Dissociation kinetics of macrocyclic trivalent lanthanide complexes of 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (DO2A).
The [H(+)]-catalyzed dissociation rate constants of several trivalent lanthanide (Ln) complexes of 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (LnDO2A(+), Ln = La, Pr, Eu, Er and Lu) have been determined in two pH ranges: 3.73-5.11 and 1.75-2.65 at four different temperatures (19-41.0 °C) in aqueous media at a constant ionic strength of 0.1 mol dm(-3) (LiClO(4)). For the study in the higher pH range, i.e. pH 3.73-5.11, copper(II) ion was used as the scavenger for the free ligand DO2A in acetate/acetic acid buffer medium. The rates of Ln(III) complex dissociation have been found to be independent of [Cu(2+)] and all the Ln(III) complexes studied show [H(+)]-dependence at low acid concentrations but become [H(+)]-independent at high acid concentrations. Influence of the acetate ion content in the buffer on the dissociation rate has also been investigated and all the complexes exhibit a first-order dependence on [Acetate]. The dissociation reactions follow the rate law: k(obs) = k(Ac)[Acetate] + K'k(lim)[H(+)]/(1 + K'[H(+)]) where k(AC) is the dissociation rate constant for the [Acetate]-dependent pathway, k(lim) is the limiting rate constant, and K' is the equilibrium constant for the reaction LnDO2A(+) + H(+) ⇔ LnDO2AH(2+). In the lower pH range, i.e. pH 1.75-2.65, the dye indicator, cresol red, was used to monitor the dissociation rate, and all the Ln(III) complexes also show [H(+)]-dependence dissociation pathways but without the rate saturation observed at higher pH range. The dissociation reactions follow the simple rate law: k(obs) = k(H)[H(+)], where k(H) is the dissociation rate constant for the pathway involving monoprotonated species. The absence of an [H(+)]-independent pathway in both pH ranges indicates that LnDO2A(+) complexes are kinetically rather inert. The obtained k(AC) values follow the order: LaDO2A(+) > PrDO2A(+) > EuDO2A(+) > ErDO2A(+) > LuDO2A(+), whereas the k(lim) and k(H) values follow the order: LaDO2A(+) > PrDO2A(+) > ErDO2A(+) > EuDO2A(+) > LuDO2A(+), mostly consistent with their thermodynamic stability order, i.e. the more thermodynamically stable the more kinetically inert. In both pH ranges, activation parameters, ΔH*, ΔS* and ΔG*, for both acetate-dependent and proton-catalyzed dissociation pathways have been obtained for most of the La(III), Pr(III), Eu(III), Er(III) and Lu(III) complexes, from the temperature dependence measurements of the rate constants in the 19-41 °C range. An isokinetic (linear) relationship is found between ΔH* and ΔS* values, which supports a common reaction mechanism.


Multivariate Stratified Metal-Organic Frameworks: Diversification Using Domain Building Blocks.
We introduce the concept of domain building blocks (DBBs) as an effective approach to increasing the diversity and complexity of metal-organic frameworks (MOFs). DBBs are defined as distinct structural or compositional regions within a MOF material. Using the DBB approach, we illustrate how an immense number of multivariate MOF materials can be prepared from a small collection of molecular building blocks comprising the distinct domains. The multivariate nature of the MOFs is determined by the sequence of DBBs within the MOF. We then apply this approach to the construction of a rich library of UiO-67 stratified MOF (sMOF) particles consisting of multiple concentric DBBs. We discuss and highlight the negative consequences of linker exchange reactions on the compositional integrity of DBBs in the UiO-67 sMOFs and propose and demonstrate mitigation strategies. We also demonstrate that individual strata can be specifically postsynthetically addressed and manipulated. Finally, we demonstrate the versatility of these synthetic strategies through the preparation of sMOF-nanoparticle composite materials.


Asthma and COPD in primary health care, quality according to national guidelines: a cross-sectional and a retrospective study.
In recent decades international and national guidelines have been formulated to ensure that patients suffering from specific diseases receive evidence-based care. In 2004 the National Swedish Board of Health and Welfare (SoS) published guidelines concerning the management of patients with asthma and COPD. The guidelines identify quality indicators that should be fulfilled. The aim of this study was to survey structure and process indicators, according to the asthma and COPD guidelines, in primary health care, and to identify correlations between structure and process quality results. A cross-sectional study of existing structure by using a questionnaire, and a retrospective study of process quality based on a review of measures documented in asthma and COPD medical records. All 42 primary health care centres in the county council of Ostergötland, Sweden, were included. All centres showed high quality regarding structure, although there was a large difference in time reserved for Asthma and COPD Nurse Practice (ACNP). The difference in reserved time was reflected in process quality results. The time needed to reach the highest levels of spirometry and current smoking habit documentation was between 1 and 1 1/2 hours per week per 1000 patients registered at the centre. Less time resulted in fewer patients examined with spirometry, and fewer medical records with smoking habits documented. More time did not result in higher levels, but in more frequent contact with each patient. In the COPD group more time resulted in higher levels of pulse oximetry and weight registration. To provide asthma and COPD patients with high process quality in primary care according to national Swedish guidelines, at least one hour per week per 1000 patients registered at the primary health care centre should be reserved for ACNP.


Multi-omics data integration by generative adversarial network.
Accurate disease phenotype prediction plays an important role in the treatment of heterogeneous diseases like cancer in the era of precision medicine. With the advent of high throughput technologies, more comprehensive multi-omics data is now available that can effectively link the genotype to phenotype. However, the interactive relation of multi-omics datasets makes it particularly challenging to incorporate different biological layers to discover the coherent biological signatures and predict phenotypic outcomes. In this study, we introduce omicsGAN, a generative adversarial network model to integrate two omics data and their interaction network. The model captures information from the interaction network as well as the two omics datasets and fuse them to generate synthetic data with better predictive signals. Large-scale experiments on The Cancer Genome Atlas breast cancer, lung cancer and ovarian cancer datasets validate that (i) the model can effectively integrate two omics data (e.g. mRNA and microRNA expression data) and their interaction network (e.g. microRNA-mRNA interaction network). The synthetic omics data generated by the proposed model has a better performance on cancer outcome classification and patients survival prediction compared to original omics datasets. (ii) The integrity of the interaction network plays a vital role in the generation of synthetic data with higher predictive quality. Using a random interaction network does not allow the framework to learn meaningful information from the omics datasets; therefore, results in synthetic data with weaker predictive signals. Source code is available at: https://github.com/CompbioLabUCF/omicsGAN. Supplementary data are available at Bioinformatics online.


Diabetes mellitus and inflammation.
Type 2 diabetes mellitus (T2DM) is increasingly common worldwide. Related complications account for increased morbidity and mortality, and enormous healthcare spending. Knowledge of the pathophysiological derangements involved in the occurrence of diabetes and related complications is critical for successful prevention and control solutions. Epidemiologic studies have established an association between inflammatory biomarkers and the occurrence of T2DM and complications. Adipose tissue appears to be a major site of production of those inflammatory biomarkers, as a result of the cross-talk between adipose cells, macrophages, and other immune cells that infiltrate the expanding adipose tissue. The triggering mechanisms of the inflammation in T2DM are still ill-understood. Inflammatory response likely contributes to T2DM occurrence by causing insulin resistance, and is in turn intensified in the presence of hyperglycemia to promote long-term complications of diabetes. Targeting inflammatory pathways could possibly be a component of the strategies to prevent and control diabetes and related complications.


CD-Search: protein domain annotations on the fly.
We describe the Conserved Domain Search service (CD-Search), a web-based tool for the detection of structural and functional domains in protein sequences. CD-Search uses BLAST(R) heuristics to provide a fast, interactive service, and searches a comprehensive collection of domain models. Search results are displayed as domain architecture cartoons and pairwise alignments between the query and domain-model consensus sequences. Search results may be visualized in further detail by embedding the query sequence into multiple alignment displays and by mapping onto three-dimensional molecular graphic displays of known structures within the domain family. CD-Search can be accessed at http://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi.


Human cardiac troponin I: a Langmuir monolayer study.
Human cardiac troponin I (cTnI) is the preferred biomarker in the assessment of myocardial infarction. It is known to interact with troponin C and T to form a trimeric complex. Whereas small amounts are found in the cytoplasm, most of cTnI is in the form of a complex with actin located in myofilaments. To understand these interactions of cTnI better, we first investigated the surface chemistry of cTnI as a Langmuir monolayer spread at the air-water interface. We investigated the optimal conditions for obtaining a stable Langmuir monolayer in terms of changing the ionic strength of the subphase using different concentrations of potassium chloride. Monolayer stability was investigated by compressing the cTnI monolayer to a specific surface pressure and keeping the surface pressure constant while measuring the decrease in the molecular area as a function of time. Aggregation and/or domain formation was investigated by using compression-decompression cycles, in situ UV-vis spectroscopy, Brewster angle microscopy (BAM), and epifluorescence microscopy. To ensure that the secondary structure is maintained, we used infrared reflection-absorption spectroscopy (IRRAS) directly at the air-subphase interface. It was found that cTnI forms a very stable monolayer (after more that 5000 s) that does not aggregate at the air-subphase interface. The cTnI molecules maintain their secondary structure and, on the basis of the low reflectivity observed using BAM measurements and the low reflection-absorption intensities measured with IRRAS spectroscopy, lie flat on the subphase with the alpha-helices parallel to the air-subphase interface.


The clinical significance of extracellular matrix in gangliogliomas.
Based on in vitro studies which demonstrate that collagen IV and laminin inhibit the proliferation and invasiveness of glioma cells, we investigated the clinical significance of these extracellular matrix proteins (ECM) in patients with gangliogliomas, tumors in which ECM is often a prominent feature. Our study compared the relative presence and deposition pattern of collagen IV and laminin in 19 gangliogliomas and in 18 gliomas without ganglion cell differentiation (8 low-grade astrocytomas, 7 anaplastic astrocytomas, and 3 anaplastic mixed gliomas). We also examined whether the presence of collagen IV and laminin correlated with other features often observed in gangliogliomas, including perivascular lymphocytic inflammation, granular bodies, microcalcification, and subarachnoid extension, and whether any of these features were associated with the patient's clinical course. Significant deposition of collagen IV and laminin was found in 9 gangliogliomas (47%), but in none of the other gliomas. The presence of these extracellular proteins in gangliogliomas correlated with both perivascular inflammation (P = 0.003), and involvement of the leptomeninges by tumor (P = 0.008). The duration of symptoms prior to surgical resection was significantly longer for patients whose tumors showed extracellular deposition of collagen IV and laminin than for patients whose tumors lacked deposition of these proteins (mean 13.7 vs 5.1 years; P = 0.02). In addition, the duration of symptoms was significantly longer for patients whose tumors exhibited perivascular inflammation than for patients whose tumors displayed little or no perivascular inflammation (mean 14.8 vs 4.8 years; P = 0.01). These findings suggests that collagen IV and laminin and perivascular inflammation are related to the indolent behavior of gangliogliomas.


