The gut-brain interaction in opioid tolerance.
The prevailing opioid crisis has necessitated the need to understand mechanisms leading to addiction and tolerance, the major contributors to overdose and death and to develop strategies for developing drugs for pain treatment that lack abuse liability and side-effects. Opioids are commonly used for treatment of pain and symptoms of inflammatory bowel disease. The significant effect of opioids in the gut, both acute and chronic, includes persistent constipation and paradoxically may also worsen pain symptoms. Recent work has suggested a significant role of the gastrointestinal microbiome in behavioral responses to opioids, including the development of tolerance to its pain-relieving effects. In this review, we present current concepts of gut-brain interaction in analgesic tolerance to opioids and suggest that peripheral mechanisms emanating from the gut can profoundly affect central control of opioid function.


Clinical impact of transcatheter atrial septal defect closure on new onset atrial fibrillation in adult patients: Comparison with surgical closure.
Previous studies demonstrated that the incidence of atrial fibrillation (AF) was significantly increased when patients aged ≥40 years had surgical atrial septal defect (ASD) closure (sASD). However, limited information is available on such findings in transcatheter ASD closure (tASD). The purpose of this study was to investigate the incidence of newly developed AF after tASD in patients aged ≥40 years in whom preoperative AF or atrial flutter (AFL) had not been detected and to compare with the incidence after sASD. The medical records of patients aged ≥40 years without a history of AF or AFL who underwent tASD (n = 281) or sASD (n = 24) were reviewed. Patients who had catheter ablation before the ASD closure were excluded. Patients with a patent foramen ovale were also excluded. The incidence of newly developed AF after ASD closure and the risk factors for that were evaluated statistically. Eleven patients had newly developed AF (5 in tASD and 6 in sASD) postoperatively including 6 persistent AF (3 each after tASD and sASD). The cumulative incidence of newly developed AF was 0.7% in tASD and 16.7% in sASD, and 2.7% and 20.8% at 1 and 5 years, respectively (p < 0.001). ASD diameter ≥30 mm and sASD were potential risk factors for newly developed AF after ASD closure and postoperative persistent AF. In patients aged ≥40 years without a history of AF or AFL, the incidence of newly developed AF after tASD closure was lower than that after sASD. A large ASD more than 30 mm diameter was a potential risk factor for development of AF even if it is closed by transcatheter procedure. Further long-term evaluation after tASD is required to clarify preventive benefit for new onset AF in adult ASD population.


Nonlinear Oscillatory Shear Tests in Viscoelastic Holography.
We provide the first characterization of the nonlinear and time dependent rheologic response of viscoelastic bottom-up holographic models. More precisely, we perform oscillatory shear tests in holographic massive gravity theories with finite elastic response, focusing on the large amplitude oscillatory shear (LAOS) regime. The characterization of these systems is done using several techniques: (i) the Lissajous figures, (ii) the Fourier analysis of the stress signal, (iii) the Pipkin diagram and (iv) the dependence of the storage and loss moduli on the amplitude of the applied strain. We find substantial evidence for a strong strain stiffening mechanism, typical of hyperelastic materials such as rubbers and complex polymers. This indicates that the holographic models considered are not a good description for rigid metals, where strain stiffening is not commonly observed. Additionally, a crossover between a viscoelastic liquid regime at small graviton mass (compared to the temperature scale), and a viscoelastic solid regime at large values is observed. Finally, we discuss the relevance of our results for soft matter and for the understanding of the widely used homogeneous holographic models with broken translations.


Responsible Epidemiologic Research Practice: a guideline developed by a working group of the Netherlands Epidemiological Society.
To develop a guideline on Responsible Epidemiologic Research Practice that will increase value and transparency, increase the accountability of the epidemiologists, and reduce research waste. A working group of the Netherland Epidemiological Society was given the task of developing a guideline that would meet these objectives. Several publications about the need to prevent Detrimental Research Practices triggered this work. Among these were a series in the Lancet on research waste and a subsequent series on transparency in the Journal of Clinical Epidemiology. The reputation and trust in epidemiologic research is still high, and the Netherlands Epidemiological Society wishes to keep it that way. The guideline deals with how epidemiologic research should be conducted, archived, and disclosed. It does not deal with the more technical aspects, such as required sample size, choice of study design, and so forth. The guideline describes each step in the process of conducting an epidemiologic study, from the first idea to the ultimate publication and beyond. The working group reviewed the literature on responsible research conduct, including the various existing codes of conduct. It applied the general principles from these codes to the elements of an epidemiologic study and formulated specific recommendations for each of these. Next step was to draft the guideline. Preceding the 2016 annual national epidemiology conference in Wageningen, a preconference was organized to discuss the draft guideline and to assess support. Support was clearly present, and the provided recommendations were incorporated into the draft guideline. In March 2017, a draft version of the guideline was sent to all 1,100 members of the society with the request to review and provide comments. All received responses were positive, and some minor additions were made. The Responsible Epidemiologic Research Practice guideline has now been approved by the board of the Netherlands Epidemiological Society. With the Responsible Epidemiologic Research Practice guideline, we hope to contribute to better research practices in epidemiology but perhaps also in adjacent disciplines.


ACT2 peer-driven intervention increases enrollment into HIV/AIDS medical studies among African Americans/Blacks and Hispanics: A cluster randomized controlled trial.
African American/Black and Hispanic persons living with HIV/AIDS ("AABH-PLHA") are under-represented in HIV/AIDS medical studies (HAMS). This paper evaluates the efficacy of a social/behavioral intervention to increase rates of screening for and enrollment into HAMS in these populations. Participants (N = 540) were enrolled into a cluster randomized controlled trial of an intervention designed to overcome multi-level barriers to HAMS. Primary endpoints were rates of screening for and enrollment into therapeutic/treatment-oriented and observational studies. Intervention arm participants were 30 times more likely to be screened than controls (49.3 % vs. 3.7 %; p < .001). Half (55.5 %) of those screened were eligible for HAMS, primarily observational studies. Nine out of ten found eligible enrolled (91.7 %), almost all into observational studies (95.2 %), compared to no enrollments among controls. Achieving appropriate representation of AABH-PLHA in HAMS necessitates modification of study inclusion criteria to increase the proportion found eligible for therapeutic HAMS, in addition to social/behavioral interventions.


Allele frequency dynamics in a pedigreed natural population.
A central goal of population genetics is to understand how genetic drift, natural selection, and gene flow shape allele frequencies through time. However, the actual processes underlying these changes-variation in individual survival, reproductive success, and movement-are often difficult to quantify. Fully understanding these processes requires the population pedigree, the set of relationships among all individuals in the population through time. Here, we use extensive pedigree and genomic information from a long-studied natural population of Florida Scrub-Jays (Aphelocoma coerulescens) to directly characterize the relative roles of different evolutionary processes in shaping patterns of genetic variation through time. We performed gene dropping simulations to estimate individual genetic contributions to the population and model drift on the known pedigree. We found that observed allele frequency changes are generally well predicted by accounting for the different genetic contributions of founders. Our results show that the genetic contribution of recent immigrants is substantial, with some large allele frequency shifts that otherwise may have been attributed to selection actually due to gene flow. We identified a few SNPs under directional short-term selection after appropriately accounting for gene flow. Using models that account for changes in population size, we partitioned the proportion of variance in allele frequency change through time. Observed allele frequency changes are primarily due to variation in survival and reproductive success, with gene flow making a smaller contribution. This study provides one of the most complete descriptions of short-term evolutionary change in allele frequencies in a natural population to date.


Variability of the QuantiFERON®-TB gold in-tube test using automated and manual methods.
The QuantiFERON®-TB Gold In-Tube test (QFT-GIT) detects Mycobacterium tuberculosis (Mtb) infection by measuring release of interferon gamma (IFN-γ) when T-cells (in heparinized whole blood) are stimulated with specific Mtb antigens. The amount of IFN-γ is determined by enzyme-linked immunosorbent assay (ELISA). Automation of the ELISA method may reduce variability. To assess the impact of ELISA automation, we compared QFT-GIT results and variability when ELISAs were performed manually and with automation. Blood was collected into two sets of QFT-GIT tubes and processed at the same time. For each set, IFN-γ was measured in automated and manual ELISAs. Variability in interpretations and IFN-γ measurements was assessed between automated (A1 vs. A2) and manual (M1 vs. M2) ELISAs. Variability in IFN-γ measurements was also assessed on separate groups stratified by the mean of the four ELISAs. Subjects (N = 146) had two automated and two manual ELISAs completed. Overall, interpretations were discordant for 16 (11%) subjects. Excluding one subject with indeterminate results, 7 (4.8%) subjects had discordant automated interpretations and 10 (6.9%) subjects had discordant manual interpretations (p = 0.17). Quantitative variability was not uniform; within-subject variability was greater with higher IFN-γ measurements and with manual ELISAs. For subjects with mean TB Responses ±0.25 IU/mL of the 0.35 IU/mL cutoff, the within-subject standard deviation for two manual tests was 0.27 (CI95 = 0.22-0.37) IU/mL vs. 0.09 (CI95 = 0.07-0.12) IU/mL for two automated tests. QFT-GIT ELISA automation may reduce variability near the test cutoff. Methodological differences should be considered when interpreting and using IFN-γ release assays (IGRAs).


A systematic review of the use of atypical antipsychotics in autism.
Conventional antipsychotic medication is commonly prescribed to patients with autistic spectrum disorder. However, a high incidence of severe adverse reactions highlights the need to find more favourable treatments. Atypical antipsychotics may combine efficacy in ameliorating some autistic symptoms with a lower incidence of some adverse reactions. This article reviews the use of atypical antipsychotics in autistic disorder, with particular focus on behaviour, cognition and physical well-being. Thirteen studies using risperidone, three using olanzapine, one using clozapine, one using amisulpride and one using quetiapine were identified. Few firm conclusions can be drawn due to the limitations of the studies; however, there is an indication that risperidone may be effective in reducing hyperactivity, aggression and repetitive behaviours, often without inducing severe adverse reactions. Olanzapine and clozapine may also be effective; however, there is little evidence for using amisulpride or quetiapine in this population. Randomized trials are required to clarify the effectiveness of these agents.


