present a new algorithm to register 3-D preoperative magnetic resonance (MR) images to intraoperative MR images of the brain which have undergone brain shift. This algorithm relies on a robust estimation of the deformation from a sparse noisy set of measured displacements. We propose a new framework to compute the displacement field in an iterative process, allowing the solution to gradually move from an approximation formulation (minimizing the sum of a regularization term and a data error term) to an interpolation formulation (least square minimization of the data error term). An outlier rejection step is introduced in this gradual registration process using a weighted least trimmed squares approach, aiming at improving the robustness of the algorithm. We use a patient-specific model discretized with the finite element method in order to ensure a realistic mechanical behavior of the brain tissue. To meet the clinical time constraint, we parallelized the slowest step of the algorithm so that we can perform a full 3-D image registration in 35 s (including the image update time) on a heterogeneous cluster of 15 personal computers. The algorithm has been tested on six cases of brain tumor resection, presenting a brain shift of up to 14 mm. The results show a good ability to recover large displacements, and a limited decrease of accuracy near the tumor resection cavity.


Phylogenetic analysis of the allometry of metabolic rate and mitochondrial basal proton leak.
The mitochondrial basal proton leak (MBPL) significantly contributes to high body temperatures (Tb) and basal metabolic rates (BMR) in endotherms. In endotherms at a given body mass (M), liver MBPL is higher than in ectotherms, supporting the notion that MBPL may partly explain the evolutionary increase in metabolic rate (MR), fostering endothermy. Here, we re-addressed this assumption by performing a phylogenetic analysis comparing all available liver MBPL data for ecto- and endotherms. While MBPL within endotherms negatively scales with M and BMR as shown previously, MBPL of ectotherms does not scale allometrically with M. Phylogenetic analysis reveals that this result is confounded by a positive scaling coefficient for MBPL with M for reptiles. Strikingly, the reptilian MBPL reaches endothermic levels above a body mass of 6.6kg. Thus, phylogenetic scaling of MBPL supports previous claims of endotherm-like physiological characteristics in large reptiles. It appears that diversification of ancestral ectothermic tetrapods to a body mass of at least 6kg may have been required to reach a MBPL that is beneficial for sustained high body temperatures. Novel MBPL data for the lesser hedgehog tenrec, a protoendothermic eutherian that displays reptile-like thermoregulatory patterns, fall within the endo- and ectothermic allometric regressions. Finally, we add additional evidence that within endotherms, phylogenetic differences in MR do not correlate with MBPL. Collectively, these data suggest that MBPL does not universally scale with metabolic rate in ecto- or endotherms and that an increasing MBPL with M may have played an important physiological role in the evolutionary history of reptilian thermoregulation.


Treatment of steroid-sensitive nephrotic syndrome: new guidelines from KDIGO.
The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on glomerulonephritis (GN) is intended to assist the practitioner caring for patients with GN. Two chapters of this guideline focus specifically on nephrotic syndrome in children. Guideline development followed a thorough evidence review, and management recommendations and suggestions were based on the best available evidence. Critical appraisal of the quality of evidence and strength of recommendations followed the Grades of Recommendation Assessment, Development and Evaluation (GRADE) approach. Chapters 3 and 4 of the guideline focus on the management of nephrotic syndrome in children aged 1-18 years. Guideline recommendations for children who have steroid-sensitive nephrotic syndrome (SNSS), defined by their response to corticosteroid therapy with complete remission, are addressed here. Recommendations for those with steroid-resistant nephrotic syndrome (SRNS) (i.e., do not achieve complete remission) are discussed in the companion article. Limitations of the evidence, including the paucity of large-scale randomized controlled trials, are discussed. This article provides a short description of the KDIGO process, the guideline recommendations for treatment of SSNS in children and a brief review of relevant treatment trials related to each recommendation.


Tracking and explanation of physical activity in young adults over a 7-year period.
Tracking and explaining physical activity in young adults was investigated in a 7-year longitudinal design. From a representative sample of 980 respondents at baseline (M age = 21 years), 172 respondents, comprising 18% of the original sample, completed psychosocial questionnaires and were interviewed at home to assess their level of physical activity at follow-up. Psychosocial variables were grouped into four groups: social variables, self-efficacy, perceived benefits, and perceived barriers. Drop-out analyses showed no major differences between the baseline and follow-up samples. The aims of the present study were: (a) to investigate tracking in physical activity and psychosocial determinants over a 7-year period, and (b) to examine baseline determinants and change in determinants in predicting physical activity change in men and women. No significant tracking of physical activity level was found for men. For women, moderate tracking scores were found for total energy expenditure and moderate-intensity energy expenditure (r = .34 and .41, respectively). There was higher tracking in psychosocial determinants than in physical activity. Relatively high tracking scores for perceived benefits and barriers suggest that cognitions related to physical activity are more stable than the behavior itself. Although baseline psychosocial variables were poor predictors of physical activity change, determinants'change scores accounted for 16-19% of the variance in physical activity in men and 7-24% in women. Significant predictors were different for men and women. Present results can inform the design of physical activity interventions for these populations.


