Functional polymorphisms in cell death pathway genes FAS and FASL contribute to risk of lung cancer.
The FAS and FASL system plays a key role in regulating apoptotic cell death and corruption of this signalling pathway has been shown to participate in immune escape and tumorigenesis. There is reduced expression of FAS but elevated expression of FASL in many types of human cancers including lung cancer. We recently reported an association between functional polymorphisms in FAS (-1377G-->A) and FASL (-844T-->C) and risk of oesophageal cancer. To examine the contribution of these polymorphisms to risk of developing lung cancer. Genotypes of 1000 lung cancer patients and 1270 controls were analysed by PCR based restriction fragment length polymorphism. Associations with risk of lung cancer were estimated by logistic regression. Compared with non-carriers, there was a 1.6 fold excess risk of developing lung cancer for carriers of the FAS -1377AA genotype (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.21 to 2.10; p = 0.001), and 1.8 fold excess risk (OR 1.79, 95% CI 1.26 to 2.52; p = 0.001) for carriers of FASL -844CC. Gene-gene interaction of FAS and FASL polymorphisms increased risk of lung cancer in a multiplicative manner (OR for the carriers of both FAS -1377AA and FASL -844CC genotypes 4.18, 95% CI 2.83 to 6.18). Gene-environment interaction of FAS or FASL polymorphism and smoking associated with increased risk of lung cancer was also found. These results are consistent with our initial findings in oesophageal cancer and further support the hypothesis that the FAS and FASL triggered apoptosis pathway plays an important role in human carcinogenesis.


Three R2R3-MYB transcription factors regulate distinct floral pigmentation patterning in Phalaenopsis spp.
Orchidaceae are well known for their fascinating floral morphologic features, specialized pollination, and distinctive ecological strategies. With their long-lasting flowers of various colors and pigmentation patterning, Phalaenopsis spp. have become important ornamental plants worldwide. In this study, we identified three R2R3-MYB transcription factors PeMYB2, PeMYB11, and PeMYB12. Their expression profiles were concomitant with red color formation in Phalaenopsis spp. flowers. Transient assay of overexpression of three PeMYBs verified that PeMYB2 resulted in anthocyanin accumulation, and these PeMYBs could activate the expression of three downstream structural genes Phalaenopsis spp. Flavanone 3-hydroxylase5, Phalaenopsis spp. Dihydroflavonol 4-reductase1, and Phalaenopsis spp. Anthocyanidin synthase3. In addition, these three PeMYBs participated in the distinct pigmentation patterning in a single flower, which was revealed by virus-induced gene silencing. In the sepals/petals, silencing of PeMYB2, PeMYB11, and PeMYB12 resulted in the loss of the full-red pigmentation, red spots, and venation patterns, respectively. Moreover, different pigmentation patterning was regulated by PeMYBs in the sepals/petals and lip. PeMYB11 was responsive to the red spots in the callus of the lip, and PeMYB12 participated in the full pigmentation in the central lobe of the lip. The differential pigmentation patterning was validated by RNA in situ hybridization. Additional assessment was performed in six Phalaenopsis spp. cultivars with different color patterns. The combined expression of these three PeMYBs in different ratios leads to a wealth of complicated floral pigmentation patterning in Phalaenopsis spp.


Regulation of human liver delta-aminolevulinic acid synthase by bile acids.
Aminolevulinic acid synthase 1 (ALAS1) is the rate-limiting enzyme of heme synthesis in the liver and is highly regulated to adapt to the metabolic demand of the hepatocyte. In the present study, we describe human hepatic ALAS1 as a new direct target of the bile acid-activated nuclear receptor farnesoid X receptor (FXR). Experiments in primary human hepatocytes and in human liver slices showed that ALAS1 messenger RNA (mRNA) and activity is increased upon exposure to chenodeoxycholic acid (CDCA), the most potent natural FXR ligand, or the synthetic FXR-specific agonist GW4064. Moreover, overexpression of a constitutively active form of FXR further increased ALAS1 mRNA expression. In agreement with these observations, an FXR response element was identified in the 5' flanking region of human ALAS1 and characterized in reporter gene assays. A highly conserved FXR binding site (IR1) within a 175-bp fragment at -13 kilobases upstream of the transcriptional start site was able to trigger an FXR-specific increase in luciferase activity upon CDCA treatment. Site-directed mutagenesis of IR1 abolished this effect. Binding of FXR/retinoid acid X receptor heterodimers was demonstrated by mobility gel shift experiments. These data strongly support a role of bile acid-activated FXR in the regulation of human ALAS1 and, consequently, hepatic porphyrin and heme synthesis. These data also suggest that elevated endogenous bile acids may precipitate neuropsychiatric attacks in patients with acute hepatic porphyrias.


Factors associated with virologic failure in HIV patients on antiretroviral therapy.
To determine the factors associated with virologic failure n HIV patients on antiretroviral treatment treated in a Colombian health institution. This was a cross-sectional observational retrospective analytical study of HIV patients receiving antiretroviral treatment between 2007‑2020. Sociodemographic, pharmacological and clinical variables were collected, including viral load, adherence, and the medication possession ratio. For statistical analysis, crude and adjusted odds ratios and confidence intervals were obtained. In a population of 5,406 patients, the proportion of virologic failure was 16.7%. Moreover, in the adjusted model, an association was found between virologic failure and time on treatment greater than one year, medication possession ratio under 80%, failure to claim medications from the pharmacy due to dose omission or discontinuation, adherence under 85%, CD4 count under 500, total cholesterol levels above 201 mg/dL, high density lipoproteins under 39 mg/dL and presence of mycosis. In our cohort of HIV patients, short treatment periods, CD4 counts under 200, a low medication possession ratio, failure to timely claim medications from the pharmacy due to omission or discontinuation, and a lower degree of adherence were factors related to virologic failure.


Cell of origin determines tumor phenotype in an oncogenic Ras/p53 knockout transgenic model of high-grade glioma.
Human high-grade gliomas (HGGs) are known for their histologic diversity. To address the role of cell of origin in glioma phenotype, transgenic mice were generated in which oncogenic Ras and p53 deletion were targeted to neural stem/progenitor cells (NSPCs) and mature astrocytes. The hGFAP-Cre/Kras/p53 mice develop multifocal HGGs that vary histopathologically and with respect to the expression of markers associated with NSPCs. One HGG pattern strongly expressed markers of NSPCs and arose near the subventricular zone. Additional nonoverlapping patterns that recapitulate human HGG variants were present simultaneously in the same brain. These neoplastic foci were more often cortical or leptomeningeal based, and the neoplastic cells lacked expression of NSPC markers. To determine whether cell of origin determines tumor phenotype, astrocytes and NSPCs were harvested from neonatal mutant pups. Onorthotopic transplantation, early-passage astrocytes and NSPCs formed tumors that differed in engraftment rates, latency to clinical signs, histopathology, and protein expression. Astrocyte-derivedtumors were more aggressive, had giant-cell histology, and glial fibrillary acidic protein expression. The NSPC-derived tumors retained NSPC markers and showed evidence of differentiation along astrocytic, oligodendroglial, and neuronal lineages. These results indicate that identical tumorigenic stimuli produce markedly different glioma phenotypes, depending on the differentiation status of the transformed cell.


Supraorbital ethmoid cell: a consistent landmark for endoscopic identification of the anterior ethmoidal artery.
To demonstrate that the supraorbital ethmoid cell (SOEC) is a consistent and reliable landmark in identification of the anterior ethmoidal artery (AEA). Retrospective radiographic study. Tertiary care rhinology practice. The computed tomography (CT) scans for 78 consecutive patients were evaluated for the presence of SOECs, degree of pneumatization, and location of the AEA in relation to fixed anatomic structures. Forty-one patients with normal SOECs were identified and compared with a group of 15 patients with pathological expansion of the SOEC secondary to inflammatory disease. The CT findings were correlated with endoscopic findings. The incidence of SOECs was 53%. Compared to normal SOECs, expanded SOECs had significantly greater pneumatization laterally (9.3 vs 18.5 mm, respectively; P < .0001) and AEAs that were significantly farther from the skull base (1.3 vs 6.6 mm, respectively; P < .0001). The distance between the AEA and the nasal beak was similar between the 2 groups (P = .1). More importantly, 68 of 68 sides with normal SOECs (100%) demonstrated the AEA within or in continuity with the posterior border of the SOEC opening. In patients with pathological expansion, the AEA remained within the posterior border of the SOEC opening in 19 of 19 sides (100%), despite significant expansion of the cell superolaterally. This is the first study to demonstrate a consistent landmark to identify the AEA even in cases of distorted anatomy of the frontal recess. Identifying the SOEC is a practical and reliable technique for minimizing the risk of injury to the AEA during frontal recess surgery.


Nuclear enlargement induced by hepatocarcinogens alters ploidy.
Treatment of rats with low doses of hepatocarcinogens is associated with a number of phenomena, including nuclear enlargement and altered nucleocytoplasmic compartmentation, which potentially reflect initiatory changes. Since a number of investigations have indicated that changes in ploidy may relate to the development of altered foci and/or hepatocellular carcinomas in liver, and since nuclear enlargement may be associated with changes in DNA content, we examined the ploidy of rat hepatocytes following essentially nontoxic low-dose carcinogen treatment. Treatments with thioacetamide, 2-acetylaminofluorene, or dimethylnitrosamine were all associated with a notable shift of nuclei from diploid to tetraploid, in the apparent absence of nuclear replication. These changes were similar in magnitude to that associated with the substantial liver regeneration induced by carbon tetrachloride. If it is argued that cell replication is a necessary prerequisite for the completion of initiation, these data suggest that there may be thresholds for initiation.


