Primary prevention in geriatric psychiatry.
It is estimated that the number of older adults with mental illness will increase from 4 million in 1970 to 15 million by 2030. The cost of untreated mental illness in the United States is estimated to be >$100 billion annually and nearly half of that cost can be attributed to persons age ≥60. In this paper we present a comprehensive review of empiric data available on primary prevention for the most common psychiatric illnesses in this patient population. We did an English language literature review of published studies and selected only those with the strongest emphasis on primary prevention for the most common psychiatric illnesses in older adults. Modifiable and nonmodifiable risk factors and several primary prevention strategies have been described, several of them with positive outcomes mainly for depressive disorders and suicide. In conditions such as bipolar disorder, dementias, and geriatric schizophrenia, there is either a paucity of studies or no robust primary prevention strategies identified. Modification of risk factors, a healthy lifestyle that includes a healthy diet, exercise, socialization, and education are important aspects of primary prevention in elderly patients. Genetic engineering and vaccine therapies may open new and exciting opportunities for prevention of many psychiatric illnesses in the near future.


The RRM domain of MINT, a novel Msx2 binding protein, recognizes and regulates the rat osteocalcin promoter.
Msx2 is a homeodomain transcriptional repressor that exerts tissue-specific actions during craniofacial skeletal and neural development. To identify coregulatory molecules that participate in transcriptional repression by Msx2, we applied a Farwestern expression cloning strategy to identify transcripts encoding proteins that bind Msx2. A lambdagt11 expression library from mouse brain was screened with radiolabeled GST-Msx2 fusion protein encompassing the core suppressor domain of Msx2. A cDNA was isolated that encodes a novel protein fragment that binds radiolabeled Msx2. Homeoprotein binding activity was confirmed by Farwestern analysis of the T7-epitope-tagged recombinant protein fragment, and interactions in vitro require Msx2 residues necessary for transcriptional suppression in vivo. On the basis of biochemical analyses, this novel protein was named MINT, an acronym for Msx2-interacting nuclear target protein. The original clone is part of a 12.6 kb transcript expressed at high levels in testis and at lower levels in calvarial osteoblasts and brain. Multiple clones isolated from a mouse testis library were sequenced to construct a MINT cDNA contig of 11 kb. Starting from an initiator Met in good Kozak context, a large nascent polypeptide of 3576 amino acids is predicted, in contiguous open reading frame with the Msx2 interaction domain residues 2070-2394. Protein sequence analysis reveals that MINT has three N-terminal RNA recognition motifs (RRMs) and four nuclear localization signals. Western blot analysis of fractionated cell extracts reveals that mature approximately 110 kDa (N-terminal) and approximately 250 kDa (C-terminal) MINT protein fragments accumulate in chromatin and nuclear matrix fractions, cosegregating with Msx2 and topoisomerase II. In gel shift assays, the MINT RRM domain selectively binds T- and G-rich DNA sequences; this includes a large G/T-rich inverted repeat element present in the proximal rat osteocalcin (OC) promoter, overlapping three cognates that support OC expression in osteoblasts. MINT and OC mRNAs are reciprocally regulated during differentiation of MC3T3E1 calvarial osteoblasts. Consistent with its proposed role as a nuclear transcriptional factor, transient expression of MINT(1-812) suppresses the FGF/forskolin-activated OC promoter, does not significantly regulate CMV promoter activity, but markedly upregulates the HSV thymidine kinase promoter in MC3T3E1 cells. In toto, these data indicate that the novel nuclear protein MINT binds the homeoprotein Msx2 and coregulates OC during craniofacial development. Msx2 and MINT both target an information-dense, osteoblast-specific regulatory region of the OC proximal promoter, nucleotides -141 to -111. The N-terminal MINT RRM domain represents an authentic dsDNA binding module for this novel vertebrate nuclear matrix protein. Acting as a scaffold protein, MINT potentially exerts both positive and negative regulatory actions by organizing transcriptional complexes in the nuclear matrix.


Detection of manipulations on printed images to address crime scene analysis: A case study.
Photographic documents both in digital and in printed format plays a fundamental role in crime scene analysis. Photos are crucial to reconstruct what happened and also to freeze the fact scenario with all the different present objects and evidences. Consequently, it is immediate to comprehend the paramount importance of the assessment of the authenticity of such images, to avoid that a possible malicious counterfeiting leads to a wrong evaluation of the circumstance. In this paper, a case study in which some printed photos, brought as documental evidences of a familiar murder, had been fraudulently modified to bias the final judgement is presented. In particular, the usage of CADET image forensic tool, to verify printed photos integrity, is introduced and discussed.


Magnetic targeting and ultrasound mediated drug delivery: benefits, limitations and combination.
This paper reviews the uses of magnetism and ultrasound in therapeutic delivery applications. Emphasis is placed upon magnetic nanoparticles and microbubble ultrasound contrast agents. The underlying physical principles, history, key developments and limitations of these techniques for drug and gene delivery in vitro and in vivo are explored. The combination of ultrasonic and magnetic techniques is also reviewed with particular focus on magnetic microbubbles as delivery agents with the potential to combine the advantages of both methods whilst addressing many of their limitations. Finally, results are presented from a study of a new magnetic microbubble formulation which shows great applicability as a therapeutic delivery vehicle.


Effect of setting of initial surgical drainage on outcome of finger infections.
This study sought to determine the optimal treatment setting (emergency department vs. operating room) for the initial incision and drainage of acute suppurative finger infections. A search of hospital medical records over a 5-year period identified 152 cases. In 108 cases (71%), a single drainage successfully resolved infection; 44 cases (29%) required multiple drainage procedures. Treatment setting did not decrease the risk for multiple procedures. Seventy-six cases (57%) of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) were identified. Bivariate analysis identified CA-MRSA infection as a significant, independent risk factor for multiple procedures. Obtaining initial cultures correlated with a decreased need for multiple procedures. In conclusion, initial surgical drainage in the emergency department is a safe alternative to the operating room. However, patients with CA-MRSA infection have an increased risk for persistent infection requiring multiple procedures. Prompt organism identification and appropriate antibiotics following surgical drainage remain most crucial for the successful treatment of finger infections.


New Zealand's drug development industry.
The pharmaceutical industry's profitability depends on identifying and successfully developing new drug candidates while trying to contain the increasing costs of drug development. It is actively searching for new sources of innovative compounds and for mechanisms to reduce the enormous costs of developing new drug candidates. There is an opportunity for academia to further develop as a source of drug discovery. The rising levels of industry outsourcing also provide prospects for organisations that can reduce the costs of drug development. We explored the potential returns to New Zealand (NZ) from its drug discovery expertise by assuming a drug development candidate is out-licensed without clinical data and has anticipated peak global sales of $350 million. We also estimated the revenue from NZ's clinical research industry based on a standard per participant payment to study sites and the number of industry-sponsored clinical trials approved each year. Our analyses found that NZ's clinical research industry has generated increasing foreign revenue and appropriate policy support could ensure that this continues to grow. In addition the probability-based revenue from the out-licensing of a drug development candidate could be important for NZ if provided with appropriate policy and financial support.


Biosynthesis of cellulose-enriched tension wood in Populus: global analysis of transcripts and metabolites identifies biochemical and developmental regulators in secondary wall biosynthesis.
Stems and branches of angiosperm trees form tension wood (TW) when exposed to a gravitational stimulus. One of the main characteristics of TW, which distinguishes it from normal wood, is the formation of fibers with a thick inner gelatinous cell wall layer mainly composed of crystalline cellulose. Hence TW is enriched in cellulose, and deficient in lignin and hemicelluloses. An expressed sequence tag library made from TW-forming tissues in Populus tremula (L.) x tremuloides (Michx.) and data from transcript profiling using microarray and metabolite analysis were obtained during TW formation in Populus tremula (L.) in two growing seasons. The data were examined with the aim of identifying the genes responsible for the change in carbon (C) flow into various cell wall components, and the mechanisms important for the formation of the gelatinous cell wall layer (G-layer). A specific effort was made to identify carbohydrate-active enzymes with a putative function in cell wall biosynthesis. An increased C flux to cellulose was suggested by a higher abundance of sucrose synthase transcripts. However, genes related to the cellulose biosynthetic machinery were not generally affected, although the expression of secondary wall-specific CesA genes was modified in both directions. Other pathways for which the data suggested increased activity included lipid and glucosamine biosynthesis and the pectin degradation machinery. In addition, transcripts encoding fasciclin-like arabinogalactan proteins were particularly increased and found to lack true Arabidopsis orthologs. Major pathways for which the transcriptome and metabolome analysis suggested decreased activity were the pathway for C flux through guanosine 5'-diphosphate (GDP) sugars to mannans, the pentose phosphate pathway, lignin biosynthesis, and biosynthesis of cell wall matrix carbohydrates. Several differentially expressed auxin- and ethylene-related genes and transcription factors were also identified.


Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states.
Mortality rates are used as global measures of a population's health status and as indicators for public health efforts and medical treatments. Elevated mortality rates among individuals with mental illness have been reported in various studies, but very little focus has been placed on interstate comparisons and congruency of mortality and causes of death among public mental health clients. Using age-adjusted death rates, standardized mortality ratios, and years of potential life lost, we compared the mortality of public mental health clients in eight states with the mortality of their state general populations. The data used in our study were submitted by public mental health agencies in eight states (Arizona, Missouri, Oklahoma, Rhode Island, Texas, Utah, Vermont, and Virginia) for 1997 through 2000 during the Sixteen-State Study on Mental Health Performance Measures, a multistate study federally funded by the Center for Mental Health Services in collaboration with the National Association of State Mental Health Program Directors. In all eight states, we found that public mental health clients had a higher relative risk of death than the general populations of their states. Deceased public mental health clients had died at much younger ages and lost decades of potential life when compared with their living cohorts nationwide. Clients with major mental illness diagnoses died at younger ages and lost more years of life than people with non-major mental illness diagnoses. Most mental health clients died of natural causes similar to the leading causes of death found nationwide, including heart disease, cancer, and cerebrovascular, respiratory, and lung diseases. Mental health and physical health are intertwined; both types of care should be provided and linked together within health care delivery systems. Research to track mortality and primary care should be increased to provide information for additional action, treatment modification, diagnosis-specific risk, and evidence-based practices.