Methyltransferase expression and tumor suppressor gene methylation in sporadic and familial colorectal cancer.
Molecular mechanisms underlying coordinated hypermethylation of multiple CpG islands in cancer remain unclear and studies of methyltransferase enzymes have arrived at conflicting results. We focused on DNMT1 and DNMT3B, DNA methyltransferases responsible for (de novo) methylation, and EZH2, histone (H3K27) methyltransferase, and examined their roles in tumor suppressor gene (TSG) methylation patterns we have previously established in sporadic and familial cancers. Our investigation comprised 165 tumors, stratified by tissue of origin (117 colorectal and 48 endometrial carcinomas) and sporadic vs. familial disease (57 sporadic vs. 60 familial, mainly Lynch syndrome, colorectal carcinomas). By immunohistochemical evaluation, EZH2 protein expression was associated with a TSG methylator phenotype. DNMT1, DNMT3B, and EZH2 were expressed at significantly higher levels in tumor vs. normal tissues. DNMT1 and EZH2 expression were positively correlated and higher in microsatellite-unstable vs. microsatellite-stable tumors, whether sporadic or hereditary. Ki-67 expression mirrored the same pattern. Promoter methylation of the methyltransferase genes themselves was addressed as a possible cause behind their altered expression. While DNMT1 or EZH2 did not show differential methylation between normal and tumor tissues, DNMT3B analysis corroborated the regulatory role of a distal promoter region. Our study shows that methyltransferase expression in cancer depends on the tissue of origin, microsatellite-instability status, cellular proliferation, and--in the case of DNMT3B--promoter methylation of the respective gene. Translation of methyltransferase expression into DNA methylation appears complex as suggested by the fact that except for EZH2, no clear association between methyltransferase protein expression and TSG methylation was observed.


Cardiovascular Function of Modern Pigs Does not Comply with Allometric Scaling Laws.
Growing concerns have been expressed regarding cardiovascular performance in modern farm pigs, which has been proposed as a critical factor contributing to the reduced adaptability of modern pigs to stress. Here we tested the hypothesis that cardiac dimensions and pump function in modern heavy farm pigs are disproportionally low for their body weight, and investigated potential underlying mechanisms. The results from the present study indeed demonstrate disproportionally low values for stroke volume and cardiac output in pigs with bodyweights over 150 kg. Importantly, these low values were not the result of impaired left ventricular (LV) systolic contractile function, but were due to a disproportionally small LV end-diastolic volume. The latter was associated with changes in determinants of LV passive stiffness, including (i) an increase in LV myocardial collagen, (ii) a shift from the compliant N2BA titin isoform towards the stiff N2B, and (iii) a marked elevation of aortic blood pressure. Taken together, these results demonstrate reduced pumping capacity of the hearts of heavy modern pigs, due to structural abnormalities in the LV myocardium.


[Analysis of bacterial composition of the pink mat from spectacles hot spring in Tengchong by culture-independent approach].
The bacterial composition of the pink mat was studied by culture-independent approach. 23 complete 16S rDNA sequences were obtained. According to the sequences alignment and analysis of comparability, the bacteria of the pink mat was consisted of Proteobacteria, Firmicutes, Bacteroidetes, Actinobacter, Deinococcus-thermus, Aquificals. And compared with bacterial composition of the mats from Octopus spring in Yellowstone Park and Haegindi and Fluidir spring, Olkelduhals, Grensdalur spring in Iceland, the pink mat in spectacles spring had highest bacterial diversity among them because it perhaps included lots of bacteria at lower temperature. And the result indicated the same community lived in the same niche and Aquficales was dominant group among bacterial composition of the mat in higher temperature and near-neutral hot spring.


Integrated analysis of microRNA and mRNA expression and association with HIF binding reveals the complexity of microRNA expression regulation under hypoxia.
In mammalians, HIF is a master regulator of hypoxia gene expression through direct binding to DNA, while its role in microRNA expression regulation, critical in the hypoxia response, is not elucidated genome wide. Our aim is to investigate in depth the regulation of microRNA expression by hypoxia in the breast cancer cell line MCF-7, establish the relationship between microRNA expression and HIF binding sites, pri-miRNA transcription and microRNA processing gene expression. MCF-7 cells were incubated at 1% Oxygen for 16, 32 and 48 h. SiRNA against HIF-1α and HIF-2α were performed as previously published. MicroRNA and mRNA expression were assessed using microRNA microarrays, small RNA sequencing, gene expression microarrays and Real time PCR. The Kraken pipeline was applied for microRNA-seq analysis along with Bioconductor packages. Microarray data was analysed using Limma (Bioconductor), ChIP-seq data were analysed using Gene Set Enrichment Analysis and multiple testing correction applied in all analyses. Hypoxia time course microRNA sequencing data analysis identified 41 microRNAs significantly up- and 28 down-regulated, including hsa-miR-4521, hsa-miR-145-3p and hsa-miR-222-5p reported in conjunction with hypoxia for the first time. Integration of HIF-1α and HIF-2α ChIP-seq data with expression data showed overall association between binding sites and microRNA up-regulation, with hsa-miR-210-3p and microRNAs of miR-27a/23a/24-2 and miR-30b/30d clusters as predominant examples. Moreover the expression of hsa-miR-27a-3p and hsa-miR-24-3p was found positively associated to a hypoxia gene signature in breast cancer. Gene expression analysis showed no full coordination between pri-miRNA and microRNA expression, pointing towards additional levels of regulation. Several transcripts involved in microRNA processing were found regulated by hypoxia, of which DICER (down-regulated) and AGO4 (up-regulated) were HIF dependent. DICER expression was found inversely correlated to hypoxia in breast cancer. Integrated analysis of microRNA, mRNA and ChIP-seq data in a model cell line supports the hypothesis that microRNA expression under hypoxia is regulated at transcriptional and post-transcriptional level, with the presence of HIF binding sites at microRNA genomic loci associated with up-regulation. The identification of hypoxia and HIF regulated microRNAs relevant for breast cancer is important for our understanding of disease development and design of therapeutic interventions.


