Ascl1 expression defines a subpopulation of lineage-restricted progenitors in the mammalian retina.
The mechanisms of cell fate diversification in the retina are not fully understood. The seven principal cell types of the neural retina derive from a population of multipotent progenitors during development. These progenitors give rise to multiple cell types concurrently, suggesting that progenitors are a heterogeneous population. It is thought that differences in progenitor gene expression are responsible for differences in progenitor competence (i.e. potential) and, subsequently, fate diversification. To elucidate further the mechanisms of fate diversification, we assayed the expression of three transcription factors made by retinal progenitors: Ascl1 (Mash1), Ngn2 (Neurog2) and Olig2. We observed that progenitors were heterogeneous, expressing every possible combination of these transcription factors. To determine whether this progenitor heterogeneity correlated with different cell fate outcomes, we conducted Ascl1- and Ngn2-inducible expression fate mapping using the CreER™/LoxP system. We found that these two factors gave rise to markedly different distributions of cells. The Ngn2 lineage comprised all cell types, but retinal ganglion cells (RGCs) were exceedingly rare in the Ascl1 lineage. We next determined whether Ascl1 prevented RGC development. Ascl1-null mice had normal numbers of RGCs and, interestingly, we observed that a subset of Ascl1+ cells could give rise to cells expressing Math5 (Atoh7), a transcription factor required for RGC competence. Our results link progenitor heterogeneity to different fate outcomes. We show that Ascl1 expression defines a competence-restricted progenitor lineage in the retina, providing a new mechanism to explain fate diversification.


Cytosine-5 RNA methylation links protein synthesis to cell metabolism.
Posttranscriptional modifications in transfer RNA (tRNA) are often critical for normal development because they adapt protein synthesis rates to a dynamically changing microenvironment. However, the precise cellular mechanisms linking the extrinsic stimulus to the intrinsic RNA modification pathways remain largely unclear. Here, we identified the cytosine-5 RNA methyltransferase NSUN2 as a sensor for external stress stimuli. Exposure to oxidative stress efficiently repressed NSUN2, causing a reduction of methylation at specific tRNA sites. Using metabolic profiling, we showed that loss of tRNA methylation captured cells in a distinct catabolic state. Mechanistically, loss of NSUN2 altered the biogenesis of tRNA-derived noncoding fragments (tRFs) in response to stress, leading to impaired regulation of protein synthesis. The intracellular accumulation of a specific subset of tRFs correlated with the dynamic repression of global protein synthesis. Finally, NSUN2-driven RNA methylation was functionally required to adapt cell cycle progression to the early stress response. In summary, we revealed that changes in tRNA methylation profiles were sufficient to specify cellular metabolic states and efficiently adapt protein synthesis rates to cell stress.


Phosphoproteomic identification of ULK substrates reveals VPS15-dependent ULK/VPS34 interplay in the regulation of autophagy.
Autophagy is a process through which intracellular cargoes are catabolised inside lysosomes. It involves the formation of autophagosomes initiated by the serine/threonine kinase ULK and class III PI3 kinase VPS34 complexes. Here, unbiased phosphoproteomics screens in mouse embryonic fibroblasts deleted for Ulk1/2 reveal that ULK loss significantly alters the phosphoproteome, with novel high confidence substrates identified including VPS34 complex member VPS15 and AMPK complex subunit PRKAG2. We identify six ULK-dependent phosphorylation sites on VPS15, mutation of which reduces autophagosome formation in cells and VPS34 activity in vitro. Mutation of serine 861, the major VPS15 phosphosite, decreases both autophagy initiation and autophagic flux. Analysis of VPS15 knockout cells reveals two novel ULK-dependent phenotypes downstream of VPS15 removal that can be partially recapitulated by chronic VPS34 inhibition, starvation-independent accumulation of ULK substrates and kinase activity-regulated recruitment of autophagy proteins to ubiquitin-positive structures.


The changing course of diabetic nephropathy: low-density lipoprotein cholesterol and blood pressure correlate with regression of proteinuria.
Diabetic nephropathy (DN) as manifested by persistent and clinically evident proteinuria, has long been considered an irreversible process that predicts a rapid decline in renal function. The observation of reversal of DN in several individuals enrolled in a prospective study of the natural course of diabetes complications challenged this view and led to the current investigation into the correlates of such regression of proteinuria. DN was defined as a median albumin excretion rate (AER) over 200 microg/min in two or three urine collections obtained at baseline, and again at 2 and 4 years of follow-up. Among 658 individuals with childhood-onset insulin-dependent diabetes mellitus (IDDM), 146 had DN at baseline. Nine subsequently died without renal failure, and 13 were lost to follow-up. Of the 124 subjects with at least survey follow-up data, 32 (24%) developed renal failure, and 78 of the remaining 92 provided full quantitative data. AER decreased by > or = 10-fold into the microalbuminuric (20 to 200 microg/min) or normal range (<20 microg/min) in 7 of these individuals and are called "regressors of proteinuria." Compared with the remaining 71 subjects, the strongest correlate of regression of proteinuria was an improvement in fasting plasma low-density lipoprotein cholesterol (LDL-C) in the 7 regressors (P < 0.008). Improved glycemic control was not a significant predictor of improved AER. Five of the 7 individuals with improved AER had a baseline median AER below 500 microg/min. When the 7 regressors of proteinuria were combined with an additional 38 individuals who also experienced smaller decreases in median AER, such improvement was associated with a more favorable systolic (or diastolic) blood pressure (BP) change (P < 0.01), and a decrease in plasma LDL-C level (P = 0.01). These data suggest that proteinuria in DN may substantially regress in approximately 6% and improve in at least 34% of individuals with IDDM over a 4-year period, often in association with a decrease in plasma LDL-C concentration or stabilization or improvement in BP. Furthermore, the data suggest that the nonreversibility threshold for diabetic nephropathy may be higher (500 mg/min) than previously reported (200 microg/min).


Evaluation of cell-based and tissue-based immunofluorescent assays for detection of glial fibrillary acidic protein autoantibodies in the cerebrospinal fluid of dogs with meningoencephalitis of unknown origin and other central nervous system disorders.
To evaluate whether cell-based and tissue-based immunofluorescent assays (IFAs) run in parallel could be used to detect glial fibrillary acidic protein (GFAP) autoantibodies in the CSF of dogs with meningoencephalitis of unknown origin (MUO) and other CNS disorders. 15 CSF samples obtained from dogs with presumed MUO (n = 5), CNS disease other than MUO (5), and idiopathic epilepsy (5). All CSF samples underwent parallel analysis with a cell-based IFA that targeted the α isoform of human GFAP and a tissue-based IFA that involved mouse brain cryosections. Descriptive data were generated. Only 1 CSF sample yielded mildly positive results on the cell-based IFA; that sample was from 1 of the dogs with presumed MUO. The remaining 14 CSF samples tested negative on the cell-based IFA. All 15 CSF samples yielded negative results on the tissue-based IFA. Results suggested that concurrent use of a cell-based IFA designed to target the human GFAP-α isoform and a tissue-based IFA that involved mouse tissue cryosections was inadequate for detection of GFAP autoantibodies in canine CSF samples. Given that GFAP autoantibodies were likely present in the CSF samples analyzed, these findings suggested that epitopes differ substantially between canine and human GFAP and that canine GFAP autoantibody does not bind to mouse GFAP. Without a positive control, absence of GFAP autoantibody in this cohort cannot be ruled out. Further research is necessary to develop a noninvasive and sensitive method for diagnosis of MUO in dogs.


[Coronary artery disease from a perspective of genomic risk score, ethical approaches and suggestions].
As a leading cause of mortality, coronary artery disease is on the focus of genetic research as a complex trait. Although predictive genetic testing for cardiovascular diseases is on the counter, it is still hard to aggregate information from multiple genetic variants, environmental factors and family history into a single score. Every susceptibility allele provides small contribution to disease formation. Biomarkers play a role in various metabolic pathways. Genetic information and data depend heavily on probabilities. This should be clearly explained by genetic counselor to the patient and relatives who are looking for certain answers. Presence of susceptibility alleles can be a source of anxiety and it may result as a reduced self-confidence in ability to change health behavior. Complex diseases set a new stage to study novel techniques that can elucidate interactions among genetic, environmental and ethnic factors. The cookbook approach to treat a complex disease can often be misleading. Future studies may provide personalized information, which can improve the outcome of standardized treatments. As knowing one's own genetic risk is becoming a task for the responsible individual, it surely will add new challenges to ethical framework. Publicly marketing genetic tests for complex diseases raises ethical concerns. To avoid discriminatory use of genetic information; genetic risk scoring, therapeutic process, ethical policies must have a multifaceted progress. In this review, we summarized the attempts to resolve ethical issues related to genetic testing in complex diseases to resolve patient autonomy with individual responsibility and to aim the patient beneficence and confidentiality.


Roles for wbtC, wbtI, and kdtA Genes in Lipopolysaccharide Biosynthesis, Protein Glycosylation, Virulence, and Immunogenicity in Francisella tularensis2 Strain SCHU S4.
Using a strategy of gene deletion mutagenesis, we have examined the roles of genes putatively involved in lipopolysaccharide biosynthesis in the virulent facultative intracellular bacterial pathogen, Francisella tularensis subspecies tularensis, strain SCHU S4 in LPS biosynthesis, protein glycosylation, virulence and immunogenicity. One mutant, ΔwbtI, did not elaborate a long chain O-polysaccharide (OPS), was completely avirulent for mice, and failed to induce a protective immune response against challenge with wild type bacteria. Another mutant, ΔwbtC, produced a long chain OPS with altered chemical and electrophoretic characteristics. This mutant showed markedly reduced glycosylation of several known glycoproteins. Additionally this mutant was highly attenuated, and elicited a protective immune response against systemic, but not respiratory challenge with wild type SCHU S4. A third mutant, ΔkdtA, produced an unconjugated long chain OPS, lacking a detectable core structure, and which was not obviously expressed at the surface. It was avirulent and elicited partial protection against systemic challenge only.