Brain PET and functional MRI: why simultaneously using hybrid PET/MR systems?
In the last 20 years growing attention has been devoted to multimodal imaging. The recent literature is rich of clinical and research studies that have been performed using different imaging modalities on both separate and integrated positron emission tomography (PET) and magnetic resonance (MR) scanners. However, today, hybrid PET/MR systems measure signals related to brain structure, metabolism, neurochemistry, perfusion, and neuronal activity simultaneously, i.e. in the same physiological conditions. A frequently raised question at meeting and symposia is: "Do we really need a hybrid PET/MR system? Are there any advantages over acquiring sequential and separate PET and MR scans?" The present paper is an attempt to answer these questions specifically in relation to PET combined with functional magnetic resonance imaging (fMRI) and arterial spin labeling. We searched (last update: June 2017) the databases PubMed, PMC, Google Scholar and Medline. We also included additional studies if they were cited in the selected articles. No language restriction was applied to the search, but the reviewed articles were all in English. Among all the retrieved articles, we selected only those performed using a hybrid PET/MR system. We found a total of 17 papers that were selected and discussed in three main groups according to the main radiopharmaceutical used: 18F-fluorodeoxyglucose (18F-FDG) (N.=8), 15O-water (15O-H2O) (N.=3) and neuroreceptors (N.=6). Concerning studies using 18F-FDG, simultaneous PET/fMRI revealed that global aspects of functional organization (e.g. graph properties of functional connections) are partially associated with energy consumption. There are remarkable spatial and functional similarities across modalities, but also discrepant findings. More work is needed on this point. There are only a handful of papers comparing blood flow measurements with PET 15O-H2O and MR arterial spin label (ASL) measures, and they show significant regional CBF differences between these two modalities. However, at least in one study the correlation at the level of gray, white matter, and whole brain is rather good (r=0.94, 0.8, 0.81 respectively). Finally, receptor studies show that simultaneous PET/fMRI could be a useful tool to characterize functional connectivity along with dynamic neuroreceptor adaptation in several physiological (e.g. working memory) or pathological (e.g. pain) conditions, with or without drug administrations. The simultaneous acquisition of PET (using a number of radiotracers) and functional MRI (using a number of sequences) offers exciting opportunities that we are just beginning to explore. The results thus far are promising in the evaluation of cerebral metabolism/flow, neuroreceptor adaptation, and network's energetic demand.


Survival and reoperation in acute aortic syndromes-a single-centre experience of 912 patients.
Acute aortic syndromes are associated with poor outcomes, despite diagnostic and therapeutic advances. We analysed trends in volumes and outcomes from 2000 to 2021. The study population includes 494 type A acute aortic syndromes (TAAAS) (54.2%) and 418 type B acute aortic syndromes (TBAAS) (45.8%). Primary outcomes were in-hospital mortality, long-term survival and freedom from aortic reoperation. Regardless the type of acute aortic syndrome, patient volumes increased over time. Patients with TBAAS were older, more likely to have comorbid conditions and previous cardiac surgery (P < 0.001), while cerebrovascular accidents were more frequent in TAAAS (P < 0.05). Among TAAAS, 143 (28.9%) required total arch and 351 (71.1%) hemiarch replacement. TBAAS management was medical therapy in 182 (43.5%), endovascular in 198 (47.4%) and surgical in 38 (9.1%) cases. Overall in-hospital mortality was 14.6% [18.2% in TAAAS (95% confidence interval (CI) 14.4-21.2%) vs 10.7% in TBAAS (95% CI 7.8%-13.7%); P = 0.0027]. After propensity score adjustment, in-hospital mortality exhibited a significantly decreasing trend from 2000 to 2021 (P < 0.001) in TAAAS and TBAAS. 1-, 5- and 10-year survival was 74.2%, 62.2% and 45.5% in TAAAS and 75.4%, 60.7% and 41.0% in TBAAS (P = 0.975), with no differences among treatment strategies. The adjusted cumulative reoperation risk at 10 years was more than two-fold in TBAAS versus TAAAS (9.5% vs 20.5%, hazard ratio (HR) = 2.30, 95% I 1.31-4.04). In the last decades, better patient triage and surgical/endovascular techniques led to substantial improvements in the management of acute aortic syndrome, with reduction in early mortality and reoperation rate. However, long-term mortality is still >50%.


Association of variants at UMOD with chronic kidney disease and kidney stones-role of age and comorbid diseases.
Chronic kidney disease (CKD) is a worldwide public health problem that is associated with substantial morbidity and mortality. To search for sequence variants that associate with CKD, we conducted a genome-wide association study (GWAS) that included a total of 3,203 Icelandic cases and 38,782 controls. We observed an association between CKD and a variant with 80% population frequency, rs4293393-T, positioned next to the UMOD gene (GeneID: 7369) on chromosome 16p12 (OR = 1.25, P = 4.1x10(-10)). This gene encodes uromodulin (Tamm-Horsfall protein), the most abundant protein in mammalian urine. The variant also associates significantly with serum creatinine concentration (SCr) in Icelandic subjects (N = 24,635, P = 1.3 x 10(-23)) but not in a smaller set of healthy Dutch controls (N = 1,819, P = 0.39). Our findings validate the association between the UMOD variant and both CKD and SCr recently discovered in a large GWAS. In the Icelandic dataset, we demonstrate that the effect on SCr increases substantially with both age (P = 3.0 x 10(-17)) and number of comorbid diseases (P = 0.008). The association with CKD is also stronger in the older age groups. These results suggest that the UMOD variant may influence the adaptation of the kidney to age-related risk factors of kidney disease such as hypertension and diabetes. The variant also associates with serum urea (P = 1.0 x 10(-6)), uric acid (P = 0.0064), and suggestively with gout. In contrast to CKD, the UMOD variant confers protection against kidney stones when studied in 3,617 Icelandic and Dutch kidney stone cases and 43,201 controls (OR = 0.88, P = 5.7 x 10(-5)).


Chaperones as thermodynamic sensors of drug-target interactions reveal kinase inhibitor specificities in living cells.
The interaction between the HSP90 chaperone and its client kinases is sensitive to the conformational status of the kinase, and stabilization of the kinase fold by small molecules strongly decreases chaperone interaction. Here we exploit this observation and assay small-molecule binding to kinases in living cells, using chaperones as 'thermodynamic sensors'. The method allows determination of target specificities of both ATP-competitive and allosteric inhibitors in the kinases' native cellular context in high throughput. We profile target specificities of 30 diverse kinase inhibitors against >300 kinases. Demonstrating the value of the assay, we identify ETV6-NTRK3 as a target of the FDA-approved drug crizotinib (Xalkori). Crizotinib inhibits proliferation of ETV6-NTRK3-dependent tumor cells with nanomolar potency and induces the regression of established tumor xenografts in mice. Finally, we show that our approach is applicable to other chaperone and target classes by assaying HSP70/steroid hormone receptor and CDC37/kinase interactions, suggesting that chaperone interactions will have broad application in detecting drug-target interactions in vivo.


D-mannose-specific Immunoglobulin M in Grass Puffer (Takifugu niphobles), a Nonhost Fish of a Monogenean Ectoparasite Heterobothrium okamotoi, Can Act as a Trigger for its Parasitism.
Heterobothrium okamotoi, a monogenean gill parasite, exhibits high host specificity for the tiger puffer, Takifugu rubripes, and it has been experimentally verified that the parasite cannot colonize either closely related species such as the grass puffer Takifugu niphobles or distantly related fish such as the red seabream Pagrus major. Previously, we demonstrated in T. rubripes that immunoglobulin M (IgM) with d-mannose affinity induced deciliation of the oncomiracidia, the first step of parasitism, indicating that the parasite utilizes the molecule as a receptor for infection. In the present study, we purified mannose-specific IgM from 2 nonhost species, T. niphobles and P. major, by affinity and gel-filtration chromatography techniques and compared their deciliation-inducing activity against H. okamotoi oncomiracidia. The IgM of the former showed activity, whereas the latter had no effect, suggesting that in addition to d-mannose-binding ability, the crystallizable fragment domain of IgM, which is not part of the antigen-binding domain, plays an important role in host recognition by the oncomiracidia, such as direct binding to the parasites. It also suggests that the host specificity of H. okamotoi is relatively low upon initial recognition, and the specificity is established by exclusion in nonhosts during a later stage.


Corticosterone secretion after inhibition of prostaglandin synthesis by indomethacin.
Systemic indomethacin (Ind) administration decreased prostaglandin F (PGF) content of the rat adrenal to less than 1.4 pg/mg. This was less than 5% of the adrenal PGF content in the gelatin-treated (Gel) control group (34 pg/mg). Basal plasma corticosterone levels were increased by the Ind treatment. Since the calculated metabolic clearance rate for corticosterone was unchanged, this increase was attributed to an enhanced adrenal secretion rate that was secondary to elevated plasma ACTH concentration. Ether exposure in the presence of Ind did not stimulate a normal rise in plasma corticosterone or adrenal corticosteroidogenesis. Adrenal responsiveness to exogenous ACTH was reduced after Ind treatment. There was a normal rise in plasma ACTH levels following ether exposure confirming the adrenal as the site of inhibition. Systemic Ind treatment thus appears to have two sites of action in altering plasma corticosterone levels: 1) a direct effect on the adrenal, inhibiting normal secretion in response to acute elevations of plasma ACTH, and 2) an action at the pituitary or hypothalamic level, eliciting an increase in basal ACTH secretion.


Association between total, processed, red and white meat consumption and all-cause, CVD and IHD mortality: a meta-analysis of cohort studies.
An association between processed and red meat consumption and total mortality has been reported by epidemiological studies; however, there are many controversial reports regarding the association between meat consumption and CVD and IHD mortality. The present meta-analysis was carried out to summarise the evidence from prospective cohort studies on the association between consumption of meat (total, red, white and processed) and all-cause, CVD and IHD mortality. Cohort studies were identified by searching the PubMed and ISI Web of Knowledge databases. Risk estimates for the highest v. the lowest consumption category and dose-response meta-analysis were calculated using a random-effects model. Heterogeneity among the studies was also evaluated. A total of thirteen cohort studies were identified (1 674 272 individuals). Subjects in the highest category of processed meat consumption had 22 and 18 % higher risk of mortality from any cause and CVD, respectively. Red meat consumption was found to be associated with a 16 % higher risk of CVD mortality, while no association was found for total and white meat consumption. In the dose-response meta-analysis, an increase of 50 g/d in processed meat intake was found to be positively associated with all-cause and CVD mortality, while an increase of 100 g/d in red meat intake was found to be positively associated with CVD mortality. No significant associations were observed between consumption of any type of meat and IHD mortality. The results of the present meta-analysis indicate that processed meat consumption could increase the risk of mortality from any cause and CVD, while red meat consumption is positively but weakly associated with CVD mortality. These results should be interpreted with caution due to the high heterogeneity observed in most of the analyses as well as the possibility of residual confounding.