Efficacy and safety of sclerotherapy for digital mucous cysts.
Digital mucous cysts (DMCs) are common tumor of the adjacent distal interphalangeal joint that causes leakage of mucinous material from the joint. There are various treatment modalities for DMCs, among which sclerotherapy has been reported as an effective alternative treatment. To evaluate the safety and efficacy of sclerotherapy for DMC. We retrospectively reviewed 12 patients with DMC treated with sclerotherapy. 0.5% Sodium tetradecyl sulfate 0.2-0.3 cc was injected into the pseudocystic lesions after the complete evacuation of mucinous material. Eleven of 12 lesions regressed successfully, including four lesions that resolved after a single treatment. The mean number of treatments was 2.4. The mean follow-up period was 18.3 months after the last treatment. There was one case of recurrence after the last treatment. Complications such as mild edema, inflammation and pain were noted in three patients, which resolved within few days. According to the results of the present study, sclerotherapy is a feasible alternative treatment modality for DMCs. Treatment was well tolerated with few side effects, and resulted in high cure rate. Due to its less invasive nature, high accessibility and favorable outcomes, sclerotherapy should be considered a satisfactory option for the treatment of DMC.


Symptom severity but not psychopathology predicts visceral hypersensitivity in irritable bowel syndrome.
Visceral hypersensitivity is a hallmark of irritable bowel syndrome (IBS), but the relationship with clinical symptoms and psychological factors has not been fully established. We aimed to (1) evaluate these variables in a large cohort of IBS patients, recruited from both hospital and general practice, and in healthy controls and (2) assess which of these factors predicts the occurrence of visceral hypersensitivity in IBS. Rectal compliance and perception (intensity, perception thresholds; visual analogue scale, 0-100 mm) were assessed by a rectal barostat study (ramp distention) in 101 IBS patients and 40 healthy volunteers. IBS symptom severity was scored by using a 14-day 5-item diary. Anxiety, depression, somatization, vigilance, pain coping, dysfunctional cognitions, psychoneuroticism, and quality of life were assessed with psychometric questionnaires. Rectal compliance was significantly reduced in IBS patients compared with controls (P < .01), as were thresholds for pain (27 +/- 15 vs 35 +/- 8 mm Hg; P < .01) and urge (P < .05). Levels of anxiety, depression, neuroticism, somatization, and dysfunctional cognitions were significantly increased in IBS patients versus controls, whereas pain coping and quality of life were significantly worse. Hypersensitivity to rectal distention occurred in 33% of patients and was associated with increased symptom severity (P = .016), but not with demographic characteristics or psychological disturbances. Hypersensitivity to balloon distention occurs in 33% of IBS patients and is predicted by symptom severity but not by psychological or demographic characteristics.


Evolutionary history of histone demethylase families: distinct evolutionary patterns suggest functional divergence.
Histone methylation can dramatically affect chromatin structure and gene expression and was considered irreversible until recent discoveries of two families of histone demethylases, the KDM1 (previously LSD1) and JmjC domain-containing proteins. These two types of proteins have different functional domains and distinct substrate specificities. Although more and more KDM1 and JmjC proteins have been shown to have histone demethylase activity, our knowledge about their evolution history is limited. We performed systematic phylogenetic analysis of these histone demethylase families and uncovered different evolutionary patterns. The KDM1 genes have been maintained with a stable low copy number in most organisms except for a few duplication events in flowering plants. In contrast, multiple genes for JmjC proteins with distinct domain architectures were present before the split of major eukaryotic groups, and experienced subsequent birth-and-death evolution. In addition, distinct evolutionary patterns can also be observed between animal and plant histone demethylases in both families. Furthermore, our results showed that some JmjC subfamilies contain only animal genes with specific demethylase activities, but do not have plant members. Our study improves the understanding about the evolutionary history of KDM1 and JmjC genes and provides valuable insights into their functions. Based on the phylogenetic relationship, we discussed possible histone demethylase activities for several plant JmjC proteins. Finally, we proposed that the observed differences in evolutionary pattern imply functional divergence between animal and plant histone demethylases.


Biochemical and genomic characterization of muscovy duck parvovirus.
A duck parvovirus (DPV) isolated from muscovy ducks during the epizootic in France in 1989 was purified from inoculated allanto-amniotic fluids by CsCl density gradient centrifugation and characterized. Full and empty non-enveloped icosahedral viral particles were observed banding at densities of 1.39 to 1.42 and 1.38 respectively, with a diameter of 22 to 23 nm. Viral proteins were analyzed by SDS-PAGE and the estimated molecular weights of the 3 major proteins were 91, 78 and 58 kDa. The nucleic acid was shown to be a single-stranded DNA of about 5,300 bases with terminal palindromic hairpins. These results confirm the previous classification of the virus in the family Parvoviridae established by Jestin et al. [14] on morphological and serological bases. The DPV DNA was reannealed indicating that complementary DNA strands were encapsidated. A partial restriction endonuclease map was also established. This work constitutes the first biochemical and genomic description of a muscovy duck parvovirus.


An approach to molecular analysis of T-cell clones by two-dimensional gel electrophoresis: is there interclonal and intraclonal heterogeneity?
To understand the regulation of immunity one must understand the processes and the consequences of the activation of the lymphoid cell, its clonal proliferation, and the ultimate differentiation of the progeny into the effector elements that constitute the immune system. By use of polyclonal mitogens, individual T-cell precursors can be activated for study of their clonal growth and generation of T effector cells. We used two-dimensional gel electrophoresis to study the gene products expressed by such T-cell clones. On comparing the radiofluorograms of such gels for a large set of T-cell clones we find that many gene products are expressed in common, as expected, but that another large set of products varies from one clone to the other and might be designated as markers of T-cell subsets or stages of differentiation. By subdividing the growing clone and analyzing the family of daughter clones, we find considerable variation in gene expression during clonal expansion.


Mutations in the SAM domain of the ETV6-NTRK3 chimeric tyrosine kinase block polymerization and transformation activity.
The 12p13 ETV6 (TEL) gene is frequently targeted by chromosomal translocations in human malignancies, resulting in the formation of oncogenic ETV6 gene fusions. Many of the known partner genes encode protein tyrosine kinases (PTKs), generating fusion proteins that function as chimeric PTKs. ETV6-NTRK3 (EN), comprised of the ETV6 SAM domain fused to the NTRK3 PTK, is unique among ETV6 chimeric oncoproteins, as it is expressed in cancers of multiple lineages. We initially hypothesized that, similar to other ETV6-PTK chimeras, SAM-mediated dimerization of EN leads to constitutive activation of the PTK and downstream signaling cascades. However, when the EN SAM domain was replaced with an inducible FK506 binding protein (FKBP) dimerization system, resulting FKBP-NTRK3 chimeras failed to transform NIH 3T3 cells even though PTK activation was preserved. It was recently shown that the ETV6 SAM domain has two potential interacting surfaces, raising the possibility that this domain can mediate protein polymerization. We therefore mutated each EN SAM binding interface in a manner shown previously to abolish self-association of wild-type ETV6. Each mutation completely blocked the ability of EN to polymerize, to activate its PTK, and to transform NIH 3T3 cells. Furthermore, EN itself formed large polymeric structures within cells while mutant EN proteins were present only as monomers. Finally, we observed a dominant negative effect on the transformation of isolated SAM domains coexpressed in EN-transformed cells. Taken together, our results suggest that higher-order polymerization may be a critical requirement for the transformation activity of EN and possibly other ETV6-PTK fusion proteins.


Lower threshold to NFκB activity sensitizes murine β-cells to streptozotocin.
The β-cell response to injury may be as critical for the development of diabetes as the specific insult. In the current study, we used streptozotocin (STZ) to injure the β-cell in order to study the response with a focus on NFκB. MIN6 cells were exposed to STZ (0.5-8 mM, 0-24h) ±TNFα (100 ng/mL) and ±IκBβ siRNA to lower the threshold to NFκB activation. Cell viability was determined by trypan blue exclusion. NFκB activation was determined by the expression of the target genes Nos2 and Cxcl10, localization of the NFκB proteins p65 and p50, and expression and localization of the NFκB inhibitors, IκBβ and IκBα. There was no NFκB activation in MIN6 cell exposed to STZ (2 mM) alone. However, knocking down IκBβ expression using siRNA resulted in STZ-induced expression of NFκB target genes and increased cell death, while co-incubation with STZ and TNFα enhanced cell death compared to either exposure alone. Adult male IκBβ-/- and WT mice were exposed to STZ and monitored for diabetes. The IκBβ-/- mice developed hyperglycemia and diabetes more frequently than controls following STZ exposure. Based on these results we conclude that STZ exposure alone does not induce NFκB activity. However, lowering the threshold to NFκB activation by co-incubation with TNFα or lowering IκBβ levels by siRNA sensitizes the NFκB response to STZ and results in a higher likelihood of developing diabetes in vivo. Therefore, increasing the threshold to NFκB activation through stabilizing NFκB inhibitory proteins may prevent β-cell injury and the development of diabetes.


Intermittent preventive therapy with sulfadoxine-pyrimethamine for malaria in pregnancy: a cross-sectional study from Tororo, Uganda.
Intermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is widely recommended in sub-Saharan Africa to reduce the risk of malaria and improve birth outcomes. However, there are reports that the efficacy of IPTp with SP is waning, especially in parts of Africa where antimalarial resistance to this drug has become widespread. We conducted a cross-sectional study of 565 HIV-uninfected women giving birth at Tororo District Hospital in southeastern Uganda. The primary objective of the study was to measure associations between use of SP during pregnancy from antenatal records and the risk of adverse outcomes including placental malaria, low birth weight, maternal parasitemia and maternal anemia. The proportion of women who reported taking 0, 1, 2, and 3 doses of SP during pregnancy was 5.7%, 35.8%, 56.6% and 2.0% respectively. Overall, the prevalence of placental malaria was 17.5%, 28.1%, and 66.2% by placental smear, PCR, and histopathology, respectively. In multivariate analyses controlling for potential confounders, ≥ 2 doses of SP was associated with non-significant trends towards lower odds of placental malaria by placental smear (OR = 0.75, p = 0.25), placental malaria by PCR (OR = 0.93, p = 0.71), placental malaria by histopathology (OR = 0.75, p = 0.16), low birth weight (OR = 0.63, p = 0.11), maternal parasitemia (OR = 0.88, p = 0.60) and maternal anemia (OR = 0.88, p = 0.48). Using a composite outcome, ≥ 2 doses of SP was associated with a significantly lower odds of placental malaria, low birth weight, maternal parasitemia, or maternal anemia (OR = 0.52, p = 0.01). In this area of Uganda with intense malaria transmission, the prevalence of placental malaria by histopathology was high even among women who reported taking at least 2 doses of SP during pregnancy. The reported use of ≥ 2 doses of SP was not associated with protection against individual birth and maternal outcome measures but did protect against a composite measure of any adverse outcome.