Dynamics of maternal androgens and its metabolites during early embryonic development: embryonic modification of a maternal effect.
In birds, exposure to maternal (yolk) testosterone affects a diversity of offspring post-hatching traits, which eventually affect offspring competitiveness. However, maternal testosterone is heavily metabolized at very early embryonic developmental stages to hydrophilic metabolites that are often assumed to be much less biologically potent. Either the rapid metabolism could either keep the maternal testosterone from reaching the embryos, opening the possibility for a mother-offspring conflict or the metabolites may facilitate the uptake of the lipophilic testosterone from the yolk into the embryonic circulation after which they are either converted back to the testosterone or functioning directly as metabolites. To test these possibilities, we injected isotope-labeled testosterone (T-[D5]) into the yolk of freshly laid Rock pigeon (Columba livia) eggs and determined the concentration and distribution of T-[D5] and its labeled metabolites within different egg fractions by liquid chromatography combined with tandem mass spectrometry at day 2, 5 and 10 of incubation. Although under a supraphysiological dosage injection, yolk testosterone decreased within 2 days and was metabolized into androstenedione, conjugated testosterone, etiocholanolone and other components that were unidentifiable due to methodological limitation. We show for the first time that testosterone, androstenedione and conjugated testosterone, but not etiocholanolone, reached the embryo including its brain. Their high concentrations in the yolk and extraembryonic membranes suggest that conversion takes place here. We also found no sex-specific metabolism, explaining why maternal testosterone does not affect sexual differentiation. Our findings showed that maternal testosterone is quickly converted by the embryo, with several but not all metabolites reaching the embryo providing evidence for both hypotheses.


Bomapin is a redox-sensitive nuclear serpin that affects responsiveness of myeloid progenitor cells to growth environment.
Haematopoiesis is a process of formation of mature blood cells from hematopoietic progenitors in bone marrow. Haematopoietic progenitors are stimulated by growth factors and cytokines to proliferate and differentiate, and they die via apoptosis when these factors are depleted. An aberrant response to growth environment may lead to haematological disorders. Bomapin (serpinb10) is a hematopoietic- and myeloid leukaemia-specific protease inhibitor with unknown function. We found that the majority of naturally expressed bomapin was located in the nucleus. Both the natural and recombinant bomapin had a disulfide bond which linked the only two bomapin cysteines: one located in the CD-loop and the other near the C-terminus. Computer modelling showed that the cysteines are distant in the reduced bomapin, but can easily be disulfide-linked without distortion of the overall bomapin structure. Low-level ectopic expression of bomapin in bomapin-deficient K562 cells resulted in about 90% increased cell proliferation under normal growth conditions. On the other hand, antisense-downregulation of natural bomapin in U937 cells resulted in a decreased cell proliferation. Bomapin C395S mutant, representing the reduced form of the serpin, had no effect on cell proliferation, suggesting that the disulfide bond-linked conformation of bomapin is biologically important. The bomapin-dependent effect was specific for myeloid cells, since ectopic expression of the serpin in HT1080 cells did not change cell proliferation. In contrast to the survival-promoting activity of bomapin in cells cultured under optimal growth conditions, bomapin enhanced cell apoptosis following growth factor withdrawal. We propose that bomapin is a redox-sensitive nuclear serpin that augments proliferation or apoptosis of leukaemia cells, depending on growth factors availability.


Face recognition using nearest feature space embedding.
Face recognition algorithms often have to solve problems such as facial pose, illumination, and expression (PIE). To reduce the impacts, many researchers have been trying to find the best discriminant transformation in eigenspaces, either linear or nonlinear, to obtain better recognition results. Various researchers have also designed novel matching algorithms to reduce the PIE effects. In this study, a nearest feature space embedding (called NFS embedding) algorithm is proposed for face recognition. The distance between a point and the nearest feature line (NFL) or the NFS is embedded in the transformation through the discriminant analysis. Three factors, including class separability, neighborhood structure preservation, and NFS measurement, were considered to find the most effective and discriminating transformation in eigenspaces. The proposed method was evaluated by several benchmark databases and compared with several state-of-the-art algorithms. According to the compared results, the proposed method outperformed the other algorithms.


Exploring the underperformance of male and minority ethnic medical students in first year clinical examinations.
Evidence shows that medical students from Minority Ethnic (ME) backgrounds and male medical students underperform in undergraduate examinations. Our study confirmed these findings in first year clinical (year 3) medical students, and further explored this disparity in performance. We conducted a series of meta-analyses to measure the effects of sex and ethnic group on the written examination and Objective Structured Clinical Examination (OSCE) scores of three groups of year 3 medical students at two London UK medical schools (n = 1,051; 46.0% male; 48.7% White). Male and ME students scored lower on written and OSCE assessments. Both assessments were statistically significantly correlated (mean r = 0.45) and therefore the effects of sex and ethnic group were measured on each exam after being adjusted for the effect of the other. Although sex and ethnic differences remained on the OSCE when adjusted for written performance, these differences disappeared on the written when it was adjusted for OSCE performance. These findings may reflect a relative deficit in practical clinical knowledge in male and ME year 3 students. Results were unlikely to be due to examiner bias, as the machine-marked unadjusted written exam results showed significant sex and ethnic differences.


Variations of renal vascular anatomy in a nigerian population: A computerized tomography studys.
A broad spectrum of renal vascular variations has been reported by anatomists and radiologists. The prevalence of these variations is extremely divergent in different populations. Therefore, radiologists and surgeons in different climes must be knowledgeable about the type and prevalence of the variants in their area of practice to avoid diagnostic pitfalls and for optimization of surgical techniques. The objective of this study is to describe the types and prevalence of renal vascular variations among patients undergoing contrast-enhanced computerized tomography (CECT) of the abdomen in a Nigerian population, as well as provide a concise review of literature on the embryological basis and clinical significance of the identified variations. This study was a retrospective review of 200 CECT of the abdomen to identify variations of arterial (accessory, early branching, and precaval) and venous (multiple, retroaortic, and circumaortic) anatomy of the kidneys. We studied 200 patients, 102 (51%) females and 98 (49%) males. Age range is 18-90 years (mean = 53.08 ± 17.01). Prevalence of any renal vascular variations was 50%, arterial variations were 37%, and venous variations were 13%. Variations were significantly more common in males, P = 0.000075. The most common arterial variant was the accessory renal artery (23%) seen in 10% (right) and 13.0% (left); early branching was seen in 4.0% (right) and 0.5% (left) as well as precaval right renal artery seen in 4.5%. Venous variants were late confluence 3.0% (right) and 2.5% (left); multiple veins was seen in 2.5% (right) and 2.5% (left) as well as retroaortic left renal vein seen in 2.0%. The inferior polar accessory artery was the most prevalent accessory artery. Early arterial bifurcation was significantly more common on the right (P = 0.016) while other vascular variants showed no statistically significant association with laterality. Variation of renal vascular anatomy is a frequent finding among Nigerians. Radiologists and surgeons must be aware of these variants for optimization of surgical techniques.


Study of the Langat virus RNA-dependent RNA polymerase through homology modeling.
Langat virus is a member of the Flaviviridae family and a close relative of a group of important tick-borne viruses that cause human encephalitis. RNA-dependent RNA polymerase is a significant component of the replication mechanism of the Flaviviridae viral family. In the present work, a three-dimensional model of the Langat virus RNA-dependent RNA polymerase was designed through homology modeling. The experimentally determined structure of the RNA-dependent RNA polymerase of Dengue virus type II, another member of the same viral family, was employed as template for the homology modeling process. The resulting model underwent a series of optimisations and its quality was verified using the Verify3D algorithm. Important functional characteristics of the family of viral RNA-dependent RNA polymerases were identified in the generated model, thus affirming the potential for its use in the possible design of anti-viral agents for Langat virus.


Assessing the health of the U.S. west coast with a regional-scale application of the Ocean Health Index.
Management of marine ecosystems increasingly demands comprehensive and quantitative assessments of ocean health, but lacks a tool to do so. We applied the recently developed Ocean Health Index to assess ocean health in the relatively data-rich US west coast region. The overall region scored 71 out of 100, with sub-regions scoring from 65 (Washington) to 74 (Oregon). Highest scoring goals included tourism and recreation (99) and clean waters (87), while the lowest scoring goals were sense of place (48) and artisanal fishing opportunities (57). Surprisingly, even in this well-studied area data limitations precluded robust assessments of past trends in overall ocean health. Nonetheless, retrospective calculation of current status showed that many goals have declined, by up to 20%. In contrast, near-term future scores were on average 6% greater than current status across all goals and sub-regions. Application of hypothetical but realistic management scenarios illustrate how the Index can be used to predict and understand the tradeoffs among goals and consequences for overall ocean health. We illustrate and discuss how this index can be used to vet underlying assumptions and decisions with local stakeholders and decision-makers so that scores reflect regional knowledge, priorities and values. We also highlight the importance of ongoing and future monitoring that will provide robust data relevant to ocean health assessment.


Investigations into the Use of a Protein Sensor Assay for Metabolite Analysis.
Rapid and definitive classification of biological samples has application in industrial, agricultural, and clinical settings. Considerable effort has been given to analytical methods to address such applications over the past 50 years, with the majority of successful solutions focusing on a single molecular target. However, in many cases, a single or even a few features are insufficient for accurate characterization or classification. Serum albumin (SA) proteins are a class of cargo-carrying proteins in blood that have evolved to transport a wide variety of metabolites and peptides in mammals. These proteins have up to seven binding sites which communicate allosterically to orchestrate a complex pick-up and delivery system involving a large number of different molecules at any time. The ability of SA proteins to bind multiple molecular species in a sophisticated manner inspired the development of assays to differentiate complex biological solutions. The combination of SA and high-resolution liquid chromatography mass spectrometry (LC-MS) is showing exciting promise as a protein sensor assay (PSA) for classification of complex biological samples. In this study, the PSA has been applied to cells undergoing and recovering from mild oxidative stress. Analysis using traditional LC-MS-based metabolomics failed to differentiate samples into treatment or temporal groups, whereas samples first treated with the PSA were cleanly classified into both correct treatment and temporal groups. The success of the PSA could be attributed to selective binding of metabolites, leading to a reduction in sample complexity and a general reduction in chemical noise. Metabolites important to successful sample classification were often enriched by 100-fold or more yet displayed a wide range of affinities for SA. The end result of PSA treatment is better classification of samples with a reduction in the number of features seen overall. Together, these results demonstrate how the use of a protein-based assay before LC-MS analysis can greatly improve separation and lead to more accurate and successful tracking of the metabolic state in an organism, suggesting potential application in a wide range of fields.