The interaction of CGRP and adrenomedullin with a receptor expressed in the rat pulmonary vascular endothelium.
An abundant, seven trans-membrane domain receptor related to the calcitonin receptor has been studied by a number of groups without identification of its ligand. A recent report claimed that the receptor was a type 1 CGRP receptor (Aiyar et al J. Biol. Chem. 271 11325-11329 (1996)). We have studied the equivalent rat sequence in transfected cells. When expressed in 293 cells the receptor interacts with CGRP and adrenomedullin with KD values of 1.2 nM for CGRP and 11 nM for adrenomedullin. Both ligands cause an elevation of intracellular cAMP with EC50 values of 4 nM and 20 nM respectively and these effects are inhibited by the antagonist CGRP8-37. The receptor is expressed at high levels in the pulmonary vascular endothelium. Both the pharmacological data and the localisation are consistent with the conclusion that the orphan receptor is a type J CGRP receptor. However, when expressed in COS-7 cells, no receptor activity could be demonstrated suggesting that 293 cells contain a factor necessary for functional receptor expression.


Efficient discontinuous Galerkin scheme for analyzing nanostructured photoconductive devices.
Incorporation of plasmonic nanostructures in the design of photoconductive devices (PCDs) has significantly improved their optical-to-terahertz conversion efficiency. However, this improvement comes at the cost of increased complexity for the design and simulation of these devices. Indeed, accurate and efficient modeling of multiphysics processes and intricate device geometries of nanostructured PCDs is challenging due to the high computational cost resulting from multiple characteristic scales in time and space. In this work, a discontinuous Galerkin (DG)-based unit-cell scheme for efficient simulation of PCDs with periodic nanostructures is proposed. The scheme considers two physical stages of the device and models them using two coupled systems: a system of Poisson and drift-diffusion equations describing the nonequilibrium steady state, and a system of Maxwell and drift-diffusion equations describing the transient stage. A "potential-drop" boundary condition is enforced on the opposing boundaries of the unit cell to mimic the effect of the bias voltage. Periodic boundary conditions are used for carrier densities and electromagnetic fields. The unit-cell model described by these coupled equations and boundary conditions is discretized using DG methods. Numerical results demonstrate that the proposed DG-based unit-cell scheme has the same accuracy in predicting the THz photocurrent as the DG framework that takes into account the whole device, while it significantly reduces the computational cost.


Agroinfiltration and PVX agroinfection in potato and Nicotiana benthamiana.
Agroinfiltration and PVX agroinfection are two efficient transient expression assays for functional analysis of candidate genes in plants. The most commonly used agent for agroinfiltration is Agrobacterium tumefaciens, a pathogen of many dicot plant species. This implies that agroinfiltration can be applied to many plant species. Here, we present our protocols and expected results when applying these methods to the potato (Solanum tuberosum), its related wild tuber-bearing Solanum species (Solanum section Petota) and the model plant Nicotiana benthamiana. In addition to functional analysis of single genes, such as resistance (R) or avirulence (Avr) genes, the agroinfiltration assay is very suitable for recapitulating the R-AVR interactions associated with specific host pathogen interactions by simply delivering R and Avr transgenes into the same cell. However, some plant genotypes can raise nonspecific defense responses to Agrobacterium, as we observed for example for several potato genotypes. Compared to agroinfiltration, detection of AVR activity with PVX agroinfection is more sensitive, more high-throughput in functional screens and less sensitive to nonspecific defense responses to Agrobacterium. However, nonspecific defense to PVX can occur and there is a risk to miss responses due to virus-induced extreme resistance. Despite such limitations, in our experience, agroinfiltration and PVX agroinfection are both suitable and complementary assays that can be used simultaneously to confirm each other's results.


A common functional regulatory variant at a type 2 diabetes locus upregulates ARAP1 expression in the pancreatic beta cell.
Genome-wide association studies (GWASs) have identified more than 70 loci associated with type 2 diabetes (T2D), but for most, the underlying causal variants, associated genes, and functional mechanisms remain unknown. At a T2D- and fasting-proinsulin-associated locus on 11q13.4, we have identified a functional regulatory DNA variant, a candidate target gene, and a plausible underlying molecular mechanism. Fine mapping, conditional analyses, and exome array genotyping in 8,635 individuals from the Metabolic Syndrome in Men study confirmed a single major association signal between fasting proinsulin and noncoding variants (p = 7.4 × 10(-50)). Measurement of allele-specific mRNA levels in human pancreatic islet samples heterozygous for rs11603334 showed that the T2D-risk and proinsulin-decreasing allele (C) is associated with increased ARAP1 expression (p < 0.02). We evaluated four candidate functional SNPs for allelic effects on transcriptional activity by performing reporter assays in rodent pancreatic beta cell lines. The C allele of rs11603334, located near one of the ARAP1 promoters, exhibited 2-fold higher transcriptional activity than did the T allele (p < 0.0001); three other candidate SNPs showed no allelic differences. Electrophoretic mobility shift assays demonstrated decreased binding of pancreatic beta cell transcriptional regulators PAX6 and PAX4 to the rs11603334 C allele. Collectively, these data suggest that the T2D-risk allele of rs11603334 could abrogate binding of a complex containing PAX6 and PAX4 and thus lead to increased promoter activity and ARAP1 expression in human pancreatic islets. This work suggests that increased ARAP1 expression might contribute to T2D susceptibility at this GWAS locus.


Blood-based protein biomarkers for diagnosis of Alzheimer disease.
To identify plasma biomarkers for the diagnosis of Alzheimer disease (AD). Baseline plasma screening of 151 multiplexed analytes combined with targeted biomarker and clinical pathology data. General community-based, prospective, longitudinal study of aging. A total of 754 healthy individuals serving as controls and 207 participants with AD from the Australian Imaging Biomarker and Lifestyle study (AIBL) cohort with identified biomarkers that were validated in 58 healthy controls and 112 individuals with AD from the Alzheimer Disease Neuroimaging Initiative (ADNI) cohort. A biomarker panel was identified that included markers significantly increased (cortisol, pancreatic polypeptide, insulinlike growth factor binding protein 2, β(2) microglobulin, vascular cell adhesion molecule 1, carcinoembryonic antigen, matrix metalloprotein 2, CD40, macrophage inflammatory protein 1α, superoxide dismutase, and homocysteine) and decreased (apolipoprotein E, epidermal growth factor receptor, hemoglobin, calcium, zinc, interleukin 17, and albumin) in AD. Cross-validated accuracy measures from the AIBL cohort reached a mean (SD) of 85% (3.0%) for sensitivity and specificity and 93% (3.0) for the area under the receiver operating characteristic curve. A second validation using the ADNI cohort attained accuracy measures of 80% (3.0%) for sensitivity and specificity and 85% (3.0) for area under the receiver operating characteristic curve. This study identified a panel of plasma biomarkers that distinguish individuals with AD from cognitively healthy control subjects with high sensitivity and specificity. Cross-validation within the AIBL cohort and further validation within the ADNI cohort provides strong evidence that the identified biomarkers are important for AD diagnosis.


Evaluation of novel computerized tomography scoring systems in human traumatic brain injury: An observational, multicenter study.
Traumatic brain injury (TBI) is a major contributor to morbidity and mortality. Computerized tomography (CT) scanning of the brain is essential for diagnostic screening of intracranial injuries in need of neurosurgical intervention, but may also provide information concerning patient prognosis and enable baseline risk stratification in clinical trials. Novel CT scoring systems have been developed to improve current prognostic models, including the Stockholm and Helsinki CT scores, but so far have not been extensively validated. The primary aim of this study was to evaluate the Stockholm and Helsinki CT scores for predicting functional outcome, in comparison with the Rotterdam CT score and Marshall CT classification. The secondary aims were to assess which individual components of the CT scores best predict outcome and what additional prognostic value the CT scoring systems contribute to a clinical prognostic model. TBI patients requiring neuro-intensive care and not included in the initial creation of the Stockholm and Helsinki CT scoring systems were retrospectively included from prospectively collected data at the Karolinska University Hospital (n = 720 from 1 January 2005 to 31 December 2014) and Helsinki University Hospital (n = 395 from 1 January 2013 to 31 December 2014), totaling 1,115 patients. The Marshall CT classification and the Rotterdam, Stockholm, and Helsinki CT scores were assessed using the admission CT scans. Known outcome predictors at admission were acquired (age, pupil responsiveness, admission Glasgow Coma Scale, glucose level, and hemoglobin level) and used in univariate, and multivariable, regression models to predict long-term functional outcome (dichotomizations of the Glasgow Outcome Scale [GOS]). In total, 478 patients (43%) had an unfavorable outcome (GOS 1-3). In the combined cohort, overall prognostic performance was more accurate for the Stockholm CT score (Nagelkerke's pseudo-R2 range 0.24-0.28) and the Helsinki CT score (0.18-0.22) than for the Rotterdam CT score (0.13-0.15) and Marshall CT classification (0.03-0.05). Moreover, the Stockholm and Helsinki CT scores added the most independent prognostic value in the presence of other known clinical outcome predictors in TBI (6% and 4%, respectively). The aggregate traumatic subarachnoid hemorrhage (tSAH) component of the Stockholm CT score was the strongest predictor of unfavorable outcome. The main limitations were the retrospective nature of the study, missing patient information, and the varying follow-up time between the centers. The Stockholm and Helsinki CT scores provide more information on the damage sustained, and give a more accurate outcome prediction, than earlier classification systems. The strong independent predictive value of tSAH may reflect an underrated component of TBI pathophysiology. A change to these newer CT scoring systems may be warranted.