Individual karyotypes at the origins of cervical carcinomas.
In 1952 Papanicolaou et al. first diagnosed and graded cervical carcinomas based on individual "abnormal DNA contents" and cellular phenotypes. Surprisingly current papilloma virus and mutation theories of carcinomas do not mention these individualities. The viral theory holds that randomly integrated, defective genomes of papilloma viruses, which are often untranscribed, cause cervical carcinomas with unknown cofactors 20-50 years after infection. Virus-free carcinomas are attributed to mutations of a few tumor-suppressor genes, especially the p53 gene. But the paradox of how a few mutations or latent defective viral DNAs would generate carcinomas with endless individual DNA contents, degrees of malignancies and cellular phenotypes is unsolved. Since speciation predicts individuality, we test here the theory that cancers are autonomous species with individual clonal karyotypes and phenotypes. This theory postulates that carcinogens induce aneuploidy. By unbalancing mitosis genes aneuploidy catalyzes chain reactions of karyotypic evolutions. Most such evolutions end with non-viable karyotypes but a few become new cancer karyotypes. Despite congenitally unbalanced mitosis genes cancer karyotypes are stabilized by clonal selections for cancer-specific autonomy. To test the prediction of the speciation theory that individual carcinomas have individual clonal karyotypes and phenotypes, we have analyzed here the phenotypes and karyotypes of nine cervical carcinomas. Seven of these contained papilloma virus sequences and two did not. We determined phenotypic individuality and clonality based on the morphology and sociology of carcinoma cells in vitro. Karyotypic individuality and clonality were determined by comparing all chromosomes of 20 karyotypes of carcinomas in three-dimensional arrays. Such arrays list chromosome numbers on the x-axis, chromosome copy numbers on the y-axis and the number of karyotypes arrayed on the z-axis. We found (1) individual clonal karyotypes and phenotypes in all nine carcinomas, but no virus-specific markers, (2) 1-to-1 variations between carcinoma-specific karyotypes and phenotypes, e.g. drug-resistance and cell morphology, (3) proportionality between the copy numbers of chromosomes and the copy numbers of hundreds of over- and under-expressed mRNAs, (4) evidence that tobacco-carcinogens induce cervical carcinomas via aneuploidy, consistent with the speciation theory. Since the individual clonal karyotypes of nine carcinomas correlated and co-varied 1-to-1 with complex individual transcriptomes and phenotypes, we have classical genetic and functional transcriptomic evidence to conclude that these karyotypes encode carcinomas - much like the clonal karyotypes that encode conventional species. These individual karyotypes explain the individual "DNA contents", the endless grades of malignancies and the complex individual transcriptomes and phenotypes of carcinomas.


The impact of utilizing mobile phones to promote physical activity among post-secondary students: a scoping review.
A commitment to regular physical activity may reduce the risks of chronic diseases for young adults. Internationally, the majority of post-secondary students are insufficiently active for health benefits. Novel health strategies and interventions utilizing mobiles phones could increase post-secondary students' physical activity levels. However, there is contradictory evidence to support the use of mobile phones to promote physical activity, and a scoping review could provide further insights into this topic. The purpose of this study was to conduct a scoping review to explore the existing literature and investigate what is currently known about the use of mobile phones to enhance physical activity levels among post-secondary students. A total of 84 articles were identified from the literature search, and six studies were selected for data analysis. Two major themes were supported by the evidence, which included: (I) the relationship between mobile phones and physical activity levels; and (II) students' perceptions of mobile phones. Goal setting principles combined with text message interventions were reported to have significant influences on students' physical activity levels. Students expressed mixed feelings about coaching elements of apps and posting personal results on social networking websites. No studies reported the use of objective physical activity measurements. In conclusion, mobile phone technologies such as text message reminders could be included in health interventions to enhance post-secondary students' physical activity levels. There is limited evidence available on this topic and additional research is warranted to establish a clearer understanding of the relationship between mobile phones and post-secondary students' physical activity.


The Relationship Between Severe Complications, Beta-Blocker Therapy and Long-Term Survival Following Emergency Surgery for Colon Cancer.
Emergency surgery for colon cancer carries significant morbidity, and studies show more than doubled mortality when comparing elective to emergency surgery. The relationship between postoperative complications and survival has been outlined. Beta-blocker therapy has been linked to improved postoperative outcomes. This study aims to assess the impact of postoperative complications on long-term survival following emergency surgery for colon cancer and to determine whether beta-blockade can reduce complications. This cohort study utilized the prospective Swedish Colorectal Cancer Registry to identify adults undergoing emergency colon cancer surgery between 2011 and 2016. Prescription data for preoperative beta-blocker therapy were collected from the national drug registry. Cox regression was used to evaluate the effect of beta-blocker exposure and complications on 1-year mortality, and Poisson regression was used to evaluate beta-blocker exposure in patients with major complications. A total of 3139 patients were included with a mean age of 73.1 [12.4] of which 671 (21.4%) were prescribed beta-blockers prior to surgery. Major complications occurred in 375 (11.9%) patients. Those suffering major complications showed a threefold increase in 1-year mortality (adjusted HR = 3.29; 95% CI 2.75-3.94; p < 0.001). Beta-blocker use was linked to a 60% risk reduction in 1-year mortality (adjusted HR = 0.40; 95% CI 0.26-0.62; p < 0.001) but did not show a statistically significant association with reductions in major complications (adjusted IRR = 0.77; 95% CI 0.59-1.00; p = 0.055). The development of major complications after emergency colon cancer surgery is associated with increased mortality during one year after surgery. Beta-blocker therapy may protect against postoperative complications.


Selective changes of resting-state networks in individuals at risk for Alzheimer's disease.
Alzheimer's disease (AD) is a neurodegenerative disorder that prominently affects cerebral connectivity. Assessing the functional connectivity at rest, recent functional MRI (fMRI) studies reported on the existence of resting-state networks (RSNs). RSNs are characterized by spatially coherent, spontaneous fluctuations in the blood oxygen level-dependent signal and are made up of regional patterns commonly involved in functions such as sensory, attention, or default mode processing. In AD, the default mode network (DMN) is affected by reduced functional connectivity and atrophy. In this work, we analyzed functional and structural MRI data from healthy elderly (n = 16) and patients with amnestic mild cognitive impairment (aMCI) (n = 24), a syndrome of high risk for developing AD. Two questions were addressed: (i) Are any RSNs altered in aMCI? (ii) Do changes in functional connectivity relate to possible structural changes? Independent component analysis of resting-state fMRI data identified eight spatially consistent RSNs. Only selected areas of the DMN and the executive attention network demonstrated reduced network-related activity in the patient group. Voxel-based morphometry revealed atrophy in both medial temporal lobes (MTL) of the patients. The functional connectivity between both hippocampi in the MTLs and the posterior cingulate of the DMN was present in healthy controls but absent in patients. We conclude that in individuals at risk for AD, a specific subset of RSNs is altered, likely representing effects of ongoing early neurodegeneration. We interpret our finding as a proof of principle, demonstrating that functional brain disorders can be characterized by functional-disconnectivity profiles of RSNs.


The endothelium: dysfunction and beyond.
Since its anatomic discovery in the 19th century, the endothelium was considered to fulfill no other purpose than that of a physical barrier between blood and tissue, until Furchgott and colleagues defined endothelium-dependent vasoreactivity in the late 1970s. Henceforth, a functional paradigm defined the balance between endothelium-derived relaxing factors and endothelium-derived contracting factors as the hallmark of endothelial cell integrity. As a consequence, any reflection of a deviation from this state was defined as endothelial dysfunction, most notably the impairment of vasorelaxation in response to pharmacologic stimuli such as acetylcholine or nonpharmacologic stimuli such as shear stress and cold pressor. Within the coronary artery tree these alterations have been recognized before the development of obstructive coronary artery disease, affecting the microcirculation before the epicardial conduit vessel. Furthermore, recent clinical trials outlined the prognostic significance of these changes, whereby impairment of increase in coronary blood flow in response to endothelium-dependent stimuli seemed to be of utmost importance. Thus it is intriguing to speculate on the evolving role of myocardial perfusion imaging in combination with pharmacologic and nonpharmacologic stimuli for the noninvasive assessment of coronary endothelial dysfunction in patients at risk for future adverse events. At a minimum, this review aims to put endothelial dysfunction into an imaging perspective beyond the scope of the conventional approach.


Clinical determinants of a positive visual inspection after treatment with acetic acid for cervical cancer screening.
To examine the determinants of a positive visual inspection after acetic acid (VIA), including the relationship of testing positive for high-risk human papillomavirus (HR-HPV), which is the necessary cause of cervical cancer. A prospective cohort study. Three clinical sites in rural China. A total of 7541 women aged 25-65 years. All women underwent VIA, DNA testing, by two DNA tests performed on both clinician- and self-collected specimens, and HPV E6 oncoprotein testing. Those positive by any test underwent colposcopy and four-quadrant biopsy evaluation. A random sample of women with negative screening results also underwent colposcopy and, if colposcopic abnormalities were observed, four-quadrant biopsy evaluation was performed. Women diagnosed with cervical intraepithelial neoplasia grade 2 (CIN2), or more severe grades (CIN2 + ), underwent treatment. Testing positive for VIA. Overall, 7.6% (95% confidence interval, 95% CI, 7.0-8.2%) had a positive VIA. Women who tested positive for HPV were more likely to have a positive VIA than women who tested negative for HPV (15.0%, 95% CI 12.9-17.2% versus 6.3%, 95% CI 5.7-6.9%; P < 0.001). Older women were less likely to have a positive VIA (Ptrend < 0.001), including women with CIN2 + (Ptrend < 0.001). A logistic regression model demonstrated that diagnosis (CIN2 + versus <CIN2; odds ratio, OR, 32; 95% CI 11-100), testing HPV positive with a higher viral load (highest versus lowest; OR 4.3; 95% CI 2.5-7.4), and age (51 years and older versus <38 years; OR 0.22; 95% CI 0.17-0.30) were independent determinants of having a positive VIA. VIA was more likely to be positive for women with CIN2 + having an abnormal colposcopic impression versus women with CIN2 + regardless of colposcopic impression (71.4 versus 47.2%). The age of the population and method of disease ascertainment should be considered in the interpretation of any VIA performance.