Developing multipurpose reproductive health technologies: an integrated strategy.
WOMEN WORLDWIDE CONFRONT TWO FREQUENTLY CONCURRENT REPRODUCTIVE HEALTH CHALLENGES: the need for contraception and for protection from sexually transmitted infections, importantly HIV/AIDS. While conception and infection share the same anatomical site and mode of transmission, there are no reproductive health technologies to date that simultaneously address that reality. Relevant available technologies are either contraceptive or anti-infective, are limited in number, and require different modes of administration and management. These "single-indication" technologies do not therefore fully respond to what is a substantial reproductive health need intimately linked to pivotal events in many women's lives. This paper reviews an integrated attempt to develop multipurpose prevention technologies-"MPTs"-products explicitly designed to simultaneously address the need for both contraception and protection from sexually transmitted infections. It describes an innovative and iterative MPT product development strategy with the following components: identifying different needs for such technologies and global variations in reproductive health priorities, defining "Target Product Profiles" as the framework for a research and development "roadmap," collating an integrated MPT pipeline and characterizing significant pipeline gaps, exploring anticipated regulatory requirements, prioritizing candidates for problem-solving and resource investments, and implementing an ancillary advocacy agenda to support this breadth of effort.


Abnormal serum lipoprotein levels as a risk factor for the development of human lenticular opacities.
To determine whether an association exists between the different plasma lipoprotein constituents and the prevalence of lenticular opacities in dyslipidaemic subjects. Adult patients (n = 115) of both genders were included if their fasting total serum cholesterol concentrations exceeded the 95th percentile of normal or their serum low-density lipoprotein (LDL): high-density lipoprotein (HDL) ratios exceeded 5. Patients were excluded if they suffered from any condition known to cause, or predispose them to, elevated lipoprotein levels or lenticular opacification. Lenticular changes were assessed by means of a slit-lamp through the fully dilated pupil. An extremely strong association (p<0.0001) was found to exist between HDL cholesterol levels and the development of lens opacities. Below an HDL-C level of 1.5 mmol/l subjects had a seven-fold higher calculated probability of falling in the lens opacity subgroup than those with HDL-C levels above 1.5 mmol/l [odds ratio =7.33 (95% CI = 2.06-26.10; p = 0.0001)]. An equally strong association was found between high (>5) LDL:HDL ratios and the development of lens opacities (p<0.0003). The risk of falling into the cataract subgroup if the individual's LDL:HDL ratio exceeded 5 was 2.35 (95% CI = 1.09-5.04; p = 0.014). This study strongly suggests that an association exists between low levels of HDL cholesterol and high LDL:HDL ratios on one hand and the development of adult lens opacification on the other.


A randomized controlled trial of a transdiagnostic cognitive-behavioral intervention for Afro-descendants' survivors of systemic violence in Colombia.
Exposure to violence has negative consequences on mental health. Armed-conflict in Colombia has widely affected Afro-descendants in the Pacific region. Evidence regarding effectiveness of mental health interventions is lacking in low-income settings, especially in areas with active conflict. The objective of this study is to evaluate an individualized Common Elements Treatment Approach (CETA), a transdiagnostic psychotherapy model based on Cognitive-Behavioral Therapy, for adult trauma survivors. A referred sample of 521 adult Afro-descendants from Buenaventura and Quibdó, Colombia, experiencing significant sadness, suffering or fear (score>0.77 in Total Mental Health Symptoms), with history of traumatic experiences, and with associated functional impairment were randomly allocated to CETA intervention, standby group without intervention, but under monthly monitoring, or a Narrative Community-Based Group Therapy. CETA was provided by trained Lay Psychosocial Community Workers without previous mental health experience, supervised by psychologists, during 12-14 weekly, 1.5-hour sessions. Symptoms were assessed with a locally validated survey built based on the Hopkins Symptom Checklist, the Harvard Trauma Questionnaire, the PTSD CheckList-Civilian Version, a qualitative study for additional general symptoms and a gender-specific functional impairment scale. CETA was compared with the control group and the intervention effects were calculated with mixed models using intention to treat analysis. Participant completion of follow-up was 75.1% and 13.2% voluntarily withdrew. Reduction in post-traumatic stress symptoms was significant in both municipalities when comparing intervention and control groups (mean difference), with a with a moderate effect size in Buenaventura (Cohen's d = 0.70) and a small effect size in Quibdó (d = 0.31). In Buenaventura, the intervention also had significant effects on depression (large effect size d = 1.03), anxiety (large effect size d = 0.80) and functional impairment (moderate effect size d = 0.70). In Quibdó, it had no significant effect on these outcomes. Changes in Total Mental Health Symptoms were not significant in neither city. This trial suggests that CETA, can be effective in improving depression, anxiety, post-traumatic stress and function among victims of systematized violence in low-income and active conflict settings. Nonetheless, the difference of effectiveness between the two cities of intervention may indicate that we cannot assume that a mental health intervention known to be effective in one setting will be effective in another, even in similar circumstances and population. This may have special importance when implementing and reproducing these types of intervention in non-controlled circumstances. Further research should address these concerns. Results can be of use by governmental decision-makers when defining mental health programs for survivors. ClinicalTrials.gov NCT01856673 (https://clinicaltrials.gov/ct2/show/NCT01856673).