Psychological therapies for people with borderline personality disorder.
Psychotherapy is regarded as the first-line treatment for people with borderline personality disorder. In recent years, several disorder-specific interventions have been developed. This is an update of a review published in the Cochrane Database of Systematic Reviews in 2006. To assess the effects of psychological interventions for borderline personality disorder (BPD). We searched the following databases: CENTRAL 2010(3), MEDLINE (1950 to October 2010), EMBASE (1980 to 2010, week 39), ASSIA (1987 to November 2010), BIOSIS (1985 to October 2010), CINAHL (1982 to October 2010), Dissertation Abstracts International (31 January 2011), National Criminal Justice Reference Service Abstracts (15 October 2010), PsycINFO (1872 to October Week 1 2010), Science Citation Index (1970 to 10 October 2010), Social Science Citation Index (1970 to 10 October 2010), Sociological Abstracts (1963 to October 2010), ZETOC (15 October 2010) and the metaRegister of Controlled Trials (15 October 2010). In addition, we searched Dissertation Abstracts International in January 2011 and ICTRP in August 2011. Randomised studies with samples of patients with BPD comparing a specific psychotherapeutic intervention against a control intervention without any specific mode of action or against a comparative specific psychotherapeutic intervention. Outcomes included overall BPD severity, BPD symptoms (DSM-IV criteria), psychopathology associated with but not specific to BPD, attrition and adverse effects. Two review authors independently selected studies, assessed the risk of bias in the studies and extracted data. Twenty-eight studies involving a total of 1804 participants with BPD were included. Interventions were classified as comprehensive psychotherapies if they included individual psychotherapy as a substantial part of the treatment programme, or as non-comprehensive if they did not.Among comprehensive psychotherapies, dialectical behaviour therapy (DBT), mentalisation-based treatment in a partial hospitalisation setting (MBT-PH), outpatient MBT (MBT-out), transference-focused therapy (TFP), cognitive behavioural therapy (CBT), dynamic deconstructive psychotherapy (DDP), interpersonal psychotherapy (IPT) and interpersonal therapy for BPD (IPT-BPD) were tested against a control condition. Direct comparisons of comprehensive psychotherapies included DBT versus client-centered therapy (CCT); schema-focused therapy (SFT) versus TFP; SFT versus SFT plus telephone availability of therapist in case of crisis (SFT+TA); cognitive therapy (CT) versus CCT, and CT versus IPT.Non-comprehensive psychotherapeutic interventions comprised DBT-group skills training only (DBT-ST), emotion regulation group therapy (ERG), schema-focused group therapy (SFT-G), systems training for emotional predictability and problem solving for borderline personality disorder (STEPPS), STEPPS plus individual therapy (STEPPS+IT), manual-assisted cognitive treatment (MACT) and psychoeducation (PE). The only direct comparison of an non-comprehensive psychotherapeutic intervention against another was MACT versus MACT plus therapeutic assessment (MACT+). Inpatient treatment was examined in one study where DBT for PTSD (DBT-PTSD) was compared with a waiting list control. No trials were identified for cognitive analytical therapy (CAT).Data were sparse for individual interventions, and allowed for meta-analytic pooling only for DBT compared with treatment as usual (TAU) for four outcomes. There were moderate to large statistically significant effects indicating a beneficial effect of DBT over TAU for anger (n = 46, two RCTs; standardised mean difference (SMD) -0.83, 95% confidence interval (CI) -1.43 to -0.22; I(2) = 0%), parasuicidality (n = 110, three RCTs; SMD -0.54, 95% CI -0.92 to -0.16; I(2) = 0%) and mental health (n = 74, two RCTs; SMD 0.65, 95% CI 0.07 to 1.24 I(2) = 30%). There was no indication of statistical superiority of DBT over TAU in terms of keeping participants in treatment (n = 252, five RCTs; risk ratio 1.25, 95% CI 0.54 to 2.92).All remaining findings were based on single study estimates of effect. Statistically significant between-group differences for comparisons of psychotherapies against controls were observed for BPD core pathology and associated psychopathology for the following interventions: DBT, DBT-PTSD, MBT-PH, MBT-out, TFP and IPT-BPD. IPT was only indicated as being effective in the treatment of associated depression. No statistically significant effects were found for CBT and DDP interventions on either outcome, with the effect sizes moderate for DDP and small for CBT. For comparisons between different comprehensive psychotherapies, statistically significant superiority was demonstrated for DBT over CCT (core and associated pathology) and SFT over TFP (BPD severity and treatment retention). There were also encouraging results for each of the non-comprehensive psychotherapeutic interventions investigated in terms of both core and associated pathology.No data were available for adverse effects of any psychotherapy. There are indications of beneficial effects for both comprehensive psychotherapies as well as non-comprehensive psychotherapeutic interventions for BPD core pathology and associated general psychopathology. DBT has been studied most intensely, followed by MBT, TFP, SFT and STEPPS. However, none of the treatments has a very robust evidence base, and there are some concerns regarding the quality of individual studies. Overall, the findings support a substantial role for psychotherapy in the treatment of people with BPD but clearly indicate a need for replicatory studies.


Mechanistic origins of chemo- and regioselectivity of Ru(II)-catalyzed reactions involving ortho-alkenylarylacetylene, alkyne, and methanol: the crucial role of a chameleon-like intermediate.
M06-DFT computations have been applied to understand four catalytic systems which involved [Ru(Cp*)(MeCN)3]PF6 or [Ru(Tp)(PPh3)(MeCN)2]PF6 as mediator and ortho-alkenylarylacetylene, terminal alkyne, and methanol as reactants. Potentially, the products of these systems could be dihydrobiphenylenes, 1,3-dienyl ether, and naphthalene. Remarkably, each system afforded product selectively. Our computed mechanisms successfully account for the chemo- and regioselectivities of these systems. Furthermore, the study demonstrates that the chameleon-like mono(carbene) intermediates formed via the intermolecular alkyne-alkyne oxidative coupling play a crucial role to complete the reactions. According to their geometric and electronic structures, three resonance structures were introduced to characterize their reactivity properties, which address the features of the classical alkyne-alkyne oxidative coupling intermediates, mono(carbene) species, and electrophilicity of the intermediates, respectively. The reactivity properties lead to three channels isomerizing the intermediates to three isomers. Surprisingly, the bis(carbene) isomers, which are similar to the bis(carbene) intermediates generally considered to be crucial in the neutral RuCp*Cl-catalyzed systems, are accessible but not reactive enough to continue the subsequent reaction steps partially due to aromaticity. The other two isomers continue subsequent reaction steps. These findings may help not only to understand the four specific catalytic reactions but also to advance the [2 + 2 + 2] synthetic methodology.


Self modulating, derivative optical spectroscopy. Part II: experimental.
The present paper follows a previous one that dealt with the theoretical principles of a self modulating derivative optical spectrometer (SMODOS). In this paper the complete description is given of a prototype of such an instrument, namely, of its optical as well as electronic components. The project criteria are thoroughly discussed, and some examples of performance that demonstrate the power of the method are presented.


Hypoxic ventilatory decline: site of action.
Although superficially similar, HVD appears to arise from different mechanisms in the awake animal as compared with the anesthetized animal. Consequently, the good evidence supporting a central site of action for hypoxia in the genesis of HVD in the anesthetized animal cannot be used as evidence for a central site of action for hypoxia in the awake animal. In their paper on HVD in the awake cat, Long et al. (10) conclude: "The striking similarity between feline and human ventilatory responses to moderate hypoxia illustrated by this and previous experiments leads us to believe that it is likely similar mechanisms apply to both species. Thus it seems probable that working out the mechanisms of the ventilatory response to hypoxia in the awake cat will go a long way toward solving the same problems in humans." This activity should not neglect a consideration of whether adaptation at the carotid body during sustained hypoxia may be involved in the genesis of HVD in the awake state.


Does anterior trunk pain predict a different course of recovery in chronic low back pain?
Patient characteristics associated with the course and severity of low back pain (LBP) and disability have been the focus of extensive research, however, known characteristics do not explain much of the variance in outcomes. The relationship between anterior trunk pain (ATP) and LBP has not been explored, though mechanisms for visceral referred pain have been described. Study objectives were: (1) determine prevalence of ATP in chronic LBP patients, (2) determine whether ATP is associated with increased pain and disability in these patients, and (3) evaluate whether ATP predicts the course of pain and disability in these patients. In this study, spinal outpatient department patients mapped the distribution of their pain and patients describing pain in their chest, abdomen or groin were classified with ATP. Generalized estimating equations were performed to investigate the relationship between ATP and LBP outcomes. A total of 2974 patients were included and 19.6% of patients reported ATP. At all time points, there were significant differences in absolute pain intensity and disability in those with ATP compared with those without. The presence of ATP did not affect the clinical course of LBP outcomes. The results of this study suggest that patients who present with LBP and ATP have higher pain and disability levels than patients with localised LBP. Visceral referred pain mechanisms may help to explain some of this difference.


Modeling the adsorption and coagulation of fulvic acids on colloids by Brownian dynamics simulations.
Humic substances (HS) play an important role in the reactivity and transport of colloids in natural environments. In particular, the presence of fulvic acids (FA) in natural waters modifies the interactions between inorganic particles and biopolymers and makes difficult to predict their stability with regard to aggregation processes. In this study, Brownian dynamics (BD) modeling is applied to quantify the interactions between negatively charged FA and (i) a positively charged inorganic particle and (ii) a rigid neutral polysaccharide in aqueous solutions. Hematite and schizophyllan are respectively used as model colloids. Modeling the adsorption of FA at the hematite particle surface and on the polysaccharide is based on van der Waals attractive forces and electrostatic interactions. Possible applications of the model, however, are not restricted to this system and any interaction potential or colloidal particle can be considered. The competition between FA adsorption and FA homocoagulation in solution is studied as function of the solution ionic strength. Results show that, under the conditions used, the amount of adsorbed FA is largely controlled by the solution ionic strength. At low ionic strength the amount of adsorbed FA is limited by the electrostatic repulsion between FA at the colloid surfaces and FA monolayers are formed. By increasing the ionic strength the number of adsorbed FA is found to increase. At a sufficiently large ionic strength, however, FA coagulation in solution may strongly compete with FA adsorption at the hematite and polysaccharide surfaces. FA aggregates then adsorb at the colloid surfaces to form extended and porous structures. Results also suggest that FA adsorption and structure of the adsorbed layers are mainly driven by the complex interplay between electrostatic attractive and repulsive interactions.