Utility of In Vitro Mutagenesis of RPE65 Protein for Verification of Mutational Pathogenicity Before Gene Therapy.
Next-generation sequencing can detect variants of uncertain significance (VUSs), for some of which gene therapy would not be advantageous. Therefore, the pathogenicity of compound heterozygous or homozygous variants should be confirmed before bilateral vitrectomy and administration of voretigene neparvovec-rzyl. To describe an in vitro mutagenesis assay for assessing the pathogenicity of variants in the RPE65 gene. This case series was conducted at 2 tertiary referral centers. Clinical history, imaging, and electrophysiologic testing results were reviewed from September 5, 2008, to December 31, 2019. Participants were 4 pediatric patients with Leber congenital amaurosis who were evaluated for or met the inclusion criteria for phase 1 to 3 clinical trials or were referred for voretigene neparvovec-rzyl treatment. A functional assay was used to confirm the pathogenicity of novel RPE65 VUSs in 4 patients with Leber congenital amaurosis. Four patients with Leber congenital amaurosis had VUSs in RPE65. Patients 1 and 2 were siblings with the homozygous VUS c.311G>T p.(G104V). Patient 3 was a compound heterozygote with 1 known pathogenic allele, c.1202_1203insCTGG p.(Glu404AlafsTer4), and 1 VUS, c.311G>T p.(G104V), which segregated to separate alleles. Patient 4 was also a compound heterozygote with 1 pathogenic variant, c.11 + 5G>A, and 1 variant in trans, c.1399C>T p.(P467S). In vitro mutagenesis revealed that the G104V and P467S RPE65 proteins were catalytically inactive (0% isomerase activity). Patients 1 and 2 were excluded from participation in a phase 1 trial owing to high Adeno-associated virus 2 capsid-neutralizing antibodies. Patients 3 (G104V) and 4 (P467S) underwent successful surgical gene therapy with voretigene neparvovec-rzyl, and their response to lower white light intensity and visual field increased in fewer than 30 days after gene therapy intervention. Findings from this study suggest that, in patients with missense mutations in RPE65, functional assays of protein function can be performed to assess the pathogenicity of variants in both compound heterozygous and homozygous cases. Given the potential risks of gene therapy operations, in vitro RPE65 activity testing should be considered to avoid the possibility of treating a false genotype.


Renal candidiasis in neonates with candiduria.
Candida species commonly cause urinary tract infection in infants admitted to neonatal intensive care units. The purpose of this study was to describe the natural history of renal candidiasis as evidenced by sonography in infants with candiduria. The medical records of all infants who developed candiduria during their neonatal intensive care hospitalization between 1982 and 1993 were reviewed. Candiduria was defined as the isolation of Candida from (1) one or more specimens obtained by bladder catheterization or suprapubic aspiration, (2) one or more voided specimens and concurrent positive cultures from another sterile body site or (3) one or more voided specimens and changes on renal ultrasound consistent with renal candidiasis. Renal ultrasounds were retrospectively reviewed by one pediatric radiologist. Nonshadowing echogenic foci were considered evidence of renal fungus balls. Forty-one infants with candiduria were identified. Thirty-six infants underwent 1 or more renal imaging studies (ultrasonography, 35; computerized tomography, 1). The incidence of renal candidiasis in neonates with candiduria, defined as renal fungus balls or renal fungal abscess, was 42%. Of the 13 patients who had sonographic abnormalities suggestive of renal fungus balls, 7 had abnormalities on the first ultrasound obtained after the discovery of candiduria, whereas 6 patients developed abnormalities between 8 and 39 days later. Serial renal ultrasounds are required to reliably detect late appearing renal fungus balls in neonates with candiduria. Complications requiring surgical intervention, like urinary tract obstruction, were uncommon.


[Successful endovascular treatment for orbital varix: case report and literature review].
The pathogenesis and clinical manifestations of orbital varix and choice of its surgical treatment are described. Complete occlusion of abnormal portions of the superior ophthalmic vein with preserved blood flow along the main trunk is a specific feature of this observation. By analyzing the data available in the literature and their clinical observation of successful endovascular treatment for orbital varix with a complete regression of its clinical symptoms, the authors substantiate indications for transvenous orbital varix occlusion.


Somite boundary determination in normal and clock-less vertebrate embryos.
Vertebrate segments called somites are generated by periodic segmentation of the presomitic mesoderm (PSM). In the most accepted theoretical model for somite segmentation, the clock and wavefront (CW) model, a clock that ticks to determine particular timings and a wavefront that moves posteriorly are presented in the PSM, and somite positions are determined when the clock meets the posteriorly moving wavefront somewhere in the PSM. Over the last two decades, it has been revealed that the molecular mechanism of the clock and wavefront in vertebrates is based on clock genes including Hes family transcription factors and Notch effectors that oscillate within the PSM to determine particular timings and fibroblast growth factor (FGF) gradients, acting as the posteriorly moving wavefront to determine the position of somite segmentation. A clock-less condition in the CW model was predicted to form no somites; however, irregularly sized somites were still formed in mice and zebrafish, suggesting that this was one of the limitations of the CW model. Recently, we performed interdisciplinary research of experimental and theoretical biological studies and revealed the mechanisms of somite boundary determination in normal and clock-less conditions by characterization of the FGF/extracellular signal-regulated kinase (ERK) activity dynamics. Since features of the molecular clock have already been described in-depth in several reviews, we summarized recent findings regarding the role of FGF/ERK signaling in somite boundary formation and described our current understanding of how FGF/ERK signaling contributes to somitogenesis in normal and clock-less conditions in this review.


Enantioselective organocatalytic alpha-fluorination of aldehydes.
The first direct enantioselective catalytic alpha-fluorination of aldehydes has been accomplished. The use of enamine catalysis has provided a new organocatalytic strategy for the enantioselective fluorination of aldehydes to generate alpha-fluoro aldehydes, an important chiral synthon for medicinal agent synthesis. The use of imidazolidinone 1 as the asymmetric catalyst has been found to mediate the fluorination of a large variety of aldehyde substrates with N-fluorobenzenesulfonimide serving as the electrophilic source of fluorine. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. While catalyst quantities of 20 mol % were generally employed in this study, successful halogenation can be accomplished using catalyst loadings as low as 2.5 mol %.


Layer-by-layer assembly of Cu3(BTC)2 on chitosan non-woven fabrics: a promising haemostatic decontaminant composite material against sulfur mustard.
Cu3(BTC)2 (H3BTC = 1,3,5-benzenetricarboxylic acid) was anchored onto the surface of carboxymethylated chitosan non-woven fabrics by a controllable layer-by-layer technique in alternating solution baths of Cu(OAc)2·H2O and H3BTC solutions, and the resulting [Cu3(BTC)2]n@chitosan non-woven fabric composite materials (n = number of alternate deposition cycles) were thoroughly characterized. The results showed that the composite materials not only exhibited excellent decontamination ability against sulfur mustard (HD), with an enhanced degradation rate of HD with increasing n, but also possessed remarkable haemostasis performance. The degradation efficiency of sulfur mustard by [Cu3(BTC)2]4@chitosan was found to be much higher than that of pristine [Cu3(BTC)2]4. The inherent haemostatic capabilities of the chitosan non-woven fabrics were not affected by the growth of Cu3(BTC)2 on the surface of chitosan. Oral and histological toxicity examinations of the pristine Cu3(BTC)2 sample showed that damage and toxicity in the viscera of mice was very low, even if the intra-gastric administration dose of Cu3(BTC)2 reached a very high level (50 mg of Cu3(BTC)2 per kg of mouse). The results have shown that the as-prepared composite can be used safely as a promising haemostatic decontaminant with good recyclability against sulfur mustard.


Species composition and seasonal abundance of stink bugs (Hemiptera: Pentatomidae) in Louisiana soybean.
In Louisiana during the last decade, the redbanded stink bug, Piezodorus guildinii (Westwood), has become a significant and yield-limiting pest of soybean. The redbanded stink bug was previously reported in the United States in 1892, but was never considered an economically important pest until recently. Soybeans representing four maturity groups (MG) III, IV, V, and VI were sampled weekly from beginning bloom (R1) to physiological maturity (R8) during 2008-2010 at five locations across Louisiana to determine the Pentatomidae composition. In total, 13,146 stink bugs were captured and subsequently identified to species. The predominant species included the redbanded stink bug (54.2%); southern green stink bug (27.1%), Nezara viridula L.; brown stink bug (6.6%), Euschistus servus (Say); and green stink bug (5.5%), Acrosternum hilare (Say). Redbanded stink bug comprised the largest percentage of the complex collected at four of the five survey sites. Numbers exceeding action thresholds of this stink bug complex were only detected during R4 to R7 growth stages. Redbanded stink bug accounted for the largest percentage of the stink bug complex in early maturing soybean varieties (MG III [86%] and IV [60%]) and declined in later maturing soybeans (MG V [54%] and VI [50%]). The redbanded stink bug was initially identified in southern Louisiana during 2000 and had been reported in all soybean producing regions in Louisiana by 2006. This survey is the first to report the redbanded stink bug as a predominant pest of soybeans from locations within the United States.


Early SNS-Based Monitoring System for the COVID-19 Outbreak in Japan: A Population-Level Observational Study.
The World Health Organization declared the novel coronavirus outbreak (COVID-19) to be a pandemic on March 11, 2020. Large-scale monitoring for capturing the current epidemiological situation of COVID-19 in Japan would improve preparation for and prevention of a massive outbreak. A chatbot-based healthcare system named COOPERA (COvid-19: Operation for Personalized Empowerment to Render smart prevention And care seeking) was developed using the LINE app to evaluate the current Japanese epidemiological situation. LINE users could participate in the system either though a QR code page in the prefectures' websites or a banner at the top of the LINE app screen. COOPERA asked participants questions regarding personal information, preventive actions, and non-specific symptoms related to COVID-19 and their duration. We calculated daily cross correlation functions between the reported number of infected cases confirmed using polymerase chain reaction and the symptom-positive group captured by COOPERA. We analyzed 206,218 participants from three prefectures reported between March 5 and 30, 2020. The mean age of participants was 44.2 (standard deviation, 13.2) years. No symptoms were reported by 96.93% of participants, but there was a significantly positive correlation between the reported number of COVID-19 cases and self-reported fevers, suggesting that massive monitoring of fever might help to estimate the scale of the COVID-19 epidemic in real time. COOPERA is the first real-time system being used to monitor trends in COVID-19 in Japan and provides useful insights to assist political decisions to tackle the epidemic.


Positive Emotion Specificity and Mood Symptoms in an Adolescent Outpatient Sample.
Research on positive emotion disturbance has gained increasing attention, yet it is not clear which specific positive emotions are affected by mood symptoms, particularly during the critical period of adolescence. This is especially pertinent for identifying potential endophenotypic markers associated with mood disorder onset and course. The present study examined self-reported discrete positive and negative emotions in association with clinician-rated manic and depressive mood symptoms in a clinically and demographically diverse group of 401 outpatient adolescents between 11-18 years of age. Results indicated that higher self reported joy and contempt were associated with increased symptoms of mania, after controlling for symptoms of depression. Low levels of joy and high sadness uniquely predicted symptoms of depression, after controlling for symptoms of mania. Results were independent of age, ethnicity, gender and bipolar diagnosis. These findings extend work on specific emotions implicated in mood pathology in adulthood, and provide insights into associations between emotions associated with goal driven behavior with manic and depressive mood symptom severity in adolescence. In particular, joy was the only emotion associated with both depressive and manic symptoms across adolescent psychopathology, highlighting the importance of understanding positive emotion disturbance during adolescent development.