A study of high-sensitivity C-reactive protein in bronchial asthma.
Relevance of C-reactive protein an acute phase reactant and a sensitive marker of low-grade systemic inflammation in bronchial asthma has not been fully studied. To evaluate the significance of high-sensitivity C-reactive protein (hs-CRP) in atopic and non-atopic asthma using an ultra sensitive assay. The levels of hs-CRP of 200 patients with bronchial asthma and 50 non-asthmatic control subjects were measured using a Latex enhanced immunoturbidimetric test. Spirometry with reversibility study, serum immunoglobulin-E (IgE) measurement and skin test for allergy was done in all the patients. There was a significant increase in hs-CRP levels with age in atopic asthmatics but no such association was observed in the non-atopic asthmatics and control subjects. The hs-CRP levels were not influenced by sex in any group. Smokers in all the three groups had a significantly higher hs-CRP levels as compared to non-smokers. Patients with asthma had higher hs-CRP values as compared to controls. Patients with non-allergic asthma had higher mean hs-CRP as compared to atopic asthmatics and control subjects. The study suggests that there exists a certain degree of low-grade systemic inflammation in addition to the local bronchial inflammation in non-atopic asthmatics. Hence, hs-CRP may be used as a surrogate marker for the airway inflammation in non-atopic asthma patients.


Pharmacological strategies for the prevention of Alzheimer's disease.
This review examines key pharmacological strategies that have been clinically studied for the primary or secondary prevention of Alzheimer's disease. Much information (neuropsychological, genetic and imaging) is already available to characterise an individual's risk for developing Alzheimer's disease. However, regulatory pathways for obtaining a prevention indication are less well charted, and such trials tend to involve 3- to 7-year studies of 1000 - 5000 individuals, depending on baseline status. Treatments developed for prevention will also need to have superior safety. For these reasons, > 100 proprietary pharmacological products are currently being developed for an Alzheimer's disease treatment, but only a few are being studied for prevention. Randomised trial data are available for antihypertensive agents (calcium channel blockers, angiotensin-converting enzyme inhibitors), pravastatin, simvastatin, conjugated oestrogen, raloxifene, rofecoxib, CX516 (AMPA agonist) and cholinesterase inhibitors regarding efficacy for Alzheimer's disease prevention. At least four large prevention trials of conjugated oestrogen, selenium and vitamin E, Ginkgo biloba and statins are currently underway. Strategies using other agents have not yet been evaluated in Alzheimer's disease prevention clinical trials. These include anti-amyloid antibodies, active immunisation, selective secretase inhibitors and modulators, microtubule stabilisers (e.g., paclitaxel), R-flurbiprofen, xaliproden, ONO-2506, FK962 (somatostatin releaser), SGS 742 (GABA(B) antagonist), TCH 346 (apoptosis inhibitor), Alzhemedtrade mark, phophodiesterase inhibitors, rosiglitazone, leuprolide, interferons, metal-protein attenuating compounds (e.g., PBT2), CX717, rasagaline, huperzine A, antioxidants and memantine. Studies combining lifestyle modification and drug therapy have not been conducted. Full validation of surrogate markers for disease progression (such as amyloid imaging) should further facilitate drug development. Reducing the complexity of prevention trials and gaining regulatory consensus of design is a high priority for the field.


Setting Healthcare Priorities at the Macro and Meso Levels: A Framework for Evaluation.
Priority setting in healthcare is a key determinant of health system performance. However, there is no widely accepted priority setting evaluation framework. We reviewed literature with the aim of developing and proposing a framework for the evaluation of macro and meso level healthcare priority setting practices. We systematically searched Econlit, PubMed, CINAHL, and EBSCOhost databases and supplemented this with searches in Google Scholar, relevant websites and reference lists of relevant papers. A total of 31 papers on evaluation of priority setting were identified. These were supplemented by broader theoretical literature related to evaluation of priority setting. A conceptual review of selected papers was undertaken. Based on a synthesis of the selected literature, we propose an evaluative framework that requires that priority setting practices at the macro and meso levels of the health system meet the following conditions: (1) Priority setting decisions should incorporate both efficiency and equity considerations as well as the following outcomes; (a) Stakeholder satisfaction, (b) Stakeholder understanding, (c) Shifted priorities (reallocation of resources), and (d) Implementation of decisions. (2) Priority setting processes should also meet the procedural conditions of (a) Stakeholder engagement, (b) Stakeholder empowerment, (c) Transparency, (d) Use of evidence, (e) Revisions, (f) Enforcement, and (g) Being grounded on community values. Available frameworks for the evaluation of priority setting are mostly grounded on procedural requirements, while few have included outcome requirements. There is, however, increasing recognition of the need to incorporate both consequential and procedural considerations in priority setting practices. In this review, we adapt an integrative approach to develop and propose a framework for the evaluation of priority setting practices at the macro and meso levels that draws from these complementary schools of thought.