Genealogical lineage sorting leads to significant, but incorrect Bayesian multilocus inference of population structure.
Over the past decades, the use of molecular markers has revolutionized biology and led to the foundation of a new research discipline-phylogeography. Of particular interest has been the inference of population structure and biogeography. While initial studies focused on mtDNA as a molecular marker, it has become apparent that selection and genealogical lineage sorting could lead to erroneous inferences. As it is not clear to what extent these forces affect a given marker, it has become common practice to use the combined evidence from a set of molecular markers as an attempt to recover the signals that approximate the true underlying demography. Typically, the number of markers used is determined by either budget constraints or by statistical power required to recognize significant population differentiation. Using microsatellite markers from Drosophila and humans, we show that even large numbers of loci (>50) can frequently result in statistically well-supported, but incorrect inference of population structure using the software BAPS. Most importantly, genomic features, such as chromosomal location, variability of the markers, or recombination rate, cannot explain this observation. Instead, it can be attributed to sampling variation among loci with different realizations of the stochastic lineage sorting. This phenomenon is particularly pronounced for low levels of population differentiation. Our results have important implications for ongoing studies of population differentiation, as we unambiguously demonstrate that statistical significance of population structure inferred from a random set of genetic markers cannot necessarily be taken as evidence for a reliable demographic inference.


Structural effects of fibulin 5 missense mutations associated with age-related macular degeneration and cutis laxa.
AMD has a complex etiology with environmental and genetic risk factors. Ten fibulin 5 sequence variants have been associated with AMD and two other fibulin 5 mutations cause autosomal-recessive cutis laxa. Fibulin 5 is a 52-kDa calcium-binding epidermal growth factor (cbEGF)-rich extracellular matrix protein that is essential for the formation of elastic tissues. Biophysical techniques were used to detect structural changes in the fibulin 5 mutants and to determine whether changes are predictive of pathogenicity. Native PAGE, nonreduced SDS-PAGE, size-exclusion column multiangle laser light scattering, sedimentation velocity, and circular dichroism (CD) were used to investigate the mobility, hydrodynamic radii, folding, and oligomeric states of the fibulin 5 mutants in the absence and presence of Ca(2+). CD showed that all mutants are folded, although perturbations to secondary structure contents were detected. Both cutis laxa mutants increased dimerization. Most other mutants slightly increased self-association in the absence of Ca(2+) but this was also demonstrated by G202R, a polymorphism detected in a control individual. The AMD-associated mutant G412E showed lower-than-expected mobility during native-PAGE, the largest hydrodynamic radius for the monomer form and the highest levels of aggregation in both the absence and presence of Ca(2+). The results identified structural differences for the disease-causing cutis laxa mutants and for one AMD variant (G412E), suggesting that this may also be pathogenic. Although the other AMD-associated mutants showed no gross structural differences, they cannot be excluded as pathogenic by differences outside the scope of this study-for example, disruption of heterointeractions.


Response rate, durability of response, and survival after thalidomide therapy for relapsed multiple myeloma.
To assess response rate, duration of response, progression-free survival, and toxicity of thalidomide in patients with relapsed multiple myeloma. Thirty-two patients with relapsed multiple myeloma were entered into the study between April 29, 1999, and June 20, 2000. They were given oral thalidomide at a dosage of 200 mg/d for 2 weeks, which was then increased as tolerated to a maximum of 800 mg/d. The primary end point of the study was response rate. The median age of the patients was 67 years (range, 36-78 years). Prior chemotherapy had failed in all patients, and stem cell transplantation had failed in 5 patients (16%). There were 10 confirmed responses, yielding a response rate of 31%. In addition, there was 1 unconfirmed partial response and 7 minimal responses with no complete responses. The median duration of response was 11.9 months (range, 3.7-203 months). Overall, 20 patients have died, and 26 patients have experienced disease progression. The median follow-up of surviving patients was 28.5 months (range, 193-34.0 months), with a median progression-free survival of 8.6 months (95% confidence interval [CI], 4.7-16 months). The median progression-free survival among the responding patients was 15.7 months (95% CI, 8.6-25.6 months). The median overall survival for the entire group was 22 months (95% CI, 10.6-35.9 months). The most common treatment-related nonhematologic toxic effects (grade >3) were neuropathy (16%), sedation (13%), febrile neutropenia (6%), and constipation (6%). Thalidomide is useful in the treatment of patients with relapsed multiple myeloma and produced durable response in approximately one third of patients, with median response duration of nearly 1 year.


Excellence and Durability: A Normally Functioning Björk-Shiley Flat-Disc Prosthesis 42 Years Post Implantation.
Mechanical heart valves have been used worldwide for more than 60 years. While the composition and design of the valves, and the surgical techniques employed to implant them, have changed and advanced over that time, some of the earlier mechanical heart valves showed such great durability that they are still functioning in patients today. One of the most often-used and long-lasting mechanical prostheses was the Björk-Shiley heart valve. While many versions of this valve were used during its 25 years of production, the most durable was the Björk-Shiley flat-disc valve. This valve was first implanted in 1971 and was the first successful tilting-disc valve. Here, the complex medical history is reported of an elderly patient with a well-functioning Björk-Shiley flat-disc valve in the aortic position that was placed over 42 years ago. The history of mechanical heart valves - in particular the Björk-Shiley heart valve, including the flat-disc mechanical valve - is also briefly reviewed.


Effects of ambient pollen concentrations on frequency and severity of asthma symptoms among asthmatic children.
Previous studies on the associations between ambient pollen exposures and daily respiratory symptoms have produced inconsistent results. We investigated these relationships in a cohort of asthmatic children using pollen exposure models to estimate individual ambient exposures. Daily symptoms of wheeze, night symptoms, shortness of breath, chest tightness, persistent cough, and rescue medication use were recorded in a cohort of 430 children with asthma (age 4-12 years) in Connecticut, Massachusetts, and New York. Daily ambient exposures to tree, grass, weed, and total pollen were estimated using mixed-effects models. We stratified analyses by use of asthma maintenance medication and sensitization to grass or weed pollens. Separate logistic regression analyses using generalized estimating equations were performed for each symptom outcome and pollen type. We adjusted analyses for maximum daily temperature, maximum 8-hour average ozone, fine particles (PM2.5), season, and antibiotic use. Associations were observed among children sensitized to specific pollens; these associations varied by use of asthma maintenance medication. Exposures to even relatively low levels of weed pollen (6-9 grains/m(3)) were associated with increased shortness of breath, chest tightness, rescue medication use, wheeze, and persistent cough, compared with lower exposure among sensitized children on maintenance medication. Grass pollen exposures ≥ 2 grains/m(3) were associated with wheeze, night symptoms, shortness of breath, and persistent cough compared with lower exposure among sensitized children who did not take maintenance medication. Even low-level pollen exposure was associated with daily asthmatic symptoms.


Readmission and mortality in patients ≥70 years with acute myocardial infarction or heart failure in the Netherlands: a retrospective cohort study of incidences and changes in risk factors over time.
To determine the risk of first unplanned all-cause readmission and mortality of patients ≥70 years with acute myocardial infarction (AMI) or heart failure (HF) and to explore which effects of baseline risk factors vary over time. A retrospective cohort study was performed on hospital and mortality data (2008) from Statistics Netherlands including 5,175 (AMI) and 9,837 (HF) patients. We calculated cumulative weekly incidences for first unplanned all-cause readmission and mortality during 6 months post-discharge and explored patient characteristics associated with these events. At 6 months, 20.4% and 9.9% (AMI) and 24.6% and 22.4% (HF) of patients had been readmitted or had died, respectively. The highest incidences were found in week 1. An increased risk for 14-day mortality after AMI was observed in patients who lived alone (hazard ratio (HR) 1.57, 95% confidence interval (CI) 1.01-2.44) and within 30 and 42 days in patients with a Charlson Comorbidity Index ≥3. In HF patients, increased risks for readmissions within 7, 30 and 42 days were found for a Charlson Comorbidity Index ≥3 and within 42 days for patients with an admission in the previous 6 months (HR 1.42, 95% CI 1.12-1.80). Non-native Dutch HF patients had an increased risk of 14-day mortality (HR 1.74, 95% CI 1.09-2.78). The risk of unplanned readmission and mortality in older AMI and HF patients was highest in the 1st week post-discharge, and the effect of some risk factors changed over time. Transitional care interventions need to be provided as soon as possible to prevent early readmission and mortality.


Quantitative genetic insights into the coevolutionary dynamics of male and female genitalia.
The spectacular variability that typically characterizes male genital traits has largely been attributed to the role of sexual selection. Among the evolutionary mechanisms proposed to account for this diversity, two processes in particular have generated considerable interest. On the one hand, females may exploit postcopulatory mechanisms of selection to favour males with preferred genital traits (cryptic female choice; CFC), while on the other hand females may evolve structures or behaviours that mitigate the direct costs imposed by male genitalia (sexual conflict; SC). A critical but rarely explored assumption underlying both processes is that male and female reproductive traits coevolve, either via the classic Fisherian model of preference-trait coevolution (CFC) or through sexually antagonistic selection (SC). Here, we provide evidence for this prediction in the guppy (Poecilia reticulata), a polyandrous livebearing fish in which males transfer sperm internally to females via consensual and forced matings. Our results from a paternal half-sibling breeding design reveal substantial levels of additive genetic variation underlying male genital size and morphology-two traits known to predict mating success during non-consensual matings. Our subsequent finding that physically interacting female genital traits exhibit corresponding levels of genetic (co)variation reveals the potential intersexual coevolutionary dynamics of male and female genitalia, thereby fulfilling a fundamental assumption underlying CFC and SC theory.