Medium effects on the photophysical properties of terbium(III) complexes with pyridine-2,6-dicarboxylate.
Emission quantum yields and excited-state lifetimes of mono-, bis- and tris-complexes of terbium(III) with pyridine-2,6-dicarboxylate (DPA) have been measured for aqueous solutions as a function of pH and in the presence of six different anions: bromide, chloride, sulfate, perchlorate, acetate and nitrate. The state of ligation of the terbium ion had a more dramatic effect on photophysical properties of the complexes in comparison with the alteration of other medium parameters. An increase in the number of DPA ligands, coordinated with Tb3+ (from zero to three) resulted in an increase in the emission quantum yield from 0.06 to approximately 0.4, with concurrent prolongation of the excited-state lifetime from 0.5 to approximately 2 ms. It was determined that both an increase in the non-radiative decay rates and a decrease in the values of the radiative decay rate constants, contribute to the luminescence quenching that was detected when the number of DPA ligands was decreased and/or the media acidified. The purpose of this investigation is to aid in the establishment of optimal conditions for conducting terbium(III)-based emission assays for DPA, which is found in the coats of endospores.


A multilevel model to address batch effects in copy number estimation using SNP arrays.
Submicroscopic changes in chromosomal DNA copy number dosage are common and have been implicated in many heritable diseases and cancers. Recent high-throughput technologies have a resolution that permits the detection of segmental changes in DNA copy number that span thousands of base pairs in the genome. Genomewide association studies (GWAS) may simultaneously screen for copy number phenotype and single nucleotide polymorphism (SNP) phenotype associations as part of the analytic strategy. However, genomewide array analyses are particularly susceptible to batch effects as the logistics of preparing DNA and processing thousands of arrays often involves multiple laboratories and technicians, or changes over calendar time to the reagents and laboratory equipment. Failure to adjust for batch effects can lead to incorrect inference and requires inefficient post hoc quality control procedures to exclude regions that are associated with batch. Our work extends previous model-based approaches for copy number estimation by explicitly modeling batch and using shrinkage to improve locus-specific estimates of copy number uncertainty. Key features of this approach include the use of biallelic genotype calls from experimental data to estimate batch-specific and locus-specific parameters of background and signal without the requirement of training data. We illustrate these ideas using a study of bipolar disease and a study of chromosome 21 trisomy. The former has batch effects that dominate much of the observed variation in the quantile-normalized intensities, while the latter illustrates the robustness of our approach to a data set in which approximately 27% of the samples have altered copy number. Locus-specific estimates of copy number can be plotted on the copy number scale to investigate mosaicism and guide the choice of appropriate downstream approaches for smoothing the copy number as a function of physical position. The software is open source and implemented in the R package crlmm at Bioconductor (http:www.bioconductor.org).


The neutral, hydrophobic isoleucine at position I521 in the extracellular S4 domain of hERG contributes to channel gating equilibrium.
The human ether-a-go-go related (hERG) potassium channel has unusual functional characteristics in that the rates of channel activation and deactivation are much slower than inactivation, which is attributed to specific structural elements within the NH2 terminus and the S1-S4 voltage-sensing domains (VSD). Although the charged residues in the VSD have been extensively modified and mutated as a result, the role and importance of specific hydrophobic residues in the S4 has been much less explored in studies of hERG gating. We found that charged, but not neutral or hydrophobic, amino acid substitution of isoleucine 521 at the outer end of the S4 transmembrane domain resulted in channels activating at much more negative voltages associated with a marked hyperpolarization of the conductance-voltage (G-V) relationship. The contributions of different physicochemical properties to this effect were probed by chemical modification of channels substituted with cysteine at position I521. When positively charged reagents including tetramethyl-rhodamine-5-maleimide (TMRM), 1-(2-maleimidylethyl)-4-[5-(4-methoxyphenyl)oxazol-2-yl] pyridinium methane-sulfonate (PyMPO), [2-(trimethylammonium)ethyl] methanethiosulfonate chloride (MTSET), and 2-aminoethyl methanethiosulfonate hydrobromide (MTSEA) were bound to the cysteine, I521C channels activated at more negative membrane potentials. To examine the contributions to hERG gating of other residues at the outer end of S4 (520-528), we performed a cysteine scan combined with MTSET modification. Only L520C, along with I521C, shows a substantial hyperpolarizing shift of the G-V relationship upon MTSET modification. The data indicate that the neutral, hydrophobic residue I521 at the extracellular end of S4 is critical for stabilizing the closed conformation of the hERG channel relative to the open state and by comparison with Shaker supports the alignment of hERG I521 with Shaker L361.


Developmental Trajectories of Maternal Sensitivity across the First Year of Life: Relations among Emotion Competence and Dyadic Reciprocity.
Maternal sensitivity is a commonly used construct to capture the quality of mother-child interactions, but inconsistencies in conceptualizing and defining maternal sensitivity limit understanding of how sensitive caregiving may be associated with child development. The purposes of this study are to (1) examine and compare the developmental trajectories of individual maternal sensitivity behaviors to that of a global index of sensitivity across the first year of infant life and (2) determine whether differences in trajectories of sensitivity are meaningful for infant emotion competence and dyadic reciprocity at 12 months. A total of 322 low-income, Mexican American mothers and infants were observed during a free play task at 3, 4.5, 6, and 12 months. Observations were coded for 11 distinct behaviors known to compose maternal sensitivity. At 12 months, mother-infant interactions were also coded for dyadic reciprocity, and mothers reported on infant emotion competence. Latent growth models indicated that individual sensitivity behaviors differed from the global index of sensitivity with respect to initial levels and slopes, with increasing (e.g., vocal appropriateness), decreasing (e.g., touch), and stable (e.g., elaboration) trajectories. The individual and global indices of sensitivity differed in prediction of emotion competence and dyadic reciprocity. Trajectories of global and individual indices of maternal sensitivity operated similarly in predicting dyadic reciprocity, with the exception of consistency of style. In contrast, the global index of sensitivity was unrelated to emotion competence, and only initial levels of positive affect emerged as significant predictors of emotion competence. The findings offer a more nuanced understanding of maternal sensitivity and suggest that component aspects of maternal sensitivity uniquely contribute to child and family competencies.


Two large virion envelope glycoproteins mediate Epstein-Barr virus binding to receptor-positive cells.
The four major Epstein-Barr virion envelope components were separated by column chromatography and reconstituted into artificial liposomes. These liposomes were tested for their ability to bind selectively to Epstein-Barr virus receptor-positive cells. Only when the two high-molecular-weight glycoproteins, VE1 and VE2, were present together was a stable binding complex formed. The addition of the other virion envelope components did not increase the levels of binding. This binding was inhibited by unlabeled viable virions and by neutralizing antisera, which recognized the two components. Adsorption of viable virus was also eliminated by the antisera. The enzyme susceptibility pattern of the cell-liposome interaction is similar to that of the virus-cell interaction, thus confirming the specificity of the binding site. A model for Epstein-Barr virus binding in which VE1 and VE2 coordinately recognize the same binding site is presented.


Red-Emissive Center Formation within Carbon Dots Based on Citric Acid and Formamide.
The formation of red-emissive optical centers in carbon dots based on citric acid and formamide was investigated by varying the synthesis parameters with focus on finding optimal─necessary and sufficient─amount of precursors to decrease byproduct amount and to increase the chemical yield of red-emissive carbon dots. The emission is observed at 640 nm excited at 590 nm and quantum yield reaches up 19%. A high chemical yield of carbon dots of 26% was achieved at an optimal molar ratio of citric acid to formamide of 1:4.


Pre- and postsynaptic plasticity underlying augmented glutamatergic inputs to hypothalamic presympathetic neurons in spontaneously hypertensive rats.
Increased sympathetic outflow plays an important role in the pathogenesis of hypertension. Glutamatergic inputs in the paraventricular nucleus (PVN) of the hypothalamus maintain resting sympathetic vasomotor tone in spontaneously hypertensive rats (SHR). In this study, we determined the synaptic and cellular mechanisms of increased glutamatergic inputs to PVN presympathetic neurons in SHR. The spinally projecting PVN neurons were retrogradely labelled by fluorescent microspheres injected into the intermediolateral cell column of the spinal cord. Blockade of NMDA and non-NMDA receptors significantly decreased the firing activity of labelled PVN neurons in brain slices in SHR, but not in normotensive Wistar-Kyoto rats (WKY). The basal frequency of glutamatergic spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs, respectively) of labelled PVN neurons was significantly greater in SHR than in WKY. But the frequency of neither sEPSCs nor mEPSCs stimulated by 4-aminopyridine or capsaicin differed significantly between WKY and SHR. Furthermore, the amplitude of postsynaptic NMDA currents elicited by either electrical stimulation or puff application in labelled PVN neurons was significantly higher in SHRs than in WKY. However, the evoked AMPA current amplitude in PVN neurons was similar in WKY and SHR. This study provides new evidence of how the glutamatergic synaptic inputs to PVN presympathetic neurons are increased and how they contribute to the elevated firing activity of these neurons in SHR. The augmented glutamatergic tone in the PVN is maintained by an increase in presynaptic glutamate release and an up-regulation of postsynaptic NMDA receptor function in SHR.


Delay in transfer to inpatient stroke rehabilitation: the role of acute hospital medical complications and stroke characteristics.
An increased delay between stroke onset and transfer to rehabilitation has been associated with poorer outcomes after stroke rehabilitation. The purpose of this study was to examine the relationships between selected clinical factors and the interval from stroke onset to rehabilitation admission. A cohort of 2,457 patients consecutively admitted for inpatient stroke rehabilitation was studied. Patient demographic data, stroke characteristics, stroke onset to rehabilitation admission interval (ORAI), and medical complications that occurred during the acute post-stroke hospitalization were documented. Univariate and multiple regression analyses were used to determine relationships between patient demographic data, stroke characteristics, and acute medical complications with ORAI. The average ORAI was 17.2 days, with a median of 12 days. Stroke characteristics and acute medical complications were the two groups of factors that were most strongly associated with longer ORAIs. These two groups each explained approximately 15.5% and 17.3% of the variance in the model, respectively. The most significant individual factors included the presence of an enteral feeding tube, a hemorrhagic stroke, a cortical stroke, pneumonia, urinary tract infection, and younger age at stroke onset. Although some medical problems associated with longer ORAI are functions of the severity of the stroke and patient characteristics, attention to preventable medical complications may be associated with a more rapid transition to the inpatient rehabilitation setting.