Comparison of similarity coefficients used for cluster analysis with amplified fragment length polymorphism markers in the silkworm, Bombyx mori.
Establishing accurate genetic similarity and dissimilarity between individuals is an essential and decisive point for clustering and analyzing inter and intra population diversity because different similarity and dissimilarity indices may yield contradictory outcomes. We assessed the variations caused by three commonly used similarity coefficients including Jaccard, Sorensen-Dice and Simple matching in the clustering and ordination of seven Iranian native silkworm, Bombyx mori L. (Lepidoptera: Bombycidae), strains analyzed by amplified fragment length polymorphism markers. Comparisons among the similarity coefficients were made using the Spearman correlation analysis, dendrogram evaluation (visual inspection and consensus fork index--CI(C)), projection efficiency in a two-dimensional space, and groups formed by the Tocher optimization procedure. The results demonstrated that for almost all methodologies, the Jaccard and Sorensen-Dice coefficients revealed extremely close results, because both of them exclude negative co-occurrences. Due to the fact that there is no guarantee that the DNA regions with negative cooccurrences between two strains are indeed identical, the use of coefficients such as Jaccard and Sorensen-Dice that do not include negative co-occurrences was imperative for closely related organisms.


Effect of increasing bromide concentration on toxicity in treated drinking water.
Research is increasingly indicating the potential chronic health effects of brominated disinfection by-products (DBPs). This is likely to increase with elevated bromide concentrations resulting from the impacts of climate change, projected to include extended periods of drought and the sudden onset of water quality changes. This will demand more rigorous monitoring throughout distribution systems and improved water quality management at water treatment plants (WTPs). In this work the impact of increased bromide concentration on formation of DBPs following conventional treatment and chlorination was assessed for two water sources. Bioanalytical tests were utilised to determine cytotoxicity of the water post disinfection. Coagulation was shown to significantly reduce the cytotoxicity of the water, indicating that removal of natural organic matter DBP precursors continues to be an important factor in drinking water treatment. Most toxic species appear to form within the first half hour following disinfectant addition. Increasing bromide concentration across the two waters was shown to increase the formation of trihalomethanes and shifted the haloacetic acid species distribution from chlorinated to those with greater bromine substitution. This correlated with increasing cytotoxicity. This work demonstrates the challenges faced by WTPs and the possible effects increasing levels of bromide in source waters could have on public health.


Steroid ring hydroxylation patterns govern cooperativity in human bile acid binding protein.
Human ileal bile acid binding protein (I-BABP) is a member of the intracellular lipid binding protein family. This protein is thought to function in the transcellular transport and enterohepatic circulation of bile salts. Human I-BABP binds two molecules of glycocholate, the physiologically most abundant bile salt, with modest intrinsic affinity but a remarkably high degree of positive cooperativity. Here we report a calorimetric analysis for the binding of a broad panel of bile salts to human I-BABP. The interaction of I-BABP with nine physiologically relevant derivatives of cholic acid, chenodeoxycholic acid, and deoxycholic acid in their conjugated (glycine and taurine) and unconjugated forms was monitored by isothermal titration calorimetry. All bile salts bound to I-BABP with a 2:1 stoichiometry and similar overall affinity, but the derivatives of cholic acid displayed much higher Hill coefficients, a measure of macroscopic positive cooperativity. To test whether the cooperativity was dependent on individual structural features of the bile salt side chain, a series of side-chain-extended bile salts that lacked a hydrogen bond donor or acceptor at C-24 were chemically synthesized. These synthetic variants exhibited the same energetic and cooperativity profile as the naturally occurring bile salts. Our findings indicate that cooperativity in bile salt-I-BABP recognition is governed by the pattern of steroid B- and C-ring hydroxylation and not the presence or type of side-chain conjugation.


Sandwich and half-sandwich metal complexes derived from cross-conjugated 3-methylene-penta-1,4-diynes.
The cross-conjugated ethynyl-vinylidene [Ph2C[double bond, length as m-dash]C(C[triple bond, length as m-dash]CH){C(H)[double bond, length as m-dash]CRu(PPh3)2Cp}]PF6 ([4a]PF6), and [FcC(H)[double bond, length as m-dash]C(C[triple bond, length as m-dash]CH){C(H)[double bond, length as m-dash]CRu(PPh3)2Cp}]PF6 ([4b]PF6), and ethynyl-alkynyl Ph2C[double bond, length as m-dash]C(C[triple bond, length as m-dash]CH){C[triple bond, length as m-dash]CRu(PPh3)2Cp} (5a), and FcC(H)[double bond, length as m-dash]C(C[triple bond, length as m-dash]CH){C[triple bond, length as m-dash]CRu(PPh3)2Cp} (5b) compounds (Cp = η5-cyclopentadienyl) have been prepared from reactions of the known 3-methylene-penta-1,4-diynes Ph2C[double bond, length as m-dash]C(C[triple bond, length as m-dash]CH)2 (3a) and [FcCH[double bond, length as m-dash]C(C[triple bond, length as m-dash]CH)2] (3b) with [RuCl(PPh3)2Cp]. The compounds derived from 3b incorporating the more electron-rich alkene proved to be unstable during work-up, and attempts to prepare bis(ruthenium) complexes from 3a and 3b or from transmetallation reactions of the bis(alkynylgold) complex FcCH[double bond, length as m-dash]C(C[triple bond, length as m-dash]CAuPPh3)2 (7) with RuCl(PPh3)2Cp were unsuccessful. The related bis- and tris(ferrocenyl) derivatives Ph2C[double bond, length as m-dash]C(C[triple bond, length as m-dash]CFc)2 (6a) and FcCH[double bond, length as m-dash]C(C[triple bond, length as m-dash]CFc)2 (6b) were more readily obtained from Pd(ii)/Cu(i) catalysed cross-coupling reactions of FcC[triple bond, length as m-dash]CH with the 1,1-dibromo vinyl complexes PhC[double bond, length as m-dash]CBr2 (1a) and FcC(H)[double bond, length as m-dash]CBr2 (1b). Cyclic voltammetry of 6a and 6b using n-Bu4N[PF6] as the supporting electrolyte shows broad, overlapping waves arising from the sequential oxidation of the ferrocenyl moieties in electronically and chemically similar environments. Electrostatic effects between the ferrocenyl moieties are enhanced in solutions of the weakly ion-pairing electrolyte n-Bu4N[B{C6H3(CF3)2-3,5}4], leading to better resolution of the individual electrochemical processes. The comparative IR spectroelectrochemical response of 6a and 6b suggest the vinyl ferrocene moiety in 6b undergoes oxidation before the ethynyl ferrocene fragments. There is no evidence of electronic coupling between the metallocene moieties and [6a]+, [6b]n+ (n = 1, 2) are best described as Class I mixed-valence compounds.