Dynamic unfolding of a regulatory subunit of cAMP-dependent protein kinase by capillary electrophoresis: Impact of cAMP dissociation on protein stability.
Characterization of the unfolding dynamics of a recombinant type IA regulatory subunit (RIalpha) of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (cAPK) was examined by CE with UV detection. Electrophoretic separation of RIalpha by CE in a buffer devoid of cAMP resulted in rapid dissociation of the complex from the original sample due to the high negative mobility of the ligand relative to receptor. This process enabled in-capillary generation of cAMP-stripped RIalpha, which was used to estimate the apparent dissociation constant (Kd) of 0.6 +/- 0.2 microM. A comparison of RIalpha dynamic unfolding processes with urea denaturation was performed by CE with (i.e., RIalpha-cAMP) and without (i.e., cAMP-stripped RIalpha) excess cAMP in the buffer during electromigration. The presence of cAMP in the buffer confirmed greater stabilization of the protein, as reflected by a higher standard free energy change (DeltaG(U) degrees) of 10.1 +/- 0.5 kcal x mol(+1) and greater cooperativity in unfolding (m) of -2.30 +/- 0.11 kcal x mol(-1) M(-1). CE offers a rapid, yet versatile platform for probing the thermodynamics of cAPK and other types of receptor-ligand complexes in free solution.


Impact of curriculum-based bone loading and nutrition education program on bone accrual in children.
The purpose of this study was to investigate the influence of jumping activities and nutrition education on bone accretion in prepubescents. Fourth-grade children were divided into four groups: jumping (n = 61), nutrition (n = 9), jumping plus nutrition (n = 14), and control (n = 28). Interventions spanned the fourth and fifth grade academic years. Assessments were gathered at 0, 8 and 20 months. Baseline BMD values were (mean +/- SD): lumbar (0.752 +/- 0.095 g/cm2), neck (0.794 +/- 0.089 g/cm2) and total (0.907 +/- 0.060 g/cm2). There was a significant increase in BMD over time. However, the interventions produced no significant effects. Twice weekly jumping and/or biweekly nutrition education did not influence bone accrual.


Intracervical block and pain perception during the performance of a hysterosalpingogram: a randomized controlled trial.
To estimate whether an intracervical block of 1% lidocaine decreased pain perception compared with placebo during the performance of a hysterosalpingogram. A randomized controlled trial was conducted with 120 patients assessing pain perception during a hysterosalpingogram. Patients were randomly assigned to one of three groups. Patients received either a 1% lidocaine intracervical block, an intracervical saline injection, or no injection. Visual analog (VAS) and qualitative scales were used to assess study participants' pain at six different time points during the hysterosalpingogram. Subjects receiving the lidocaine block had significantly less pain (P<.001) by VAS during tenaculum placement (approximately 61% less, 1.303 cm) and with tenaculum traction (approximately 40% less, 2.804 cm) compared with both the intracervical saline injection group and the no injection group (tenaculum placement, 3.384 cm and 3.354 cm, and tenaculum traction, 4.705cm and 4.961 cm, respectively). There was no improvement seen with pain perception during instillation of the contrast in the lidocaine group compared with the saline or no injection group (P<.073). Subjects who received the saline injection had statistically more pain (P<.001) by VAS (2.647 cm) immediately after the injection compared with the lidocaine (approximately 79% greater, 1.476 cm) and no injection groups (115% greater, 1.232 cm). Lidocaine intracervical block provides better pain relief than placebo during tenaculum placement and tenaculum traction during a hysterosalpingogram. This study suggests that patients should be offered an intracervical block before placement of the cervical tenaculum to decrease pain during the performance of a hysterosalpingogram. (www.ClinicalTrials.gov), NCT00372658 I.


Clinical observations in autosomal recessive spastic paraplegia in childhood and further evidence for genetic heterogeneity.
Among our 23 families (32 cases) with autosomal recessive hereditary spastic paraplegia (AR-HSP) all presenting in childhood, 9 families had the "pure" form. Occasional patients with this form had upper extremity hyperreflexia, pes cavus and sphincter disturbances, even at the early stages. Fourteen families were classified as the "complicated" types which manifested with mental retardation and cerebellar abnormalities. The evolution and severity was variable, but was generally consistent within families. Carriers (parents) did not manifest any signs. A total of 5 multiplex families with "complicated" type were used to test for a genetic heterogeneity to the region on chromosome 8p12-q13 where the "pure" AR-HSP has been mapped previously. No evidence in favor of linkage was detected in 3 of our families, thus we further supported genetic heterogeneity for AR-HSP.


The peer model advantage in infants' imitation of familiar gestures performed by differently aged models.
Infants' imitation of differently aged models has been predominately investigated with object-related actions and so far has lead to mixed evidence. Whereas some studies reported an increased likelihood of imitating peer models in contrast to adult models, other studies reported the opposite pattern of results. In the present study, 14-month-old infants were presented with four familiar gestures (e.g., clapping) that were demonstrated by differently aged televised models (peer, older child, adult). Results revealed that infants were more likely to imitate the peer model than the older child or the adult. This result is discussed with respect to a social function of imitation and the mechanism of imitating familiar behavior.


Spirituality As a Coping Mechanism for Individuals with Parkinson's Disease.
Parkinson's disease (PD) is a chronic neurodegenerative disease that can render individuals totally disabled. Spiritual practices can help mitigate stress and provide a source of strength in PD. This article demonstrates a gap that exists between PD and spiritual coping specific research; discusses existing spiritual coping research in chronic illness; and explores the use of spirituality in managing PD care. Healthcare providers need to provide holistic care and explore mechanisms to assist individuals to manage the demands of living with PD.


Immunological mechanisms of synergy between fungus Metarhizium robertsii and bacteria Bacillus thuringiensis ssp. morrisoni on Colorado potato beetle larvae.
The synergistic effect between the entomopathogenic fungus Metarhizium robertsii and a sublethal dose of the bacterium Bacillus thuringiensis ssp. morrisoni var. tenebrionis was studied in terms of immune defense reactions and detoxification system activity of the Colorado potato beetle, Leptinotarsa decemlineata, fourth instar larvae. Bacterial infection led to more rapid germination of fungal conidia on integuments. We found a significant decrease of cellular immunity parameters, including total hemocyte count and encapsulation response, under the influence of bacteria. Phenoloxidase activity in integuments was increased under bacteriosis, mycosis and combined infection compared to controls. However, phenoloxidase activity in the hemolymph was enhanced under bacteriosis alone, and it was decreased under combined infection. Activation of both nonspecific esterases and glutathione-S-transferases in the hemolymph was shown at the first day of mycosis and third day of bacteriosis. However, inhibition of detoxification enzymes was detected under combined infection. The suppression of cellular immunity and detoxification reactions in Colorado potato beetle larvae with a sublethal dose of bacteria is discussed as a reason for synergy between B. thuringiensis and M. robertsii.


Acetylenic scaffolding with subphthalocyanines - synthetic scope and elucidation of electronic interactions in dimeric structures.
Boron subphthalocyanines (SubPcs) are powerful chromophoric heterocycles that can be synthetically modified at both axial and peripheral positions. Acetylenic scaffolding offers the possibility of building large, unsaturated carbon-rich frameworks that can exhibit excellent electron-accepting properties, and when combined with SubPcs it presents a convenient method for preparing interesting chromophore-acceptor architectures. Here we present synthetic methodologies for the post-functionalization of the relatively sensitive SubPc chromophore via acetylenic coupling reactions. By gentle AlCl3-mediated alkynylation at the axial boron position, we managed to anchor two SubPcs to the geminal positions of a tetraethynylethene (TEE) acceptor. Convenient conditions that allow for stepwise desilylations of trimethylsilyl (TMS) and triisopropylsilyl (TIPS) protected SubPc-decorated acetylenes using silver(i) fluoride were developed. The resulting terminal alkynes were successfully used as coupling partners in metal-catalyzed couplings, providing access to larger acetylenic SubPc scaffolds and multiple chromophore systems. Moreover, conditions allowing for the conversion of a terminal alkyne into an iodoalkyne in the presence of SubPc were developed, and the product was subjected to cross-coupling reactions affording unsymmetrical 1,3-butadiynes. The degree of interactions between two SubPc units as a function of the acetylenic bridge was studied by UV-Vis absorption spectroscopy and cyclic voltammetry. A TEE bridging unit was found to strongly influence the reductions and oxidations of the two SubPc units, while a more flexible bridge had no influence.


Molecular mechanisms of drug resistance in Mycobacterium tuberculosis.
In spite of forty years of effective chemotherapy for tuberculosis, the molecular mechanisms of antibacterial compounds in Mycobacterium tuberculosis have only recently been revealed. Broad spectrum antibacterials, including streptomycin, rifampicin, and fluoroquinolones have been demonstrated to act on the same targets in M. tuberculosis as they do in E. coli. Resistance to these agents results from single mutagenic events that lead to amino acid substitutions in their target proteins. The mechanisms of action of the unique antitubercular drugs, including isoniazid, ethambutol, and pyrazinamide have also recently been defined. Resistance to isoniazid can be caused either by mutations in the katG-encoded catalase-peroxidase, the enzyme responsible for drug activation, or by the molecular target, the inhA-encoded long chain enoyl-ACP reductase. Ethambutol appears to block specifically the biosynthesis of the arabinogalactan component of the mycobacterial cell envelope, and pyrazinamide has no known target. With the resurgence of tuberculosis and the appearance of strains which are multiply resistant to the above compounds, present tuberculosis chemotherapies are threatened. New approaches to the treatment of multi drug-resistant tuberculosis are needed.