Imaging of fluorescent yield and lifetime from multiply scattered light reemitted from random media.
The feasibility of employing fluorescent contrast agents to perform optical imaging in tissues and other scattering media has been examined through computational studies. Fluorescence lifetime and yield can give crucial information about local metabolite concentrations or environmental conditions within tissues. This information can be employed toward disease detection, diagnosis, and treatment if noninvasively quantitated from reemitted optical signals. However, the problem of inverse image reconstruction of fluorescence yield and lifetime is complicated because of the highly scattering nature of the tissue. Here a light propagation model employing the diffusion equation is used to account for the scattering of both the excitation and fluorescent light. Simulated measurements of frequency-domain parameters of fluorescent modulated ac amplitude and phase lag are used as inputs to an inverse image-reconstruction algorithm, which employs the diffusion model to predict frequency-domain measurements resulting from a modulated input at the phantom periphery. In the inverse image-reconstruction algorithm, a Newton-Raphson technique combined with a Marquardt algorithm is employed to converge on the fluorescent properties within the medium. The successful reconstruction of both the fluorescence yield and lifetime in the case of a heterogeneous fluorophore distribution within a scattering medium has been demonstrated without a priori information or without the necessity of obtaining absence images.


Serum gamma-glutamyltransferase and the burden of atherosclerosis in patients with acute coronary syndrome.
We evaluated the relationship between serum gamma-glutamyltransferase (GGT) levels and the burden of atherosclerosis in patients with acute coronary syndrome (ACS). This study involved 180 patients (139 male, 41 female; mean age 63±11 years) with the diagnosis of ACS (non-ST elevation myocardial infarction and unstable angina) who underwent coronary angiography on the first day after hospital admission. The burden of atherosclerosis was assessed by the number of involved vessels, and the Gensini and Syntax scores. Serum GGT levels were measured by enzymatic caloric test. Patients with high Syntax scores (>=33) were more frequently diabetic, hypertensive, and had higher GGT and creatinine levels compared to the patients with low Syntax scores (<=23). Similarly, patients with >=3 diseased vessels were more frequently diabetic, hypertensive, and smokers. In addition, these patients were older and had higher serum glucose, urea and GGT levels. Correlation analysis revealed that the level of GGT was significantly associated with Gensini and Syntax scores, number of diseased vessels, and the number of critical lesions (r=0.378 p<0.001, r=0.301 p<0.001, r=0.159 p=0.036, r=0.355 p<0.001, respectively). Multivariate linear regression analysis demonstrated that increased GGT level was an independent risk factor for high Gensini and Syntax scores (p=0.029 and p=0.035, respectively), together with age (p=0.001 and p=0.002, respectively) and serum glucose levels (p=0.017 and p=0.012, respectively). Serum GGT levels on admission are associated with increased burden of atherosclerosis in patients with ACS. This may account for the cardiovascular outcomes associated with increased GGT levels.


Genome-wide characterization of light-regulated genes in Neurospora crassa.
The filamentous fungus Neurospora crassa responds to light in complex ways. To thoroughly study the transcriptional response of this organism to light, RNA-seq was used to analyze capped and polyadenylated mRNA prepared from mycelium grown for 24 hr in the dark and then exposed to light for 0 (control) 15, 60, 120, and 240 min. More than three-quarters of all defined protein coding genes (79%) were expressed in these cells. The increased sensitivity of RNA-seq compared with previous microarray studies revealed that the RNA levels for 31% of expressed genes were affected two-fold or more by exposure to light. Additionally, a large class of mRNAs, enriched for transcripts specifying products involved in rRNA metabolism, showed decreased expression in response to light, indicating a heretofore undocumented effect of light on this pathway. Based on measured changes in mRNA levels, light generally increases cellular metabolism and at the same time causes significant oxidative stress to the organism. To deal with this stress, protective photopigments are made, antioxidants are produced, and genes involved in ribosome biogenesis are transiently repressed.


Immunological effects of Oenothein B, an ellagitannin dimer, on dendritic cells.
Oenothein B is a unique macrocyclic ellagitannin dimer that has been found in various medicinal plants belonging to Onagraceae, Lythraceae, and Myrtaceae, with diverse biological activities. The immunological effects of tannins in terms of cytokine-release from macrophages and monocytes have been discussed, while the effects on other immunocompetent cells have been the subject of minimal investigation. We evaluated the immunomodulatory effects induced by tannin treatment in human dendritic cells (DCs), which play a critical role in the initial immune response, by measuring the changes in cytokine production, cell differentiation, and cell viability. Oenothein B showed significant down-regulation of the expression of cell surface molecules, CD1a and CD83, suggesting the inhibition of DC differentiation and/or maturation. The suppressive effect on DCs was associated with the induction of apoptosis without the activation of caspase-3/7, 8, and 9, and this was supported by the morphological features indicating significant nuclear condensation. Oenothein B also markedly suppressed the production of inflammatory cytokines, such as IL-1β and IL-6, in a dose-dependent manner. These data may, in part, be able to explain the traditional use of tannin-containing medicinal plants for the treatment of a variety of inflammatory diseases, including inflammatory bowel disease, celiac disease, and rheumatoid arthritis.


Metastatic pancreatic carcinoma to the orbital apex presenting as a superior divisional third cranial nerve palsy.
Metastatic tumors to the orbit are rare, especially from a primary pancreatic carcinoma. A 59-year-old man presented with 4 weeks of right eye pain and eyelid swelling. There was right upper eyelid ptosis associated with a right supraduction deficit consistent with a superior divisional third cranial nerve (CN III) palsy. Magnetic resonance imaging revealed a right orbital apex lesion. A right orbital exenteration was performed for intractable and severe pain. Surgical pathology demonstrated a poorly differentiated carcinoma that was ultimately felt to be derived from the pancreas. In this report, we describe the clinical and neurological imaging findings of a superior divisional CN III palsy as the presenting manifestation of a presumed metastatic pancreatic carcinoma to the orbital apex, and review the neuroanatomy of CN III with particular emphasis on the anatomical bifurcation of the nerve into a superior and inferior division.


Disease activity outcomes with different washout periods after switching from natalizumab to an alternative disease-modifying therapy.
Washout periods (WPs) are increasingly shortened due to concerns of disease rebound when patients on natalizumab are switched to alternative disease-modifying therapies (DMTs). To characterize disease activity outcomes with different WPs when switching from natalizumab. We conducted a retrospective review of patients switching from natalizumab in our MS clinics. Disease activity (relapse, new T2 lesions and/or gadolinium enhancing lesions) between different WPs (days): 0-30, 31-60, and 61-180 were compared, during the first year after switching from natalizumab. To determine predictors of disease activity when switching to any DMT, multivariate logistic regression analysis was used. Post hoc analyses were performed to evaluate the impact of individual DMTs on disease activity. 335 patients discontinued natalizumab with WP: 0-30 (n = 104), 31-60 (n = 113), and 61-180 (n = 136). Disease activity occurred in 44.2% of patients in the 0-30 WP group, 18.6% in the 31-60 WP group, and 27.2% in the 61-180 WP group. There was a significant decrease in odds of disease activity with longer WP when compared to the 0-30 group: 31-60 (OR 0.241, 95% CI 0.108-0.514, p value < 0.001), and 61-180 (OR 0.439, 95% CI 0.218-0.871, p value < 0.05). Unexpectedly, in our study, patients who had the shortest WP 0-30 days had the most disease activity. Shortening WPs may not be enough to suppress disease activity post-natalizumab switch.


Progression of osteosarcoma after high-dose methotrexate: over-rescue by folinic acid.
A 16-year-old girl with a distal femur osteosarcoma became pain-free with the first treatment of methotrexate 12.5 g/m(2) and folinic acid 760 mg/m(2). She was inadvertently given 1275 mg folinic acid after the third dose. Four days later, pain and swelling recurred. Appreciating that this was "over rescue" rather than drug resistance led to the successful use of a further 8 doses of high-dose methotrexate when a suboptimal response was achieved with cisplatinum, Adriamycin, and ifosfamide. This is the first time "over rescue" has been documented in humans from high-dose folinic acid after methotrexate.


Mesenchymal stem cells administered in the early phase of tumorigenesis inhibit colorectal tumor development in rats.
To investigate the differences between the effects of mesenchymal stem cells (MSCs) administered in the early and late phases of tumorigenesis, MSCs were isolated from bone marrow and colorectal tumors were produced by exposing 7-week-old F344 rats to 1,2-dimethylhydrazine and dextran sulfate sodium. We evaluated tumor number and volume (week 25), MSC localization, number of aberrant crypt foci (ACF), transforming growth factor (TGF)-β1 protein levels in the rectum after administration of MSCs (week 5 or 15), and the effects of MSC-conditioned medium on ACL15 cell proliferation. Administered MSCs labeled with PKH26 were observed in the rectum. Administered MSCs in the early phase (week 5) before tumor occurrence (week 12) significantly decreased tumor number and volume (1.5 vs 4 and 21 mm(3) vs 170 mm(3); p<0.01), but not administered MSCs in the late phase (week 15). Administered MSCs in the early phase reduced ACF number on days 14 and 35 (1.9 vs 4.1 and 3.7 vs 7.3; p<0.01). Rectal TGF-β1 increased 1.3 fold on day 3, and MSC-conditioned medium containing TGF-β1 abundantly inhibited ACL15 cell proliferation. MSCs administered in the early phase but not late phase inhibited colorectal tumor development in a rat model.


[Differential light perception threshold of the visual field and ERG following operatively attached retinal detachment].
After surgical treatment of retinal detachment with a spontaneously pigmented demarcation line the visual fields of twelve patients were tested. The increment threshold of all positions (determined with the Octopus automatic perimeter system) was compared with the reduction in the scotopic and photopic ERG amplitudes (determinated with the CEMIDA system). This reduction in the ERG amplitudes was evaluated using the difference between the amplitude of the ERG waves of the eye with cured retinal detachment and of the healthy fellow eye. No great correlation between the two parameters was found, but it appeared that a reduced mean increment threshold correlated with a reduction in the a-wave amplitude.