Water/alcohol soluble conjugated polymers for the interface engineering of highly efficient polymer light-emitting diodes and polymer solar cells.
Water/alcohol soluble conjugated polymers (WSCPs), which can be processed from water/alcohol and other polar solvents, are suitable for the solution processing of multi-layer organic electronic devices. By using a thin layer WSCP as the cathode interfacial material, the resulting polymer light-emitting diodes (PLEDs) and polymer solar cells (PSCs) exhibited significant enhancements in their device performances. In this Feature Article, the authors aim to introduce a brief review of the recent developments and applications of WSCPs in highly efficient multi-layer solution processed PLEDs and PSCs.


Towards universal quantum computation through relativistic motion.
We show how to use relativistic motion to generate continuous variable Gaussian cluster states within cavity modes. Our results can be demonstrated experimentally using superconducting circuits where tuneable boundary conditions correspond to mirrors moving with velocities close to the speed of light. In particular, we propose the generation of a quadripartite square cluster state as a first example that can be readily implemented in the laboratory. Since cluster states are universal resources for universal one-way quantum computation, our results pave the way for relativistic quantum computation schemes.


Validation of the cancer needs questionnaire (CNQ) short-form version in an ambulatory cancer setting.
The short-form Cancer Needs Questionnaire (CNQ) is a self-administered cancer-specific questionnaire designed to assess patients' needs across several domains. The purpose of this study is to further evaluate its internal consistency and construct validity, in a group of ambulatory patients with cancer. Four hundred and fifty patients with a variety of cancer types participated. Factor analysis reproduced five domains: psychological; health information; physical and daily living; patient care and support; and interpersonal communication needs. Cronbach's alpha coefficients ranged from 0.94 to 0.77, indicating substantial consistency across items grouped in the five domains. A priori predictions regarding convergent and contrasting groups construct validity were explored using bivariate relationships between domains of the short-form CNQ, the EORTC QLQC-30 and Beck Depression Inventory (short-form), with support provided for most of the predictions. The current study provides supportive evidence that the short-form CNQ is a reliable and valid instrument for assessing the needs of patients with cancer in an ambulatory care setting.


Ultrasmooth metal nanolayers for plasmonic applications: surface roughness and specific resistivity.
The future of plasmonic devices depends on effective reduction of losses of surface plasmon-polariton waves propagating along metal-dielectric interfaces. Energy dissipation is caused by resistive heating at the skin-deep-thick outer layer of metal and scattering of surface waves on rough metal-dielectric interfaces. Fabrication of noble metal nanolayers with a smooth surface still remains a challenge. In this paper, Ag layers of 10, 30, and 50 nm thickness deposited directly on fused-silica substrates and with a 1 nm wetting layer of Ge, Ti, and Ni are examined using an atomic-force microscope and four-probe resistivity measurements. In the case of all three wetting layers, the specific resistivity of silver film decreases as the thickness increases. The smallest, equal 0.4 nm root mean squared roughness of Ag surface of 10 nm thickness is achieved for Ge interlayer; however, due to Ge segregation the specific resistivity of silver film in Ag/Ge/SiO₂ structures is about twice higher than that in Ag/Ti/SiO₂ and Ag/Ni/SiO₂ sandwiches.


Minimally Invasive Sacroiliac Joint Fusion: 2-Year Radiographic and Clinical Outcomes with a Principles-Based SIJ Fusion System.
Sacroiliac joint (SIJ) degeneration is a common source of low back pain (LBP). Minimally invasive (MI) SIJ fusion procedures have demonstrated meaningful clinical improvement. A recently developed MI SIJ fusion system incorporates decortication, placement of bone graft and fixation with threaded implants (DC/BG/TF). Nineteen patients who had MI SIJ fusion with DC/BG/TF were enrolled at three centers. Fusion was assessed in CT images obtained 12 and 24 months postoperatively by an independent radiographic core laboratory. LBP was assessed using a 0-10 numerical pain scale (NPS) preoperatively and at 12 and 24 months postoperatively. At 12 months, 15/19 patients (79%) had bridging bone across the SIJ, and at 24 months 17/18 patients (94%) available for follow-up had SIJ fusion. Of the patients with bridging bone 88% had fusion within the decorticated area, with solid fusion in 83%. A significant reduction in NPS scores was demonstrated, representing a 73% reduction in average low back pain. The patients in this series demonstrated significant improvement in LBP. Fusion rates at 24 months demonstrate promise for this system, which utilizes the established orthopedic principles of DC/BG/TF to achieve arthrodesis. Further study is warranted to demonstrate comparative fusion rates for different implant systems.


Dynamics of preventive vs post-diagnostic cancer control using low-impact measures.
Cancer poses danger because of its unregulated growth, development of resistance, and metastatic spread to vital organs. We currently lack quantitative theory for how preventive measures and post-diagnostic interventions are predicted to affect risks of a life threatening cancer. Here we evaluate how continuous measures, such as life style changes and traditional treatments, affect both neoplastic growth and the frequency of resistant clones. We then compare and contrast preventive and post-diagnostic interventions assuming that only a single lesion progresses to invasive carcinoma during the life of an individual, and resection either leaves residual cells or metastases are undetected. Whereas prevention generally results in more positive therapeutic outcomes than post-diagnostic interventions, this advantage is substantially lowered should prevention initially fail to arrest tumour growth. We discuss these results and other important mitigating factors that should be taken into consideration in a comparative understanding of preventive and post-diagnostic interventions.


Analyzing Upward Deviation of Actual vs Predicted Drug Sales in Japan for a Reasonable Drug-Pricing Policy.
Predictions of drug sales play an important role in setting drug prices in Japan, where drug prices are highly regulated. One of 2 primary Japanese drug-pricing methodologies-the cost calculation method- refers extensively to the prediction of drug sales in establishing drug prices. Deviations from predicted sales can induce disproportionate drug prices and unexpected pharmaceutical expenditures. This study aimed to estimate the upward deviation of actual sales from predicted sales and to explore the predictors of such upward deviation. Estimates of upward deviation in 2015 were produced for new molecular entities (NMEs) approved in 2006-2015. To identify the predictors associated with upward deviation through binary logistic regression analyses, sales within 3 years of launch and in the predicted year in which peak sales would be reached were used. Estimated upward deviation was more than 1220 billion yen in 2015 for the targeted drugs. Drugs priced by the cost calculation method or by obtaining additional indications were significantly more likely to show an upward deviation from predicted peak sales. There is substantial upward deviation between actual and predicted drug sales in Japan. So long as drug sales predictions are used in drug price calculations, a flexible repricing system is needed to buffer unexpected pharmaceutical expenditures.


How Bonding in Manganous Phosphates Affects their Mn(II)-(31)P Hyperfine Interactions.
Manganous phosphates have been postulated to play an important role in cells as antioxidants. In situ Mn(II) electron-nuclear double resonance (ENDOR) spectroscopy has been used to measure their speciation in cells. The analyses of such ENDOR spectra and the quantification of cellular Mn(II) phosphates has been based on comparisons to in vitro model complexes and heuristic modeling. In order to put such analyses on a more physical and theoretical footing, the Mn(II)-(31)P hyperfine interactions of various Mn(II) phosphate complexes have been measured by 95 GHz ENDOR spectroscopy. The dipolar components of these interactions remained relatively constant as a function of pH, esterification, and phosphate chain length, while the isotropic contributions were significantly affected. Counterintuitively, although the manganese-phosphate bonds are weakened by protonation and esterification, they lead to larger isotropic values, indicating higher unpaired-electron spin densities at the phosphorus nuclei. By comparison, extending the phosphate chain with additional phosphate groups lowers the spin density. Density functional theory calculations of model complexes quantitatively reproduced the measured hyperfine couplings and provided detailed insights into how bonding in Mn(II) phosphate complexes modulates the electron-spin polarization and consequently their isotropic hyperfine couplings. These results show that various classes of phosphates can be identified by their ENDOR spectra and provide a theoretical framework for understanding the in situ (31)P ENDOR spectra of cellular Mn(II) complexes.


Evolution of nephrology in east Africa in the last seventy years--studies and practice.
Interest in renal disease and practice in East Africa started as far back as the first quarter of this century. Work in this colonial era concentrated on establishing the existence of renal diseases and identifying the nature and incidence of these diseases. This was achieved by case identification and reporting as well as retrospective studies on post mortem and medical notes. The post independence period has not only identified the existence of even more renal diseases but also concentrated on getting a deeper understanding of the aetiology, nature, pattern, regional variations, complications and outcome of these diseases as seen in our environment. Apart from the better understanding of the prevalent renal diseases, emphasis has also been put on the expansion and delivery of renal services. Investigative and treatment facilities have been improved and a lot has been put into the training of the required local team of experts to man these services. This article reviews what has gone on in the last 70 years from the pure case-report and postmortem reports era to the era of locally available modern facilities including haemodialysis, peritoneal dialysis and kidney transplantation.


Multi-network-based diffusion analysis reveals vertical cultural transmission of sponge tool use within dolphin matrilines.
Behavioural differences among social groups can arise from differing ecological conditions, genetic predispositions and/or social learning. In the past, social learning has typically been inferred as responsible for the spread of behaviour by the exclusion of ecological and genetic factors. This 'method of exclusion' was used to infer that 'sponging', a foraging behaviour involving tool use in the bottlenose dolphin (Tursiops aduncus) population in Shark Bay, Western Australia, was socially transmitted. However, previous studies were limited in that they never fully accounted for alternative factors, and that social learning, ecology and genetics are not mutually exclusive in causing behavioural variation. Here, we quantified the importance of social learning on the diffusion of sponging, for the first time explicitly accounting for ecological and genetic factors, using a multi-network version of 'network-based diffusion analysis'. Our results provide compelling support for previous findings that sponging is vertically socially transmitted from mother to (primarily female) offspring. This research illustrates the utility of social network analysis in elucidating the explanatory mechanisms behind the transmission of behaviour in wild animal populations.