Challenges and opportunities of a paperless baseline survey in Sri Lanka.
Personal digital assistants (PDAs) have been shown to reduce costs associated with survey implementation and digitisation, and to improve data quality when compared to traditional paper based data collection. Few studies, however, have shared their experiences of the use of these devices in rural settings in Asia. This paper reports on our experiences of using a PDA device for data collection in Sri Lanka as part of a large cluster randomised control trial. We found that PDAs were useful for collecting data for a baseline survey of a large randomised control trial (54,000 households). We found that the PDA device and survey format was easy to use by inexperienced field staff, even though the survey was programmed in English. The device enabled the rapid digitisation of survey data, providing a good basis for continuous data quality assurance, supervision of staff and survey implementation. An unexpected advantage was the improved community opinion of the research project as a result of the device, because the use of the technology gave data collectors an elevated status amongst the community. In addition the global positioning system (GPS) functionality of the device allowed precise mapping of households, and hence distinct settlements to be identified as randomisation clusters. Future users should be mindful that to save costs the piloting should be completed before programming. In addition consideration of a local after-care service is important to avoid costs and time delays associated with sending devices back to overseas providers. Since the start of this study, PDA devices have rapidly developed and are increasingly used. The use of PDA or similar devices for research is not without its problems; however we believe that the universal lessons learnt as part of this study are even more important for the effective utilisation of these rapidly developing technologies in resource poor settings.


Comparison of point-of-care tests for the rapid diagnosis of visceral leishmaniasis in East African patients.
The development of rK39-based rapid diagnostic tests (RDTs) has greatly aided the diagnosis of visceral leishmaniasis, especially in the Indian subcontinent and Brazil, by offering high sensitivity and specificity. However, these tests have been less sensitive and less specific in sub-Saharan Africa. To improve upon the performance of rK39 in Africa, we engineered the fusion molecule rK28, which retained some of the rK39 repeats and combined them with repeat sequences from two additional Leishmania genes. This polyprotein was used in the development of several prototype RDTs by different commercial manufacturers with the goal of assessing relative performance in inexpensive formats. Here, we report field studies showing that the rK28 antigen could be readily adapted to a variety of RDT formats to achieve high sensitivity, generally > 90%, and adequate specificity to aid in the diagnosis of human visceral leishmaniasis in East Africa, Asia, and South America.


Clinicians were oblivious to incorrect logging of test dates and the associated risks in an online pathology application: a case study.
UK primary care physicians receive their laboratory test results electronically. This study reports a computerised physician order entry (CPOE) system error in the pathology test request date that went unnoticed in family practices. We conducted a case study using a causation of risk theoretical framework; comprising interviews with clinicians and the manufacturer to explore the identification of and reaction to the error. The primary outcome was the evolution and recognition of and response to the problem. The secondary outcome was to identify other issues with this system noted by users. The problem was defined as the incorrect logging of test dates ordered through a CPOE system. The system assigned the test request date to the results, hence a blood test taken after a therapeutic intervention (e.g. an increase in cholesterol-lowering therapy) would appear in the computerised medical record as though it had been tested prior to the increase in treatment. This case demonstrates that: the manufacturers failed to understand family physician workflow; regulation of medical software did not prevent the error; and inherent user trust in technology exacerbated this problem. It took three months before users in two practices independently noted the date errors. This case illustrates how users take software on trust and suppliers fail to make provision for risks associated with new software. Resulting errors led to inappropriate prescribing, follow-up, costs and risk. The evaluation of such devices should include utilising risk management processes (RMP) to minimise and manage potential risk.


Repositioning of a domain in a modular polyketide synthase to promote specific chain cleavage.
Macrocyclic polyketides exhibit an impressive range of medically useful activities, and there is great interest in manipulating the genes that govern their synthesis. The 6-deoxyerythronolide B synthase (DEBS) of Saccharopolyspora erythraea, which synthesizes the aglycone core of the antibiotic erythromycin A, has been modified by repositioning of a chain-terminating cyclase domain to the carboxyl-terminus of DEBS1, the multienzyme that catalyzes the first two rounds of polyketide chain extension. The resulting mutant markedly accelerates formation of the predicted triketide lactone, compared to a control in which the repositioned domain is inactive. Repositioning of the cyclase should be generally useful for redirecting polyketide synthesis to obtain polyketides of specified chain lengths.


The use of smartphone health apps and other mobile health (mHealth) technologies in dietetic practice: a three country study.
Smartphone health applications (apps) and other mobile health (mHealth) technologies may assist dietitians in improving the efficiency of patient care. The present study investigated the use of health apps and text messaging in dietetic practice and formulated intervention recommendations for supporting app uptake by dietitians based on the behavioural 'COM-B' system, where interactions between capability, opportunity and motivation influence behaviour. A 52-item online survey tool, taking 20 min to complete, was developed and piloted, with questions exploring the use of health apps and text messaging in dietetic practice, types of apps dietitians recommended and that patients used, and barriers and enablers to app use in dietetic practice. The Australian, New Zealand and British dietetic associations distributed the survey to their members. A 5% response rate was achieved internationally, with 570 completed responses included for further analysis. Health apps, namely nutrition apps, were used by 62% of dietitians in their practice, primarily as an information resource (74%) and for patient self-monitoring (60%). The top two nutrition apps recommended were MyFitnessPal® (62%) and the Monash University Low FODMAP Diet® (44%). Text messaging was used by 51% of respondents, mainly for appointment-related purposes (84%). Although the reported use of smartphone health apps in dietetic practice is high, health apps and other mHealth technologies are not currently being used for behaviour change, nor are they an integral part of the nutrition care process. Dietetic associations should provide training, education and advocacy to enable the profession to more effectively engage with and implement apps into their practice.


Bisphosphonate treatment of aggressive primary, recurrent and metastatic Giant Cell Tumour of Bone.
Giant cell tumour of bone (GCTB) is an expansile osteolytic tumour which contains numerous osteoclast-like giant cells. GCTB frequently recurs and can produce metastatic lesions in the lungs. Bisphosphonates are anti-resorptive drugs which act mainly on osteoclasts. In this study, we have examined clinical and radiological outcomes of treatment with aminobisphosphonates on 25 cases of aggressive primary, recurrent and metastatic GCTB derived from four European centres. We also analysed in vitro the inhibitory effect of zoledronic acid on osteoclasts isolated from GCTBs. Treatment protocols differed with several different aminobisphosphonates being employed, but stabilisation of disease was achieved in most of these cases which were refractory to conventional treatment. Most inoperable sacral/pelvic tumours did not increase in size and no further recurrence was seen in GCTBs that had repeatedly recurred in bone and soft tissues. Lung metastases did not increase in size or number following treatment. Zoledronic acid markedly inhibited lacunar resorption by GCTB-derived osteoclasts in vitro. Our findings suggest that bisphosphonates may be useful in controlling disease progression in GCTB and that these agents directly inhibit GCTB - derived osteoclast resorption. These studies highlight the need for the establishment of standardised protocols to assess the efficacy of bisphosphonate treatment of GCTB.


A Randomized Controlled Trial of Vildagliptin Versus Alogliptin: Effective Switch From Sitagliptin in Patients With Type 2 Diabetes.
We investigated the effects of vildagliptin or alogliptin on blood glucose and hemoglobin A1c (HbA1c) in patients with type 2 diabetes inadequately controlled by sitagliptin. In a single-center open-label trial, 35 patients with inadequate glycemic control on sitagliptin therapy (50 mg once daily) were randomly switched to treatment with vildagliptin (50 mg twice daily) or alogliptin (25 mg once daily). After 12 weeks, patients who failed to achieve the target HbA1c level of < 7.0% with vildagliptin or alogliptin treatment were switched to high-dose sitagliptin (100 mg once daily) and the effect on glycemic control was assessed. Vildagliptin did not significantly alter the mean plasma glucose level (175.5 ± 54.4 mg/dL vs. 179.1 ± 73.4 mg/dL) or HbA1c (8.01% vs. 8.02%) after 12 weeks. With alogliptin, mean plasma glucose increased from 175.4 ± 50.9 mg/dL to 195.3 ± 55.0 mg/dL after 12 weeks and HbA1c increased significantly from 8.0% to 8.3% (P < 0.05). At 12 weeks after switching from vildagliptin to high-dose sitagliptin (100 mg daily), HbA1c was increased to 8.3%, but it was significantly (P < 0.05) reduced to the baseline level of 8.0% after switching from alogliptin. The reduction of HbA1c was significantly greater in the vildagliptin group than the alogliptin group (P = 0.008), but the response rate (achieving the target HbA1c < 7.0%) did not differ significantly between the two groups. The glucose-lowering effects of these three dipeptidyl peptidase-4 (DPP-4) inhibitors (vildagliptin, alogliptin, and sitagliptin) were different, and the effects of vildagliptin and sitagliptin were stronger than that of alogliptin.


Five cryptic species in the amazonian catfish Centromochlus existimatus identified based on biogeographic predictions and genetic data.
Accurately quantifying biodiversity is fundamental for both evolutionary theory and conservation strategies. DNA-based studies are exposing high cryptic diversity irrespective of taxonomic group or environmental setting, and increasing the ever-growing estimates of global biodiversity. This has severe implications for under-sampled and species-rich tropical regions, such as the Amazon Basin. We used biogeographic predictions derived from geomorphological history and contemporary hydrochemical and genetic data to examine cryptic diversity in the Amazonian driftwood catfish Centromochlus existimatus. Using both nuclear and mitochondrial DNA markers, five deeply divergent cryptic lineages are reported, for which at least three are sympatric in distribution. These lineages appear relatively old, with divergence times dating back to middle Miocene. Diversification events appear to be chronologically associated with the formation of the modern Amazon River system, and perhaps influenced by hydrochemical gradients between tributaries. The cause of apparent morphological stasis in the C. existimatus species complex is speculated within the context of hydrochemistry and non-visual mating cues and a full taxonomic revision is recommended. Our findings suggest that the diversity of Amazonian ichthyofauna is vastly underestimated and highlight the relevance of biogeographic predictions to guide sampling efforts in ecologically complex and under-studied ecosystems.