Diverticular disease of the colon: new perspectives in symptom development and treatment.
Diverticular disease of the colon is a common disease worldwide. Although the disease is asymptomatic in about 70-80 % of patients, it represents, at least in Western countries, one of the most important gastrointestinal diseases in terms of direct and indirect health costs. Pathogenesis of the disease is still unknown. However, it is the result of complex interactions between colonic structure, intestinal motility, diet and genetic factors. Whilst efficacious preventive strategies remain to be identified, fibre supplementation in the diet is recommended. Why symptoms develop is still unclear. Results of recent experimental studies on irritable bowel syndrome speculated that low grade inflammation of colonic mucosa, induced by changes in bacterial microflora, could affect the enteric nervous system, which is crucial for normal gut function, thus favouring symptom development. This hypothesis could be extrapolated also for diverticular disease, since bacterial overgrowth is present, at least in a subgroup of patients. These perspectives on symptom development are reviewed and new therapeutic approaches are hypothesized.


Chromatographic resolution of amino acid adducts of aliphatic halides.
Numerous xenobiotics are known to be bioactivated and to covalently and to proteins, but the resulting amino acid adducts (AAAs) are unknown. In this study the AAAs of twelve 14C-labeled aliphatic halides were examined after formation in an in vitro microsomal system. After exhaustive solvent extraction of the precipitated microsomal protein, the AAAs were isolated by Pronase digestion, followed by filtration through a 500 mol. wt. exclusion membrane. The liberated AAAs were applied to a constant flow DC-4A cation exchange column, resolved by stepwise buffer elution, collected and counted for radioactivity. Column recovery for applied radioactivity was 100 +/- 4%. Generally, 1-4 different AAAs (defined by eluting radioactivity) were resolved, with each organohalogen displaying a characteristic elution profile. Methyl iodide, trichloroethylene and 1,2-dichloroethylene had a single major AAA while bromotrichloromethane, 1,2-dibromoethane, 1,1,1-trichloroethane, 1,2-dichloroethane, 1,1,2-trichloroethane, 2-bromo-2-chloro-1,1,1-trifluoroethane, chloroform and carbon tetrachloride had up to 4 AAAs or more, indicating combinations of binding site(s) and reactive intermediate(s). The single AAA formed following incubation of methyl iodide with the microsomes was identified as S-methylcysteine. Thus, this method appears capable of resolving binding sites and is the initial isolation step for identifying specific adducts to proteins.


Computed tomography overestimation of esophageal tumor length: Implications for radiotherapy planning.
To assess the relationship between preoperative computed tomography (CT) and postoperative pathological measurements of esophageal tumor length and the prognostic significance of CT tumor length data. A retrospective study was carried out in 56 patients who underwent curative esophagogastrectomy. Tumor lengths were measured on the immediate preoperative CT and on the post-operative resection specimens. Inter- and intra-observer variations in CT measurements were assessed. Survival data were collected. There was a weak correlation between CT and pathological tumor length (r = 0.30, P = 0.025). CT lengths were longer than pathological lengths in 68% (38/56) of patients with a mean difference of 1.67 cm (95% CI: 1.18-2.97). The mean difference in measurements by two radiologists was 0.39 cm (95% CI: -0.59-1.44). The mean difference between repeat CT measured tumor length (intra-observer variation) were 0.04 cm (95% CI: -0.59-0.66) and 0.47 cm (95% CI: -0.53-1.47). When stratified, patients not receiving neoadjuvant chemotherapy showed a strong correlation between CT and pathological tumor length (r = 0.69, P = 0.0014, n = 37) than patients that did (r = 0.13, P = 0.43, n = 19). Median survival with CT tumor length > 5.6 cm was poorer than with smaller tumors, but the difference was not statistically significant. Esophageal tumor length assessed using CT does not reflect pathological tumor extent and should not be the only modality used for management decisions, particularly for planning radiotherapy.


Reduction of 14-3-3 proteins correlates with increased sensitivity to killing of human lung cancer cells by ionizing radiation.
The 14-3-3 proteins have a wide range of ligands and are involved in a variety of biological pathways. Importantly, 14-3-3 proteins are known to be overexpressed in some human lung cancers, suggesting that they may play a role in tumorigenesis. Here we examined 14-3-3 expression in several lung cancer-derived cell lines and found that four of the seven 14-3-3 isoforms, beta, epsilon, theta and zeta, were highly expressed in both lung cancer cell lines and normal lung fibroblasts. Two isoforms, sigma and gamma, were present only at very low levels. Immunoprecipitation data showed 14-3-3zeta could bind to CDC25C in irradiated A549 cells, and suppression of 14-3-3zeta in A549 cells with antisense resulted in a decrease in CDC25C localization in cytoplasm and CDC2 phosphorylation on Tyr15. As a consequence, CDC2 activity remained elevated which resulted in release from radiation-induced G(2)/M-phase arrest. Moreover, 16% 14-3-3zeta antisense-transfected cells underwent apoptosis when exposed to 10 Gy ionizing radiation. These data indicate that 14-3-3zeta is involved in G(2) checkpoint activation and that inhibition of 14-3-3 may be a useful approach to sensitize human lung cancers to ionizing radiation.


The role of iron in the hexachlorobenzene induced porphyria. I. Studies on different types of iron and its relation with porphyrinogen carboxy-lyase decrease.
Studies were carried out to elucidate if in the hexachlorobenzene (HCB) porphyria, total, nonhaem and haem iron contents in liver are altered and if any relation exists between these alterations and the hepatic porphyrinogen carboxy-lyase (PCL) decrease in rats treated with the drug. It was observed that in porphyric livers total and non-haem iron levels increased significantly as a consequence of HCB intoxication while this treatment produced a non significant decrease in the haem iron content. Enzymic preparations of porphyric livers filtered through Sephadex G-25 columns which separate the free iron and that has a content of iron-protein greater than those in normals, exhibited a strong inhibition of PCL. Chelating agents, alpha' alpha' bipyridyl and 8-hydroxyquinoline do not revert such inhibition. The effect in vitro of ferritin, haemin and inorganic iron at different concentrations on normal PCL activity was also assayed. So, it could be observed that inorganic iron and haemin produce slight inhibition of PCL when added in concentrations higher than those corresponding to a porphyric liver (0.08 mM and 10(-6) M, respectively, as mean in the incubation media). So, they have not physiological significance. Ferritin does not modify the decarboxylation process. From these results it arises that iron does not play a direct role in the decrease of PCL activity in the experimental porphyria by HCB, not being the inhibitor made evident by heating assays. Iron could perhaps stimulate the metabolization of HCB, giving rise to active metabolite.


Effectiveness of a Self-monitoring Device for Urinary Sodium-to-Potassium Ratio on Dietary Improvement in Free-Living Adults: a Randomized Controlled Trial.
Reducing the urinary sodium-to-potassium ratio is important for reducing both blood pressure and risk of cardiovascular disease. Among free-living Japanese individuals, we carried out a randomized trial to clarify the effect of lifestyle modification for lowering urinary sodium-to-potassium ratio using a self-monitoring device. This was an open, prospective, parallel randomized, controlled trial. Ninety-two individuals were recruited from Japanese volunteers. Participants were randomly allocated into intervention and control groups. A month-long dietary intervention on self-monitoring urinary sodium-to-potassium ratio was carried out using monitors (HEU-001F, OMRON Healthcare Co., Ltd., Kyoto, Japan). All participants had brief dietary education and received a leaflet as usual care. Monitors were handed out to the intervention group, but not to the control group. The intervention group was asked to measure at least one spot urine sodium-to-potassium ratio daily, and advised to lower their sodium-to-potassium ratio toward the target of less than 1. Outcomes included changes in 24-hour urinary sodium-to-potassium ratio, sodium excretion, potassium excretion, blood pressure, and body weight in both groups. Mean measurement frequency of monitoring was 2.8 times/day during the intervention. Changes in urinary sodium-to-potassium ratio were -0.55 in the intervention group and -0.06 in the control group (P = 0.088); respective sodium excretion changes were -18.5 mmol/24 hours and -8.7 mmol/24 hours (P = 0.528); and corresponding potassium excretion was 2.6 mmol/24 hours and -1.5 mmol/24 hours (P = 0.300). No significant reductions were observed in either blood pressure or body weight after the intervention. Providing the device to self-monitor a sodium-to-potassium ratio did not achieve the targeted reduction of the ratio in "pure self-management" settings, indicating further needs to study an effective method to enhance the synergetic effect of dietary programs and self-monitoring practice to achieve the reduction. However, we cannot deny the possibility of reducing sodium-to-potassium ratio using a self-monitoring device.


Enhanced EGFR Targeting Activity of Plasmonic Nanostructures with Engineered GE11 Peptide.
Plasmonic nanostructures show important properties for biotechnological applications, but they have to be guided on the target for exploiting their potentialities. Antibodies are the natural molecules for targeting. However, their possible adverse immunogenic activity and their cost have suggested finding other valid substitutes. Small molecules like peptides can be an alternative source of targeting agents, even if, as single molecules, their binding affinity is usually not very good. GE11 is a small dodecapeptide with specific binding to the epidermal growth factor receptor (EGFR) and low immunogenicity. The present work shows that thousands of polyethylene glycol (PEG) chains modified with lysines and functionalized with GE11 on clusters of naked gold nanoparticles, obtained by laser ablation in water, achieves a better targeting activity than that recorded with nanoparticles decorated with the specific anti-EGFR antibody Cetuximab (C225). The insertion of the cationic spacer between the polymeric part of the ligand and the targeting peptide allows for a proper presentation of GE11 on the surface of the nanosystems. Surface enhanced resonance Raman scattering signals of the plasmonic gold nanoparticles are used for quantifying the targeting activity. Molecular dynamic calculations suggest that subtle differences in the exposition of the peptide on the PEG sea are important for the targeting activity.