Combination of Ru(ii) complexes and light: new frontiers in cancer therapy.
The synergistic action of light, oxygen and a photosensitizer (PS) has found applications for decades in medicine under the name of photodynamic therapy (PDT) for the treatment of skin diseases and, more recently, for the treatment of cancer. However, of the thirteen PSs currently approved for the treatment of cancer over more than 10 countries, only two contain a metal ion. This fact is rather surprising considering that nowadays around 50% of conventional chemotherapies involve the use of cisplatin and other platinum-containing drugs. In this perspective article, we review the opportunities brought by the use of Ru(ii) complexes as PSs in PDT. In addition, we also present the recent achievements in the application of Ru(ii) complexes in photoactivated chemotherapy (PACT). In this strategy, the presence of oxygen is not required to achieve cell toxicity. This is of significance since tumors are generally hypoxic. Importantly, this perspective article focuses particularly on the Ru(ii) complexes for which an in vitro biological evaluation has been performed and the mechanism of action (partially) unveiled.


[Cytology and phospholipid content of the bronchoalveolar lavage liquid in diffuse interstitial pneumopathies and in sarcoidosis. Apropos of 96 lavages].
The phospholipid content of bronchoalveolar lavage (LBA) has been little studied till now. This work involved 96 LBA on 7 cases of allergic alveolitis, 11 cases of diffuse interstitial fibrosis (FID) and 42 of sarcoidosis. The liquid collected was submitted to a cellular study (cellularity, total and differential) and biochemical (total proteins, total phospholipids separated into their different fractions by chromatography which enabled the identification of phosphatidyl-choline, phosphatidyl-serine and phosphatidyl-inositol in particular). The cytological results were close to the classical data, a rise in the lymphocyte level in allergic alveolitis and active sarcoid, a rise in polymorphonuclear cells in FID. Biochemical analysis showed a fall in total phospholipids for the whole group, the drop being the greatest in the FID. Phosphatidyl-choline, the principle phospholipid of surfactant in normals, was reduced in all three groups of patient when expressed as a percentage of total phospholipids. This fall was greatest with an allergic alveolitis and occurred on a pro rata basis with a rise in phosphatidyl-serine and inositol. The protein phospholipid ratio (PL/P) expressed in micrograms of phospholipid and milligrams of protein fell in a significant fashion in all the pathological groups. This fall was significantly larger in allergic alveolitis than FID and active sarcoid. The PL/P ratio seems to be a good marker of active sarcoid, correlating with the activity of the disease inversely with the lymphocyte level, and was unchanged by steroids unlike the lymphocyte count. A rise in this ratio correlates with an improvement in the radiological and clinical state.


Two monoclonal antibodies identifying a subset of human peripheral mononuclear cells with natural killer cell activity.
Two monoclonal antibodies (H25 and H366) raised against the cultured T lymphoid cell line HSB-2 were shown to define a subset of peripheral mononuclear cells with natural killer and killer cell activity. The two antibodies show similar tissue distributions. Radioimmune trace binding assay shows that H25 and H366 react with all T cell lines tested and with the monocyte line U937, but weakly or not at all with cell lines of B, myeloid or erythroid origin. Both antibodies react with about 10% of E rosette-forming cells and a proportion of nonrosetting lymphocytes and monocytes. They do not react with B lymphocytes, granulocytes, red cells or platelets. A proportion of thymocytes and low numbers of tonsil and spleen mononuclear cells are positive. H25+ and H366+ lymphocytes are medium-sized cells with abundant granular cytoplasm, and most carry Fc receptors for IgG. H25 and H366 immunoprecipitate two polypeptide chains of 96 and 53kDa from surface-labeled HSB-2 cells.


The Adenosine Monophosphate (AMP) Analog, 5-Aminoimidazole-4-Carboxamide Ribonucleotide (AICAR) Inhibits Hepatosteatosis and Liver Tumorigenesis in a High-Fat Diet Murine Model Treated with Diethylnitrosamine (DEN).
BACKGROUND The development and progression of hepatocellular carcinoma (HCC) are associated with obesity and hepatosteatosis. AMP-activated protein kinase (AMPK) regulates metabolic homeostasis. This study aimed to investigate the effects of treatment with the adenosine monophosphate (AMP) analog, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) on hepatosteatosis in a mouse model fed a high-fat diet (HFD), and on hepatocellular carcinoma (HCC) induced by diethylnitrosamine (DEN) in the HFD mouse model. MATERIAL AND METHODS Male C57BL/6 male mice from two weeks of age were fed a high-fat diet, resulting in hepatosteatosis. HFD mice (15-20 per group) were treated with AICAR and without AICAR. HFD mice were treated with DEN, with and without AICAR. Mouse liver tissues were examined histologically using lipid histochemical stains, immunohistochemistry, and immunofluorescence. Levels of cytokines, alanine transaminase (ALT), triacylglyceride (TAG), and apoptosis were determined. Western blot was used to detect AMPK, pAMPK, STAT3, and pSTAT3. Real-time polymerase chain reaction (RT-PCR) detected expression of the ACL, FAS, CD36, ATGL, CPT1, and IL6 genes. RESULTS In the HFD mouse model, AICAR treatment inhibited hepatic lipid synthesis and IL-6 expression. In the DEN-treated mice, AICAR treatment reduced tumorigenesis, IL-6 signaling, and STAT3 activation. Short-term AICAR treatment had no significant effect in advanced HCC. CONCLUSIONS In an HFD mouse model, treatment with AICAR reduced the development of hepatosteatosis, and following treatment with the liver carcinogen, DEN, AICAR reduced the development of HCC. These preliminary findings support further studies on the role of AICAR in fatty liver disease and HCC.


A retrospective study of clubhouse-based transitional employment.
This study of clubhouse-based transitional employment (TE) examined the ability of demographic data, diagnosis, and data on TE participation to predict TE tenure and a one-year competitive employment outcome following TE among clubhouse members. Baseline data on 138 club members who participated in TE over a 6-year period were retrospectively retrieved from a computerized database and written records. Most of the jobs held by members were maintenance or production jobs; members' average tenure on TE was 131.26 days. Older members, those with a longer club membership before their last TE job, and those working more days per week had longer average tenure on TE. Average tenure was unrelated to the severity of disability. Forty-two (30.4%) members obtained competitive employment in the one year following their last TE job. Members who worked more total hours on TE were more likely to obtain competitive employment. While aspects of the TE experience predict the move to competitive employment, further studies are needed.


Detection of dynamic spatiotemporal response to periodic chemical stimulation in a Xenopus embryonic tissue.
Embryonic development is guided by a complex and integrated set of stimuli that results in collective system-wide organization that is both time and space regulated. These regulatory interactions result in the emergence of highly functional units, which are correlated to frequency-modulated stimulation profiles. We have determined the dynamic response of vertebrate embryonic tissues to highly controlled, time-varying localized chemical stimulation using a microfluidic system with feedback control. Our approach has enabled localized spatiotemporal manipulation of the steroid hormone dexamethasone (DEX) in Animal Cap (AC) tissues isolated from gastrulating Xenopus embryos. Using this approach we investigated cell-scale responses to precisely controlled stimulation by tracking the redistribution of a GFP-tagged DEX-reporter constructed from the human glucocorticoid receptor (GR). We exposed defined regions of a single AC explant to different stimulation conditions--continuous stimulation, periodic stimulation, and no stimulation. We observed collective behavior of the GR transport into the nucleus was first-order. Furthermore, the dynamic response was well-modeled by a first-order differential equation with a single time derivative. The model predicted that responses to periodic stimulations closely matched the results of the frequency-based experiments. We find that stimulation with localized bursts versus continuous stimulation can result in highly distinct responses. This finding is critical as controlled space and time exposure to growth factors is a hallmark of complex processes in embryonic development. These complex responses to cellular signaling and transport machinery were similar to emergent behaviors in other complex systems, suggesting that even within a complex embryonic tissue, the overall system can converge toward a predictive first-order response.


Utilization of nitrogen and energy from diets containing protein and fat derived from either goat milk or cow milk.
Consumption of whole milk and related dairy products has decreased considerably as a result of negative aspects associated with the consumption of saturated fats. The main difference between the composition of goat milk and cow milk concerns the composition of the fat, that of goat milk containing a larger proportion of medium-chain triglycerides. The metabolic utilization of these compounds is fundamentally oriented towards their use as sources of energy, and they may even contribute to the synthesis of proteins. This study was carried out, using 40 rats at weaning, in order to determine whether, on the basis of their fat and protein composition, there is any difference between the nutritional utilization of the N and the energy from goat and cow milk. Eight animals were killed on arrival at the laboratory, and the rest were divided into four groups of eight animals and killed at the end of the experiment. Each group was given a different diet: diet 1 contained fat and protein from goat milk; diet 2 had fat from cow milk and protein from goat milk; diet 3 had fat from goat milk and protein from cow milk; diet 4 had fat and protein from cow milk. The animals were allowed to feed ad libitum for 30 d and a balance assay was performed during the final 7 d to determine N and energy utilization. At the same time and by the comparative slaughter method, the protein and fat deposition for each group was established. It was concluded that goat milk protein is more digestible than that of cow milk. Moreover, the metabolic utilization of digestible N was found to be dependent on the sources of both the protein and the fat in the diet; a higher degree of utilization was recorded for the digestible N obtained using diets with protein or fat from goat milk. Consumption of diets with goat milk fat led to a lower level of thermogenesis associated with protein oxidation and a higher one for that associated with fat oxidation, which in turn implied a protein-sparing effect of the goat milk fat. These results should be taken into account when deciding upon the type of goat milk to be used (whole, skim or semi-skim), in accordance with the dairy product to be produced from this milk.