Epsin binds to clathrin by associating directly with the clathrin-terminal domain. Evidence for cooperative binding through two discrete sites.
Epsin is a recently identified protein that appears to play an important role in clathrin-mediated endocytosis. The central region of epsin 1, the so-called DPW domain, binds to the heterotetrameric AP-2 adaptor complex by associating directly with the globular appendage of the alpha subunit. We have found that this central portion of epsin 1 also associates with clathrin. The interaction with clathrin is direct and not mediated by epsin-bound AP-2. Alanine scanning mutagenesis shows that clathrin binding depends on the sequence (257)LMDLADV located within the epsin 1 DPW domain. This sequence, related to the known clathrin-binding sequences in the adaptor beta subunits, amphiphysin, and beta-arrestin, facilitates the association of epsin 1 with the terminal domain of the clathrin heavy chain. Unexpectedly, inhibiting the binding of AP-2 to the GST-epsin DPW fusion protein by progressively deleting DPW triplets but leaving the LMDLADV sequence intact, diminishes the association of clathrin in parallel with AP-2. Because the beta subunit of the AP-2 complex also contains a clathrin-binding site, optimal association with soluble clathrin appears to depend on the presence of at least two distinct clathrin-binding sites, and we show that a second clathrin-binding sequence (480)LVDLD, located within the carboxyl-terminal segment of epsin 1, also interacts with clathrin directly. The LMDLADV and LVDLD sequences act cooperatively in clathrin recruitment assays, suggesting that they bind to different sites on the clathrin-terminal domain. The evolutionary conservation of similar clathrin-binding sequences in several metazoan epsin-like molecules suggests that the ability to establish multiple protein-protein contacts within a developing clathrin-coated bud is an important aspect of epsin function.


Education in a pediatric emergency mass critical care setting.
An emergency mass critical care event puts significant strains on all healthcare resources, including equipment, supplies, and manpower; it leads to extraordinary stresses on healthcare providers, many of whom will be expected to deliver care outside of their usual scope of practice. Education and educational resources will be critically important for training providers and diminishing the stress, anxiety, and chaos of delivering pediatric emergency mass critical care. This article suggests educational tools, as well as potential resources, that need to be developed to cope with a pediatric emergency mass critical care event. In May 2008, the Task Force for Mass Critical Care published guidance on provision of mass critical care to adults. Acknowledging that the critical care needs of children during disasters were unaddressed by this effort, a 17-member Steering Committee, assembled by the Oak Ridge Institute for Science and Education with guidance from members of the American Academy of Pediatrics, convened in April 2009 to determine priority topic areas for pediatric emergency mass critical care recommendations.Steering Committee members established subgroups by topic area and performed literature reviews of MEDLINE and Ovid databases. The Steering Committee produced draft outlines through consensus-based study of the literature and convened October 6-7, 2009, in New York, NY, to review and revise each outline. Eight draft documents were subsequently developed from the revised outlines as well as through searches of MEDLINE updated through March 2010.The Pediatric Emergency Mass Critical Care Task Force, composed of 36 experts from diverse public health, medical, and disaster response fields, convened in Atlanta, GA, on March 29-30, 2010. Feedback on each manuscript was compiled and the Steering Committee revised each document to reflect expert input in addition to the most current medical literature. Identifying educational needs to prepare for a pediatric emergency mass critical care event is essential for all healthcare organizations. Educational strategies and tactics should be developed at multiple levels for a comprehensive approach to preparing for pediatric emergency mass critical care.


A review of nutrients and botanicals in the integrative management of cognitive dysfunction.
Dementias and other severe cognitive dysfunction states pose a daunting challenge to existing medical management strategies. An integrative, early intervention approach seems warranted. Whereas, allopathic treatment options are highly limited, nutritional and botanical therapies are available which have proven degrees of efficacy and generally favorable benefit-to-risk profiles. This review covers five such therapies: phosphatidylserine (PS), acetyl-l-carnitine (ALC), vinpocetine, Ginkgo biloba extract (GbE), and Bacopa monniera (Bacopa). PS is a phospholipid enriched in the brain, validated through double-blind trials for improving memory, learning, concentration, word recall, and mood in middle-aged and elderly subjects with dementia or age-related cognitive decline. PS has an excellent benefit-to-risk profile. ALC is an energizer and metabolic cofactor which also benefits various cognitive functions in the middle-aged and elderly, but with a slightly less favorable benefit-to-risk profile. Vinpocetine, found in the lesser periwinkle Vinca minor, is an excellent vasodilator and cerebral metabolic enhancer with proven benefits for vascular-based cognitive dysfunction. Two meta-analyses of GbE demonstrate the best preparations offer limited benefits for vascular insufficiencies and even more limited benefits for Alzheimer's, while "commodity" GbE products offer little benefit, if any at all. GbE (and probably also vinpocetine) is incompatible with blood-thinning drugs. Bacopa is an Ayurvedic botanical with apparent anti-anxiety, anti-fatigue, and memory-strengthening effects. These five substances offer interesting contributions to a personalized approach for restoring cognitive function, perhaps eventually in conjunction with the judicious application of growth factors.


Automated Detection of DCIS in Whole-Slide H&E Stained Breast Histopathology Images.
This paper presents and evaluates a fully automatic method for detection of ductal carcinoma in situ (DCIS) in digitized hematoxylin and eosin (H&E) stained histopathological slides of breast tissue. The proposed method applies multi-scale superpixel classification to detect epithelial regions in whole-slide images (WSIs). Subsequently, spatial clustering is utilized to delineate regions representing meaningful structures within the tissue such as ducts and lobules. A region-based classifier employing a large set of features including statistical and structural texture features and architectural features is then trained to discriminate between DCIS and benign/normal structures. The system is evaluated on two datasets containing a total of 205 WSIs of breast tissue. Evaluation was conducted both on the slide and the lesion level using FROC analysis. The results show that to detect at least one true positive in every DCIS containing slide, the system finds 2.6 false positives per WSI. The results of the per-lesion evaluation show that it is possible to detect 80% and 83% of the DCIS lesions in an abnormal slide, at an average of 2.0 and 3.0 false positives per WSI, respectively. Collectively, the result of the experiments demonstrate the efficacy and accuracy of the proposed method as well as its potential for application in routine pathological diagnostics. To the best of our knowledge, this is the first DCIS detection algorithm working fully automatically on WSIs.


Effects of low dose dexmedetomidine infusion on haemodynamic stress response, sedation and post-operative analgesia requirement in patients undergoing laparoscopic cholecystectomy.
Dexmedetomidine is a α2 agonist with sedative, sympatholytic and analgesic properties and hence, it can be a very useful adjuvant in anaesthesia as stress response buster, sedative and analgesic. We aimed primarily to evaluate the effects of low dose dexmedetomidine infusion on haemodynamic response to critical incidences such as laryngoscopy, endotracheal intubation, creation of pneumoperitoneum and extubation in patients undergoing laparoscopic cholecystectomy. The secondary aims were to observe the effects on extubation time, sedation levels, post-operative analgesia requirements and occurrence of adverse effects. Sixty patients of American Society of Anaesthesiologists(ASA) physical grades I and II undergoing laparoscopic cholecystectomy were randomly allocated into three groups of 20 patients each. Group NS patients received normal saline, Group Dex 0.2 and Group Dex 0.4 patients received dexmedetomidine infusion at 0.2 mcg/kg/h and 0.4 mcg/kg/h respectively, starting 15 min before induction and continued till end of surgery. Parameters noted were pulse rate, mean arterial pressure, oxygen saturation, post-operative sedation and analgesia requirements. SPSS 15.0 version software was used for statistical analysis. ANOVA test for continuous variables, post-hoc test for intergroup comparison, and Chi-square test for discrete values were applied. In Group NS significant haemodynamic stress response was seen following laryngoscopy, tracheal intubation, creation of pneumoperitoneum and extubation. In dexmedetomidine groups, the haemodynamic response was significantly attenuated. The results, however, were statistically better in Dex 0.4 group compared with Dex 0.2 group. Post-operative 24 hour analgesic requirements were much less in dexmedetomidine groups. No significant side effects were noted. Low dose dexmedetomidine infusion in the dose of 0.4 mcg/kg/h effectively attenuates haemodynamic stress response during laparoscopic surgery with reduction in post-operative analgesic requirements.


Effects of UV radiation on the lipids and proteins of bacteria studied by mid-infrared spectroscopy.
Knowledge of the molecular effects of UV radiation (UVR) on bacteria can contribute to a better understanding of the environmental consequences of enhanced UV levels associated with global climate changes and will help to optimize UV-based disinfection strategies. In the present work, the effects of exposure to UVR in different spectral regions (UVC, 100-280 nm; UVB, 280-320 nm; and UVA, 320-400 nm) on the lipids and proteins of two bacterial strains ( Acinetobacter sp. strain PT5I1.2G and Pseudomonas sp. strain NT5I1.2B) with distinct UV sensitivities were studied by mid-infrared spectroscopy. Exposure to UVR caused an increase in methyl groups associated with lipids, lipid oxidation, and also led to alterations in lipid composition, which were confirmed by gas chromatography. Additionally, mid-infrared spectroscopy revealed the effects of UVR on protein conformation and protein composition, which were confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), oxidative damage to amino acids, and changes in the propionylation, glycosylation and/or phosphorylation status of cell proteins. Differences in the targets of UVR in the two strains tested were identified and may explain their discrepant UV sensitivities. The significance of the results is discussed from an ecological standpoint and with respect to potential improvements in UV-based disinfection technologies.


Modulation of hepatic inflammation and energy-sensing pathways in the rat liver by high-fructose diet and chronic stress.
High-fructose consumption and chronic stress are both associated with metabolic inflammation and insulin resistance. Recently, disturbed activity of energy sensor AMP-activated protein kinase (AMPK) was recognized as mediator between nutrient-induced stress and inflammation. Thus, we analyzed the effects of high-fructose diet, alone or in combination with chronic stress, on glucose homeostasis, inflammation and expression of energy sensing proteins in the rat liver. In male Wistar rats exposed to 9-week 20% fructose diet and/or 4-week chronic unpredictable stress we measured plasma and hepatic corticosterone level, indicators of glucose homeostasis and lipid metabolism, hepatic inflammation (pro- and anti-inflammatory cytokine levels, Toll-like receptor 4, NLRP3, activation of NFκB, JNK and ERK pathways) and levels of energy-sensing proteins AMPK, SIRT1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α). High-fructose diet led to glucose intolerance, activation of NFκB and JNK pathways and increased intrahepatic IL-1β, TNFα and inhibitory phosphorylation of insulin receptor substrate 1 on Ser307. It also decreased phospho-AMPK/AMPK ratio and increased SIRT1 expression. Stress alone increased plasma and hepatic corticosterone but did not influence glucose tolerance, nor hepatic inflammatory or energy-sensing proteins. After the combined treatment, hepatic corticosterone was increased, glucose tolerance remained preserved, while hepatic inflammation was partially prevented despite decreased AMPK activity. High-fructose diet resulted in glucose intolerance, hepatic inflammation, decreased AMPK activity and reduced insulin sensitivity. Chronic stress alone did not exert such effects, but when applied together with high-fructose diet it could partially prevent fructose-induced inflammation, presumably due to increased hepatic glucocorticoids.