Inhibition of T-lymphocyte-mediated tumor-specific lysis by alloantisera directed against the H-2 serological specificities of the tumor.
After appropriate in vivo or in vitro immunization, cytotoxic T lymphocytes (CTL) are generated which efficiently kill cells bearing particular membrane antigens in common with the immunizing cell (reviewed in reference 1). Such CTL have been most thoroughly studied in mice, employing alloimmunization with cells differing at the major histocompatibility locus, H-2. in such cases, the predominant cell surface antigens recognized by the CTL appear to be the molecules carrying the serologically defined H-2 specificities, coded for by the K and D regions of the H-2 complex (2). In other syngeneic models of cell-mediated specific cytolysis, involving lymphocyte chariomeningitis (LCM) virus- or ectromelia virus-infected cells or TNP-modified lymphoid cells, thymus-derived cells also constitute the main effector cell type. The CTL generated in these latter systems function most efficiently when virus-infected or TNP-modified target cells share identitites at the H-2K or H-2D loci with the effector CTL and stimulator cells (3-5). Another set of experimental systems in which CTL are generated and play a significant biological role is that of immunity to tumor-associated antigens (TAA) (6). The nature of the TAA which the CTL recognize is only beginning to be understood. Several recent reports indicated the existence of physiochemical and/or antigenic relationships between TAA and H-2 antigens (7,8). These relationships, together with the genetic restrictions cited above in the generation of CTL involving products of the H-2K or H-2D loci suggested the possibility that in certain tumor systems, the TAA which are able to most effectively stimulate CTL responses might be structurally similar to, or linked with, the H-2K or H- 2D molecules on the tumor surface. It has been previously demonstrated in allogenic models that antisera specific for the appropriate H-2K or H-2D products present on a target cell could specifically block CTL-mediated lysis (1,9). This report demonstrates that certain anti-H-2 alloantisera specific for the target tumor cells can block lysis of those target cells mediated by syngeneic tumor-specific CTL effector cells.


Status of memory loss.
A 72-year-old woman presented with first onset of seizure with no prior history of cognitive dysfunction. EEG revealed focal non-convulsive status epilepticus. MRI brain showed a left temporal non-enhancing lesion. Temporal pole biopsy showed acute neuronal necrosis and astrocyte hyperplasia together with extensive amyloid plaques and neurofibrillary tangles. Perivascular oligodendroglial hyperplasia was present. Postmortem examination revealed extensive plaque and tangle disease. Perivascular oligodendroglial hyperplasia was limited to the left temporal area. The presence of focal perivascular oligodendroglial hyperplasia in the left temporal cortex, combined with extensive plaque and tangle disease may have contributed to the focal status epilepticus in this patient. Although the presence of focal perivascular oligodendroglial hyperplasia has been reported in cases of temporal lobe epilepsy, it has not been reported as a cause of seizure in patients with Alzheimer's disease previously. Further studies for clinical-pathologic correlation would be required to confirm this hypothesis.


The embodiment of adverse childhood experiences and cancer development: potential biological mechanisms and pathways across the life course.
To explore current evidence of the physiological embedding of stress to discuss whether adverse childhood experiences (ACE) causing chronic or acute stress responses may alter fundamental biological functions. A non-systematic review of the literature was carried out using keyword searches in Pubmed and the web of science from May to October 2011. In reference to the literature identified, we examine the potential biological pathways potentially linking exposure to ACE and cancer development and progression in adulthood. These mechanisms, in interaction with social position, and mediated by subsequent environmental exposures, may ultimately lead to the development of cancer. The experience of acute or chronic stressors during sensitive periods of childhood development which can induce several known biological responses, are likely to have an impact on subsequent biological and behavioural functions depending on the timing of initial exposures, and subsequently mediated by later exposures. For this reason, childhood exposure to adversity is a likely source of both acute and chronic stressors, and can be examined as an important initial exposure on a pathway towards adult ill health. Such pathways justify a life course approach to understanding cancer aetiology, which may have its origins early in life.


High-Intensity Variable Stepping Training in Patients With Motor Incomplete Spinal Cord Injury: A Case Series.
Previous data suggest that large amounts of high-intensity stepping training in variable contexts (tasks and environments) may improve locomotor function, aerobic capacity, and treadmill gait kinematics in individuals poststroke. Whether similar training strategies are tolerated and efficacious for patients with other acute-onset neurological diagnoses, such as motor incomplete spinal cord injury (iSCI), is unknown. Individuals with iSCI potentially have greater bilateral impairments. This case series evaluated the feasibility and preliminary short- and long-term efficacy of high-intensity variable stepping practice in ambulatory participants for more than 1 year post-iSCI. Four participants with iSCI (neurological levels C5-T3) completed up to 40 one-hour sessions over 3 to 4 months. Stepping training in variable contexts was performed at up to 85% maximum predicted heart rate, with feasibility measures of patient tolerance, total steps/session, and intensity of training. Clinical measures of locomotor function, balance, peak metabolic capacity, and gait kinematics during graded treadmill assessments were performed at baseline and posttraining, with more than 1-year follow-up. Participants completed 24 to 40 sessions over 8 to 15 weeks, averaging 2222 ± 653 steps per session, with primary adverse events of fatigue and muscle soreness. Modest improvements in locomotor capacity where observed at posttraining, with variable changes in lower extremity kinematics during treadmill walking. High-intensity, variable stepping training was feasible and tolerated by participants with iSCI although only modest gains in gait function or quality were observed. The utility of this intervention in patients with more profound impairments may be limited.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A200).


Assessing gene significance from cDNA microarray expression data via mixed models.
The determination of a list of differentially expressed genes is a basic objective in many cDNA microarray experiments. We present a statistical approach that allows direct control over the percentage of false positives in such a list and, under certain reasonable assumptions, improves on existing methods with respect to the percentage of false negatives. The method accommodates a wide variety of experimental designs and can simultaneously assess significant differences between multiple types of biological samples. Two interconnected mixed linear models are central to the method and provide a flexible means to properly account for variability both across and within genes. The mixed model also provides a convenient framework for evaluating the statistical power of any particular experimental design and thus enables a researcher to a priori select an appropriate number of replicates. We also suggest some basic graphics for visualizing lists of significant genes. Analyses of published experiments studying human cancer and yeast cells illustrate the results.


Tree-ring stable isotopes record the impact of a foliar fungal pathogen on CO(2) assimilation and growth in Douglas-fir.
Swiss needle cast (SNC) is a fungal disease of Douglas-fir (Pseudotsuga menziesii) that has recently become prevalent in coastal areas of the Pacific Northwest. We used growth measurements and stable isotopes of carbon and oxygen in tree-rings of Douglas-fir and a non-susceptible reference species (western hemlock, Tsuga heterophylla) to evaluate their use as proxies for variation in past SNC infection, particularly in relation to potential explanatory climate factors. We sampled trees from an Oregon site where a fungicide trial took place from 1996 to 2000, which enabled the comparison of stable isotope values between trees with and without disease. Carbon stable isotope discrimination (Δ(13)C) of treated Douglas-fir tree-rings was greater than that of untreated Douglas-fir tree-rings during the fungicide treatment period. Both annual growth and tree-ring Δ(13)C increased with treatment such that treated Douglas-fir had values similar to co-occurring western hemlock during the treatment period. There was no difference in the tree-ring oxygen stable isotope ratio between treated and untreated Douglas-fir. Tree-ring Δ(13)C of diseased Douglas-fir was negatively correlated with relative humidity during the two previous summers, consistent with increased leaf colonization by SNC under high humidity conditions that leads to greater disease severity in following years.


Ab initio calculations of heavy-actinide hexahalide compounds: do these heavy actinides behave like their isoelectronic lanthanide analogues?
Research on heavy actinides has experienced an increased interest in the last few years due to new synthetic techniques and recent technological advances that have allowed for obtaining important information even from very small samples. This area presents challenges not only from the experimental point of view but also from the theoretical perspective. This work deals with a multiconfigurational CASSCF and NEVPT2 benchmark study based on a two-step methodology that considers first correlation effects and then the spin-orbit coupling applied to berkelium (Bk), californium (Cf), einsteinium (Es) and fermium (Fm) hexahalides. Optical properties, such as f → d transitions and crystal-field parameters, have been calculated and rationalized. The results for these trivalent actinides indicate that the electronic structure of the low-lying states is reproduced accurately with small basis sets. The ground-state multiplets are isolated, in the same manner as their isoelectronic lanthanide counterparts. In the case of tetravalent berkelium, the picture is different regarding the electronic structure where crystal-field theory fails due to considerable ligand-to-metal charge transfer contributions to the ground state.


Indications for stenting during thrombolysis.
The most important vein segment to thrombolyse after deep venous thrombosis (DVT) is the outflow tract meaning the iliofemoral vein. Iliofemoral DVT is defined as DVT in the iliac vein and the common femoral vein. Spontaneous recanalization is less than 50%, particularly on the left side. The compression from adjacent structures, predominantly on the left side is known as the iliac vein compression syndrome. Therefore, it is essential that supplementary endovenous procedures have to be performed in case of persistent obstructive lesions following catheter-directed thrombolysis. Insertion of a stent in this position is the treatment of choice facilitating the venous flow into an unobstructed outflow tract either from the femoral vein or the deep femoral vein or both. The stent, made of stainless steel or nitinol, has to be self-expandable and flexible with radial force to overcome the challenges in this low-pressure system. The characteristics of the anatomy with external compression and often a curved vein segment with diameter difference make stent placement necessary. Ballooning alone has no place in this area. The proportion of inserted stents varies in the published materials with catheter-directed thrombolysis of iliofemoral deep venous thrombosis.


Associations between Dietary Intake of Fruits and Vegetables in relation to Urinary Estrogen DNA Adduct Ratio.
Estrogen exposure plays a role in breast cancer (BC) development. A novel estrogen biomarker, the estrogen DNA adduct (EDA) ratio, was shown to be elevated in women at high-risk of BC and among BC cases. Modifiable factors may impact the EDA ratio, with studies demonstrating that resveratrol reduces EDA ratio in vitro. We sought to examine the hypothesis that dietary intake of fruits and vegetables is inversely associated with EDA ratio. This analysis was conducted in 53 pre-menopausal, healthy women aged 40-45 years from a cross-sectional study in which participants provided first-void urine samples and 3-day food records. Urine samples were analyzed using ultraperformance liquid chromatography/tandem mass spectrometry. The EDA ratio was calculated as the estrogen-DNA adducts divided by estrogen metabolites and conjugates. A trend test was used to assess associations between tertiles of dietary intake using linear regression. After adjustment for age, total energy, percent adiposity, serum estradiol and estrone-sulfate, we observed inverse associations of EDA ratio with carbohydrate consumption (P=0.01) and vegetable intake (P =0.01). EDA ratio was inversely associated with 5 botanical groups (Chenopodiaceae: P=0.02; Umbelliferae: P=0.03; Compositae: P=0.01; Ericaceae: P=0.01; Musaceae: P=0.03) but not fruit intake overall. Although these data require replication before conclusions are drawn, this report suggests an inverse association between vegetable and carbohydrate consumption and EDA ratio. While more information is still needed, these findings suggest a link between dietary intake and a biomarker that is both associated with high-risk BC status and associated with modifiable factors.