Crystal structures of the transpeptidase domain of the Mycobacterium tuberculosis penicillin-binding protein PonA1 reveal potential mechanisms of antibiotic resistance.
Mycobacterium tuberculosis is a human respiratory pathogen that causes the deadly disease tuberculosis. The rapid global spread of antibiotic-resistant M. tuberculosis makes tuberculosis infections difficult to treat. To overcome this problem new effective antimicrobial strategies are urgently needed. One promising target for new therapeutic approaches is PonA1, a class A penicillin-binding protein, which is required for maintaining physiological cell wall synthesis and cell shape during growth in mycobacteria. Here, crystal structures of the transpeptidase domain, the enzymatic domain responsible for penicillin binding, of PonA1 from M. tuberculosis in the inhibitor-free form and in complex with penicillin V are reported. We used site-directed mutagenesis, antibiotic profiling experiments, and fluorescence thermal shift assays to measure PonA1's sensitivity to different classes of β-lactams. Structural comparison of the PonA1 apo-form and the antibiotic-bound form shows that binding of penicillin V induces conformational changes in the position of the loop β4'-α3 surrounding the penicillin-binding site. We have also found that binding of different antibiotics including penicillin V positively impacts protein stability, while other tested β-lactams such as clavulanate or meropenem resulted in destabilization of PonA1. Our antibiotic profiling experiments indicate that the transpeptidase activity of PonA1 in both M. tuberculosis and M. smegmatis mediates tolerance to specific cell wall-targeting antibiotics, particularly to penicillin V and meropenem. Because M. tuberculosis is an important human pathogen, these structural data provide a template to design novel transpeptidase inhibitors to treat tuberculosis infections. Structural data are available in the PDB database under the accession numbers 5CRF and 5CXW.


Measuring response in solid tumors: unidimensional versus bidimensional measurement.
Tumor shrinkage is a common end point used in screening new cytotoxic agents. The standard World Health Organization criterion for partial response is a 50% or more decrease in the sum of the products of two measurements (the maximum diameter of a tumor and the largest diameter perpendicular to this maximum diameter) of individual tumors. However, theoretically, the simple sum of the maximum diameters of individual tumors is more linearly related to cell kill than is the sum of the bidimensional products. It has been hypothesized that the calculation of bidimensional products is unnecessary, and a 30% decrease in the sum of maximum diameters of individual tumors (assuming spherical shape and equivalence to a 50% reduction in the sum of the bidimensional products) was proposed as a new criterion. We have applied the standard response and the new response criteria to the same data to determine whether the same number of responses in the same patients would result. Data from 569 patients included in eight studies of a variety of cancers were reanalyzed. The two response criteria were separately applied, and the results were compared using the kappa statistic. The importance of confirmatory measurements and the frequency of nonspherical tumors were also examined. In addition, for a subset of 128 patients, a unidimensional criterion for disease progression (30% increase in the sum of maximum diameters) was applied and compared with the standard definition of a 25% increase in the sum of the bidimensional products. Agreement between the unidimensional and bidimensional criteria was generally found to be good. The kappa statistic for concordance for overall response was 0.95. We conclude that one dimensional measurement of tumor maximum diameter may be sufficient to assess change in solid tumors.


Hyperhomocysteinemia and venous thromboembolic disease.
In spite of the large number of reports showing that hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis and arterial occlusive disease, this metabolite of the methionine pathway is measured in relatively few laboratories and its importance is not fully appreciated. Recent data strongly suggest that mild HHcy is also involved in the pathogenesis of venous thromboembolic disease. The aim of this paper is to analyze the most recent advances in this field. The material examined in the present review includes articles and abstracts published in journals covered by the Science Citation Index and Medline. In addition the authors of the present article have been working in the field of mild HHcy as cause of venous thromboembolic disease. The studies examined provide very strong evidence supporting the role of moderate HHcy in the development of premature and/or recurrent venous thromboembolic disease. High plasma homocysteine levels are also a risk factor for deep vein thrombosis in the general population. Folic acid fortification of food has been proposed as a major tool for reducing coronary artery disease mortality in the United States. Vitamin supplementation may also reduce recurrence of venous thromboembolic disease in patients with HHcy. At the present time, however, the clinical efficacy of this approach has not been tested. In addition, the bulk of evidence indicates that fasting total homocysteine determinations can identify up to 50% of the total population of hyperhomocysteinemic subjects. Patients with isolated methionine intolerance may benefit from vitamin B6 supplementation. Homocysteine-lowering vascular disease prevention trials are urgently needed. Such controlled studies, however, should not focus exclusively on fasting homocysteine determinations and folic acid monotherapy.


Clones of normal keratinocytes and a variety of simultaneously present epidermal neoplastic lesions contain a multitude of p53 gene mutations in a xeroderma pigmentosum patient.
A patient with xeroderma pigmentosum group C was extensively examined for mutations in the p53 gene in normal skin exposed to varying degrees of sunlight and in excisional biopsies of basal cell cancer, squamous cell cancer, and squamous cell dysplasia. Seventy-three samples were analyzed by microdissection of small cell clusters, followed by PCR and direct DNA sequencing. In skin taken from areas that most likely had never been exposed to the sun, no mutations were found. However, in skin exposed to the sun, we observed a multitude of mutations in the p53 gene. UV light-induced mutations were found in all types of lesions, as well as in clusters of morphologically normal epidermal cells. Twenty-nine distinct mutations were found in exons 5-8, all missense or nonsense, of which 27 (93%) were UV-specific C --> T or CC --> TT transitions at dipyrimidine sites of the nontranscribed strand. Two types of normal skin areas containing p53 mutations were observed: areas that stain strongly with p53 antibody (p53 patches) and those that do not stain. Because no silent or intron mutations were found in these cell clusters, the alterations in the p53 gene of morphologically normal cells are likely to have resulted in a selective growth advantage. The poor correlation between mutations and morphological phenotypes demonstrates that p53 mutations alone do not determine the phenotypes observed.


The Obligate Intracellular Bacterium Orientia tsutsugamushi Targets NLRC5 To Modulate the Major Histocompatibility Complex Class I Pathway.
Orientia tsutsugamushi is an obligate intracellular bacterium that infects mononuclear and endothelial cells to cause the emerging global health threat scrub typhus. The ability of O. tsutsugamushi to survive in monocytes facilitates bacterial dissemination to endothelial cells, which can subsequently lead to several potentially fatal sequelae. As a strict intracellular pathogen that lives in the cytoplasm of host cells, O. tsutsugamushi has evolved to counter adaptive immunity. How the pathogen does so and the outcome of this strategy in monocytes versus endothelial cells are poorly understood. This report demonstrates that O. tsutsugamushi reduces cellular levels of NOD-, LRR-, and CARD-containing 5 (NLRC5), a recently identified specific transactivator of major histocompatibility complex class I (MHC-I) component gene expression, to inhibit MHC-I biosynthesis. Importantly, the efficacy of this approach varies with the host cell type infected. In nonprofessional antigen-presenting HeLa and primary human aortic endothelial cells, the O. tsutsugamushi-mediated reduction of NLRC5 results in lowered MHC-I component transcription and, consequently, lower total and/or surface MHC-I levels throughout 72 h of infection. However, in infected THP-1 monocytes, which are professional antigen-presenting cells, the reductions in NLRC5 and MHC-I observed during the first 24 h reverse thereafter. O. tsutsugamushi is the first example of a microbe that targets NLRC5 to modulate the MHC-I pathway. The differential ability of O. tsutsugamushi to modulate this pathway in nonprofessional versus professional antigen-presenting cells could influence morbidity and mortality from scrub typhus.


Group medical visits after heart failure hospitalization: Study protocol for a randomized-controlled trial.
A primary goal of this research project is to better understand how shared medical appointments (SMAs) can improve the health status and decrease hospitalization and death for patients recently discharged with heart failure (HF) by providing education, disease state monitoring, medication titration, and social support to patients and their caregivers. We propose a 3-site randomized-controlled efficacy trial with mixed methods to test a SMA intervention, versus usual care. Patients within 12 weeks of a HF hospitalization will be randomized to receive either HF-SMA (intervention arm) with optional co-participation with their caregivers, versus usual care (control arm). The HF-SMA will be provided by a non-physician team composed of a nurse, a nutritionist, a health psychologist, a nurse practitioner and/or a clinical pharmacist and will consist of four sessions of 2-h duration that occur every other week for 8 weeks. Each session will start with an assessment of patient needs followed by theme-based disease self-management education, followed by patient-initiated disease management discussion, and conclude with break-out sessions of individualized disease monitoring and medication case management. The study duration will be 180 days for all patients from the day of randomization. The primary study hypothesis is that, compared with usual care, patients randomized to HF-SMA will experience better cardiac health status at 90 and 180 days follow-up. The secondary hypotheses are that, compared to usual care, patients randomized to HF-SMA will experience better overall health status, a combined endpoint of hospitalization and death, better HF self-care behavior, and lower B-type natriuretic peptide levels.


Metformin Use Is Associated With Lower Mortality in Veterans With Diabetes Hospitalized With Pneumonia.
Recent studies suggest that metformin use may be associated with improved infectious disease-related outcomes, whereas other papers suggest potentially worse outcomes in serious bacterial infections. Our purpose was to examine the association of prior outpatient prescription of metformin on 30- and 90-day mortality for older veterans with pre-existing diabetes hospitalized with pneumonia. We conducted a retrospective cohort study using national Department of Veterans Affairs data of patients ≥65 years with a prior history of diabetes who were hospitalized with pneumonia over a 10-year period (fiscal years 2002-2012.) For our primary analysis, we created a propensity score and matched metformin users to nonusers 1:1. We identified 34 759 patients who met the inclusion criteria, 20.3% of whom were prescribed metformin. Unadjusted 30-day mortality was 9.6% for those who received metformin versus 13.9% in nonusers (P < .003), and 90-day mortality was 15.8% for those who received metformin versus 23.0% for nonusers (P < .0001). For the propensity score model, we matched 6899 metformin users to 6899 nonusers. After propensity matching, both 30-day (relative risk [RR]: .86; 95% confidence interval [CI]: .78-.95) and 90-day (RR: .85; 95% CI: .79-.92) mortality was significantly lower for metformin users. Prior receipt of metformin was associated with significantly lower mortality after adjusting for potential confounders. Additional research is needed to examine the safety and potential benefits of metformin use in patients with respiratory infections.