Late adverse reactions to intravascular iodine based contrast media: an update.
Late adverse reactions (LAR) to contrast media (CM) are defined as reactions occurring 1 h to 1 week after exposure. In view of more prospective studies of LAR and new data about their pathophysiology, the Contrast Medium Safety Committee (CMSC) of the European Society of Urogenital Radiology (ESUR) reviewed the literature on LAR and updated their guidelines. LAR after CM include symptoms such as nausea, vomiting, headache, itching, skin rash, musculoskeletal pain, and fever. Skin reactions are well-documented LAR to CM with an incidence of approximately 2%-4% after nonionic monomers. LAR are commoner by a factor of three to four after nonionic dimers. The commonest skin reactions are maculopapular rashes, erythema and skin swelling. These reactions are T cell-mediated immune reactions, and the diagnosis may be confirmed using skin tests (patch or delayed reading intradermal). The main risk factors for LAR are a previous reaction to contrast medium, a history of allergy, and interleukin-2 treatment. Most skin reactions are mild or moderate and self-limiting. Management is symptomatic and similar to the management of other drug-induced skin reactions. To reduce the risk of repeat reactions avoidance of the relevant CM and any cross-reacting agents identified by skin testing is recommended.


Validity of enthesis ultrasound assessment in spondyloarthropathy.
To develop an ultrasound enthesis score and to assess its validity in the diagnostic classification of the spondyloarthropathies (SpAs). Twenty-five patients with SpA and 29 healthy controls participated in a blinded, gender-matched, cross-sectional study involving ultrasound assessment. The following entheses were explored bilaterally: proximal plantar fascia, distal Achilles tendon, distal and proximal patellar ligament, distal quadriceps and brachial triceps tendons. The ultrasound score evaluated enthesis thickness, structure, calcifications, erosions, bursae and power Doppler signal. The value of each elemental lesion was calculated using a three-model analysis. Validity was analysed by receiver operating characteristic (ROC) curves. Inter-reader and interexplorer intraclass correlation coefficients (ICCs) were calculated. The logistic regression model overestimated the score of three elemental lesions: calcification (0-3), Doppler (0 or 3) and erosion (0 or 3), while scoring tendon structure, tendon thickness and bursa as 0 or 1. ROC curves established an ultrasound score of >or=18 as the best cut-off point for differentiation between cases and controls. This cut-off point was exceeded by 5/29 controls (17%) and by 21/25 patients with SpA (84%). The sensitivity, specificity, positive and negative likelihood ratios (LR+, LR-) were 83.3%, 82.8%, 4.8% and 0.2%, respectively. The inter-reader and interexplorer ICCs were 0.60 and 0.86, respectively. The findings suggest that the ultrasound enthesis score could be a valid tool in the diagnosis of SpA.


Bortezomib, thalidomide and dexamethasone, with or without cyclophosphamide, for patients with previously untreated multiple myeloma: 5-year follow-up.
This follow-up extension of a randomised phase II study assessed differences in long-term outcomes between bortezomib-thalidomide-dexamethasone (VTD) and VTD-cyclophosphamide (VTDC) induction therapy in multiple myeloma. Newly diagnosed patients (n = 98) were randomised 1:1 to intravenous bortezomib (1·3 mg/m(2); days 1, 4, 8, 11), thalidomide (100 mg; days 1-21), and dexamethasone (40 mg; days 1-4, 9-12), with/without cyclophosphamide (400 mg/m(2); days 1, 8), for four 21-day cycles before stem-cell mobilisation/transplantation. After a median follow-up of 64·8 months, median time-to-next therapy was 51·8 and 47·9 months with VTD and VTDC, respectively. Type of subsequent therapy was similar in both arms. After adjusting for asymmetric censoring, median time to progression was not significantly different between VTD and VTDC [35·7 vs. 34·5 months; Hazard ratio (HR) 1·26, 95% confidence interval: 0·76-2·09; P = 0·370]. Five-year survival was 69·1% and 65·3% with VTD and VTDC, respectively. When analysed by minimal residual disease (MRD) status, overall survival was longer in MRD-negative versus MRD-positive patients with bone marrow-confirmed complete response (HR 3·66, P = 0·0318). VTD induction followed by transplantation provides long-term disease control and, consistent with the primary analysis, there is no additional benefit from adding cyclophosphamide. This study was registered at ClinicalTrials.gov (NCT00531453).


Fast transient networks in spontaneous human brain activity.
To provide an effective substrate for cognitive processes, functional brain networks should be able to reorganize and coordinate on a sub-second temporal scale. We used magnetoencephalography recordings of spontaneous activity to characterize whole-brain functional connectivity dynamics at high temporal resolution. Using a novel approach that identifies the points in time at which unique patterns of activity recur, we reveal transient (100-200 ms) brain states with spatial topographies similar to those of well-known resting state networks. By assessing temporal changes in the occurrence of these states, we demonstrate that within-network functional connectivity is underpinned by coordinated neuronal dynamics that fluctuate much more rapidly than has previously been shown. We further evaluate cross-network interactions, and show that anticorrelation between the default mode network and parietal regions of the dorsal attention network is consistent with an inability of the system to transition directly between two transient brain states. DOI: http://dx.doi.org/10.7554/eLife.01867.001.


Examination of Resistance Settings Based on Body Weight for the 3-Minute All-Out Critical Power Test.
There are conflicting suggestions regarding the most valid resistance (3-5% of body weight) to use for the critical power (CP) 3-min all-out (CP3min) test to estimate CP and anaerobic work capacity (AWC). The purpose of this study was to determine if the CP and AWC estimates from the CP3min test were affected by the percentage of body weight used to set the resistance on a Monark cycle ergometer. Ten recreationally trained participants (mean ± SD: Age: 22.2 ± 2.2 yrs.) completed the CP3min test at resistances of 4.5% (CP4.5%) and 3% (CP3%) of body weight to determine the CP and AWC. There were no significant differences between the CP4.5% (167 ± 34 W) and CP3% (156 ± 36 W) estimates. The AWC3% (5.6 ± 2.5 kJ) estimates were significantly lower than the AWC4.5% (9.0 ± 4.0 kJ). The CP and AWC estimates from the CP4.5% were consistent with values reported in the literature, however, the AWC estimate from the CP3% was lower than typically reported. These findings suggested that a resistance set at 3% of body weight for the CP3min test may be too low to accurately estimate AWC, but 3% and 4.5% resulted in the same estimation of CP. Thus, the principal finding of this study was that a resistance of 4.5% of body weight for CP3-min in recreationally trained participants resulted in more accurate estimates of AWC, compared to a resistance of 3%, and supports the use of 4.5% body weight resistance to measure both CP and AWC.


Involvement of Heparanase in the Pathogenesis of Mesothelioma: Basic Aspects and Clinical Applications.
Mammalian cells express a single functional heparanase, an endoglycosidase that cleaves heparan sulfate and thereby promotes tumor metastasis, angiogenesis, and inflammation. Malignant mesothelioma is highly aggressive and has a poor prognosis because of the lack of markers for early diagnosis and resistance to conventional therapies. The purpose of this study was to elucidate the mode of action and biological significance of heparanase in mesothelioma and test the efficacy of heparanase inhibitors in the treatment of this malignancy. The involvement of heparanase in mesothelioma was investigated by applying mouse models of mesothelioma and testing the effect of heparanase gene silencing (n = 18 mice per experiment; two different models) and heparanase inhibitors (ie, PG545, defibrotide; n = 18 per experiment; six different models). Synchronous pleural effusion and plasma samples from patients with mesothelioma (n = 35), other malignancies (12 non-small cell lung cancer, two small cell lung carcinoma, four breast cancer, three gastrointestinal cancers, two lymphomas), and benign effusions (five patients) were collected and analyzed for heparanase content (enzyme-linked immunosorbent assay). Eighty-one mesothelioma biopsies were analyzed by H-Score for the prognostic impact of heparanase using immunohistochemistry. All statistical tests were two-sided. Mesothelioma tumor growth, measured by bioluminescence or tumor weight at termination, was markedly attenuated by heparanase gene silencing (P = .02) and by heparanase inhibitors (PG545 and defibrotide; P < .001 and P = .01, respectively). A marked increase in survival of the mesothelioma-bearing mice (P < .001) was recorded. Heparanase inhibitors were more potent in vivo than conventional chemotherapy. Clinically, heparanase levels in patients' pleural effusions could distinguish between malignant and benign effusions, and a heparanase H-score above 90 was associated with reduced patient survival (hazard ratio = 1.89, 95% confidence interval = 1.09 to 3.27, P = .03). Our results imply that heparanase is clinically relevant in mesothelioma development. Given these preclinical and clinical data, heparanase appears to be an important mediator of mesothelioma, and heparanase inhibitors are worthy of investigation as a new therapeutic modality in mesothelioma clinical trials.