Optimizing care in osteoporosis: the Canadian quality circle project.
While the Osteoporosis Canada 2002 Canadian guidelines provided evidence based strategies in preventing, diagnosing, and managing this condition, publication and distribution of guidelines have not, in and of themselves, been shown to alter physicians clinical approaches. We hypothesize that primary care physicians enrolled in the Quality Circle project would change their patient management of osteoporosis in terms of awareness of osteoporosis risk factors and bone mineral density testing in accordance with the guidelines. The project consisted of five Quality Circle phases that included: 1) Training & Baseline Data Collection, 2) First Educational Intervention & First Follow-Up Data Collection 3) First Strategy Implementation Session, 4) Final Educational Intervention & Final Follow-up Data Collection, and 5) Final Strategy Implementation Session. A total of 340 circle members formed 34 quality circles and participated in the study. The generalized estimating equations approach was used to model physician awareness of risk factors for osteoporosis and appropriate utilization of bone mineral density testing pre and post educational intervention (first year of the study). Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated. After the 1st year of the study, physicians' certainty of their patients' risk factor status increased. Certainty varied from an OR of 1.4 (95% CI: 1.1, 1.8) for prior vertebral fracture status to 6.3 (95% CI: 2.3, 17.9) for prior hip fracture status. Furthermore, bone mineral density testing increased in high risk as compared with low risk patients (OR: 1.4; 95% CI: 1.2, 1.7). Quality Circle methodology was successful in increasing both physicians' awareness of osteoporosis risk factors and appropriate bone mineral density testing in accordance with the 2002 Canadian guidelines.


Overlapping fragments method for electronic structure calculation of large systems.
We present a method for the calculation of the electronic structure of systems that contain tens of thousands of atoms. The method is based on the division of the system into mutually overlapping fragments and the representation of the single-particle Hamiltonian in the basis of eigenstates of these fragments. In practice, for the range of the system size that we studied (up to tens of thousands of atoms), the dominant part of the calculation scales linearly with the size of the system when all the states within a fixed energy interval are required. The method is highly suitable for making good use of parallel computing architectures. We illustrate the method by applying it to diagonalize the single-particle Hamiltonian obtained using the density functional theory based charge patching method in the case of amorphous alkane and polythiophene polymers.


Relationships between sport and exercise participation and subjective well-being among adults with physical disabilities: Is participation quality more important than participation quantity?
Sport and exercise participation are associated with small, albeit positive changes in subjective well-being (SWB). Recent theorizing has emphasized the importance of distinguishing between performance aspects (i.e., frequency, intensity, time engaged) and the experiential aspects of sport and exercise participation among people with disabilities. This study assessed the relative contributions of time spent participating in sport and exercise (a performance measure) versus measures of participation experiences, in explaining variance in SWB. Participants were 535 adults with physical disabilities, recruited through a nation-wide survey, who participated in sport (n = 271; 62% male; 44 ± 14 years) or exercise (n = 264; 42% male; 57 ± 14 years). They completed measures of minutes/week of sport or exercise participation, experiential aspects of participation, and SWB (overall life satisfaction, satisfaction with physical, psychological and social life-domains, and positive/negative affect). Hierarchical multiple regression analyses showed minutes/week of sport did not explain significant variance in any SWB measure, but sport participation experiences explained significant variance (9.2%-20.9%) in all SWB measures (p < 0.05). Similarly, minutes/week of exercise explained significant variance only in physical life-domain satisfaction (ΔR2 = 2.6%, p = 0.026), but exercise participation experiences explained significant variance (4.8%-10.7%) in all SWB measures (p < 0.05). Experiences of belonging and mastery were particularly strong, consistent predictors across SWB outcomes. These results suggest participation experiences better explain relationships between sport and exercise participation and SWB than time spent performing sport and exercise. Findings have implications for designing future studies to test the effects of sport and exercise on SWB, and developing theories and interventions to explain and maximize the use of sport and exercise to improve SWB in adults with disabilities.


Clinical and hemodynamical findings in legs with previous surgery of the great saphenous vein: role of the small saphenous vein.
To assess the role of small saphenous vein (SSV) reflux in patients with a long history of varicose disease and previous stripping of the great saphenous vein (GSV). Consecutive patients with a history of GSV stripping 5-19 years earlier were enrolled in this prospective clinical study. A total of 101 legs of 75 consecutive patients fulfilled the study criteria: previous stripping of GSV from ankle to groin at least 5 years earlier, no history of thromboembolism and no previous surgery of deep veins or SSV. All patients were studied clinically using standardized classifications: clinical class, clinical disability score (CDS) and venous clinical scoring system (VCSS). Colour flow duplex imaging (CFDI) was used to assess reflux in deep and superficial veins. Details of prior surgery were evaluated. Overall, SSV reflux was noted in 28 (28%) of the legs, recurrent GSV (rGSV) in the thigh in 41 (41%), reflux in tributaries alone in 28 (28%) and a combination of SSV and rGSV reflux in 4 (3%). Segmental deep reflux was measured in 23 (23%) of the legs; the prevalence of deep reflux was significantly higher in complicated than in uncomplicated legs (12% versus 47%; P<0.05). Deep reflux was more frequently associated with SSV reflux than with rGSV reflux (50% versus 22%; P<0.05). The prevalence of SSV with or without deep reflux increased from 17% to 50% (P<0.05) when uncomplicated (C2-3) and complicated (C4-6) legs were compared. A similar increase was not seen in the legs with rGSV (39% versus 44%; P>0.05). SSV reflux without deep reflux was observed in 25% of the legs with complicated (C4-6) disease, whereas the prevalence of SSV reflux was low (9%) in uncomplicated (C2-3) legs. VCSS was higher in the legs with SSV reflux than in those with rGSV reflux. CDS scores tended to be higher in the SSV reflux group than in the legs with rGSV reflux or tributary reflux alone. After exclusion of deep reflux, the results remained at the same level. Small saphenous vein (SSV) reflux is common in legs with recurrent varicose veins and previous stripping of the GSV. SSV reflux alone is frequent in complicated legs, and SSV reflux is typically associated with segmental deep reflux. Clinical and hemodynamical findings stress the role of SSV reflux in this selected venous population.


Association of Alzheimer's disease onset with ginkgo biloba and other symptomatic cognitive treatments in a population of women aged 75 years and older from the EPIDOS study.
Peripheral C4A treatment (cerebral and peripheral vasotherapeutics) and especially Ginkgo biloba extracts are prescribed for a number of symptoms, particularly memory impairment, in elderly patients. It is postulated that because of its pharmacological actions, this treatment could prevent the decline of cognitive function, but no studies have been published to date to test its efficacy in prevention of Alzheimer's disease. The potential association between use of C4A treatments, in particular EGb 761 (standardized Ginkgo biloba extracts), and dementia of the Alzheimer type was investigated. A case-control study was nested in a cohort of 1462 community-dwelling elderly women aged over 75 years. Sixty-nine women with Alzheimer-type dementia were compared with 345 paired women whose cognitive function remained normal. This study involved women whose cognitive function was evaluated at baseline by use of Pfeiffer's test and whose medication history was taken. The onset of cognitive impairment was investigated over a 7-year follow-up period. In order to study the factors associated with the onset of dementia, the data concerning women with a score of > or = 8 on Pfeiffer's test at inclusion, indicating normal cognitive function, were analyzed. A multivariate analysis including potential confounding factors showed that fewer women who developed Alzheimer's dementia had been prescribed C4A treatment (including EGb 761) for at least 2 years (odds ratio = 0.31, 95% confidence interval = 0.12-0.82, p =.018). Figures for EGb 761 alone were similar but did not reach statistical significance (odds ratio = 0.38, 95% confidence interval = 0.08-1.76, p =.22). These results suggest that C4A treatment may reduce the risk of developing Alzheimer's dementia in elderly women. The potential preventive effect of C4A treatments, including EGb 761, requires further examination. To establish a causal relationship, these findings have to be confirmed with prospective studies.


Dental service utilization and immigrant family structure.
To determine the patterns and time trends of dental services received and access to dental care among immigrant and US-born children living in the United States. We analyzed the nationally representative Medical Expenditure Survey data for 2007-2015. Survey weighted mean and frequency were calculated for all the years and for each year for the complete cohort and for the four subgroups of children categorized based on the child's and parents' birthplace (United States or Foreign). These groups were compared to detect differences in dental service received. Overall 34,482 children aged <18 years were included in the analysis representing the weighted sample size of 564,255,643. Utilization of preventive dental services increased from 37.2 percent in 2007 to 44.4 percent in 2015 overall (P < 0.0001), with similar trend seen within all subgroups. Immigrant children compared to US-born children had higher numbers of surgical and restorative procedures (17 versus 16 per 100-person years, P = 0.03), fewer had at least one preventive dental visit in a year (32.8 percent versus 43.0 percent, P < 0.0001) and were less likely be unable to access dental care (3.0 percent versus 1.7 percent, P = 0.005). Fewer children had delayed access to dental care in recent years (2.0 percent in 2007 to 1.5 percent in 2015) and the decline was consistent in all the subgroups. Stratification into the different subgroups allowed for improved understanding of dental procedure utilization and dental services utilization in all subgroups increased over time. Immigrant children had lower utilization of preventive procedures and higher utilization of surgical and restorative procedures.


Performance on clinical tests of balance in Parkinson's disease.
Due to the high incidence of falls in people with idiopathic Parkinson's disease (PD), the assessment of standing balance is a key component of physical therapist evaluation. This study investigated performance on clinical tests of standing balance in subjects with and without PD. The subjects were 10 persons with PD who had a history of falls (age range = 60-80 years), 10 persons with PD who had no history of falls (age range = 63-79 years), and 10 persons with no known neurological impairment (age range = 60-78 years) who served as a comparison group. Subjects were tested on their ability to maintain stability in 3 conditions: (1) steady standing (feet apart, feet together, tandem stance, step stance, and single-limb stance), (2) in response to perturbations generated by self-initiated movements (arm raise, functional reach, bend-reach, and step tests), and (3) in response to an external perturbation to upright stance (shoulder tug). Balance was measured at peak dosage in the levodopa medication cycle (in the morning) and 7 days later. The mean Hoehn and Yahr Disability Scale score was 3.0 for the fallers with PD and 2.5 for the nonfallers with PD. Performance on the tandem stance, single-limb stance, functional reach, and shoulder tug tests demonstrated differences between the subjects with PD and the comparison group and between the fallers and nonfallers with PD. The results of these tests were highly repeatable over 7 days (ICC = .61-.94). Although there was a small sample size, performance was highly consistent across 7 days when testing occurred during peak dosage of levodopa. A small battery of tests were sensitive enough to discriminate between people with PD who fall and those with no history of falls.