Performance and prognostic utility of the 92-gene assay in the molecular subclassification of ampullary adenocarcinoma.
Ampullary adenocarcinoma is a rare gastrointestinal cancer associated with diverse outcomes due to clinical and pathological heterogeneity. Standardized methods to better prognosticate and inform therapeutic selection for ampullary adenocarcinoma are needed. This study explored the novel use and potential prognostic utility of a 92-gene cancer classifier in ampullary adenocarcinomas. In this prospectively-defined, blinded study of ampullary adenocarcinoma [N =54; stage T3 or higher (57 %); Grade III (44 %); Node positive (55 %)], the performance of a 92-gene classifier was examined to predict the ampullary subtype that was derived from histomorphological examination of resected ampullary samples. Outcome data for relapse-free survival (RFS) and overall survival (OS) were plotted to compare the prognostic utility of histological subtyping, histomolecular phenotyping, and the 92-gene classifier. Multivariate analysis was used to determine clinicopathological variables that were independently associated with overall survival. The 92-gene classifier demonstrated sensitivities and specificities of 85 % [95 % CI, 66-94] and 68 % [95 % CI, 48-84] and 64 % [95 % CI, 46-79] and 88 % [95 % CI, 70-98] for the pancreaticobiliary and intestinal histological subtypes, respectively. For the 92-gene classifier, improved outcomes were observed for the intestine versus the pancreaticobiliary prediction (median OS 108.1 v 36.4 months; HR, 2.17; 95 % CI, 0.98 to 4.79; P = 0.05). Similar results were seen for ampullary adenocarcinoma stratification by histological subtype (P = 0.04) and histomolecular phenotype (P = 0.02). Within poorly differentiated ampullary adenocarcinomas only the 92-gene classifier demonstrated statistically significant differences in RFS and OS (P < 0.05). Prognostic stratification of ampullary adenocarcinoma was similar for the 92-gene classifier, histological subtype, and histomolecular phenotype. The 92-gene classifier provides an unbiased standardized molecular-based approach to stratify ampullary tumors.


Responses of soil fungi to logging and oil palm agriculture in Southeast Asian tropical forests.
Human land use alters soil microbial composition and function in a variety of systems, although few comparable studies have been done in tropical forests and tropical agricultural production areas. Logging and the expansion of oil palm agriculture are two of the most significant drivers of tropical deforestation, and the latter is most prevalent in Southeast Asia. The aim of this study was to compare soil fungal communities from three sites in Malaysia that represent three of the most dominant land-use types in the Southeast Asia tropics: a primary forest, a regenerating forest that had been selectively logged 50 years previously, and a 25-year-old oil palm plantation. Soil cores were collected from three replicate plots at each site, and fungal communities were sequenced using the Illumina platform. Extracellular enzyme assays were assessed as a proxy for soil microbial function. We found that fungal communities were distinct across all sites, although fungal composition in the regenerating forest was more similar to the primary forest than either forest community was to the oil palm site. Ectomycorrhizal fungi, which are important associates of the dominant Dipterocarpaceae tree family in this region, were compositionally distinct across forests, but were nearly absent from oil palm soils. Extracellular enzyme assays indicated that the soil ecosystem in oil palm plantations experienced altered nutrient cycling dynamics, but there were few differences between regenerating and primary forest soils. Together, these results show that logging and the replacement of primary forest with oil palm plantations alter fungal community and function, although forests regenerating from logging had more similarities with primary forests in terms of fungal composition and nutrient cycling potential. Since oil palm agriculture is currently the mostly rapidly expanding equatorial crop and logging is pervasive across tropical ecosystems, these findings may have broad applicability.


Escaping Host Factor PI4KB Inhibition: Enterovirus Genomic RNA Replication in the Absence of Replication Organelles.
Enteroviruses reorganize cellular endomembranes into replication organelles (ROs) for genome replication. Although enterovirus replication depends on phosphatidylinositol 4-kinase type IIIβ (PI4KB), its role, and that of its product, phosphatidylinositol 4-phosphate (PI4P), is only partially understood. Exploiting a mutant coxsackievirus resistant to PI4KB inhibition, we show that PI4KB activity has distinct functions both in proteolytic processing of the viral polyprotein and in RO biogenesis. The escape mutation rectifies a proteolytic processing defect imposed by PI4KB inhibition, pointing to a possible escape mechanism. Remarkably, under PI4KB inhibition, the mutant virus could replicate its genome in the absence of ROs, using instead the Golgi apparatus. This impaired RO biogenesis provided an opportunity to investigate the proposed role of ROs in shielding enteroviral RNA from cellular sensors. Neither accelerated sensing of viral RNA nor enhanced innate immune responses was observed. Together, our findings challenge the notion that ROs are indispensable for enterovirus genome replication and immune evasion.


Genetic profiling of noncultivated bacteria from the rhizospheres of sugar beet (Beta vulgaris) reveal field and annual variability but no effect of a transgenic herbicide resistance.
In this field study, we compared the bacterial communities inhabiting the rhizosphere of a transgenic, herbicide-resistant sugar beet (Beta vulgaris) cultivar with those of its nonengineered counterpart, using a genetic profiling technique based on PCR amplifications of partial 16S rRNA gene sequences and single-strand conformation polymorphism (SSCP). As a control for the plasticity of the bacterial community, we also analyzed the influence of herbicides, the field heterogeneity, and the annual variation. DNA was isolated from bacterial cell consortia that were directly collected from root material. PCR was carried out with primers that hybridized to evolutionarily conserved regions flanking variable regions 4 and 5 of the 16S rRNA gene. SSCP patterns of these PCR products were composed of approximately 50 distinguishable bands, as detected by silver staining of the gels after electrophoresis. Patterns of the replicates and the different treatments were highly similar, but digital image and similarity analyses revealed differences that corresponded to the positions of the replicates in the field. In addition, communities collected from sugar beet in two successive growing seasons could be distinguished. In contrast, no effect of the transgenic herbicide resistance was detectable. Sequencing of 24 dominant products of the SSCP profiles indicated the presence of bacteria from different phylogenetic groups, with Proteobacteria and members of the Cytophaga-Flavobacterium-Bacteroides group being most abundant.


D-cycloserine facilitates extinction of cocaine self-administration in rats.
Previous research has indicated that D-cycloserine [DCS; a N-methyl-D-aspartate (NMDA) partial agonist] facilitates the extinction of conditioned fear as well as the extinction of cocaine conditioned place preference. Sprague Dawley rats were first trained to self-administer cocaine and then we compared their extinction behavior (lever pressing) following treatment with vehicle; 15 mg/kg DCS; or 30 mg/kg DCS. We showed that 30 mg/kg DCS, but not 15 mg/kg significantly accelerated extinction of cocaine self-administration behavior when compared with saline by almost half (4 days vs. 9 days). At 2 weeks when all animals had extinguished, there were no longer differences between the groups. The present findings support of the potential of NMDA partial agonists as prospectively valuable in facilitating the extinction of cocaine-seeking behavior. More specifically, we demonstrate that 30 mg/kg DCS was effective at significantly accelerating the extinction of cocaine self-administration behavior in rats. These results provide further support for the potential of DCS as a treatment strategy for addiction.


Annotating Temporal Relations to Determine the Onset of Psychosis Symptoms.
For patients with a diagnosis of schizophrenia, determining symptom onset is crucial for timely and successful intervention. In mental health records, information about early symptoms is often documented only in free text, and thus needs to be extracted to support clinical research. To achieve this, natural language processing (NLP) methods can be used. Development and evaluation of NLP systems requires manually annotated corpora. We present a corpus of mental health records annotated with temporal relations for psychosis symptoms. We propose a methodology for document selection and manual annotation to detect symptom onset information, and develop an annotated corpus. To assess the utility of the created corpus, we propose a pilot NLP system. To the best of our knowledge, this is the first temporally-annotated corpus tailored to a specific clinical use-case.


Blood Pressure-Lowering Effects of Alacalase-Hydrolyzed Camellia Seed Hull In Vitro and in Spontaneous Hypertensive Rats.
High blood pressure is one of the major risk factors for various diseases and angiotensin-converting enzyme (ACE) plays a critical role in blood pressure regulation. In our study, the responsive surface methodology was adopted to establish optimal Alcalase-hydrolysis conditions of camellia seed hull against ACE activity. The optimum conditions are hydrolysis temperature of 50.98°C, enzyme/substrate ratio of 2.85%, and hydrolysis pH of 7.12. In an animal feeding study, spontaneously hypertensive rats were treated with either a low or high dose of hydrolyzed Camellia japonica seed cake over 5 weeks. Even though systolic blood pressure was not statistically different, the high dose of C. japonica hydrolysate lowered diastolic blood pressure (106 ± 4.4 mmHg vs. 145 ± 5.9 mmHg) at the 5th week. A similar trend was also observed in serum ACE activity. Considering that this camellia seed hull is a major resource of this plant, our study provides important data to utilize this plant for both academic and industrial applications.


Boron-loaded liposomes in the treatment of hepatic metastases: preliminary investigation by autoradiography analysis.
Boronophenylalanine (BPA)-loaded conventional and stabilized liposomes were prepared by the reversed phase evaporation method to treat liver metastases by boron neutron capture therapy. Conventional vesicles were composed of phosphatidylcholine and cholesterol, molar ratio 1:1. To obtain stealth liposomes, GM1 or PEG were included in the lipidic bilayer at a concentration of 6.67 or 5 mol%, respectively. Large unilamellar vesicles were formulated encapsulating BPA in the liposome aqueous compartment as a complex with fructose; BPA free base also was embedded into the lipidic bilayer. In vivo experiments were carried out after intravenous injection of liposome suspensions in BD-IX strain rats in which liver metastases had been induced. Alpha particle spectroscopy associated with histological analysis was performed to visualize boron spatial distribution in liver. Simultaneously, tissue boron concentrations were determined using inductively coupled plasma-mass spectroscopy. Results showed that PEG-modified liposomes accumulated boron in therapeutic concentrations (> 30 micrograms boron/g tissue) in metastatic tissue. The PEG-liposomes could be further explored in enhancing boron delivery to tumor cells.