Chlorhexidine bathing and health care-associated infections among adult intensive care patients: a systematic review and meta-analysis.
Health care-associated infections (HAI) have been shown to increase length of stay, the cost of care, and rates of hospital deaths (Kaye and Marchaim, J Am Geriatr Soc 62(2):306-11, 2014; Roberts and Scott, Med Care 48(11):1026-35, 2010; Warren and Quadir, Crit Care Med 34(8):2084-9, 2006; Zimlichman and Henderson, JAMA Intern Med 173(22):2039-46, 2013). Importantly, infections acquired during a hospital stay have been shown to be preventable (Loveday and Wilson, J Hosp Infect 86:S1-70, 2014). In particular, due to more invasive procedures, mechanical ventilation, and critical illness, patients cared for in the intensive care unit (ICU) are at greater risk of HAI and associated poor outcomes. This meta-analysis aims to summarise the effectiveness of chlorhexidine (CHG) bathing, in adult intensive care patients, to reduce infection. A systematic literature search was undertaken to identify trials assessing the effectiveness of CHG bathing to reduce risk of infection, among adult intensive care patients. Infections included were: bloodstream infections; central line-associated bloodstream infections (CLABSI); catheter-associated urinary tract infections; ventilator-associated pneumonia; methicillin-resistant Staphylococcus aureus (MRSA); vancomycin-resistant Enterococcus; and Clostridium difficile. Summary estimates were calculated as incidence rate ratios (IRRs) and 95% confidence/credible intervals. Variation in study designs was addressed using hierarchical Bayesian random-effects models. Seventeen trials were included in our final analysis: seven of the studies were cluster-randomised crossover trials, and the remaining studies were before-and-after trials. CHG bathing was estimated to reduce the risk of CLABSI by 56% (Bayesian random effects IRR = 0.44 (95% credible interval (CrI), 0.26, 0.75)), and MRSA colonisation and bacteraemia in the ICU by 41% and 36%, respectively (IRR = 0.59 (95% CrI, 0.36, 0.94); and IRR = 0.64 (95% CrI, 0.43, 0.91)). The numbers needed to treat for these specific ICU infections ranged from 360 (CLABSI) to 2780 (MRSA bacteraemia). This meta-analysis of the effectiveness of CHG bathing to reduce infections among adults in the ICU has found evidence for the benefit of daily bathing with CHG to reduce CLABSI and MRSA infections. However, the effectiveness may be dependent on the underlying baseline risk of these events among the given ICU population. Therefore, CHG bathing appears to be of the most clinical benefit when infection rates are high for a given ICU population.


Discovery of small molecule inhibitors of adenovirus by disrupting E3-19K/HLA-A2 interactions.
The binding of the adenovirus (Ad) protein E3-19K with the human leukocyte antigen (HLA) plays an important role in Ad infections, which is the causative agent of a series of gastrointestinal, respiratory and ocular diseases. The objective of this research is to evaluate the essential interactions between E3-19K and HLA-A2 using the X-ray crystal structure of the E3-19K/HLA-A2 complex, and to identify small molecules that could potentially disrupt their binding. Computational methods, including molecular dynamic simulations, MM/GBSA calculations, and computational solvent mapping, were implemented to determine potential binding site(s) for small molecules. The previous experimentally determined hot spot residues, Q54 and E177 in HLA-A2, were also predicted to be the dominant residues for binding to E3-19K by our theoretical calculations. Several other residues were also found to play pivotal roles for the binding of E3-19K with HLA-A2. Residues adjacent to E177, including Q54 and several other residues theoretically predicted to be crucial in HLA-A2 were selected as a potential binding pocket to perform virtual screening with 1200 compounds from the Prestwick library. Seven hits were validated by surface plasmon resonance (SPR) as binders to HLA-A2 as a first step in identifying molecules that can perturb its association with the Ad E3-19K protein.


Preliminary evidence of a genetic association between tumor necrosis factor alpha and the severity of sleep disturbance and morning fatigue.
Although fatigue and sleep disturbance are prevalent symptoms in oncology patients and their family caregivers, little is known about the factors that contribute to interindividual variability in symptom severity ratings as well as in their underlying biological mechanisms. In this study, we sought to determine whether a functional genetic variation in a prominent proinflammatory cytokine, tumor necrosis factor-alpha (TNFA-308G>A [rs1800629] promoter polymorphism) was associated with overall ratings of sleep disturbance and fatigue as well as with the trajectories of these symptoms. Over 6 months, participants completed standardized measures of sleep disturbance and fatigue. Multiple linear regression was used to assess the effect of the TNFA genotype and other covariates on mean sleep disturbance and fatigue scores. Hierarchical linear modeling was used to determine the effect of TNFA genotype on the trajectories of these symptoms. Common allele homozygotes reported higher levels of sleep disturbance (p=.09) and morning fatigue (p=.02) than minor allele carriers. Multivariate analyses demonstrated that age and genotype were predictors of both mean symptom scores and the trajectories of these symptoms. Findings provide preliminary evidence of an association between a functional promoter polymorphism in the TNFA gene and the severity of sleep disturbance and morning fatigue in oncology patients and their family caregivers.


Setdb1-mediated histone H3K9 hypermethylation in neurons worsens the neurological phenotype of Mecp2-deficient mice.
Rett syndrome (RTT, OMIM # 312750), a neurodevelopmental disorder of early childhood, is primarily caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2). Various molecular functions have been ascribed to MECP2, including the regulation of histone modifications associated with repressive chromatin remodeling, but the role of these mechanisms for the pathophysiology of RTT remains unclear. Here, we explore whether or not neuronal expression of the histone H3-lysine 9 specific methyl-transferase, Setdb1 (Set domain, bifurcated 1)/Eset/Kmt1e, which is normally present only at low levels in differentiated neurons, rescues the RTT-like phenotype of Mecp2-deficient mice. A myc-tagged Setdb1 cDNA was expressed through the tau locus for ubiquitous expression in CNS neurons, or under control of the calcium/calmodulin-dependent protein kinase II (CK) promoter to selectively target postmitotic neurons in forebrain. However, the CK-Setdb1 transgene lead to an enhanced neurological deficit, and the tauSetdb1 allele further shortened life span of mice with a brain-wide deletion of Mecp2 during prenatal development. In contrast, no neurological deficits or premature death was observed in CK-Setdb1 and tauSetdb1 mice expressing wildtype Mecp2. However, levels of trimethylated H3K9 at pericentromeric repeats were fully maintained in differentiated neurons from symptomatic Mecp2 null mutant mice. Based on these results, we draw two conclusions: First, neuronal chromatin in RTT brain is not affected by a generalized deficit in H3K9 trimethylation. Second, artificial up-regulation of this repressive chromatin mark via Setdb1 gene delivery specifically to neurons is harmful for the Mecp2-deficient brain. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.


Alzheimer's disease and co-morbidity: increased prevalence and possible risk factors of excess mortality in a naturalistic 7-year follow-up.
Subjects with late-onset Alzheimer's disease (AD) have to be sufficiently healthy to live long enough to experience and to be diagnosed with dementia in later life. In contrast, neurodegeneration and cognitive deficits in AD may increase the frequency of co-morbid disorders and their possible influence on mortality. Consequently, we investigated whether the pattern of co-morbidity and its relevance for later death differed between hospitalized AD and age-matched controls subjects. Co-morbid diseases with a prevalence of more than 1% at hospital admission were compared between 634 hospitalized AD and 72,244 control subjects aged above 70 years admitted to the University of Birmingham NHS Trust between 1 January 2000 to 31 December 2007. Risk factors, i.e. co-morbid diseases that were predictors of mortality within the 7-year follow-up, were identified and compared. Subjects with AD suffer more eating disorders, infections, brain diseases and neck of femur fractures than other hospitalized elderly patients. In contrast, some cardiovascular diseases and diabetes mellitus were less prevalent in AD subjects in comparison with hospitalized controls. Diseases that might have contributed to later mortality in AD were pneumonia, ischemic heart disease and gastroenteritis, but there were no significant differences in their impact on mortality compared to other hospitalized elderly subjects with the same co-morbidities in multivariate logistic regression analyses. Patients with AD have a different pattern of co-morbidity, but die from the same diseases as other hospitalized patients. Infections including pneumonia and diseases that may occur secondary to neurodegeneration and cognitive decline may need special attention in patients with AD who may not be able to identify or report the early symptoms. Preventive measures may be helpful to reduce the high risk and fatal consequences of undetected disease in AD.


The Contribution of Vocabulary Knowledge and Spelling to the Reading Comprehension of Adolescents Who Are and Are Not English Language Learners.
This study examined the contributions of vocabulary and spelling to the reading comprehension of students in grades 6-10 who were and were not classified as English language learners. Results indicate that vocabulary accounted for greater between-grade differences and unique variance (ΔR2 = .11 to .31) in comprehension as compared to spelling (ΔR2 = .01 to .09). However, the contribution of spelling to comprehension was higher in the upper grade levels included in this cross-sectional analysis and functioned as a mediator of the impact of vocabulary knowledge at all levels. The direct effect of vocabulary was strong but lower in magnitude at each successive grade level from .58 in grade 6 to .41 in grade 10 while the indirect effect through spelling increased in magnitude at each successive grade level from .09 in grade 6 to .16 in grade 10. There were no significant differences between the language groups in the magnitude of the indirect impact, suggesting both groups of students relied more on both sources of lexical information in higher grades as compared to students in lower grades.


Phototherapy in the age of biologics.
Dermatologists are presented with a diversity of therapeutic modalities for the treatment of inflammatory, sclerosing, and neoplastic conditions, but with the development of various new irradiation devices that utilize specific parts of the electromagnetic spectrum, phototherapy has become a more viable, accessible, and efficacious option in the treatment of these conditions. The ultraviolet (UV) range (10-400 nm) is further subdivided into UVA and UVB, each of which has been particularly useful in a number of skin conditions. The most commonly used forms of UV irradiation are UVA1, psoralen plus UVA (PUVA), and narrowband (NB) UVB. Each of these modalities differ in their mechanism of action, indications, and side effect profiles, and it is important that clinicians be familiar with these differences. Today, phototherapy is a valuable option in the treatment of many nonpsoriatic conditions including atopic dermatitis, sclerosing skin conditions such as morphea, vitiligo, and mycosis fungoides. Due to its relative safety, phototherapy may be used in most populations, including children and pregnant women. However, contraindications and side effects are known and should be considered before patients begin a phototherapeutic regimen.


Coenzyme-based functional assignments of short-chain dehydrogenases/reductases (SDRs).
Short-chain dehydrogenases/reductases (SDRs) are enzymes of great functional diversity. In spite of a residue identity of only 15-30%, the folds are conserved to a large extent, with specific sequence motifs detectable. We have developed an assignment scheme based on these motifs and detect five families. Only two of these were known before, called 'Classical' and 'Extended', but are now distinguished at a further level based on patterns of charged residues in the coenzyme-binding region, giving seven subfamilies of classical SDRs and three subfamilies of extended SDRs. Three further families are novel entities, denoted 'Intermediate', 'Divergent' and 'Complex', encompassing short-chain alcohol dehydrogenases, enoyl reductases and multifunctional enzymes, respectively. The assignment scheme was applied to the genomes of human, mouse, D. melanogaster, C. elegans, A. thaliana and S. cerevisiae. In the animal genomes, genes corresponding to the extended SDRs amount to around one quarter or less of the total number of SDR genes, while in those of A. thaliana and S. cerevisiae, the extended members constitute about 40% of the SDR forms. The NAD(H)-dependent SDRs are about equally many as the NADP(H)-dependent ones in human, mouse and plant, while the proportions of NAD(H)-dependent enzymes are much lower in fruit fly, worm and yeast. We also find that NADP(H) is the preferred coenzyme among most classical SDRs, while NAD(H) is that preferred among most extended SDRs.