Minimal-access surgery for staging of malignant melanoma.
To develop a simple, minimally invasive technique of determining whether regional node metastasis has occurred in patients with melanoma. Teaching hospital tertiary care and private practice settings. Between February 1993 and October 1994, 121 patients with invasive malignant melanoma and clinically negative lymph nodes were enrolled in this clinical trial. Consecutive sample clinical trial. Within 24 hours prior to lymph node resection, a radioactive tracer was injected into the dermis around the site of the primary melanoma. Forty-four patients also had blue dye injected immediately prior to surgical resection. Measurement of radioactivity in the lymph nodes and surgical localization were made using a handheld gamma detector. Radiolabeled nodes were selectively removed with the least dissection possible. In patients with pathologically positive radiolabeled nodes, regional lymphadenectomy was performed. Successful identification of radiolabeled sentinel lymph nodes, correlation of radiolabeling with injection of blue dye, and regional node recurrence rate. Surgeons successfully resected the radiolabeled sentinel lymph nodes in 118 (98%) of 121 patients. One hundred percent of blue-stained lymph nodes were successfully radiolabeled. Fifteen patients had pathologically positive sentinel lymph nodes. In 10 patients, the sentinel node was the only node with metastasis. Two systemic and one regional node recurrences occurred during a mean follow-up of 220 days. Selective gamma probe-guided resection of the radiolabeled sentinel lymph node is possible in over 95% of patients with melanoma. This technique offers a simple and reliable method of staging of regional lymph nodes in these patients without performing a regional lymphadenectomy.


Comparison of ophthalmic training in 6 English-speaking countries.
To compare key characteristics of ophthalmology training programs in 6 different English-speaking countries: Australia, New Zealand, Canada, Ireland, the United Kingdom, and the United States. Seven ophthalmologists with personal knowledge of all 6 systems contributed. The main features examined were career pathway, duration of training, surgical training, governing bodies, and examination structure. Data were collected from the literature, online resources, and personal experience. Several differences were highlighted, including length of training (ranging from 4 to 9 years after medical school), number of surgical procedures such as cataracts (ranging from minimum 86 to approximately 600), and structure of fellowship training. As trainees increasingly seek international experience to enhance their knowledge and skills, the similarities and differences between training programs in different countries have become more relevant. Some of these differences may reflect differing needs of different patient populations and different healthcare delivery systems across the globe. However, these differences should also prompt educators to more carefully scrutinize their own training system and search for potential improvements.


Immunohistochemical identification of Propionibacterium acnes in granuloma and inflammatory cells of myocardial tissues obtained from cardiac sarcoidosis patients.
Although rare, cardiac sarcoidosis (CS) is potentially fatal. Early diagnosis and intervention are essential, but histopathologic diagnosis is limited. We aimed to detect Propionibacterium acnes, a commonly implicated etiologic agent of sarcoidosis, in myocardial tissues obtained from CS patients. We examined formalin-fixed paraffin-embedded myocardial tissues obtained by surgery or autopsy and endomyocardial biopsy from patients with CS (n = 26; CS-group), myocarditis (n = 15; M-group), or other cardiomyopathies (n = 39; CM-group) using immunohistochemistry (IHC) with a P. acnes-specific monoclonal antibody. We found granulomas in 16 (62%) CS-group samples. Massive (≥14 inflammatory cells) and minimal (<14 inflammatory cells) inflammatory foci, respectively, were detected in 16 (62%) and 11 (42%) of the CS-group samples, 10 (67%) and 10 (67%) of the M-group samples, and 1 (3%) and 18 (46%) of the CM-group samples. P. acnes-positive reactivity in granulomas, massive inflammatory foci, and minimal inflammatory foci were detected in 10 (63%), 10 (63%), and 8 (73%) of the CS-group samples, respectively, and in none of the M-group and CM-group samples. Frequent identification of P. acnes in sarcoid granulomas of originally aseptic myocardial tissues suggests that this indigenous bacterium causes granuloma in many CS patients. IHC detection of P. acnes in massive or minimal inflammatory foci of myocardial biopsy samples without granulomas may be useful for differentiating sarcoidosis from myocarditis or other cardiomyopathies.