Increased volume and impaired function: the role of the basal ganglia in writer's cramp.
The pathophysiology of writer's cramp, a task-specific dystonia, remains unclear. The objective of this study was to investigate the basal ganglia circuit and the cerebellum during a complex motor sequence learning task carried out with the nonaffected hand in writer's cramp patients. We applied structural and functional imaging in 22 writer's cramp patients and 28 matched controls using 3T MRI. With the asymptomatic left hand all participants learned a complex, sequential, five-element sequence-tapping task as accurately and quickly as possible. Functional imaging was measured during a repeated (15 times), fixed block design with tapping (30 sec) and rest (30 sec). Additionally, gray matter volume of the basal ganglia was analyzed using voxel-based morphometry (VBM). While behavior was comparable between groups, after small volume correction the anterior part of the right putamen and the left globus pallidus exhibited reduced blood oxygen level-dependent (BOLD) activity in patients during the sequential finger-tapping task. VBM analysis showed larger gray matter volume bilateral in the posterior part of the putamen and globus pallidus. There were no group differences in the cerebellum. The results indicate an impairment of anterior basal ganglia loops involved in producing complex sequential movements of the unaffected hand. These findings are in line with previous reports of reduced neuronal activity in the globus pallidus internus. Higher gray matter volume of the putamen and globus pallidus may stem from elevated activity of the direct pathway, which could reflect a compensatory phenomenon or a primary predisposition, that is, endophenotypic trait.


The development and evaluation of a holistic needs assessment and care planning learning package targeted at cancer nurses in the UK.
A project team from the United Kingdom Oncology Nursing Society developed a blended e-learning website to facilitate nurses to further develop their confidence and competencies in a range of skills related to assessing the holistic needs of people with cancer. The project team identified three areas which were integral to an holistic needs assessment (HNA) implementation project. These were project support information, project management skills, and practical competencies delivered in a blended e-learning package containing a series of accessible video presentations, supporting documents, and practical activities. The team worked with internal and external partners to ensure that a robust and inspiring programme was created. www.hnaforcancer.com was launched in October 2012 as a blended learning programme that incorporates e-learning on core subjects. These subjects are packaged as videoed presentations with supporting learning material and can be accessed via the UKONS website. By the end of the programme participants were equipped to identify and explore the essential requirements for HNA and care planning, more able to recognise potential need, and initiate care to prevent or minimise the risk of complications. Participants had also developed confidence and competency in new skills, including basic project management.


Ca(2+)-independent and Ca(2+)-dependent stimulation of quantal neurosecretion in avian ciliary ganglion neurons.
1. Although it is generally agreed that Ca2+ couples depolarization to the release of neurotransmitters, hypertonic saline and ethanol (ETOH) evoke neurosecretion independent of extracellular Ca2+. One possible explanation is that these agents release Ca2+ from an intracellular store that then stimulates Ca(2+)-dependent neurosecretion. An alternative explanation is that these agents act independently of Ca2+. 2. This work extends previous observations on the action of ETOH and hypertonic solutions (HOSM) on neurons to include effects on [Ca2+]i. We have looked for Ca(2+)-independent or -dependent neurosecretion evoked by these agents in parasympathetic postganglionic neurons dissociated from chick ciliary ganglia and maintained in tissue culture. The change in concentration of free Ca2+ in the micromolar range inside neurons ([Ca2+]i) was measured with indo-1 with the use of a Meridian ACAS 470 laser scanning microspectrophotometer. 3. Elevated concentration of extracellular KCl increased [Ca2+]i and the frequency of quantal events. Also, a twofold increase in osmotic pressure (HOSM) produced a similar increase in quantal release and a significant rise in [Ca2+]i; however, the Ca2+ appeared to come from intracellular stores. 4. In contrast, ETOH stimulated quantal neurosecretion without a measurable change in [Ca2+]i. It appears the alcohol exerts its influence on some stage in the process of exocytosis that is distal to or independent of the site of Ca2+ action. 5. The effects of high [KCl]o and osmotic pressure were occlusive. This is explained in part by the observation that hypertonicity reduced Ca2+ current, but an action on Ca2+ stores is also likely.(ABSTRACT TRUNCATED AT 250 WORDS)


Infectious Disease Threats in the Twenty-First Century: Strengthening the Global Response.
The world has developed an elaborate global health system as a bulwark against known and unknown infectious disease threats. The system consists of various formal and informal networks of organizations that serve different stakeholders; have varying goals, modalities, resources, and accountability; operate at different regional levels (i.e., local, national, regional, or global); and cut across the public, private-for-profit, and private-not-for-profit sectors. The evolving global health system has done much to protect and promote human health. However, the world continues to be confronted by longstanding, emerging, and reemerging infectious disease threats. These threats differ widely in terms of severity and probability. They also have varying consequences for morbidity and mortality, as well as for a complex set of social and economic outcomes. To various degrees, they are also amenable to alternative responses, ranging from clean water provision to regulation to biomedical countermeasures. Whether the global health system as currently constituted can provide effective protection against a dynamic array of infectious disease threats has been called into question by recent outbreaks of Ebola, Zika, dengue, Middle East respiratory syndrome, severe acute respiratory syndrome, and influenza and by the looming threat of rising antimicrobial resistance. The concern is magnified by rapid population growth in areas with weak health systems, urbanization, globalization, climate change, civil conflict, and the changing nature of pathogen transmission between human and animal populations. There is also potential for human-originated outbreaks emanating from laboratory accidents or intentional biological attacks. This paper discusses these issues, along with the need for a (possibly self-standing) multi-disciplinary Global Technical Council on Infectious Disease Threats to address emerging global challenges with regard to infectious disease and associated social and economic risks. This Council would strengthen the global health system by improving collaboration and coordination across organizations (e.g., the WHO, Gavi, CEPI, national centers for disease control, pharmaceutical manufacturers, etc.); filling in knowledge gaps with respect to (for example) infectious disease surveillance, research and development needs, financing models, supply chain logistics, and the social and economic impacts of potential threats; and making high-level, evidence-based recommendations for managing global risks associated with infectious disease.


Association of HIV and Opportunistic Infections With Incident Stroke: A Nationwide Population-Based Cohort Study in Taiwan.
HIV-associated vasculopathy and opportunistic infections (OIs) might cause vascular atherosclerosis and aneurysmal arteriopathy, which could increase the risk of incident stroke. However, few longitudinal studies have investigated the link between HIV and incident stroke. This cohort study evaluated the association of HIV and OIs with incident stroke. We identified adults with HIV infection in 2000-2012, using the Taiwan National Health Insurance Research Database. A control cohort without HIV infection, matched for age and sex, was selected for comparison. Stroke incidence until December 31, 2012 was then ascertained for all patients. A time-dependent Cox regression model was used to determine the association between OIs and incident stroke among patients with HIV. Among a total of 106,875 patients (21,375 patients with HIV and 85,500 matched controls), stroke occurred in 927 patients (0.87%) during a mean follow-up period of 5.44 years, including 672 (0.63%) ischemic strokes and 255 (0.24%) hemorrhagic strokes. After adjusting for other covariates, HIV infection was an independent risk factor for incident all-cause stroke [adjusted hazard ratio (AHR) 1.83; 95% confidence interval (CI): 1.58 to 2.13]. When the type of stroke was considered, HIV infection increased the risks of ischemic (AHR 1.33; 95% CI: 1.09 to 1.63) and hemorrhagic stroke (AHR 2.01; 95% CI: 1.51 to 2.69). The risk of incident stroke was significantly higher in patients with HIV with cryptococcal meningitis (AHR 4.40; 95% CI: 1.38 to 14.02), cytomegalovirus disease (AHR 2.79; 95% CI: 1.37 to 5.67), and Penicillium marneffei infection (AHR 2.90; 95% CI: 1.16 to 7.28). Patients with HIV had an increased risk of stroke, particularly those with cryptococcal meningitis, cytomegalovirus, or P. marneffei infection.


Structural transitions of the RING1B C-terminal region upon binding the polycomb cbox domain.
Polycomb group (PcG) proteins are required for maintaining cell identity and stem cell self-renewal. RING1B and Polycomb (Pc) are two components of a multiprotein complex called polycomb repression complex 1 (PRC1) that is essential for establishing and maintaining long-term repressed gene states. Here we characterize the interaction between the C-terminal region of RING1B (C-RING1B) and the Pc cbox domain. The C-RING1B-cbox interaction displays a 1:1 stoichiometry with dissociation constants ranging from 9.2 to 180 nM for the different Pc orthologues. NMR analysis of C-RING1B alone reveals line broadening. However, when it is in complex with the cbox domain, there is a striking change to the NMR spectrum indicative of conformational tightening. This conformational change may arise from the organization of the C-RING1B subdomains. The C-terminal regions of all PcG RING1 proteins are composed of two stretches of conserved sequences separated by a variable linker sequence. While the entire C-RING1B region is required for cbox binding, the N- and C-terminal halves of C-RING1B can be separated and are able to interact, suggesting the presence of an intramolecular interaction within C-RING1B. The flexibility within the C-RING1B structure allowing transitions between the intramolecular bound and unbound states may cause the broadened peaks of the C-RING1B NMR spectrum. Binding the cbox domain stabilizes C-RING1B, whereby broadening is eliminated. The presence of flexible regions could allow C-RING1B to bind a variety of different factors, ultimately recruiting RING1B and its associated PcG proteins to different genomic loci.


A 3-year follow-up study of inpatients with lower limb ulcers: evidence of an obesity paradox?
To determine whether body composition is related to long-term outcomes amongst vascular inpatients with lower limb ulcers. Prospective study with 3 years follow-up. Body mass index (BMI), fat, and fat-free mass were measured and associations with readmission to hospital (number, cause, length of stay) and all-cause mortality were explored. Thirty patients (22 men, 8 women) participated in the study. Ten patients (33%) had a BMI ≥ 30 kg/m(2). 18/20 (90%) patients with a BMI < 30 kg/m(2) and 9/10 (90%) patients with a BMI ≥ 30 kg/m(2) were admitted to hospital in the 3 years of follow-up. Patients with a BMI < 30 kg/m(2) were admitted more frequently, earlier and for longer compared to those with BMI ≥ 30 kg/m(2) but these did not reach statistical significance. The 3 year mortality rate for patients with BMI ≥ 30 kg/m(2) was 20% (n = 2/10) compared to 70% (n = 14/20) with a BMI < 30 kg/m(2), P = 0.019. This preliminary study suggests that higher BMI may have a protective effect against mortality in vascular patients with lower limb ulcers. These findings contradict the universal acceptance that obesity leads to poor health outcomes. Further work is required to confirm these findings and explore some of the potential mechanisms for this effect.