A PCR primer bank for quantitative gene expression analysis.
Although gene expression profiling by microarray analysis is a useful tool for assessing global levels of transcriptional activity, variability associated with the data sets usually requires that observed differences be validated by some other method, such as real-time quantitative polymerase chain reaction (real-time PCR). However, non-specific amplification of non-target genes is frequently observed in the latter, confounding the analysis in approximately 40% of real-time PCR attempts when primer-specific labels are not used. Here we present an experimentally validated algorithm for the identification of transcript-specific PCR primers on a genomic scale that can be applied to real-time PCR with sequence-independent detection methods. An online database, PrimerBank, has been created for researchers to retrieve primer information for their genes of interest. PrimerBank currently contains 147 404 primers encompassing most known human and mouse genes. The primer design algorithm has been tested by conventional and real-time PCR for a subset of 112 primer pairs with a success rate of 98.2%.


The impact of Helicobacter pylori on the presence of Barrett's esophagus in Azerbaijan, a high-prevalence area of infection.
There is a strong evidence that Helicobacter pylori infection is inversely associated with Barrett's esophagus. In a high-prevalence region of H. pylori, low rates of esophageal cancer and its precursor BE may indicate its preventive effect. The aim of this study is to determine the impact of H. pylori on characteristics of Barrett's esophagus. A total of 3317 outpatient upper endoscopy reports from 2013 to 2015 from an urban center in Azerbaijan from all patients with dyspepsia were retrospectively analyzed for patients with Barrett's esophagus. This was matched in a 1:2 ratio to age and gender matched control patients without Barrett's esophagus. The prevalence of H. pylori on Barrett's esophagus and the randomly selected control group were compared. There were 83 patients with BE and 167 control group cases. Biopsy-proven BE was diagnosed in 83 patients: 39 (47%) females, with mean age 43.1 ± 13.3 years. Of these, 13 (15.7%) had long segment and 70 (84.3%) had short segment Barrett's esophagus. A control group included 167 patients: 78 (46.7%) females, with mean age (45.8 ± 13.9). All patients were Caucasians. The rates of gastric inflammation, the presence of atrophy, and intestinal metaplasia in gastric specimens did not differ in patients versus controls. The prevalence of H. pylori was determined as 63.2% in male and 61.5 in female groups (odd ratio (OR) = 0.99 95%CI 0.97, 1.01; P = 0.22). Inflammation of gastric mucosa was strongly associated with the infection (67% vs. 33%; OR = 4.46 95% CI: 2.01, 9.92, P < 0.001). Atrophy was noted in majority of H. pylori-positive cases (OR = 1.43, 95% CI: 0.36, 5.65; P = 0.61). Gastric intestinal metaplasia was observed in 55.6% of H. pylori-positive patients and in 44.4% of negative individuals (OR = 0.74, 95% CI: 0.28, 1.94; P = 0.54). There was not a significant difference in the prevalence of HP in BE and control groups; 63.9% were positive for infection in BE cases and 61.7% of controls (OR = 1.10, 95% CI: 0.64, 1.90; P = 0.74). We found that neither presence of erosive esophagitis, length of BE nor dysplasia (45.5% of H. pylori-positive group, whereas 54.5%) was associated with the presence of the H. pylori infection (Table 1). In a predominantly Caucasian nation with a high prevalence of H. pylori gastritis, the presence of H. pylori was not inversely associated with the presence of Barrett's esophagus. These data challenge the mechanistic implications of this association.


Neuroendocrine hepatic metastases: does aggressive management improve survival?
The aim of this study was to determine whether aggressive management of neuroendocrine hepatic metastases improves survival. Survival in patients with carcinoid and pancreatic neuroendocrine tumors is significantly better than adenocarcinomas arising from the same organs. However, survival and quality of life are diminished in patients with neuroendocrine hepatic metastases. In recent years, aggressive treatment of hepatic neuroendocrine tumors has been shown to relieve symptoms. Minimal data are available, however, to document improved survival with this approach. The records of patients with carcinoid (n = 84) and pancreatic neuroendocrine tumors (n = 69) managed at our institution from January 1990 through July 2004 were reviewed. Eighty-four patients had malignant tumors, and hepatic metastases were present in 60 of these patients. Of these 60 patients, 23 received no aggressive treatment of their liver metastases, 19 were treated with hepatic resection and/or ablation, and 18 were managed with transarterial chemoembolization (TACE) frequently (n = 11) in addition to resection and/or ablation. These groups did not differ with respect to age, gender, tumor type, or extent of liver involvement. Median and 5-year survival were 20 months and 25% for the Nonaggressive group, >96 months and 72% for the Resection/Ablation group, and 50 months and 50% for the TACE group. The survival for the Resection/Ablation and the TACE groups was significantly better (P < 0.05) when compared with the Nonaggressive group. Patients with more than 50% liver involvement had a poor outcome (P < 0.001). These data suggest that aggressive management of neuroendocrine hepatic metastases does improve survival, that chemoembolization increases the patient population eligible for this strategy, and that patients with more than 50% liver involvement may not benefit from an aggressive approach.


[The problem of maxillary and mandibular mucosal condition before, during and after insertion of complete dentures].
The buccal mucosa recouvring the edentulous ridges is composed with two tissues limited by a basal membrane: a stratified squamous keratinized epithelium overlying the connective tissue. After insertion of complete denture, the most common pathology is the inflammation of the mucosa in front dentures from several causes (infection, trauma, allergy). The bacterial deposit control and effective hygiene are able to treat prosthetic stomatitis. Nevertheless it must be emphasize that prosthetic treatment must be correctly conducted and often controlled.


Bisulfighter: accurate detection of methylated cytosines and differentially methylated regions.
Analysis of bisulfite sequencing data usually requires two tasks: to call methylated cytosines (mCs) in a sample, and to detect differentially methylated regions (DMRs) between paired samples. Although numerous tools have been proposed for mC calling, methods for DMR detection have been largely limited. Here, we present Bisulfighter, a new software package for detecting mCs and DMRs from bisulfite sequencing data. Bisulfighter combines the LAST alignment tool for mC calling, and a novel framework for DMR detection based on hidden Markov models (HMMs). Unlike previous attempts that depend on empirical parameters, Bisulfighter can use the expectation-maximization algorithm for HMMs to adjust parameters for each data set. We conduct extensive experiments in which accuracy of mC calling and DMR detection is evaluated on simulated data with various mC contexts, read qualities, sequencing depths and DMR lengths, as well as on real data from a wide range of biological processes. We demonstrate that Bisulfighter consistently achieves better accuracy than other published tools, providing greater sensitivity for mCs with fewer false positives, more precise estimates of mC levels, more exact locations of DMRs and better agreement of DMRs with gene expression and DNase I hypersensitivity. The source code is available at http://epigenome.cbrc.jp/bisulfighter.


Role of GbpA protein, an important virulence-related colonization factor, for Vibrio cholerae's survival in the aquatic environment.
Vibrio cholerae N-acetyl glucosamine-binding protein A (GbpA) is a chitin binding protein and a virulence factor involved in the colonization of human intestine. We investigated the distribution and genetic variations of gbpA in 488 V. cholerae strains of environmental and clinical origin, belonging to different serogroups and biotypes. We found that the gene is consistently present and highly conserved including an environmental V. cholerae-related strain of ancestral origin. The gene was also consistently expressed in a number of representative V. cholerae strains cultured in laboratory aquatic microcosms under conditions simulating those found in temperate marine environments. Functional analysis carried out on V. cholerae O1 El Tor N16961 showed that GbpA is not involved in adhesion to inorganic surfaces but promotes interaction with environmental biotic substrates (plankton and bivalve hepatopancreas cells) representing known marine reservoir or host for the bacterium. It is suggested that the ability of GbpA to colonize human intestinal cells most probably originated from its primary function in the aquatic environment.


Clinical characteristics and evolution of hematological patients and COVID-19 in Argentina: a report from the Argentine Society of Hematology.
Individuals with malignancies and COVID-19 have a lower survival compared with the general population. However, the information about the impact of COVID-19 on the whole hematological population is scarce. We aimed to describe the 30th day overall survival (OS) after COVID-19 infection in patients with a hematological disease in Argentina. A completely anonymous survey from the Argentine Society of Hematology was delivered to all the hematologists in Argentina; it started in April 2020. A cut-off to analyze the data was performed in December 2020 and, finally, 419 patients were reported and suitable for the analysis (average age: 58 years, 90% with malignant diseases). After the COVID-19 diagnosis, the 30-day OS for the whole population was 80.2%. From the entire group (419), 101 (24.1%) individuals required intensive care unit admission, where the 30-day OS was 46.6%. Among allogeneic stem cell transplant recipients, the 30-day OS was 70.3%. Factors associated with a low OS were two or more comorbidities, an active hematological disease and history of chemotherapy. In individuals with the three factors, the 30-day OS was 49.6% while the 30-day OS in those without those factors was 100%. Patients with hematological diseases have a higher mortality than the general population. This group represents a challenge and requires careful decision-making of the treatment in order not to compromise the chances of cure.


Comparison of central adjudication of outcomes and onsite outcome assessment on treatment effect estimates.
Assessment of events by adjudication committees (ACs) is recommended in multicentre randomised controlled trials (RCTs). However, its usefulness has been questioned. The aim of this systematic review was to compare 1) treatment effect estimates of subjective clinical events assessed by onsite assessors versus by AC, and 2) treatment effect estimates according to the blinding status of the onsite assessor as well as the process used to select events to adjudicate. We searched Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, PsycINFO, CINAHL and Google Scholar (25 August 2015 as the last updated search date), using a combination of terms to retrieve RCTs with commonly used terms to describe ACs. We included all reports of RCTs and the published RCTs included in reviews and meta-analyses that reported the same subjective outcome event assessed by both an onsite assessor and an AC. We extracted the odds ratio (OR) from onsite assessment and the corresponding OR from AC assessment and calculated the ratio of the odds ratios (ROR). A ratio of odds ratios < 1 indicated that onsite assessors generated larger effect estimates in favour of the experimental treatment than ACs. Data from 47 RCTs (275,078 patients) were used in the meta-analysis. We excluded 11 RCTs because of incomplete outcome data to calculate the OR for onsite and AC assessments. On average, there was no difference in treatment effect estimates from onsite assessors and AC (combined ROR: 1.00, 95% confidence interval (CI) 0.97 to 1.04; I(2) = 0%, 47 RCTs). The combined ROR was 1.00 (95% CI 0.96 to 1.04; I(2) = 0%, 35 RCTs) when onsite assessors were blinded; 0.76 (95% CI 0.48 to 1.12, I(2) = 0%, two RCTs) when AC assessed events identified independently from unblinded onsite assessors; and 1.11 (95% CI 0.96 to 1.27, I(2) = 0%, 10 RCTs) when AC assessed events identified by unblinded onsite assessors. However, there was a statistically significant interaction between these subgroups (P = 0.03) AUTHORS' CONCLUSIONS: On average, treatment effect estimates for subjective outcome events assessed by onsite assessors did not differ from those assessed by ACs. Results of subgroup analysis showed an interaction according to the blinded status of onsite assessors and the process used to submit data to AC. These results suggest that the use of ACs might be most important when onsite assessors are not blinded and the risk of misclassification is high. Furthermore, research is needed to explore the impact of the different procedures used to select events to adjudicate.