Surfactant protein B labelled with [(99m)Tc(CO)3(H20)3](+) retains biological activity in vitro..
Labelling of the hydrophobic surfactant protein B (SP-B) under non-reducing conditions was achieved with [(99m)Tc(CO)(3)(H2O)(3)](+) prepared according to Alberto et al. (JACS, 1998). The binding of radioactivity was protein-specific, with an overall radiochemical yield of 50%. Gel electrophoresis and Westernblot analyses showed no structural changes of SP-B. Spreading properties and surface activity of (99m)Tc-labelled SP-B in an air/water interface coincided with those of unlabelled SP-B. (99m)Tc-SP-B seems to be a promising agent to observe surfactant spreading under clinical conditions. Therapeutic results for surfactant instillation in clinical trials are conflicting. The (99m)Tc-labelling of surfactant would allow to observe its spreading in the lung under clinical conditions. [(99m)Tc(CO)(3)(H2O)(3)](+) was prepared as described by Alberto et al. (JACS, 1998). This carbonyl complex was used for the direct labelling of surfactant protein B (SP-B) under non-reductive conditions by direct incubation with SP-B at elevated temperature followed by extraction into CHCl(3)/MeOH. The hydrophobic protein SP-B was labelled with [(99m)Tc(CO)(3)(H2O)(3)](+). An overall radiochemical yield of about 50% was achieved. HPLC-analysis revealed a single radiolabelled species according to UV elution profile of SP-B, supported by paper and size exclusion chromatography. Gel electrophoresis confirmed that the dimer structure of SP-B was preserved. Spreading properties of (99m)Tc-labelled SP-B in an air/water interface coincided with those of unlabelled SP-B. Spreading of radioactivity observed in a glass trough of 26 cm x 27 cm with a gamma camera was completed during the first 7-9 sec after application of (99m)Tc-labelled SP-B. The corresponding decrease of surface tension to 45 mN/m at the peripheral surface tension sensors took 7 sec +/- 2 sec (MEAN +/- STD; n = 3). Direct and specific (99m)Tc-labelling of the hydrophobic surfactant protein B was achieved using the [(99m)Tc(CO)(3)(H2O)(3)](+) precursor. This procedure can easily be used to prepare specifically labelled surfactant mixtures with spreading properties that coincide with those of unlabelled surfactant.


[European Registry on the management of Helicobacter pylori infection: features of diagnosis and treatment in Kazan].
As part of an observational multicenter prospective study European Registry on the management of Helicobacter pylori infection, conducted on the initiative of the European H. pylori and Microbiota Study Group, the compliance of clinical practice in the management of patients with Helicobacter pylori infection in Kazan with clinical guidelines was assessed. The data of 437 patients included into the register by clinical sites in Kazan in 20132019 were analyzed. The methods used for the initial diagnosis of H. pylori infection and eradication control were evaluated. The frequency of various eradication therapy regimens prescription was analyzed in 379 cases. Data regarding the effectiveness of eradication therapy was analyzed in 173 patients. The rapid urease test (44.2% of cases) and cytology/histology (60% of cases) were most often used for the initial diagnosis of H. pylori infection; however non-invasive methods such as 13C-urea breath (9.2%), serology (6.2%), H. pylori stool antigen test (2.3%) were less common. In 21.7% of patients two methods of H. pylori detection were used for primary diagnosis. The control test to evaluate the effectiveness of eradication therapy at the recommended timepoint was performed in 46.2% of patients. 13C-urea breath test (31.7%), stool PCR/stool antigen test (28.7%), rapid urease test (22.3%), cytology/histology (26.2% of cases) prevailed in the assessment of eradication rate. Standard triple therapy, including proton pump inhibitor, clarithromycin and amoxicillin was most commonly prescribed as first-line therapy (64.6% of cases). The duration of eradication therapy was 14 days in the majority of cases with pantoprazole as the most common proton pump inhibitor in standard triple therapy regimens (84.8%). The efficacy of 14-day standard triple therapy (mITT) was 87.0%. The results indicate a high frequency of non-invasive methods use for assessing the effectiveness of eradication therapy; however, the overall rate of eradication efficacy assessment is low, limiting the possibility of analyzing the eradication results. The effectiveness of the most common 14-day standard triple first-line therapy in Kazan doesnt reach the recommended 90% eradication level. This could be explained by high rate of pantoprazole use, which is not an optimal proton pump inhibitor in eradication therapy regimens.


Investigating potential sources of transmission of healthcare-associated infections in a regional hospital, Ghana.
Recent research has shown that healthcare-associated infections (HAIs) are on the increase despite education. The aims of this study were to isolate, quantify, and determine antibiotic susceptibility pattern of bacteria on formites at the Central Regional Hospital, Cape Coast, Ghana. Purposive sampling of likely areas of contamination and contact by patients and healthcare workers was undertaken. A total of 100 swabs were taken from door handles, working surfaces, beds and taps from the various wards, consulting rooms, OPDs, laboratory, and surgical theatre. Serial dilution was used in quantifying bacteria, MacConkey and blood agars were used in isolation, and the Kirby Bauer method applied in antibiotic sensitivity testing. Data were statistically analyzed using Statview from SAS Version 5.0. The means were separated using double-tailed paired means comparison. Mean bacterial count ranges from least in wards (9.67 × 10(11)), working surfaces (1.64 × 10(12)), door handles (1.71 × 10(12)), and highest in taps (2.08 × 10(12)). Door handles had the highest isolation (23) and highest number of differential isolates were from working surfaces (7). Of the total bacterial isolates, 46.14% were pathogenic, with S. aureus being the highest (14.42%), while 53.86% were nonpathogenic made up of 45.2% of Bacillus spp. Gentamicin was 100% effective, while 6 of the total 12 antibiotics tested (50%) were 100% resistant in either gram-positive or gram-negative bacteria. There was a high potential of bacterial transmission from the studied surfaces requiring hospital management to monitor and enforce cleaning regimen to prevent HAIs.


Sensing hot and cold with TRP channels.
The past decade has witnessed the cloning of a new family of ion channels that are responsive to temperature. Six of these transient receptor potential (TRP) channels are proposed to be involved in thermosensation and are located in sensory nerves and skin. The TRPV1, TRPV2, TRPV3, and TRPV4 channels have incompletely overlapping functions over a broad thermal range from warm to hot. Deletion of the individual TRPV1, TRPV3, and TRPV4 channels in mice has established their physiological role in thermosensation. In all cases thermosensation is not completely abolished - suggesting some functional redundancy among the channels. Notably, the TRPV2 channel is responsive to hot temperatures in heterologous systems, but its physiological relevance in vivo has not been established. Cool and cold temperatures are sensed by TRPM8 and TRPA1 family members. Currently, the pharmaceutical industry is developing agonists and antagonists for the various TRP channels. For instance, TRPV1 receptor agonists produce hypothermia, while antagonists induce hyperthermia. Recent investigations have found that different regions of the TRPV1 receptor are responsive to temperature, nociceptive stimuli, and various chemical agents. With this information, it has been possible to develop a TRPV1 compound that blocks responses to capsaicin and acid while leaving temperature sensitivity intact. These channels have important implications for hyperthermia research and may help to identify previously unexplored mechanisms in different tissues that are responsive to thermal stress.


Network-based modeling and intelligent data mining of social media for improving care.
Intelligently extracting knowledge from social media has recently attracted great interest from the Biomedical and Health Informatics community to simultaneously improve healthcare outcomes and reduce costs using consumer-generated opinion. We propose a two-step analysis framework that focuses on positive and negative sentiment, as well as the side effects of treatment, in users' forum posts, and identifies user communities (modules) and influential users for the purpose of ascertaining user opinion of cancer treatment. We used a self-organizing map to analyze word frequency data derived from users' forum posts. We then introduced a novel network-based approach for modeling users' forum interactions and employed a network partitioning method based on optimizing a stability quality measure. This allowed us to determine consumer opinion and identify influential users within the retrieved modules using information derived from both word-frequency data and network-based properties. Our approach can expand research into intelligently mining social media data for consumer opinion of various treatments to provide rapid, up-to-date information for the pharmaceutical industry, hospitals, and medical staff, on the effectiveness (or ineffectiveness) of future treatments.


Adaptive and maladaptive emotion processing and regulation, and the case of alexithymia.
In this conceptual review, we discuss models of emotion and its regulation and identify a spectrum of processes that characterise adaptive adjustment to the affective environment. We describe a dynamic-phasic model of emotion processing and regulation, focusing on five stages: anticipation, response, recovery, habituation and rest as part of a cascade of responses to emotional challenges, as these become progressively expected, proximal, chronic or repeated. We argue for the need to investigate beyond simple reactivity to emotional stimuli, in order to understand mental and physical health conditions where emotional dysregulation plays a role. We propose that a hallmark of an effective and adaptive emotion regulation system is its flexibility, in the service of life goals and values. Consistent with McEwen's model (1998, Stress, adaptation, and disease: Allostasis and allostatic load. Annals of the New York Academy of Sciences, 840(1), 33-44), inflexible emotion regulation can lead to increased allostatic load, from frequent stress, inadequate reactivity, failed shutdown and habituation, which may result in physical and mental illness. Alexithymia exemplifies inflexible emotion regulation, with dysfunctions potentially across all stages of emotion processing, both psychologically and physiologically. These maladaptive processes and their consequence on allostatic load potentially explain the association between alexithymia and physical and mental illness.