Light scattering at oblique incidence on two coaxial cylinders.
A solution for the problem of a plane wave at oblique incidence on two coaxial cylinders is presented. The solution of the wave equation is determined for various geometric regions, and boundary conditions are applied at the material interfaces. The resulting solution consists of a system of eight equations in eight unknown coefficients. Expressions for two of the Mueller-scattering matrix elements (S(11) and S(12)) and the extinction, scattering, and backscattering cross sections are derived. A numerical algorithm for the solution is developed and implemented. The algorithm is tested for several limiting cases: homogeneous, hollow, and metal-core cylinders at various angles of incidence for TM and TE waves. Comparisons of the results of the algorithm with the results of studies reported in the literature are made. The comparisons are favorable, achieving good agreement with published work. For two coaxial cylinders, the numerical calculations show that if one is to use light scattering as a diagnostic tool, both of the Mueller-scattering matrix elements S(11) and S(12) must be measured simultaneously. In addition, the backscattering cross section is very sensitive for monitoring change in the radii of the cylinders.


[3H]GR113808 binding to serotonin 5-HT(4) receptors in the postmortem neocortex of Alzheimer disease: a clinicopathological study.
Abnormalities in neural transmission of serotonin (5-HT) may play a role in both cognitive and neuropsychiatric features of Alzheimer disease (AD). We measured 5-HT(4) receptors in the postmortem frontal and temporal cortex of 34 AD subjects and 15 controls by radioligand binding with [3H]GR113808. Receptor binding data was then correlated with prospectively assessed cognitive (Mini-Mental State Examination, MMSE) and behavioral (Present Behavioural Examination, PBE) data. [3H]GR113808 binding affinity (K(D)) and density (B(max)) in AD were unchanged compared to controls in both cortical regions, and did not correlate with MMSE or PBE data. The binding parameters were also not related to disease duration, senile plaque and neurofibrillary tangle counts, and neuroleptic medication. We conclude that unlike other 5-HT receptors, 5-HT(4) receptor binding affinity and density do not seem to be affected in the frontal and temporal cortex in AD and may not have a direct role in the clinical features of the disease.


Spinal cord involvement in multiple sclerosis: a correlative MRI and high-resolution HLA-DRB1 genotyping study.
There have been few magnetic resonance imaging (MRI) studies of the spinal cord in large multiple sclerosis (MS) patient cohorts and little is known about correlations between cord lesions and human leukocyte antigen (HLA) alleles. To investigate the spectrum of MRI changes in the spinal cord in MS and associations with the HLA-DRB1 genotype. Two hundred and fifty two consecutive MS patients from the Perth Demyelinating Diseases Database had MRI of the spinal cord and brain and high-resolution HLA-DRB1 genotyping. The numbers, locations, shape and segmental extent of cord lesions were analysed and were correlated with carriage of individual HLA-DRB1 alleles and diplotypes. Focal cord lesions were present in 82.9% of cases, with numbers being maximal in the cervical cord and increasing with disease duration. Focal lesions were usually round or oval in shape but in 35% of cases subpial wedge-shaped lesions were present. Diffuse cord involvement was present in 10% of cases and correlated with carriage of HLA-DRB1*1501 and with higher disability. Carriage of the minor allele HLA-DRB1*0701 was significantly associated with numbers of wedge-shaped lesions and lesions in the cervical cord, while HLA-DRB1*1104 and DRB1*0103 were significantly associated respectively with higher and lower numbers of thoracic cord lesions. HLA-DRB1*1501 and the HLA-DRB1*11 sub-alleles DRB1*1101 and DRB1*1104 were significantly associated with the segmental length of cord lesions. Our study is the first to investigate the frequency of subpial wedge-shaped lesions in the cord in vivo and has provided preliminary evidence that HLA-DRB1 alleles may play a role in determining the severity and extent of spinal cord involvement in MS.


Polycomb eviction as a new distant enhancer function.
Remote distal enhancers may be located tens or thousands of kilobases away from their promoters. How they control gene expression is still poorly understood. Here, we analyze the influence of a remote enhancer on the balance between repression (Polycomb-PcG) and activation (Trithorax-TrxG) of a developmentally regulated gene associated with a CpG island. We reveal its essential, nonredundant role in clearing the PcG complex and H3K27me3 from the CpG island. In the absence of the enhancer, the H3K27me3 demethylase (JMJD3) is not recruited to the CpG island. We propose a new role of long-range regulatory elements in removing repressive PcG complexes.


Minkowski tensor shape analysis of cellular, granular and porous structures.
Predicting physical properties of materials with spatially complex structures is one of the most challenging problems in material science. One key to a better understanding of such materials is the geometric characterization of their spatial structure. Minkowski tensors are tensorial shape indices that allow quantitative characterization of the anisotropy of complex materials and are particularly well suited for developing structure-property relationships for tensor-valued or orientation-dependent physical properties. They are fundamental shape indices, in some sense being the simplest generalization of the concepts of volume, surface and integral curvatures to tensor-valued quantities. Minkowski tensors are based on a solid mathematical foundation provided by integral and stochastic geometry, and are endowed with strong robustness and completeness theorems. The versatile definition of Minkowski tensors applies widely to different types of morphologies, including ordered and disordered structures. Fast linear-time algorithms are available for their computation. This article provides a practical overview of the different uses of Minkowski tensors to extract quantitative physically-relevant spatial structure information from experimental and simulated data, both in 2D and 3D. Applications are presented that quantify (a) alignment of co-polymer films by an electric field imaged by surface force microscopy; (b) local cell anisotropy of spherical bead pack models for granular matter and of closed-cell liquid foam models; (c) surface orientation in open-cell solid foams studied by X-ray tomography; and (d) defect densities and locations in molecular dynamics simulations of crystalline copper.