SOME ECOLOGICAL ASPECTS OF THE PROBLEM OF ARTHROPOD-BORNE ANIMAL VIRUSES IN THE WESTERN PACIFIC AND SOUTH-EAST ASIA REGIONS.
In recent years there has been an increasing awareness of the importance of arthropod-borne viruses in the Western Pacific region and in South-East Asia. This realization of the importance of these viruses as causes of human morbidity and mortality and of economic loss due to infection of domestic animals has led to studies attempting to elucidate the basic ecology of some of these viruses. The author reviews the extent of knowledge of the ecology of Japanese and Murray Valley encephalitis viruses and indicates possible mechanisms for the overwintering of the viruses based on experiments in which other viruses were mainly used. He discusses the limited available knowledge on the ecology of dengue and emphasizes the necessity of research on the possibility that this disease is a zoonosis. A brief discussion is also given of the haemorrhagic diseases which are found in these regions and a brief description of the state of knowledge on the ecology of Kyasanur Forest disease and epidemic nephroso-nephritis. A brief discussion is also included on the ecology of the tick-borne Russian spring-summer encephalitis.


Interlamellar cohesion after corneal crosslinking using riboflavin and ultraviolet A light.
Collagen crosslinking treatment of progressive keratoconus using the photosensitiser riboflavin and ultraviolet A light of 370 nm wavelength has been shown to increase significantly the tensile strength of corneal collagen by about 300%. In keratoconus, interlamellar and interfibrillar slippage have been proposed as pathogenetic mechanisms. Therefore, the aim of this study was to assess the impact of collagen crosslinking on the interlamellar cohesive force. 72 post mortem porcine eyes were divided into six different treatment groups: the untreated control group, the standard crosslinking group, the hypo-osmolar crosslinking group, the stromal swelling group, the formaldehyde group and the α-amylase group. An anterior 9×4 mm strip of 400 μm thickness was prepared using a lamellar rotating microkeratome. For interlamellar cohesive force measurements a splitting plane was created at 50% depth. Force-distance profiles were recorded using a microcomputer-controlled biomaterial testing machine. The mean interlamellar cohesive force was 0.24 N/mm in the untreated control group, 0.26 N/mm in the standard crosslinking group, 0.25 N/mm in the hypo-osmolar crosslinking group, 0.23 N/mm in hydrated corneas, 0.27 N/mm in the formaldehyde group without statistically significant difference. Only the values of the α-amylase group were statistically significantly lowered by 31.5% to 0.16 N/mm. Surprisingly, corneal crosslinking does not increase the interlamellar cohesive force. In the α-amylase group the cohesive force was mainly decreased because of the digestion of proteoglycans. Crosslinking seems to stabilise only inter- and intrafibrillar, but not interlamellar cohesion.


Neonatal pemphigus vulgaris: IgG4 autoantibodies to desmoglein 3 induce skin blisters in newborns.
We report a case of neonatal pemphigus vulgaris presenting with skin lesions on the head, genital area, and right foot. Pemphigus vulgaris was diagnosed by the presence of circulating autoantibodies predominantly of the IgG4 subtype by indirect immunofluorescence microscopy and by enzyme-linked immunosorbent assay using recombinant desmoglein 3. This case demonstrates the pathogenic relevance of IgG4 autoantibodies to desmoglein 3 in the skin of neonates.


[Capgras syndrome--observations in 2 schizophrenic patients].
Two additional cases of Capgras syndrome were reported. In these schizophrenic patients, the abrupt hatred against family members seemed to contribute largely to the genesis of the syndrome in addition to delusional background. At the same time, the importance of delusional retrospective interpretation in these patients as well as in the previously reported case was discussed.


Flow increases tolerance of heat and hypoxia of an aquatic insect.
Recent experiments support the idea that upper thermal limits of aquatic insects arise, at least in part, from a lack of sufficient oxygen: rising temperatures typically stimulate metabolic demand for oxygen more than they increase rates of oxygen supply from the environment. Consequently, factors influencing oxygen supply, like water flow, should also affect thermal and hypoxia tolerance. We tested this hypothesis by measuring the effects of experimentally manipulated flows on the heat and hypoxia tolerance of aquatic nymphs of the giant salmonfly (Plecoptera: Pteronarcys californica), a common stonefly in western North America. As predicted, stoneflies in flowing water (10 cm s-1) tolerated water that was approximately 4°C warmer and that contained approximately 15% less oxygen than did those in standing water. Our results imply that the impacts of climate change on streamflow, such as changes in patterns of precipitation and decreased snowpack, will magnify the threats to aquatic insects from warmer water temperatures and lower oxygen levels.


2'-Fluoroarabinonucleic acid modification traps G-quadruplex and i-motif structures in human telomeric DNA.
Human telomeres and promoter regions of genes fulfill a significant role in cellular aging and cancer. These regions comprise of guanine and cytosine-rich repeats, which under certain conditions can fold into G-quadruplex (G4) and i-motif structures, respectively. Herein, we use UV, circular dichroism and NMR spectroscopy to study several human telomeric sequences and demonstrate that G4/i-motif-duplex interconversion kinetics are slowed down dramatically by 2'-β-fluorination and the presence of G4/i-motif-duplex junctions. NMR-monitored kinetic experiments on 1:1 mixtures of native and modified C- and G-rich human telomeric sequences reveal that strand hybridization kinetics are controlled by G4 or i-motif unfolding. Furthermore, we provide NMR evidence for the formation of a hybrid complex containing G4 and i-motif structures proximal to a duplex DNA segment at neutral pH. While the presence of i-motif and G4 folds may be mutually exclusive in promoter genome sequences, our results suggest that they may co-exist transiently as intermediates in telomeric sequences.


Energetics of overall metabolic reactions of thermophilic and hyperthermophilic Archaea and bacteria.
Thermophilic and hyperthermophilic Archaea and Bacteria have been isolated from marine hydrothermal systems, heated sediments, continental solfataras, hot springs, water heaters, and industrial waste. They catalyze a tremendous array of widely varying metabolic processes. As determined in the laboratory, electron donors in thermophilic and hyperthermophilic microbial redox reactions include H2, Fe(2+), H2S, S, S2O3(2-), S4O6(2-), sulfide minerals, CH4, various mono-, di-, and hydroxy-carboxylic acids, alcohols, amino acids, and complex organic substrates; electron acceptors include O2, Fe(3+), CO2, CO, NO3(-), NO2(-), NO, N2O, SO4(2-), SO3(2-), S2O3(2-), and S. Although many assimilatory and dissimilatory metabolic reactions have been identified for these groups of microorganisms, little attention has been paid to the energetics of these reactions. In this review, standard molal Gibbs free energies (DeltaGr(0)) as a function of temperature to 200 degrees C are tabulated for 370 organic and inorganic redox, disproportionation, dissociation, hydrolysis, and solubility reactions directly or indirectly involved in microbial metabolism. To calculate values of DeltaGr(0) for these and countless other reactions, the apparent standard molal Gibbs free energies of formation (DeltaG(0)) at temperatures to 200 degrees C are given for 307 solids, liquids, gases, and aqueous solutes. It is shown that values of DeltaGr(0) for many microbially mediated reactions are highly temperature dependent, and that adopting values determined at 25 degrees C for systems at elevated temperatures introduces significant and unnecessary errors. The metabolic processes considered here involve compounds that belong to the following chemical systems: H-O, H-O-N, H-O-S, H-O-N-S, H-O-C(inorganic), H-O-C, H-O-N-C, H-O-S-C, H-O-N-S-C(amino acids), H-O-S-C-metals/minerals, and H-O-P. For four metabolic reactions of particular interest in thermophily and hyperthermophily (knallgas reaction, anaerobic sulfur and nitrate reduction, and autotrophic methanogenesis), values of the overall Gibbs free energy (DeltaGr) as a function of temperature are calculated for a wide range of chemical compositions likely to be present in near-surface and deep hydrothermal and geothermal systems.


Nurse practitioners on the cutting edge of leadership.
For the past 10 to 15 years nurse practitioners (NPs) have been pioneers in the development of their roles within the health care system. My journey over the past 8 years has been to develop an interdependent role as the co-founder of a chronic pain rehabilitation program. Now, I believe, it is no longer sufficient to be an effective pioneer. The pioneer stage is over. We need to stop practicing from an industrial paradigm that views leadership as great men and great women who have certain preferred traits influencing followers to do what leaders want (Rost, 1994). NPs need interdependent team-based practices with the patient as a team member. We need to experience influential relationships between leaders and collaborators intending real change for mutual purposes.


Elevation of hepatic sulphotransferase activities in mice with resistance to cystic fibrosis.
The severity of intestinal disease in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) (-/-) mice has been reported to co-segregate with gene loci which contain the genes for hydroxysteroid sulphotransferase (SULT). Because of the potential involvement of steroid hormones in CF, we investigated levels of steroid SULT activity in the livers of CFTR mice to determine whether the levels of SULT activity correlate with the occurrence or severity of CF. To elucidate the possible role of SULT activity in ameliorating the deleterious effects of CF in CFTR (-/-) mice, we determined the levels of phenol SULT (PST), hydroxysteroid SULT [dehydroepiandrosterone (DHEA)-ST] and oestrogen SULT (EST) activity in control CFTR (+/+), heterozygous CFTR (+/-) and homozygous CFTR (-/-) mice, which survive to adulthood. The level of PST activity was not significantly different between any of the groups of mice, regardless of sex or genotype. Although DHEA-ST activity was significantly higher in female mice than in male mice, there was no difference in DHEA-ST activity that could be correlated with genotype. In contrast with PST and DHEA-ST activities, we found that some male and all female adult CFTR (-/-) mice had elevated, dramatically different levels of EST from both CFTR (+/+) and CFTR (+/-) mice. Results from these SULT activity experiments were confirmed by Northern-blot analysis of mouse-liver RNA. Subsequent studies with preweanling mice revealed no differences in the levels of EST that could be correlated with genotype. Thus this study indicates that EST is elevated significantly in CFTR (-/-) mice which survive to adulthood and provides important biochemical information that EST levels may be protective in CF.