Health monitoring and health indicators in Europe.
Demographic change, new health threats and inequalities in health and healthcare provision in and between European Union (EU) member states pose a great challenge to European health care systems. Not only for these reasons does it make sense to collect comparable European health data. Such information provides insights on the distribution of risk and protection factors, the prevalence of chronic diseases and the levels of care provided in the member states and supports the planning and implementation of (health) policy measures. Since 2013, in the context of the European Health Interview Survey (EHIS), all EU member states are obliged to collect data on the health status, the provision of healthcare, health determinants and socio-economic conditions of their populations. In Germany, the EHIS is integrated into health monitoring at the Robert Koch Institute (RKI). The RKI is thus Germany's interface to the European health monitoring presented here. European health monitoring relies on different indicator systems such as the European Core Health Indicators (ECHI), EU social indicators and the health indicators of the European Sustainable Development Strategy. These are based on administrative and survey data, which stem for example from the EHIS or the European Union Statistics on Income and Living Conditions (EU-SILC) survey. Comparative data analyses must take into account the differences between health care systems, socioeconomic conditions and the age structures of societies. Variances in the prevalence of allergies for example are also due to differences in the available diagnostic tools. Significant differences in the prevalence of hypertension in Europe (with a range of 20% for women and 17% for men) are also related to different levels of awareness of hypertension. Comparative analyses can support the planning of and provide information for policy measures, and enhance the sharing of experiences between EU member states. A forthcoming EU regulation aims to harmonise the content of and intervals between health and social statistical data collection. Moreover, plans exist to establish a European Research Infrastructure Consortium (ERIC), which is set to develop and institutionalise European health monitoring.


Can combining different risk interventions into a single formulation contribute to improved cardiovascular disease risk reduction? The single pill of amlodipine/atorvastatin.
In order to prevent cardiovascular events, it is essential to effectively manage overall risk of cardiovascular disease. However, despite guideline recommendations to this effect, current management of the major, modifiable cardiovascular risk factors such as hypertension and dyslipidemia is disconnected and patient adherence to therapy is poor. This is particularly important for patients with multiple cardiovascular risk factors, who are often prescribed multiple medications. The JEWEL study program investigated the use of single-pill amlodipine/atorvastatin as a strategy to improve management of these patients. The JEWEL program consisted of two 16-week, international, open-label, multicenter, titration-to-goal studies in patients with hypertension and dyslipidemia. The two studies differed based on country of enrollment and certain tertiary endpoints, but the overall designs were very similar. Patients were enrolled from 255 centers across Canada and 13 European countries. The study was designed to assess the efficacy, safety, and utility of amlodipine/atorvastatin single-pill therapy in a real-world setting. Patients were initiated at a dose of amlodipine 5 mg/atorvastatin 10 mg, unless previously treated, and were uptitrated as necessary. The primary efficacy parameter was the percentage of patients, at different levels of cardiovascular risk, achieving country-specific guideline-recommended target levels for blood pressure and lipids. A secondary analysis of efficacy measured attainment of the same single goal for blood pressure across all study participants (JEWEL I and II) and the same single goal for LDL-C across all study participants (JEWEL I and II). The program utilized a newly developed questionnaire to gain better understanding of participants' beliefs and behaviors towards medical treatment of their multiple risk factors. Approximately 2850 patients were enrolled in the program, which was completed in August 2005. The JEWEL program assessed the effectiveness of a single pill (amlodipine/atorvastatin) in targeting the two principal risk factors for cardiovascular disease simultaneously to achieve nationally applicable treatment targets in a routine clinical practice setting.


Embodying self-compassion within virtual reality and its effects on patients with depression.
Self-criticism is a ubiquitous feature of psychopathology and can be combatted by increasing levels of self-compassion. However, some patients are resistant to self-compassion. To investigate whether the effects of self-identification with virtual bodies within immersive virtual reality could be exploited to increase self-compassion in patients with depression. We developed an 8-minute scenario in which 15 patients practised delivering compassion in one virtual body and then experienced receiving it from themselves in another virtual body. In an open trial, three repetitions of this scenario led to significant reductions in depression severity and self-criticism, as well as to a significant increase in self-compassion, from baseline to 4-week follow-up. Four patients showed clinically significant improvement. The results indicate that interventions using immersive virtual reality may have considerable clinical potential and that further development of these methods preparatory to a controlled trial is now warranted. None. © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY) licence.


Growth hormone replacement in adults and bone mineral density: a systematic review and meta-analysis.
The effect of GH replacement on bone mineral density (BMD) in adults with GH deficiency (GHD) is uncertain. We carried out a systematic review of randomized trials that compared GH to no active treatment, with BMD as an outcome. We searched electronic databases to identify articles, abstracts and conference proceedings to March 2002. We also checked reference lists in included studies and expert reviews. Two reviewers independently extracted the data on study design and change in BMD. The results of individual trials were combined by fixed effects model meta-analysis using weighted mean difference (WMD) of change in BMD at the lumbar spine (our primary outcome) and other sites. Eighteen trials that included 700 patients met the inclusion criteria. Maximum follow-up was for 12 weeks (1 trial), 6 months (14 trials), 12 months (1 trial), 18 months (1 trial) and 24 months (1 trial). Reporting quality of both study design and results was poor. Ten trials (458 subjects) were included in the meta-analysis. We excluded those eight trials from which sufficient data could not be extracted. We found a mean change in BMD, at the lumbar spine with GH treatment, of 0.01 g/cm2 after 6 and 12 months, 0.02 g/cm2 after 18 months and 0.03 g/cm2 after 24 months. Statistical significance at the 0.05 level was just achieved at 6 and 12 months but was significant at 18 and 24 months. These changes are small and may be influenced by bias. There is evidence of a small effect of GH replacement on bone mineral density in adults with GH deficiency. The clinical importance of this is uncertain.


A detailed immunohistochemical analysis of 2 cases of papillary cystadenoma of the broad ligament: an extremely rare neoplasm characteristic of patients with von hippel-lindau disease.
We report 2 cases of papillary cystadenoma, a rare neoplasm characteristic of patients with Von Hippel-Lindau (VHL) disease, involving the pelvic soft tissues of women and probably arising within the broad ligament. In only one of the women was there a history of VHL disease. The other woman was investigated for VHL disease after the diagnosis of papillary cystadenoma and all tests were negative. There has been debate as to whether papillary cystadenomas in women are of mesonephric (Wolffian) or of Mullerian origin and to investigate this we undertook a detailed immunohistochemical analysis. Both tumors were positive with AE1/3, Ber EP4, epithelial membrane antigen, CK7, CD10, CA125, CA19.9, calretinin, and vimentin. One exhibited focal nuclear staining with WT1 and PAX8. The tumors were negative with estrogen receptor, progesterone receptor, androgen receptor, CK20, CEA, TTF1, inhibin, RCC marker, and hepatocyte nuclear factor 1β. Although favoring a mesonephric origin, the immunohistochemical findings are essentially inconclusive and not definitive for either a mesonephric or a Mullerian origin. We believe that patients found to have papillary cystadenoma should be investigated for VHL disease if there is no history of this. This is the second reported example of papillary cystadenoma in a woman not known to have VHL disease and the first in which investigations have excluded this disease.


Managing hypertension in rural Uganda: Realities and strategies 10 years of experience at a district hospital chronic disease clinic.
The literature on the global burden of noncommunicable diseases (NCDs) contrasts a spiraling epidemic centered in low-income countries with low levels of awareness, risk factor control, infrastructure, personnel and funding. There are few data-based reports of broad and interconnected strategies to address these challenges where they hit hardest. Kisoro district in Southwest Uganda is rural, remote, over-populated and poor, the majority of its population working as subsistence farmers. This paper describes the 10-year experience of a tri-partite collaboration between Kisoro District Hospital, a New York teaching hospital, and a US-based NGO delivering hypertension services to the district. Using data from patient and pharmacy registers and a random sample of charts reviewed manually, we describe both common and often-overlooked barriers to quality care (clinic overcrowding, drug stockouts, provider shortages, visit non-adherence, and uninformative medical records) and strategies adopted to address these barriers (locally-adapted treatment guidelines, patient-clinic-pharmacy cost sharing, appointment systems, workforce development, patient-provider continuity initiatives, and ongoing data monitoring). We find that: 1) although following CVD risk-based treatment guidelines could safely allocate scarce medications to the highest-risk patients first, national guidelines emphasizing treatment at blood pressures over 140/90 mmHg ignore the reality of "stockouts" and conflict with this goal; 2) often-overlooked barriers to quality care such as poor quality medical records, clinic disorganization and local employment practices are surmountable; 3) cost-sharing initiatives partially fill the gap during stockouts of government supplied medications, but still may be insufficient for the poorest patients; 4) frequent prolonged lapses in care may be the norm for most known hypertensives in rural SSA, and 5) ongoing data monitoring can identify local barriers to quality care and provide the impetus to ameliorate them. We anticipate that our 10-year experience adapting to the complex challenges of hypertension management and a granular description of the solutions we devised will be of benefit to others managing chronic disease in similar rural African communities.


Plasmodium falciparum strain-specific human antibody inhibits merozoite invasion of erythrocytes.
The extent to which human antibodies involved in functional immunity react with antigenic determinants varying between different isolates or strains of the human malaria parasite Plasmodium falciparum will influence the design of vaccines against malaria. We identified nine immune sera from Cambodian refugees which blocked in vitro invasion of erythrocytes by merozoites of the Camp strain of P. falciparum and agglutinated Camp strain merozoites. However, none of these sera blocked invasion of erythrocytes by merozoites of the FCR-3 strain. We conclude that antibodies in these human sera recognized antigenic determinants present on the surface of viable merozoites of the Camp strain but not the FCR-3 strain. These parasite strains and in vitro assays can be used to analyze strain-specific functional immunity in humans.