Salvage endoscopic resection as a treatment for locoregional failure or recurrence following chemoradiotherapy or radiotherapy for esophageal cancer.
Radiotherapy (RT) or chemoradiotherapy (CRT) is a potentially curative, non-surgical treatment option for esophageal cancer, although the rate of local failure within the esophagus remains relatively high. Salvage esophagectomy is not regarded as a common treatment for esophageal cancer, since it is a high-risk surgery with a relatively high surgical mortality rate. Salvage endoscopic resection (ER) for local failure is used for treatment when esophageal cancer is localized and superficial. To evaluate to usefulness of salvage ER, the present study reviewed the clinicopathological records and follow-up data of 37 patients that underwent salvage ER for esophageal cancer, following initial treatment with RT or CRT. Salvage ER was conducted on a total of 78 lesions observed in the 37 patients. Since a thick epithelium and lack of normal vessels on the surface of the mucosa are characteristics of esophageal mucosa following RT or CRT, almost all the lesions were detected using iodine dyeing, and not by narrow band imaging. The growth rate of the detected lesions was relatively high, and early treatment was required. No particular complications occurred during the endoscopic treatment. A total of 11 patients survived for >5 years subsequent to initial endoscopic treatment. Only 4 patients succumbed to esophageal cancer. In conclusion, the present study demonstrated that salvage ER following CRT or RT for esophageal cancer is a minimally invasive, safe, adaptive and curative method for superficial lesions without distant metastases in patients with esophageal cancer with local failure following CRT or RT.


A survey of the approaches for identifying differential methylation using bisulfite sequencing data.
DNA methylation is an important epigenetic mechanism that plays a crucial role in cellular regulatory systems. Recent advancements in sequencing technologies now enable us to generate high-throughput methylation data and to measure methylation up to single-base resolution. This wealth of data does not come without challenges, and one of the key challenges in DNA methylation studies is to identify the significant differences in the methylation levels of the base pairs across distinct biological conditions. Several computational methods have been developed to identify differential methylation using bisulfite sequencing data; however, there is no clear consensus among existing approaches. A comprehensive survey of these approaches would be of great benefit to potential users and researchers to get a complete picture of the available resources. In this article, we present a detailed survey of 22 such approaches focusing on their underlying statistical models, primary features, key advantages and major limitations. Importantly, the intrinsic drawbacks of the approaches pointed out in this survey could potentially be addressed by future research.


Subacute Cavernous Sinus Thrombosis following a Dental Procedure: Case Report and Review of the Literature.
Cavernous Sinus Thrombosis is a rare but serious condition. Despite increasingly effective treatment, the mortality and risk of long-term sequelae remains significant. The objective of this study is to describe the case of a 62 year old female presenting to a cardiovascular clinic with symptoms indicating an atypical subacute cavernous sinus thrombosis secondary to a dental procedure, and review the literature regarding cavernous sinus thrombosis following dental procedures and dental infections. The study design is a Case Report and Systematic Review. A PubMed literature search was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines, and limited to studies published between 2015 and 2020 (April). The case describes a 62 year old female with a 5 month history of left upper eyelid swelling, diplopia, chemosis, ptosis, and left sided cluster headache who was diagnosed with subacute cavernous sinus thrombosis treated with oral anticoagulation. The search strategy yielded a total of 15 titles, and of these, 9 were included in the qualitative synthesis. These demonstrated that cases of CST occur acutely, and clinical symptoms are variable, depending on the structures involved. Most cases are treated with IV antibiotics, and corticosteroids may be added. Anticoagulation therapy shows contradicting information regarding reduced mortality, but reduced morbidity is seen when used early and combined with antibiotics. Not all cases of CST present typically and acutely, so it is advisable to have a high clinical suspicion and obtain an MRV to rule out CST when stumbling upon ocular symptoms or infections in the danger triangle of the face following a dental procedure or infection. Despite the conflicting views on the benefits of anticoagulation in the setting of CST, the addition of oral anticoagulation yielded a positive outcome in our patient.


Polyharmonic smoothing splines and the multidimensional Wiener filtering of fractal-like signals.
Motivated by the fractal-like behavior of natural images, we develop a smoothing technique that uses a regularization functional which is a fractional iterate of the Laplacian. This type of functional was initially introduced by Duchon for the approximation of nonuniformily sampled, multidimensional data. He proved that the general solution is a smoothing spline that is represented by a linear combination of radial basis functions (RBFs). Unfortunately, this is tedious to implement for images because of the poor conditioning of RBFs and their lack of decay. Here, we present a much more efficient method for the special case of a uniform grid. The key idea is to express Duchon's solution in a fractional polyharmonic B-spline basis that spans the same space as the RBFs. This allows us to derive an algorithm where the smoothing is performed by filtering in the Fourier domain. Next, we prove that the above smoothing spline can be optimally tuned to provide the MMSE estimation of a fractional Brownian field corrupted by white noise. This is a strong result that not only yields the best linear filter (Wiener solution), but also the optimal interpolation space, which is not bandlimited. It also suggests a way of using the noisy data to identify the optimal parameters (order of the spline and smoothing strength), which yields a fully automatic smoothing procedure. We evaluate the performance of our algorithm by comparing it against an oracle Wiener filter, which requires the knowledge of the true noiseless power spectrum of the signal. We find that our approach performs almost as well as the oracle solution over a wide range of conditions.


Effect of DLK1 and RTL1 but not MEG3 or MEG8 on muscle gene expression in Callipyge lambs.
Callipyge sheep exhibit extreme postnatal muscle hypertrophy in the loin and hindquarters as a result of a single nucleotide polymorphism (SNP) in the imprinted DLK1-DIO3 domain on ovine chromosome 18. The callipyge SNP up-regulates the expression of surrounding transcripts when inherited in cis without altering their allele-specific imprinting status. The callipyge phenotype exhibits polar overdominant inheritance since only paternal heterozygous animals have muscle hypertrophy. Two studies were conducted profiling gene expression in lamb muscles to determine the down-stream effects of over-expression of paternal allele-specific DLK1 and RTL1 as well as maternal allele-specific MEG3, RTL1AS and MEG8, using Affymetrix bovine expression arrays. A total of 375 transcripts were differentially expressed in callipyge muscle and 25 transcripts were subsequently validated by quantitative PCR. The muscle-specific expression patterns of most genes were similar to DLK1 and included genes that are transcriptional repressors or affect feedback mechanisms in beta-adrenergic and growth factor signaling pathways. One gene, phosphodiesterase 7A had an expression pattern similar to RTL1 expression indicating a biological activity for RTL1 in muscle. Only transcripts that localize to the DLK1-DIO3 domain were affected by inheritance of a maternal callipyge allele. Callipyge sheep are a unique model to study over expression of both paternal allele-specific genes and maternal allele-specific non-coding RNA with an accessible and nonlethal phenotype. This study has identified a number of genes that are regulated by DLK1 and RTL1 expression and exert control on postnatal skeletal muscle growth. The genes identified in this model are primary candidates for naturally regulating postnatal muscle growth in all meat animal species, and may serve as targets to ameliorate muscle atrophy conditions including myopathic diseases and age-related sarcopenia.


Whole grain rye porridge breakfast improves satiety compared to refined wheat bread breakfast.
Previous studies show that dietary fibre-rich foods with low energy density have a stronger effect on satiety per calorie compared to more energy dense foods. To investigate subjective appetite and voluntary energy intake (24 h) after consumption of rye porridge breakfast and pasta lunch made from whole grain compared to iso-energetic reference meals made from refined cereals: wheat bread breakfast and wheat pasta lunch. In all, 22 healthy subjects, 14 females and 8 males, aged 21-64 years, BMI ranging from 18.7 to 27.5 kg/m(2), participated. A randomised, crossover design was used. Appetite was rated by visual analogue scales (VAS) regularly from just before breakfast (08:00) until bedtime. An ad libitum dinner was served at 16:00. After leaving the clinic and in the morning day 2, subjects recorded foods consumed. Whole grain rye porridge gave a significantly prolonged satiety, lowered hunger and desire to eat (p<0.05 in most point estimates) up to 8 h after consumption compared to the refined wheat bread. The two pasta lunch meals did not vary in their effects on appetite ratings. There was no significant effect on ad libitum energy intake at 16:00 or self-reported energy and macronutrient intake in the evening and breakfast meal on day 2. Whole grain rye porridge at breakfast has prolonged satiating properties up to 8 h after consumption compared to refined wheat bread, but did not diminish subsequent food intake.


Caffeine may potentiate adrenocortical stress responses in hypertension-prone men.
The effect of caffeine on blood cortisol levels and blood pressures was examined during rest and in response to a challenging psychomotor task in men with a low versus high risk of essential hypertension. Thirty-four healthy men ages 21-35 years were selected such that 17 were at high risk for hypertension (positive parental history and screening blood pressures of 135/85-155/95 mm Hg) and 17 were at low risk (negative parental history and no pressures above 132/84 mm Hg). Testing consisted of quiet rest (20 minutes); oral placebo (grapefruit juice) or caffeine administration (3.3 mg/kg in grapefruit juice); rest during a postdrug absorption period (40 minutes); work on an unsignalled simple reaction time task (15 minutes); and quiet rest (20 minutes). Blood pressures were recorded at 2-minute intervals, and blood samples were withdrawn via an indwelling catheter at the end of the baseline, drug absorption, task, and recovery periods. The combination of task plus caffeine produced the highest blood pressures in men at risk for hypertension. Cortisol levels were found to be sustained during rest in members of the high risk group after they had consumed caffeine, whereas members of the low risk group showed a modest decline. The high risk subjects also showed a significant rise in cortisol during (+3.7 micrograms/dl) and after (+4.0 micrograms/dl) work on the reaction time task after caffeine consumption.(ABSTRACT TRUNCATED AT 250 WORDS)


Mechanical and psychosocial work exposures: the construction and evaluation of a gender-specific job exposure matrix (JEM).
Objectives The aim of this study was to (i) construct and evaluate a gender-specific job exposure matrix (JEM) for mechanical and psychosocial work exposures and (ii) test its predictive validity for low-back pain. Methods We utilized data from the Norwegian nationwide Survey of Living Conditions on work environment in 2006 and 2009. We classified occupations on a 4-digit level based on the Norwegian version of the International Standard Classification of Occupations (ISCO-88). The mechanical and psychosocial exposure information was collected by personal telephone interviews and included exposures that were known risk factors for low-back pain. We evaluated the agreement between the individual- and JEM-based exposure estimates, with kappa, sensitivity and specificity measures. We assessed the JEM`s predictive validity by testing the associations between low-back pain and the individual- and JEM-based exposure. Results The results showed an overall fair-to-moderate agreement between the constructed JEM and individual work exposures. The JEM performed considerably better for mechanical work exposures compared with psychosocial work exposures. The predictive validity of the mechanical and psychosocial JEM showed a consistently lower but predominantly reproducible association with low-back pain for both genders. Conclusions The mechanical estimates and psychosocial stressors, such as psychological demands, monotonous work and decision latitude in the constructed JEM, may be useful in large epidemiological register studies. The predictive validity of the matrix was evaluated as being overall acceptable, it can thus be an effective and versatile approach to estimate the relationship between work exposures and low-back pain.