Insulin use increases risk of asthma but metformin use reduces the risk in patients with diabetes in a Taiwanese population cohort.
Recent reports have suggested that insulin promotes airway smooth muscle contraction and enhances airway hyperresponsiveness, which are cardinal features of asthma. In contrast, metformin can reduce both airway inflammatory and remodeling properties. However, these results are all from in vitro and animal studies. This study investigated whether diabetes and various antidiabetic agents associate with the risk of asthma. We used a retrospective population-based cohort study using Taiwan's National Health Insurance claim database from 2000 to 2010 and a Cox proportional hazards regression model to compare the incidence of asthma between patients with diabetes (n = 19,428) and a matched non-diabetic group (n = 38,856). We also used a case-control study nested from the above cohort including 1,982 incident cases of asthma and 1,982 age- and sex-matched controls. A time density sampling technique was used to assess the effects of various antidiabetic agents on the risk of asthma. The incidence of asthma was significantly higher in the diabetic cohort than that in the non-diabetic cohort after adjustment for age, sex, and obesity, with a hazard ratio of 1.30 (95% confidence interval [CI]: 1.24-1.38). Insulin was found to increase the risk of asthma among diabetic patients (odds ratio [OR] 2.23; 95% CI: 1.52-3.58). In contrast, the use of metformin correlated with a decreased risk of asthma (OR 0.75; 95% CI: 0.60-0.95). Individuals with diabetes are at an increased risk of asthma. Insulin may further increase the risk of asthma, but the risk could possibly be reduced by using metformin.


Nanostructured silver-gold bimetallic SERS substrates for selective identification of bacteria in human blood.
Surface-enhanced Raman spectroscopy (SERS) is a potentially important tool in the rapid and accurate detection of pathogenic bacteria in biological fluids. However, for diagnostic application of this technique, it is necessary to develop a highly sensitive, stable, biocompatible and reproducible SERS-active substrate. In this work, we have developed a silver-gold bimetallic SERS surface by a simple potentiostatic electrodeposition of a thin gold layer on an electrochemically roughened nanoscopic silver substrate. The resultant substrate was very stable under atmospheric conditions and exhibited the strong Raman enhancement with the high reproducibility of the recorded SERS spectra of bacteria (E. coli, S. enterica, S. epidermidis, and B. megaterium). The coating of the antibiotic over the SERS substrate selectively captured bacteria from blood samples and also increased the Raman signal in contrast to the bare surface. Finally, we have utilized the antibiotic-coated hybrid surface to selectively identify different pathogenic bacteria, namely E. coli, S. enterica and S. epidermidis from blood samples.


Effects of Maghnian bentonite on physical properties of sandy soils under semi-arid Mediterranean climate.
This research has for object to study the influence of clay addition, i.e., Maghnian bentonite, like deposit clay, in the physical properties of sandy materials from Mostaganem plateau (North-West Algeria) submitted to salinity and sodicity. The first result was to show that the clay content changes drastically the physical properties of clay-sand mixtures. Important differences were observed as a function of the sand particle size distribution. At given clay content, the saturated Hydraulic Conductivity (HCs) was lower when the sand size was small and spread. For the coarse sand the salinity was maintained, even for high clay contents, a significant hydraulic conductivity. One of the main characteristics of Maghnia clay is the presence of calcium carbonates in the natural material. In comparison to that of Mostaganem clay of other deposit, it appears less sensitive to sodicity. An important aspect is the initial state of the clay when used in addition to sands, i.e., disturbance, conditions of preparation of sand clay mixtures and presence of associated components such as carbonates. Maghnia clay appeared to be adapted to the improvement of sandy soils, not because its mineralogical characteristics, but for its natural cationic form and obviously the presence of calcite in it.


The Change of Vocal Tract Length in People with Parkinson's Disease.
Hypokinetic dysarthria is one of the early symptoms of Parkinson's disease (PD) and has been proposed for early detection and also for monitoring of the progression of the disease. PD reduces the control of vocal tract muscles such as the tongue and lips and, therefore the length of the active vocal tract is altered. However, the change in the vocal tract length due to the disease has not been investigated. The aim of this study was to determine the difference in the apparent vocal tract length (AVTL) between people with PD and age-matched control healthy people. The phoneme, /a/ from the UCI Parkinson's Disease Classification Dataset and the Italian Parkinson's Voice and Speech Dataset were used and AVTL was calculated based on the first four formants of the sustained phoneme (F1-F4). The results show a correlation between Parkinson's disease and an increase in vocal tract length. The most sensitive feature was the AVTL calculated using the first formants of sustained phonemes (F1). The other significant finding reported in this article is that the difference is significant and only appeared in the male participants. However, the size of the database is not sufficiently large to identify the possible confounding factors such as the severity and duration of the disease, medication, age, and comorbidity factors.Clinical relevance-The outcomes of this research have the potential to improve the identification of early Parkinsonian dysarthria and monitor PD progression.


Boon or Bane? Anti-Tumor Necrosis Factor Therapy Complicated by Listeria monocytogenes Meningitis Culminating in Colectomy for Ulcerative Colitis.
Anti-tumor necrosis factor (TNF) biologics have revolutionized the management of inflammatory bowel diseases (IBDs) by promoting mucosal healing and delaying surgical intervention in ulcerative colitis (UC). However, biologics can potentiate the risk of opportunistic infections alongside the use of other immunomodulators in IBD. As recommended by the European Crohn's and Colitis Organisation (ECCO), anti-TNF-α therapy should be suspended in the setting of a potentially life-threatening infection. The objective of this case report was to highlight how the practice of appropriately discontinuing immunosuppression can exacerbate underlying colitis. We need to maintain a high index of suspicion for complications of anti-TNF therapy, so that we can intervene early and prevent potential adverse sequelae. In this report, a 62-year-old female presented to the emergency department with non-specific symptoms including fever, diarrhea and confusion on a background of known UC. She had been commenced on infliximab (INFLECTRA®) 4 weeks earlier. Inflammatory markers were elevated, and Listeria monocytogenes was identified on both blood cultures and cerebrospinal fluid (CSF) polymerase chain reaction (PCR). The patient improved clinically and completed a 21-day course of amoxicillin advised by microbiology. After a multidisciplinary discussion, the team planned to switch her from infliximab to vedolizumab (ENTYVIO®). Unfortunately, the patient re-presented to hospital with acute severe UC. Left-sided colonoscopy demonstrated modified Mayo endoscopic score 3 colitis. She has had recurrent hospital admissions over the past 2 years for acute flares of UC, ultimately culminating in colectomy. To our knowledge, our case-based review is unique in unpacking the dilemma of holding immunosuppression at the risk of IBD worsening.


Management and monitoring of patients treated with zonisamide: the OZONE study.
To characterise patients treated with zonisamide in everyday practice and describe the effectiveness and tolerability of treatment. This was an observational, longitudinal, naturalistic study, conducted by neurologists in France. Patients who had started zonisamide treatment at least three months prior to inclusion were eligible. Data were collected at routine consultations at inclusion (Visit 1) and three to six months later (Visit 2). At Visit 1, investigators documented epilepsy-related variables based on patient records before initiation of zonisamide and at inclusion. At Visit 2, the investigators re-evaluated seizure activity and rated effectiveness. Adverse events were also documented. A total of 428 patients were included in the study based on evaluation by 132 neurologists. Zonisamide was initiated at a daily dose of 50 mg and 25 mg in 61% and 31.8% of patients, respectively. The median maintenance dose was 300 mg/day. Prior to initiation of zonisamide, the mean seizure frequency was 16.0 seizures/month. This was reduced to 8.7 seizures/month at Visit 1 and to 7.1 seizures/month at Visit 2. The response rate and proportion of seizure-free patients was 61.9 and 31.1% at Visit 1 and 65.9 and 25.6% at Visit 2, respectively. The frequency of seizures at Visit 2 decreased significantly (p<0.05) for all seizure type subgroups, except for simple partial seizures. Responder rates were >60% for all analysed subgroups. The proportion of seizure-free patients was significantly higher in patients receiving bitherapy, compared to the others (p=0.007). The most frequently reported adverse event was somnolence (5.1%); three serious adverse events were reported. In everyday practice, zonisamide is principally used in association with other antiepileptic drugs for the treatment of focal epilepsy in adults. It is effective in improving seizure control and quality of life, and is generally well-tolerated.


Characterization of Endogenous SERINC5 Protein as Anti-HIV-1 Factor.
When expressed in virus-producing cells, the cellular multipass transmembrane protein SERINC5 reduces the infectivity of HIV-1 particles and is counteracted by HIV-1 Nef. Due to the unavailability of an antibody of sufficient specificity and sensitivity, investigation of SERINC5 protein expression and subcellular localization has been limited to heterologously expressed SERINC5. We generated, via CRISPR/Cas9-assisted gene editing, Jurkat T-cell clones expressing endogenous SERINC5 bearing an extracellularly exposed hemagglutinin (HA) epitope [Jurkat SERINC5(iHA knock-in) T cells]. This modification enabled quantification of endogenous SERINC5 protein levels and demonstrated a predominant localization in lipid rafts. Interferon alpha (IFN-α) treatment enhanced cell surface levels of SERINC5 in a ruxolitinib-sensitive manner in the absence of modulation of mRNA and protein quantities. Parental and SERINC5(iHA knock-in) T cells shared the ability to produce infectious wild-type HIV-1 but not an HIV-1 Δnef mutant. SERINC5-imposed reduction of infectivity involved a modest reduction of virus fusogenicity. An association of endogenous SERINC5 protein with HIV-1 Δnef virions was consistently detectable as a 35-kDa species, as opposed to heterologous SERINC5, which presented as a 51-kDa species. Nef-mediated functional counteraction did not correlate with virion exclusion of SERINC5, arguing for the existence of additional counteractive mechanisms of Nef that act on virus-associated SERINC5. In HIV-1-infected cells, Nef triggered the internalization of SERINC5 in the absence of detectable changes of steady-state protein levels. These findings establish new properties of endogenous SERINC5 expression and subcellular localization, challenge existing concepts of HIV-1 Nef-mediated antagonism of SERINC5, and uncover an unprecedented role of IFN-α in modulating SERINC5 through accumulation at the cell surface.IMPORTANCE SERINC5 is the long-searched-for antiviral factor that is counteracted by the HIV-1 accessory gene product Nef. Here, we engineered, via CRISPR/Cas9 technology, T-cell lines that express endogenous SERINC5 alleles tagged with a knocked-in HA epitope. This genetic modification enabled us to study basic properties of endogenous SERINC5 and to verify proposed mechanisms of HIV-1 Nef-mediated counteraction of SERINC5. Using this unique resource, we identified the susceptibility of endogenous SERINC5 protein to posttranslational modulation by type I IFNs and suggest uncoupling of Nef-mediated functional antagonism from SERINC5 exclusion from virions.