Periodic Mesoporous Organosilicas: from simple to complex bridges; a comprehensive overview of functions, morphologies and applications.
Periodic Mesoporous Organosilicas (PMOs) were developed in 1999 and are basically ordered templated mesoporous organosilicas, prepared by the combination of a surfactant as template and a silsesquioxane as the organosilica precursor. They were one of the first examples of the so-called "hybrid" organic/inorganic materials. In the years that followed, an amazing variety of functional groups, morphologies and applications has been developed. Some of these high-end applications, like low-k buffer layers in microelectronics, chiral catalysts, chromatographic supports, selective adsorbents and light-harvesting devices, have clearly shown their potential. In this review, we will give a comprehensive overview of all these different functionalities and applications that have been created for Periodic Mesoporous Organosilicas.


Gene expression profiling of the response to interferon beta in Epstein-Barr-transformed and primary B cells of patients with multiple sclerosis.
The effects of interferon-beta (IFN-β), one of the key immunotherapies used in multiple sclerosis (MS), on peripheral blood leukocytes and T cells have been extensively studied. B cells are a less abundant leukocyte type, and accordingly less is known about the B cell-specific response to IFN-β. To identify gene expression changes and pathways induced by IFN-β in B cells, we studied the in vitro response of human Epstein Barr-transformed B cells (lymphoblast cell lines-LCLs), and validated our results in primary B cells. LCLs were derived from an MS patient repository. Whole genome expression analysis identified 115 genes that were more than two-fold differentially up-regulated following IFN-β exposure, with over 50 previously unrecognized as IFN-β response genes. Pathways analysis demonstrated that IFN-β affected LCLs in a similar manner to other cell types by activating known IFN-β canonical pathways. Additionally, IFN-β increased the expression of innate immune response genes, while down-regulating many B cell receptor pathway genes and genes involved in adaptive immune responses. Novel response genes identified herein, NEXN, DDX60L, IGFBP4, and HAPLN3, B cell receptor pathway genes, CD79B and SYK, and lymphocyte activation genes, LAG3 and IL27RA, were validated as IFN-β response genes in primary B cells. In this study new IFN-β response genes were identified in B cells, with possible implications to B cell-specific functions. The study's results emphasize the applicability of LCLs for studies of human B cell drug response. The usage of LCLs from patient-based repositories may facilitate future studies of drug response in MS and other immune-mediated disorders with a B cell component.


RNA aptamers directed to human immunodeficiency virus type 1 Gag polyprotein bind to the matrix and nucleocapsid domains and inhibit virus production.
Gag orchestrates the assembly and release of human immunodeficiency virus type 1 (HIV-1) particles. We explored here the potential of anti-Gag RNA aptamers to inhibit HIV-1 replication. In vitro, RNA aptamers raised against an HIV-1 Gag protein, lacking the N-terminal myristate and the C-terminal p6 (DP6-Gag), could bind to matrix protein (MA), nucleocapsid protein (NC), or entire DP6-Gag protein. Upon cotransfection with pNL4-3.Luc molecular clone into 293T cells, six of the aptamers caused mild inhibition (2- to 3-fold) in the extracellular capsid levels, and one aptamer displayed 20-fold inhibition. The reduction was not due to a release defect but reflected Gag mRNA levels. We hypothesized that the aptamers influence genomic RNA levels via perturbation of specific Gag-genomic RNA interactions. Binding studies revealed that the "NC-binders" specifically compete with the packaging signal (ψ) of HIV-1 for binding to DP6-Gag. Therefore, we tested the ability of two NC-binders to inhibit viruses containing ψ-region deletions (ΔSL1 or ΔSL3) and found that the NC-binders were no longer able to inhibit Gag synthesis. The inability of these aptamers to inhibit ψ-deleted viruses correlated with the absence of competition with the corresponding ψ transcripts lacking SL1 or SL3 for binding DP6-Gag in vitro. These results indicate that the NC-binding aptamers disrupt Gag-genomic RNA interaction and negatively affect genomic RNA transcription, processing, or stability. Our results reveal an essential interaction between HIV-1 Gag and the ψ-region that may be distinct from that which occurs during the encapsidation of genomic RNA. Thus, anti-Gag aptamers can be an effective tool to perturb Gag-genomic RNA interactions.


Visual Fixation Patterns during Reciprocal Social Interaction Distinguish a Subgroup of 6-Month-Old Infants At-Risk for Autism from Comparison Infants.
Thirty-one infant siblings of children with autism and 24 comparison infants were tested at 6 months of age during social interaction with a caregiver, using a modified Still Face paradigm conducted via a closed-circuit TV-video system. In the Still Face paradigm, the mother interacts with the infant, then freezes and displays a neutral, expressionless face, then resumes interaction. Eye tracking data on infant visual fixation patterns were recorded during the three episodes of the experiment. Using a hierarchical cluster analysis, we identified a subgroup of infants demonstrating diminished gaze to the mother's eyes relative to her mouth during the Still Face episode. Ten out of the 11 infants in this subgroup had an older sibling with autism.


Characterization of Geminivirus resistance in an accession of Capsicum chinense Jacq.
Pepper golden mosaic virus (PepGMV) and Pepper huasteco yellow vein virus (PHYVV), members of the Geminiviridae family, are important pathogens of pepper (Capsicum annuum L.) and other solanaceous crops. Accession BG-3821 of C. chinense Jacq. was reported earlier as resistant to mixed infection with PepGMV and PHYVV. In this work, we characterized the Geminivirus resistance trait present in BG-3821. Segregation analysis suggested that resistance depends on two genes. Our data showed that PepGMV replication in protoplast of resistant plants is approximately 70% lower when compared with the levels observed in protoplasts from susceptible plants. Additionally, viral movement is less efficient in resistant plants. We also evaluated several characteristics commonly associated with systemic acquired resistance (SAR), which is a conserved defensive mechanism. The concentration of salicylic acid was higher in resistant plants inoculated with PepGMV than in susceptible plants. Marker genes for SAR were induced after inoculation with PepGMV in resistant leaves. Similarly, we found a higher accumulation of reactive oxygen species on resistant leaves compared with susceptible ones. A model for the mechanism acting in the Geminivirus resistance detected in BG-3821 is proposed. Finally, the importance of BG-3821 in Geminivirus resistance breeding programs is discussed.


[Aflatoxins and ochratoxin A in food and risks to human health].
The presence of mycotoxins in food has been associated with several human diseases, and health authorities have taken actions to decrease the ingestion of these compounds in the diet. A study was carried out to assess aflatoxins and ochratoxin A concentrations found in food, and to evaluate the potential risk to human health resulting from mycotoxin exposure. Between July 1998 to December 2001, 366 food samples were analyzed, including peanuts and its products, nuts, maize, oat and/or wheat products, rice and beans. Samples were processed and the extracted mycotoxins were detected and separated using thin layer chromatography, and then quantified with fluorescence. Aflatoxins were detected in 19.6% of the samples: raw peanuts and its products, pop corn, maize and Brazilian nuts (>2mg/kg). Peanuts and its products showed the highest levels of aflatoxin contamination (34.7%) with up to 1280 mg/kg of AFB1+AFG1 and 1706 mg/kg of total aflatoxins. Of the positive samples, AFB1 was detected in 98.5%, AFB2 in 93%, AFG1 in 66.7%, and AFG2 in 65.4%. Ochratoxin A was not detected (<25 mg/kg) in any sample analyzed. It was found that contamination levels mainly seen in peanuts and its products exceed Brazilian regulated standards, and they can be a potential risk to regular consumers of these products. Food producers' awareness allied to monitoring programs is essential to reduce human exposure to these compounds and prevent ensuing chronic diseases.


H-ficolin binds Aspergillus fumigatus leading to activation of the lectin complement pathway and modulation of lung epithelial immune responses.
Aspergillus fumigatus is an opportunistic fungal pathogen that typically infects the lungs of immunocompromised patients leading to a high mortality. H-Ficolin, an innate immune opsonin, is produced by type II alveolar epithelial cells and could participate in lung defences against infections. Here, we used the human type II alveolar epithelial cell line, A549, to determine the involvement of H-ficolin in fungal defence. Additionally, we investigated the presence of H-ficolin in bronchoalveolar lavage fluid from transplant patients during pneumonia. H-Ficolin exhibited demonstrable binding to A. fumigatus conidia via l-fucose, d-mannose and N-acetylglucosamine residues in a calcium- and pH-dependent manner. Moreover, recognition led to lectin complement pathway activation and enhanced fungal association with A549 cells. Following recognition, H-ficolin opsonization manifested an increase in interleukin-8 production from A549 cells, which involved activation of the intracellular signalling pathways mitogen-activated protein kinase MAPK kinase 1/2, p38 MAPK and c-Jun N-terminal kinase. Finally, H-ficolin concentrations were significantly higher in bronchoalveolar lavage fluid of patients with lung infections compared with control subjects (n = 16; P = 0·00726). Receiver operating characteristics curve analysis further highlighted the potential of H-ficolin as a diagnostic marker for lung infection (area under the curve = 0·77; P < 0·0001). Hence, H-ficolin participates in A. fumigatus defence through the activation of the lectin complement pathway, enhanced fungus-host interactions and modulated immune responses.


MicroRNA-34c Suppresses Breast Cancer Migration and Invasion by Targeting GIT1.
Abnormal expression of microRNAs plays important role in tumor metastasis. Migration and invasion of cancer cells accord for the metastasis and deterioration of breast cancer. However, the regulatory role of microRNAs in the invasion and migration of breast cancer cells has not completely understood yet. Here we found that microRNA-34c (miR-34c) was significantly downregulated in metastatic tissue of breast cancer. In vitro study showed that miR-34c negatively regulated GIT1 protein expression by binding to the 3'UTR of GIT1 mRNA. Consistently, GIT1 protein expression was found upregulated significantly in metastatic breast cancer. Moreover, miR-34c overexpression suppressed the expression of GIT1 protein, and this effect was restored by AMO-miR-34c in breast cancer cells. Overexpression of miR-34c suppressed cell migration and invasion in both MCF-7 and MDA-MD-231 breast cancer cells. Furthermore, knockdown of endogenous GIT1 expression reduced the migration and invasion of both two breast cancer cells. Collectively, miR-34c downregulation in breast cancer cells resulted in the upregulation of GIT1, which in turn enhanced the migration and invasion of breast cancer. This study highlights molecular mechanism of migration and invasion of breast cancer cells.