Pulmonary histopathology induced by respiratory syncytial virus (RSV) challenge of formalin-inactivated RSV-immunized BALB/c mice is abrogated by depletion of CD4+ T cells.
In previous studies, it was observed that children immunized with a formalin-inactivated respiratory syncytial virus vaccine (FI-RSV) developed severe pulmonary disease with greater frequency during subsequent natural RSV infection than did controls. During earlier efforts to develop an animal model of this phenomenon, enhanced pulmonary histopathology was observed after intranasal RSV challenge of FI-RSV-immunized cotton rats. Progress in understanding the immunologic basis for these observations has been hampered by the lack of reagents useful in manipulating the immune response of the cotton rat. This problem prompted us to reinvestigate the characteristics of immunity to RSV in the mouse. In the present studies, extensive pulmonary histopathology was observed in FI-RSV-immunized or RSV-infected BALB/c mice upon RSV challenge, and studies to determine the relative contributions of CD4+ or CD8+ T cells to this process were undertaken. Mice previously immunized with FI-RSV or infected with RSV were depleted of CD4+, CD8+, or both T-cell subsets immediately prior to RSV challenge, and the magnitude of inflammatory cell infiltration around bronchioles and pulmonary blood vessels and into alveolar spaces was quantified. The magnitude of infiltration at each anatomic site in previously FI-RSV-immunized or RSV-infected, nondepleted animals was similar, indicating that this is not a relevant model for enhanced disease. However, the effect of T-cell subset depletion on pulmonary histopathology following RSV challenge was very different between the two groups. Depletion of CD4+ T cells completely abrogated pulmonary histopathology in FI-RSV-immunized mice, whereas it had a much smaller effect on mice previously infected with RSV. FI-RSV-immunized or RSV-infected animals depleted of CD8+ T cells had only a modest reduction of pulmonary histopathology. In addition, RSV infection induced high levels of major histocompatibility complex class I-restricted cytotoxic T-cell activity, whereas FI-RSV immunization induced a low level. These data indicate that immunization with FI-RSV induces a cellular immune response different from that induced by RSV infection, which likely played a role in enhanced disease observed in infants and children.


Extrapolating population size from the occupancy-abundance relationship and the scaling pattern of occupancy.
The estimation of species abundances at regional scales requires a cost-efficient method that can be applied to existing broadscale data. We compared the performance of eight models for estimating species abundance and community structure from presence-absence maps of the southern African avifauna. Six models were based on the intraspecific occupancy-abundance relationship (OAR); the other two on the scaling pattern of species occupancy (SPO), which quantifies the decline in species range size when measured across progressively finer scales. The performance of these models was examined using five tests: the first three compared the predicted community structure against well-documented macroecological patterns; the final two compared published abundance estimates for rare species and the total regional abundance estimate against predicted abundances. Approximately two billion birds were estimated as occurring in South Africa, Lesotho, and Swaziland. SPO models outperformed the OAR models, due to OAR models assuming environmental homogeneity and yielding scale-dependent estimates. Therefore, OAR models should only be applied across small, homogenous areas. By contrast, SPO models are suitable for data at larger spatial scales because they are based on the scale dependence of species range size and incorporate environmental heterogeneity (assuming fractal habitat structure or performing a Bayesian estimate of occupancy). Therefore, SPO models are recommended for assemblage-scale regional abundance estimation based on spatially explicit presence-absence data.


Fluidic sensor based on the side-opened and suspended dual-core fiber.
For accelerating the response and enhancing the sensitivity simultaneously, a novel fluidic sensor based on a side-opened and suspended dual-core fiber and dual-beam interference detection mechanism is first explored and analyzed here. The side opening ensures a fast response by allowing fluidic analyte to approach the fiber core laterally. The dual-beam Mach-Zehnder interferemetry provides a relative higher sensitivity. Calculation results show that a sensitivity of 2.1×10(-6) refractive index unit (RIU) within a response time of 10 s could be achievable, which reflects its potential impact on constructing a fluid refractometer for fast-response and high-sensitivity detection. Moreover, the relationship of the sensing sensitivity and the detected dynamic range of this suspended dual-core fiber structure, polarization, and the transmitting waveband are also analyzed.


Acute mobile phones exposure affects frontal cortex hemodynamics as evidenced by functional near-infrared spectroscopy.
This study aimed to evaluate by functional near-infrared spectroscopy (fNIRS), the effects induced by an acute exposure (40 mins) to a GSM (Global System for Mobile Communications) signal emitted by a mobile phone (MP) on the oxygenation of the frontal cortex. Eleven healthy volunteers underwent two sessions (Real and Sham exposure) after a crossover, randomized, double-blind paradigm. The whole procedure lasted 60 mins: 10-mins baseline (Bsl), 40-mins (Exposure), and 10-mins recovery (Post-Exp). Together with frontal hemodynamics, heart rate, objective and subjective vigilance, and self-evaluation of subjective symptoms were also assessed. The fNIRS results showed a slight influence of the GSM signal on frontal cortex, with a linear increase in [HHb] as a function of time in the Real exposure condition (F(4,40)=2.67; P=0.04). No other measure showed any GSM exposure-dependent changes. These results suggest that fNIRS is a convenient tool for safely and noninvasively investigating the cortical activation in MP exposure experimental settings. Given the short-term effects observed in this study, the results should be confirmed on a larger sample size and using a multichannel instrument that allows the investigation of a wider portion of the frontal cortex.