The Collaborative Study on the Genetics of Alcoholism: Overview.
Alcohol use disorders (AUD) are commonly occurring, heritable and polygenic disorders with etiological origins in the brain and the environment. To outline the causes and consequences of alcohol-related milestones, including AUD, and their related psychiatric comorbidities, the Collaborative Study on the Genetics of Alcoholism (COGA) was launched in 1989 with a gene-brain-behavior framework. COGA is a family based, diverse (~25% self-identified African American, ~52% female) sample, including data on 17,878 individuals, ages 7-97 years, in 2246 families of which a proportion are densely affected for AUD. All participants responded to questionnaires (e.g., personality) and the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) which gathers information on psychiatric diagnoses, conditions and related behaviors (e.g., parental monitoring). In addition, 9871 individuals have brain function data from electroencephalogram (EEG) recordings while 12,009 individuals have been genotyped on genome-wide association study (GWAS) arrays. A series of functional genomics studies examine the specific cellular and molecular mechanisms underlying AUD. This overview provides the framework for the development of COGA as a scientific resource in the past three decades, with individual reviews providing in-depth descriptions of data on and discoveries from behavioral and clinical, brain function, genetic and functional genomics data. The value of COGA also resides in its data sharing policies, its efforts to communicate scientific findings to the broader community via a project website and its potential to nurture early career investigators and to generate independent research that has broadened the impact of gene-brain-behavior research into AUD.


Periarterial papaverine to treat renal artery vasospasm during robot-assisted laparoscopic partial nephrectomy.
Renal artery vasospasm can be a troublesome complication during robot-assisted laparoscopic partial nephrectomy. Urologists performing this procedure, especially if utilizing selective arterial vascular microdissection, should be aware of using papaverine for both prevention and treatment of renal artery vasospasm. We present a 33-year-old male who developed severe renal artery vasospasm just with hilar dissection causing the kidney to become ischemic. Papaverine was topically applied on the renal arteries resulting in vasodilation and reperfusion of the kidney. Our objective of this report is to raise awareness of this complication as well as to review the literature on periarterial papaverine use and the dosing for topical applications.


Functional analysis of seven genes linked to body mass index and adiposity by genome-wide association studies: a review.
Genome-wide association studies (GWAS) have identified a total of about 40 single nucleotide polymorphisms (SNPs) that show significant linkage to body mass index, a widely utilised surrogate measure of adiposity. However, only 8 of these associations have been confirmed by follow-up GWAS using more sophisticated measures of adiposity (computed tomography). Among these 8, there is a SNP close to the gene FTO which has been the subject of considerable work to diagnose its function. The remaining 7 SNPs are adjacent to, or within, the genes NEGR1, TMEM18, ETV5, FLJ35779, LINGO2, SH2B1 and GIPR, most of which are less well studied than FTO, particularly in the context of obesity. This article reviews the available data on the functions of these genes, including information gleaned from studies in humans and animal models. At present, we have virtually no information on the putative mechanism associating the genes FLJ35779 and LINGO2 to obesity. All of these genes are expressed in the brain, and for 2 of them (SH2B1 and GIPR), a direct link to the appetite regulation system is known. SH2B1 is an enhancer of intracellular signalling in the JAK-STAT pathway, and GIPR is the receptor for an appetite-linked hormone (GIP) produced by the alimentary tract. NEGR1, ETV5 and SH2B1 all have suggested roles in neurite outgrowth, and hence SNPs adjacent to these genes may affect development of the energy balance circuitry. Although the genes have central patterns of gene expression, implying a central neuronal connection to energy balance, for at least 4 of them (NEGR1, TMEM18, SH2B1 and GIPR), there are also significant peripheral functions related to adipose tissue biology. These functions may contribute to their effects on the obese phenotype.


Bladder versus renal bacteriuria during pregnancy: recurrence after treatment.
Localization of bacteriuria has been shown to correlate with the pattern of recurrence after treatment. The immunofluorescent technique was used to localize infection in 233 pregnant women with asymptomatic bacteriuria to determine whether this would identify those who were at greater risk for recurrence. In both an indigent and a military population, the incidence of renal bacteriuria was 42%. Regardless of the site of infection, after one course of short-term (10-day) or long-term (21-day) antimicrobial therapy, almost two thirds of these women were abacteriuric for the remainder of gestation. Women given short-term treatment were more likely to have a recurrence within 2 weeks of completion of therapy than were women given long-term therapy (P less than 0.001). Moreover, these early recurrences were more frequent in women given short-term treatment for renal bacteriuria (P less than 0.05). Conversely, recurrences 6 or more weeks after completion of therapy, and regardless of site of infection, were more common in women given long-term treatment (P less than 0.01). Although the timing of recurrence varied significantly in relation to duration of treatment and site of infection, the ultimate risk of recurrence was not related to either. The conclusion is that localization of asymptomatic bacteriuria does not contribute to the management of pregnant women, since overall recurrence rates are independent of the site of infection.


Trapping a single vortex and reducing quasiparticles in a superconducting resonator.
Vortices trapped in thin-film superconducting microwave resonators can have a significant influence on the resonator performance. Using a variable-linewidth geometry for a weakly coupled resonator, we are able to observe the effects of a single vortex trapped in the resonator through field cooling. For resonant modes where the vortex is near a current antinode, the presence of even a single vortex leads to a measurable decrease in the quality factor and a dispersive shift of the resonant frequency. For modes with the vortex located at a current node, the presence of the vortex results in no detectable excess loss and, in fact, produces an increase in the quality factor. We attribute this enhancement to a reduction in the density of nonequilibrium quasiparticles in the resonator due to their trapping and relaxation near the vortex core.


Protein characteristics of thrombopoietin.
Thrombopoietin (TPO) was purified from irradiated thrombocytopenic rat plasma. In the process of purification, some biochemical and biological characteristics were investigated. Rat plasma TPO was extremely hydrophobic and exhibited multiple peaks of activity on gel filtration. Both the low and high molecular weight fractions were separately subjected to further purification. Consequently, a rat TPO cDNA was cloned based on the amino acid sequences of purified rat plasma TPO. It revealed that each final purified rat plasma TPO was not a full-length form. In addition, rat hepatocytes and three rat hepatoma cell lines were found to produce rat TPO. Each native TPO derived from cultured cells was also partially purified, and hepatocyte-derived TPOs were shown to be heterogeneous in molecular weight. To study the structure of TPO, various recombinant TPO molecules were generated. Two disulfide bonds (Cys7-Cys151 and Cys29-Cys85) located in the N-terminal domain of TPO have an important effect on its biological activity. The human TPO muteins, sequentially deleted from the C-terminal, were expressed in COS-1 cells. TPO (1-151) was active, but TPO (1-150), which lacks Cys151, did not exhibit TPO activity. These findings indicate that the region essential for TPO activity is the N-terminal domain, which contains two disulfide bonds. Although the role(s) of the C-terminal domain is not clear at present, the potential N-glycosylation in the C-terminal domain is not directly required for exhibiting TPO activity.


Molecular fluorescence-guided surgery of peritoneal carcinomatosis of colorectal origin: a single-centre feasibility study.
Optimum cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is essential for the curative treatment of peritoneal carcinomatosis of colorectal origin. At present, surgeons depend on visual inspection and palpation for tumour detection. Improved detection of tumour tissue using molecular fluorescence-guided surgery could not only help attain a complete cytoreduction of metastatic lesions, but might also prevent overtreatment by avoiding resection of benign lesions. For this non-randomised, single-centre feasibility study, we enrolled patients with colorectal peritoneal metastases scheduled for cytoreductive surgery and HIPEC. 2 days before surgery, 4·5 mg of the near-infrared fluorescent tracer bevacizumab-IRDye800CW was administered intravenously. The primary objectives were to determine the safety and feasibility of molecular fluorescence-guided surgery using bevacizumab-IRDye800CW. Molecular fluorescence-guided surgery was deemed safe if no allergic or anaphylactic reactions were recorded and no serious adverse events were attributed to bevacizumab-IRDye800CW. The technique was deemed feasible if bevacizumab-IRDye800CW enabled detection of fluorescence signals intraoperatively. Secondary objectives were correlation of fluorescence with histopathology by back-table imaging of the fresh surgical specimen and semi-quantitative ex-vivo analyses of formalin-fixed paraffin embedded (FFPE) tissue on all peritoneal lesions. Additionally, VEGF-α staining and fluorescence microscopy was done. This study is registered with the Netherlands Trial Registry, number NTR4632. Between July 3, 2014, and March 2, 2015, seven patients were enrolled in the study. One patient developed an abdominal sepsis 5 days postoperatively and another died from an asystole 4 days postoperatively, most probably due to a cardiovascular thromboembolic event. However, both serious adverse events were attributed to the surgical cytoreductive surgery and HIPEC procedure. No serious adverse events related to bevacizumab-IRDye800CW occurred in any of the patients. Intraoperatively, fluorescence was seen in all patients. In two patients, additional tumour tissue was detected by molecular fluorescence-guided surgery that was initially missed by the surgeons. During back-table imaging of fresh surgical specimens, a total of 80 areas were imaged, marked, and analysed. All of the 29 non-fluorescent areas were found to contain only benign tissue, whereas tumour tissue was detected in 27 of 51 fluorescent areas (53%). Ex-vivo semi-quantification of 79 FFPE peritoneal lesions showed a tumour-to-normal ratio of 6·92 (SD 2·47). Molecular fluorescence-guided surgery using the near-infrared fluorescent tracer bevacizumab-IRDye800CW is safe and feasible. This technique might be of added value for the treatment of patients with colorectal peritoneal metastases through improved patient selection and optimisation of cytoreductive surgery. A subsequent multicentre phase 2 trial is needed to make a definitive assessment of the diagnostic accuracy and the effect on clinical decision making of molecular fluorescence-guided surgery. FP-7 Framework Programme BetaCure and SurgVision BV.