Health literacy explains racial disparities in diabetes medication adherence.
Although low health literacy and suboptimal medication adherence are more prevalent in racial/ethnic minority groups than Whites, little is known about the relationship between these factors in adults with diabetes, and whether health literacy or numeracy might explain racial/ethnic disparities in diabetes medication adherence. Previous work in HIV suggests health literacy mediates racial differences in adherence to antiretroviral treatment, but no study to date has explored numeracy as a mediator of the relationship between race/ethnicity and medication adherence. This study tested whether health literacy and/or numeracy were related to diabetes medication adherence, and whether either factor explained racial differences in adherence. Using path analytic models, we explored the predicted pathways between racial status, health literacy, diabetes-related numeracy, general numeracy, and adherence to diabetes medications. After adjustment for covariates, African American race was associated with poor medication adherence (r = -0.10, p < .05). Health literacy was associated with adherence (r = .12, p < .02), but diabetes-related numeracy and general numeracy were not related to adherence. Furthermore, health literacy reduced the effect of race on adherence to nonsignificance, such that African American race was no longer directly associated with lower medication adherence (r = -0.09, p = .14). Diabetes medication adherence promotion interventions should address patient health literacy limitations.


Magnetic "fishing" assay to screen small-molecule mixtures for modulators of protein-protein interactions.
Protein-protein interactions are an intricate part of biological pathways and have become important targets for drug discovery. Here we present a two-stage magnetic bead assay to functionally screen small-molecule mixtures for modulators of protein-based interactions, with simultaneous affinity-based isolation of active compounds and identification by mass spectrometry. Proteins of interest interact in solution prior to the addition of Ni(II)-functionalized magnetic beads to recover an intact protein-protein complex through affinity capture of a polyhistidine-tagged primary target ("protein-complex fishing"). Protein-complex fishing, utilizing His(6)-tagged calmodulin (CaM) as the primary (bait) protein and melittin (Mel) as the target, was used to screen a mass-encoded library of 1000 bioactive compounds (50 mixtures, 20 compounds each) and successfully identified three known antagonists, three naturally occurring phenolic compounds previously reported to disrupt CaM-activated phosphodiesterase activity, and two newly identified modulators of the CaM-Mel interaction, methylbenzethonium and pempidine tartrate. The ability to produce quantitative inhibition data is also shown through the development of dose-dependent response curves and the determination of inhibition constants (K(I)) for the novel compound methylbenzethonium (K(I) = 14-49 nM) and two known antagonists, calmidazolium (K(I) = 1.7-7.5 nM) and trifluoperazine (K(I) = 1.2-3.0 μM), with the latter two values being in close agreement with literature values.


Development of public health program for type 1 diabetes in a university community: preliminary evaluation of behavioural change wheel.
Diabetes mellitus, including type 1 is a global public health problem among the young persons. While public health campaign and screening program is a potential strategy, but communication skills, knowledge and opinion of the healthcare personnel are indicated as variables that can impact patient's education, which will lead to better outcome of care. Thus, in designing or planning a program for public health, workforce development considers opinion and behavioural change wheel of prospective personnel. The purpose of this preliminary study was to evaluate if a university academic department has the behavioural change wheel to function as workforce infrastructure for an envisioned program. Survey of knowledge, attitude and practice (KAP) of a university community regarding diabetes type 1 was performed. The KAP were translated into behavioural change wheel comprising capacity, motivation and opportunity (CMO). There are baseline indications of the behavioural change wheel potential of the public health department to run a T1D screening program. The number of participants who knew someone with T1D was significantly higher than the subgroup with no such knowledge (p<0.0004) and this improved when age factor is considered (p<0.00005). While the public health department of a university community has the behavioural change wheel or CMO to develop a workforce infrastructure for T1D screening program, the experience that comes with age of lecturers will be an important factor to enable such program to succeed.


Very-Heavy Precipitation in the Greater New York City Region and Widespread Drought Alleviation Tied to Western US Agriculture.
Observed intensification of precipitation extremes, responsible for extensive societal impacts, are widely attributed to anthropogenic sources, which may include indirect effects of agricultural irrigation. However quantifying the effects of irrigation on far-downstream climate remains a challenge. We use three paired Community Earth System Model simulations to assess mechanisms of irrigation-induced precipitation trends and extremes in the conterminous US and the effect on the terrestrial carbon sink. Results suggest precipitation enhancement in the central US reduced drought conditions and increased regional carbon uptake, while further downstream, the heaviest precipitation events were more frequent and intense. Specifically, moisture advection from irrigation in the western U.S. and recycling of enhanced local convective precipitation produced very-heavy storm events that were 11% more intense and occurred 23% more frequently in the densely populated greater New York City region.


Imatinib mesylate as first-line therapy in patients with chronic myeloid leukemia in accelerated phase and blast phase: a retrospective analysis.
Imatinib is a bcr-abl tyrosine kinase inhibitor which has revolutionized the treatment for chronic myeloid leukemia (CML). Even though there is much data on CML chronic phase, there is limited data on imatinib-naοve advanced phase CML. We retrospectively analysed 90 patients with advanced phase CML (accelerated phase [AP]: 51 and blast crisis [BC]: 39), patients who received imatinib as frontline therapy. The median age of presentation in CML-AP and CML-BC were 32 years (12-61) and 39 years (8-59), respectively. Imatinib at 600 mg/day was initiated within 2 weeks of diagnosis. Median time to complete hematological response in both CML-AP and CML-BC was 3 months (CML-AP: 1-9 months and CML-BC: 1-14 months). At 6 months 30 (59%) CML-AP and 15 (38%) CML-BC patients achieved major cytogenetic response (MCyR), of them 24 (47%) and 10 (25.6%) being the complete cytogenetic response, respectively. At a median follow-up of 41 months, the median overall survival in CML-AP was 61 months, but in CML-BC it was 14 months. The median progression-free survival and event-free survival were 30 months and 23 months in CML-AP and 14 and 12 months in CML-BC, respectively. On univariate analysis, performance status (PS), spleen size, and MCyR predicted survival in AP, whereas in BC, platelet count, PS, and early MCyR were predictive. Non-hematologic and hematologic adverse events were observed in 80% and 60% of patients, respectively. Dose was reduced in 10% of patients for grade IV toxicity and interrupted in 30% for grade III toxicity. Front-line imatinib is an option in advanced phases of CML especially in CML-AP in low-resource countries, where stem cell transplantation and alternate TKIs are not available.


Creating multithemed ecological regions for macroscale ecology: Testing a flexible, repeatable, and accessible clustering method.
Understanding broad-scale ecological patterns and processes often involves accounting for regional-scale heterogeneity. A common way to do so is to include ecological regions in sampling schemes and empirical models. However, most existing ecological regions were developed for specific purposes, using a limited set of geospatial features and irreproducible methods. Our study purpose was to: (1) describe a method that takes advantage of recent computational advances and increased availability of regional and global data sets to create customizable and reproducible ecological regions, (2) make this algorithm available for use and modification by others studying different ecosystems, variables of interest, study extents, and macroscale ecology research questions, and (3) demonstrate the power of this approach for the research question-How well do these regions capture regional-scale variation in lake water quality? To achieve our purpose we: (1) used a spatially constrained spectral clustering algorithm that balances geospatial homogeneity and region contiguity to create ecological regions using multiple terrestrial, climatic, and freshwater geospatial data for 17 northeastern U.S. states (~1,800,000 km2); (2) identified which of the 52 geospatial features were most influential in creating the resulting 100 regions; and (3) tested the ability of these ecological regions to capture regional variation in water nutrients and clarity for ~6,000 lakes. We found that: (1) a combination of terrestrial, climatic, and freshwater geospatial features influenced region creation, suggesting that the oft-ignored freshwater landscape provides novel information on landscape variability not captured by traditionally used climate and terrestrial metrics; and (2) the delineated regions captured macroscale heterogeneity in ecosystem properties not included in region delineation-approximately 40% of the variation in total phosphorus and water clarity among lakes was at the regional scale. Our results demonstrate the usefulness of this method for creating customizable and reproducible regions for research and management applications.


Metallic nickel nitride nanosheets realizing enhanced electrochemical water oxidation.
Exploring efficient and inexpensive oxygen evolution reaction (OER) electrocatalysts is of great importance for various electrochemical energy storage and conversion technologies. Ni-based electrocatalysts have been actively pursued because of their promising activity and earth abundance. However, the OER efficiency for most of the developed Ni-based electrocatalysts has been intrinsically limited due to their low electrical conductivity and poor active site exposure yield. Herein, we report metallic Ni3N nanosheets as an efficient OER electrocatalyst for the first time. The first-principles calculations and electrical transport property measurements unravel that the Ni3N is intrinsically metallic, and the carrier concentration can be remarkably improved with dimensional confinement. The EXAFS spectra provide solid evidence that the Ni3N nanosheets have disordered structure resultant of dimensional reduction, which then could provide more active sites for OER. Benefiting from enhanced electrical conductivity with metallic behavior and atomically disordered structure, the Ni3N nanosheets realize intrinsically improved OER activity compared with bulk Ni3N and NiO nanosheets. Our finding suggests that metallic nitride nanosheets could serve as a new group of OER electrocatalysts with excellent property.


Chimeric human papillomavirus type 16 (HPV-16) L1 particles presenting the common neutralizing epitope for the L2 minor capsid protein of HPV-6 and HPV-16.
Both the Human papillomavirus (HPV) major (L1) and minor (L2) capsid proteins have been well investigated as potential vaccine candidates. The L1 protein first oligomerizes into pentamers, and these capsomers assemble into virus-like particles (VLPs) that are highly immunogenic. Here we examine the potential of using HPV type 16 (HPV-16) L1 subunits to display a well-characterized HPV-16 L2 epitope (LVEETSFIDAGAP), which is a common-neutralizing epitope for HPV types 6 and 16, in various regions of the L1 structure. The L2 sequence was introduced by PCR (by replacing 13 codons) into sequences coding for L1 surface loops D-E (chideltaC-L2), E-F (chideltaA-L2), and an internal loop C-D (chideltaH-L2); into the h4 helix (chideltaF-L2); and between h4 and beta-J structural regions (chideltaE-L2). The chimeric protein product was characterized using a panel of monoclonal antibodies (MAbs) that bind to conformational and linear epitopes, as well as a polyclonal antiserum raised to the L2 epitope. All five chimeras reacted with the L2 serum. ChideltaA-L2, chideltaE-L2, and chideltaF-L2 reacted with all the L1 antibodies, chideltaC-L2 did not bind H16:V5 and H16:E70, and chideltaH-L2 did not bind any conformation-dependent MAb. The chimeric particles elicited high-titer anti-L1 immune responses in BALB/c mice. Of the five chimeras tested only chideltaH-L2 did not elicit an L2 response, while chideltaF-L2 elicited the highest L2 response. This study provides support for the use of PV particles as vectors to deliver various epitopes in a number of locations internal to the L1 protein and for the potential of using chimeric PV particles as multivalent vaccines. Moreover, it contributes to knowledge of the structure of HPV-16 L1 VLPs and their derivatives.