Distinguishing human and possum faeces using PCR markers.
Specificity testing of two published polymerase chain reaction (PCR) markers for the detection of human faecal pollution, revealed 100% false-positive rates to brush-tailed possum faeces (n = 10), but low false-positive rates against other potential pollution sources. Cross-reaction with possums could be a problem with other human-specific markers; therefore, a possum PCR marker was developed for use in conjunction with human PCR markers. The possum PCR marker was based on Bacteroidales 16S ribosomal ribonucleic acid sequences, and was tested on 233 individual faecal samples from 11 other animal species. Sensitivity of the possum marker in possum faeces (n = 36) was high at 83.3%. Cross-reactivity of the possum marker was limited to black swan (7/20 samples), human (2/48 samples) and rabbit (1/10) faecal samples, all at marker concentrations at least four orders of magnitude lower than possum faeces. The possum marker was not detected in human sewage or the faeces of other animal species. Specificity of the possum PCR marker, therefore, was high at 95.7%. To exclude the possibility that only possum pollution is being detected, additional testing by other faecal source tracking methods is required where the water sample is positive for both human and possum markers.


Multi-country evaluation of the sensitivity and specificity of two commercially-available NS1 ELISA assays for dengue diagnosis.
Early diagnosis of dengue can assist patient triage and management and prevent unnecessary treatments and interventions. Commercially available assays that detect the dengue virus protein NS1 in the plasma/serum of patients offers the possibility of early and rapid diagnosis. The sensitivity and specificity of the Pan-E Dengue Early ELISA and the Platelia Dengue NS1 Ag assays were compared against a reference diagnosis in 1385 patients in 6 countries in Asia and the Americas. Platelia was more sensitive (66%) than Pan-E (52%) in confirmed dengue cases. Sensitivity varied by geographic region, with both assays generally being more sensitive in patients from SE Asia than the Americas. Both kits were more sensitive for specimens collected within the first few days of illness onset relative to later time points. Pan-E and Platelia were both 100% specific in febrile patients without evidence of acute dengue. In patients with other confirmed diagnoses and healthy blood donors, Platelia was more specific (100%) than Pan-E (90%). For Platelia, when either the NS1 test or the IgM test on the acute sample was positive, the sensitivity versus the reference result was 82% in samples collected in the first four days of fever. NS1 sensitivity was not associated to disease severity (DF or DHF) in the Platelia test, whereas a trend for higher sensitivity in DHF cases was seen in the Pan-E test (however combined with lower overall sensitivity). Collectively, this multi-country study suggests that the best performing NS1 assay (Platelia) had moderate sensitivity (median 64%, range 34-76%) and high specificity (100%) for the diagnosis of dengue. The poor sensitivity of the evaluated assays in some geographical regions suggests further assessments are needed. The combination of NS1 and IgM detection in samples collected in the first few days of fever increased the overall dengue diagnostic sensitivity.


Fibrin Hydrogel Based Bone Substitute Tethered with BMP-2 and BMP-2/7 Heterodimers.
Current clinically used delivery methods for bone morphogenetic proteins (BMPs) are collagen based and require large concentrations that can lead to dangerous side effects. Fibrin hydrogels can serve as osteoinductive bone substitute materials in non-load bearing bone defects in combination with BMPs. Two strategies to even further optimize such a fibrin based system include employing more potent BMP heterodimers and engineering growth factors that can be covalently tethered to and slowly released from a fibrin matrix. Here we present an engineered BMP-2/BMP-7 heterodimer where an N-terminal transglutaminase substrate domain in the BMP-2 portion provides covalent attachment to fibrin together with a central plasmin substrate domain, a cleavage site for local release of the attached BMP-2/BMP-7 heterodimer under the influence of cell-activated plasmin. In vitro and in vivo results revealed that the engineered BMP-2/BMP-7 heterodimer induces significantly more alkaline phosphatase activity in pluripotent cells and bone formation in a rat calvarial model than the engineered BMP-2 homodimer. Therefore, the engineered BMP-2/BMP-7 heterodimer could be used to reduce the amount of BMP needed for clinical effect.


Spin excitations in a single La2CuO4 layer.
Cuprates and other high-temperature superconductors consist of two-dimensional layers that are crucial to their properties. The dynamics of the quantum spins in these layers lie at the heart of the mystery of the cuprates. In bulk cuprates such as La(2)CuO(4), the presence of a weak coupling between the two-dimensional layers stabilizes a three-dimensional magnetic order up to high temperatures. In a truly two-dimensional system however, thermal spin fluctuations melt long-range order at any finite temperature. Here, we measure the spin response of isolated layers of La(2)CuO(4) that are only one-unit-cell-thick. We show that coherent magnetic excitations, magnons, known from the bulk order, persist even in a single layer of La(2)CuO(4), with no evidence for more complex correlations such as resonating valence bond correlations. These magnons are, therefore, well described by spin-wave theory (SWT). On the other hand, we also observe a high-energy magnetic continuum in the isotropic magnetic response that is not well described by two-magnon SWT, or indeed any existing theories.


LSM1 over-expression in Saccharomyces cerevisiae depletes U6 snRNA levels.
Lsm1 is a component of the Lsm1-7 complex involved in cytoplasmic mRNA degradation. Lsm1 is over-expressed in multiple tumor types, including over 80% of pancreatic tumors, and increased levels of Lsm1 protein have been shown to induce carcinogenic effects. Therefore, understanding the perturbations in cell process due to increased Lsm1 protein may help to identify possible therapeutics targeting tumors over-expressing Lsm1. Herein, we show that LSM1 over-expression in the yeast Saccharomyces cerevisiae inhibits growth primarily due to U6 snRNA depletion, thereby altering pre-mRNA splicing. The decrease in U6 snRNA levels causes yeast strains over-expressing Lsm1 to be hypersensitive to loss of other proteins required for production or function of the U6 snRNA, supporting a model wherein excess Lsm1 reduces the availability of the Lsm2-7 proteins, which also assemble with Lsm8 to form a complex that binds and stabilizes the U6 snRNA. Yeast strains over-expressing Lsm1 also display minor alterations in mRNA decay and demonstrate increased susceptibility to mutations inhibiting cytoplasmic deadenylation, a process required for both 5'-to-3' and 3'-to-5' pathways of exonucleolytic decay. These results suggest that inhibition of splicing and/or deadenylation may be effective therapies for Lsm1-over-expressing tumors.


Molecular hydrogen: a preventive and therapeutic medical gas for various diseases.
Since the 2007 discovery that molecular hydrogen (H2) has selective antioxidant properties, multiple studies have shown that H2 has beneficial effects in diverse animal models and human disease. This review discusses H2 biological effects and potential mechanisms of action in various diseases, including metabolic syndrome, organ injury, and cancer; describes effective H2 delivery approaches; and summarizes recent progress toward H2 applications in human medicine. We also discuss remaining questions in H2 therapy, and conclude with an appeal for a greater role for H2 in the prevention and treatment of human ailments that are currently major global health burdens. This review makes a case for supporting hydrogen medicine in human disease prevention and therapy.


Effective quenching of fragment formation in negative ion oligonucleotide matrix-assisted laser desorption/ionization mass spectrometry through sodium adduct formation.
Metastable decay of the sodium-free and the sodium adducts of the negatively charged hexameric nucleotides 5'-d(TTXYTT)-3' (X and Y are dC, dG or dA) in matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-ToF-MS) is reported. We show that the sodium adduct formation may be used to quantitatively quench dissociation channels in oligonucleotide MALDI-MS, and we argue, that by means of effective steps in the sample preparation that lead to per-sodiation of the sample, the sample preparation and the mass resolution of oligonucleotide mass spectra in MALDI may be improved substantially. The dependency of the fragment formation on the degree of sodiation is also discussed in context with the underlying fragmentation mechanisms.


Enhancement of the clinical activity of melphalan by the hypoxic cell sensitizer misonidazole.
One hundred patients with non-small cell lung cancer were entered by members of the Northern California Oncology Group into a randomized Phase II trial of i.v. melphalan versus i.v. melphalan with concomitant oral misonidazole. The patients had not received prior chemotherapy. Eighty-five patients were evaluable for assessment of response and 89 were evaluable for toxicity analysis. The melphalan/misonidazole group had a superior response rate (two complete and four partial responses among 42 patients or 14%) compared to the melphalan group in which there were no responses among 43 patients (p = 0.024, two-sided Fisher exact test). Since hematological toxicity was equivalent in the two groups, there was an improvement in therapeutic index. Data from 12 patients undergoing pharmacological studies demonstrated that the plasma concentration of melphalan was 25% higher in the misonidazole group, a difference that is not statistically significant. Although the mechanism of interaction has not been fully established, this randomized trial demonstrates that a chemosensitizer can enhance the clinical antitumor activity of an alkylating agent and suggests that chemosensitizers in combination with alkylating agents should be investigated in further clinical trials.