Short-term memory for duration of movement.
This study examined the short-term retention characteristics of temporal information about visually guided movements. Subjects attempted to recall a preselected movement of a particular duration either immediately or after an unfilled or filled retention interval. Subjects did not benefit from an opportunity to rehearse information about duration of movement over the interval. This finding supports a decay model of forgetting for temporal information about visually guided movements.


The H3K9 methyltransferase Setdb1 regulates TLR4-mediated inflammatory responses in macrophages.
Proinflammatory cytokine production in macrophages involves multiple regulatory mechanisms, which are affected by environmental and intrinsic stress. In particular, accumulating evidence has suggested epigenetic control of macrophage differentiation and function mainly in vitro. SET domain, bifurcated 1 (Setdb1, also known as Eset) is a histone 3 lysine 9 (H3K9)-specific methyltransferase and is essential for early development of embryos. Here we demonstrate that Setdb1 in macrophages potently suppresses Toll-like receptor 4 (TLR4)-mediated expression of proinflammatory cytokines including interleukin-6 through its methyltransferase activity. As a molecular mechanism, Setdb1-deficiency decreases the basal H3K9 methylation levels and augments TLR4-mediated NF-κB recruitment on the proximal promoter region of interleukin-6, thereby accelerating interleukin-6 promoter activity. Moreover, macrophage-specific Setdb1-knockout mice exhibit higher serum interleukin-6 concentrations in response to lipopolysaccharide challenge and are more susceptible to endotoxin shock than wildtype mice. This study provides evidence that the H3K9 methyltransferase Setdb1 is a novel epigenetic regulator of proinflammatory cytokine expression in macrophages in vitro and in vivo. Our data will shed insight into the better understanding of how the immune system reacts to a variety of conditions.


PCR-Based Detection of Cephalosporium gramineum in Winter Wheat.
A polymerase chain reaction (PCR) assay was developed amplifying a 496-bp fragment of the internal transcribed spacer region of Cephalosporium gramineum genomic DNA at concentrations of 100 fg/μl. Winter wheat seed and seedlings were collected from field plots where C. gramineum was present. Seed was tested by PCR using 20-seed samples bulked for DNA extraction. Estimates of seed infection, based on isolation of the pathogen on semiselective medium and PCR, were comparable at 0.18 and 0.13% of winter wheat 'Stephens' (P = 0.6042), and 0.45 and 0.58% of experimental line WA7970 (P = 0.5636), respectively. PCR differentiated between plants with well-developed symptoms of Cephalosporium stripe and noninoculated plants. Positive PCR was obtained from 22% of asymptomatic leaf blades from inoculated plants. We found no false positives when PCR and C. gramineum isolation on a semiselective medium were performed using tissue from the same leaf. The PCR assay has potential to diagnose Cephalosporium stripe disease prior to the appearance of symptoms. Negative PCR for some samples from which C. gramineum was isolated suggests that C. gramineum may be present below the level of detection in some asymptomatic leaves. This PCR assay may be useful for investigations into C. gramineum infection of wheat.


Iodine-mediated cross-dehydrogenative coupling of pyrazolones and alkenes.
An iodine-mediated alkenylation of pyrazolones with simple alkenes under an air atmosphere has been developed. By this protocol, the pharmaceutically relevant pyrazolone scaffold was directly adorned with a readily transformable olefinic functional group through a cross-dehydrogenative coupling process in moderate to excellent yields. The coupling products could be facilely manipulated by, for example, the Heck reaction and hydrogenation treatment, thus enriching the pyrazolone derivatives. Based on the observation of the reaction intermediate and mechanistical experiments, two possible reaction pathways were proposed.


Artificial Intelligence for Retinopathy of Prematurity: Validation of a Vascular Severity Scale against International Expert Diagnosis.
To validate a vascular severity score as an appropriate output for artificial intelligence (AI) Software as a Medical Device (SaMD) for retinopathy of prematurity (ROP) through comparison with ordinal disease severity labels for stage and plus disease assigned by the International Classification of Retinopathy of Prematurity, Third Edition (ICROP3), committee. Validation study of an AI-based ROP vascular severity score. A total of 34 ROP experts from the ICROP3 committee. Two separate datasets of 30 fundus photographs each for stage (0-5) and plus disease (plus, preplus, neither) were labeled by members of the ICROP3 committee using an open-source platform. Averaging these results produced a continuous label for plus (1-9) and stage (1-3) for each image. Experts were also asked to compare each image to each other in terms of relative severity for plus disease. Each image was also labeled with a vascular severity score from the Imaging and Informatics in ROP deep learning system, which was compared with each grader's diagnostic labels for correlation, as well as the ophthalmoscopic diagnosis of stage. Weighted kappa and Pearson correlation coefficients (CCs) were calculated between each pair of grader classification labels for stage and plus disease. The Elo algorithm was also used to convert pairwise comparisons for each expert into an ordered set of images from least to most severe. The mean weighted kappa and CC for all interobserver pairs for plus disease image comparison were 0.67 and 0.88, respectively. The vascular severity score was found to be highly correlated with both the average plus disease classification (CC = 0.90, P < 0.001) and the ophthalmoscopic diagnosis of stage (P < 0.001 by analysis of variance) among all experts. The ROP vascular severity score correlates well with the International Classification of Retinopathy of Prematurity committee member's labels for plus disease and stage, which had significant intergrader variability. Generation of a consensus for a validated scoring system for ROP SaMD can facilitate global innovation and regulatory authorization of these technologies.


Telmisartan as an add-on treatment for dogs with refractory idiopathic epilepsy: a nonrandomized, uncontrolled, open-label clinical trial.
To evaluate the effect on seizure frequency of add-on telmisartan treatment in dogs with refractory idiopathic epilepsy. 11 client-owned dogs with idiopathic epilepsy and ≥ 2 generalized seizures/mon that were currently being treated with ≥ 2 antiepileptic drugs. Telmisartan was administered at a dosage of 0.25 to 1 mg/kg, PO, every 12 hours for 4 to 16 months. Seizure frequencies before and during telmisartan treatment were recorded. 10 dogs completed the 4-month treatment protocol. One dog was excluded owing to a transient increase in serum creatinine concentration; no adverse effects of telmisartan were observed in the remaining 10 dogs. A reduction in seizure frequency greater than an estimated expected placebo effect of 30% was evident in 7 of the 10 dogs. Long-term (12 to 16 months) follow-up information was available for 6 dogs, of which 4 had a further reduction in seizure frequency. Differences in seizure frequency were not statistically significant. No significant difference was found in serum phenobarbital concentration throughout the treatment period in the 7 dogs that were tested. Telmisartan has the potential to reduce seizure frequency when administered as an add-on antiepileptic drug in dogs with refractory idiopathic epilepsy. A randomized, double-blind, placebo-controlled trial is needed to determine the true efficacy of telmisartan. On the basis of our results, a sample size of 54 dogs with refractory idiopathic epilepsy would be needed.


Lipin 2 is a liver-enriched phosphatidate phosphohydrolase enzyme that is dynamically regulated by fasting and obesity in mice.
Lipin 1 is a bifunctional intracellular protein that regulates fatty acid metabolism in the nucleus via interactions with DNA-bound transcription factors and at the endoplasmic reticulum as a phosphatidic acid phosphohydrolase enzyme (PAP-1) to catalyze the penultimate step in triglyceride synthesis. However, livers of 8-day-old mice lacking lipin 1 (fld mice) exhibited normal PAP-1 activity and a 20-fold increase in triglyceride levels. We sought to further analyze the hepatic lipid profile of these mice by electrospray ionization mass spectrometry. Surprisingly, hepatic content of phosphatidate, the substrate of PAP-1 enzymes, was markedly diminished in fld mice. Similarly, other phospholipids derived from phosphatidate, phosphatidylglycerol and cardiolipin, were also depleted. Another member of the lipin family (lipin 2) is enriched in liver, and hepatic lipin 2 protein content was markedly increased by lipin 1 deficiency, food deprivation, and obesity, often independent of changes in steady-state mRNA levels. Importantly, RNAi against lipin 2 markedly reduced PAP-1 activity in hepatocytes from both wild type and fld mice and suppressed triglyceride synthesis under conditions of high fatty acid availability. Collectively, these data suggest that lipin 2 plays an important role as a hepatic PAP-1 enzyme.


IS THERE A RELATION BETWEEN HELYBACTER PYLORI AND INTESTINAL METAPLASIA IN SHORT COLUMN EPITELIZATION UP TO 10 MM IN THE DISTAL ESOPHAGUS?
The presence of intestinal metaplasia in the distal esophagus (Barrett's esophagus) is an important precursor of adenocarcinoma. Knowledge of the risk factors and the process by which the Barrett develops is very important and Helicobacter pylori (HP) can contribute to this development. To analyze the impact of HP in the gastric mucosa with intestinal metaplasia in the distal esophagus in areas of columnar epithelialization smaller than 10 mm in length and epidemiological data on prevalence. A retrospective study in which were included 373 consecutive patients diagnosed with columnar epithelium in the distal esophagus was done. In all, HP was investigated by urease and histology, exclusion and inclusion factors were applied and patients were divided into two groups: the first grouping the ones without histological diagnosis of Barrett's esophagus (235-63%) and the second with it (138-37%). There was no significant difference between HP and non-HP patients in relation to the probability of having intestinal metaplasia (p=0.587). When related to the general group, there was an inverse association between the bacterium and the columnar epithelia in the distal esophagus. Age (p=0.031), gender (p=0.013) and HP (p=0.613) when related together to intestinal metaplasia showed no significant relation. In isolation, when related to age and gender, regardless of HP, results confirmed that patients in more advanced age and women present a higher incidence of intestinal metaplasia. There is an inverse relation between HP and the areas of columnar epithelization in the distal esophagus, regardless of the presence or absence of intestinal metaplasia. Age and gender, regardless of HP, showed higher prevalence in women and in older the number of cases with intestinal metaplasia in the distal esophagus.