Land application of domestic effluent onto four soil types: plant uptake and nutrient leaching.
Land application has become a widely applied method for treating wastewater. However, it is not always clear which soil-plant systems should be used, or why. The objectives of our study were to determine if four contrasting soils, from which the pasture is regularly cut and removed, varied in their ability to assimilate nutrients from secondary-treated domestic effluent under high hydraulic loadings, in comparison with unirrigated, fertilized pasture. Grassed intact soil cores (500 mm in diameter by 700 mm in depth) were irrigated (50 mm wk(-1)) with secondary-treated domestic effluent for two years. Soils included a well-drained Allophanic Soil (Typic Hapludand), a poorly drained Gley Soil (Typic Endoaquept), a well-drained Pumice Soil formed from rhyolitic tephra (Typic Udivitrand), and a well-drained Recent Soil formed in a sand dune (Typic Udipsamment). Effluent-irrigated soils received between 746 and 815 kg N ha(-1) and 283 and 331 kg P ha(-1) over two years of irrigation, and unirrigated treatments received 200 kg N ha(-1) and 100 kg P ha(-1) of dissolved inorganic fertilizer over the same period. Applying effluent significantly increased plant uptake of N and P from all soil types. For the effluent-irrigated soils plant N uptake ranged from 186 to 437 kg N ha(-1) yr(-1), while plant P uptake ranged from 40 to 88 kg P ha(-1) yr(-1) for the effluent-irrigated soils. Applying effluent significantly increased N leaching losses from Gley and Recent Soils, and after two years ranged from 17 to 184 kg N ha(-1) depending on soil type. Effluent irrigation only increased P leaching from the Gley Soil. All P leaching losses were less than 49 kg P ha(-1) after two years. The N and P leached from effluent treatments were mainly in organic form (69-87% organic N and 35-65% unreactive P). Greater N and P leaching losses from the irrigated Gley Soil were attributed to preferential flow that reduced contact between the effluent and the soil matrix. Increased N leaching from the Recent Soil was the result of increased leaching of native soil organic N due to the higher hydraulic loading from the effluent irrigation.


Analytical Validation and Performance of a 7-Gene Next-Generation Sequencing Panel in Uveal Melanoma.
Gene expression profiling (GEP) is widely used for prognostication in patients with uveal melanoma (UM). Because biopsy tissue is limited, it is critical to obtain as much genomic information as possible from each sample. Combined application of both GEP and next-generation sequencing (NGS) allows for analysis of RNA and DNA from a single biopsy sample, offers additional prognostic information, and can potentially inform therapy selection. This study evaluated the analytical performance of a targeted custom NGS panel for mutational profiling of 7 genes commonly mutated in UM. One hundred five primary UM tumors were analyzed, including 37 formalin-fixed paraffin-embedded (FFPE) and 68 fine-needle aspiration biopsy specimens. Sequencing was performed on the Ion GeneStudio S5 platform to an average read depth of >500X per region of interest. The 7-gene panel achieved a positive percent agreement of 100% for detection of both single-nucleotide variants and insertions/deletions, with a technical positive predictive value of 98.8% and 100%, respectively. Intra-assay and inter-assay concordance studies confirmed the assay's reproducibility and repeatability. The 7-gene panel is a robust, highly accurate NGS test that can be successfully performed, along with GEP, from a single small-gauge needle biopsy sample or FFPE specimen.


Optical study of archetypical valence-fluctuating Eu systems.
We have investigated the optical conductivity of the prominent valence-fluctuating compounds EuIr(2)Si(2) and EuNi(2)P(2) in the infrared energy range to get new insights into the electronic properties of valence-fluctuating systems. For both compounds, we observe upon cooling the formation of a renormalized Drude response, a partial suppression of the optical conductivity below 100 meV, and the appearance of a midinfrared peak at 0.15 eV for EuIr(2)Si(2) and 0.13 eV for EuNi(2)P(2). Most remarkably, our results show a strong similarity with the optical spectra reported for many Ce- or Yb-based heavy-fermion metals and intermediate valence systems, although the phase diagrams and the temperature dependence of the valence differ strongly between Eu systems and Ce- or Yb-based systems. This suggests that the hybridization between 4f and conduction electrons, which is responsible for the properties of Ce and Yb systems, plays an important role in valence-fluctuating Eu systems.


Synthesis, characterization, molecular docking and in vitro screening of new metal complexes with coumarin Schiff base as anticholine esterase and antipancreatic cholesterol esterase agents.
In this work, Combining coumarin and thiazole with 3-tertiary butyl salicylaldehyde into in a single molecule, new Schiff base (CTS), and its metal complexes with palladium and platinum were synthesized and characterized by using well-known spectroscopic techniques such as 1H-NMR, 13C-NMR, FT-IR and LC-MS. And also, the formation of these complexes were confirmed by magnetic moment and conductivity measurements. The photophysical properties of CTS were studied and it was observed that the Schiff base has a sensitivity to CN-, F-, and AcO- anions. The quantum chemical calculations based on density functional theory (DFT) were done for explaining some experimental, structural, and spectroscopic data of the dyes. Also, to evaluate the binding interactions between the ligand (CTS) and its metal complexes and enzymes, molecular docking studies were performed and all the compounds tested to determine its inhibition potential against the cholinesterase (AChE and BChE) and pancreatic cholesterol esterase (CEase) enzymes. Both in vitro and in silico the results showed that all of the compounds could act as potent inhibitors of AChE, BChE, and CEase. The Pt (II) complex showed the most potent inhibitory property against all of the enzymes with IC50 values of 12 µM for AChE, 23 µM for BChE, and 21 µM for CEase.Communicated by Ramaswamy H. Sarma.


Poorly differentiated human gastric carcinoma is more sensitive to antitumor drugs than is well differentiated carcinoma.
The chemosensitivities of 41 poorly differentiated gastric cancer tissues were compared with that of 16 well differentiated tissues, using the in vitro succinate dehydrogenase inhibition test. These human tissues obtained at the time of surgery were exposed to six different antitumor drugs: carboquone (CQ), adriamycin (ADM), mitomycin C (MMC), aclacinomycin A (ACR), cisplatin (DDP) and 5-fluorouracil (5-FU). The chemosensitivity was determined as positive when the succinate dehydrogenase (SD) activity of the drug exposed cells was decreased to below 50% of that of control cells, on day 3 of exposure. Decrease in SD activity was remarkable in the poorly differentiated tissues, compared to the well differentiated tissues, exposed to ADM, MMC, DDP and 5-FU. The sensitive rates were higher in the poorly differentiated tissues than in the well differentiated tissues, against all six antitumor drugs. Sixty-three per cent of the poorly differentiated tissues were sensitive to more than three antitumor drugs, in an identical tissue, but the rate was only 19% in the well differentiated tissues. The resistant rates to all drugs tested were 20% in the poorly differentiated and 31% in the well differentiated tissues. This would indicate that patients with a poorly differentiated gastric cancer will probably show a better response to antitumor drugs, compared to those with a well differentiated type.


Retraction Note: The relationship of kinesiophobia with depression and anxiety in nursing homes.
The article "The relationship of kinesiophobia with depression and anxiety in nursing homes", by Ö. Yükselmiş, published in Eur Rev Med Pharmacol Sci 2023; 27 (6): 2305-2313-DOI: 10.26355/eurrev_202303_31764-PMID: 37013748 has been retracted by the Editor in Chief. After publication, issues were raised about the authorship of this article by a reader stating that the article plagiarized a thesis published in Turkish. After receiving the thesis and translating it into English, the Journal compared the two texts and found they share the same results. The author re-elaborated the thesis by using the same data to create and publish a new article. The reader also stated that the Ethics Committee approval provided by the author was fake. The journal contacted the University to investigate this issue but never received a reply. After being informed, the corresponding author gave no plausible reply to these issues and asked to withdraw the manuscript. Given the evidence, the Editor in Chief decided to withdraw the manuscript and blacklisted the author for any future submissions. This manuscript has been withdrawn. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/31764.


Nifedipine versus ritodrine for suppression of preterm labor; a meta-analysis.
Since large randomized clinical trials comparing the effectiveness of nifedipine and ritodrine in the suppression of preterm labor are lacking, we performed a meta-analysis on the subject. We searched the databases Medline and EMBASE using the keywords 'nifedipine', 'ritodrine' and 'randomized' or 'randomised'. The studies were scored for blinding, method of randomization and type of analysis ('intention-to-treat' versus 'par protocol'). Subsequently, two by two tables were constructed using 'delay of labor by 48 hours or more', 'delay of labor beyond 36 weeks gestation', perinatal mortality, respiratory distress syndrome and admission to a neonatal intensive care unit as end points. Homogeneity between the studies was tested with a Breslow-Day test. Pooled odds ratios were calculated in case homogeneity could not be rejected. We could detect ten studies that were published between 1986 and 1998, incorporating data of 681 patients. Nifedipine reduced the risk of delivery within 48 hours compared to ritodrine, but this difference was not statistically significant (odds ratio 0.85, 95% confidence interval 0.54 to 1.1). Nifedipine also reduced the risk of delivery before 36 weeks compared to ritodrine, and this difference was statistically significant (odds ratio 0.59, 95% confidence interval 0.39 to 0.90). We are not aware of studies reporting on long-term outcome. Since studies reporting on long-term outcome are lacking, the choice between nifedipine and ritodrine can only be based on obstetrical and short-term neonatal outcomes. From that perspective, nifedipine should be the drug of first choice for the suppression of preterm labor.


Overexpression of the polycystin-1 C-tail enhances sensitivity of M-1 cells to ouabain.
Cells derived from renal cysts of patients with autosomal dominant polycystic kidney disease (ADPKD) are abnormally sensitive to ouabain, responding to physiological ouabain concentrations with enhanced proliferation and increased forskolin-induced transepithelial fluid secretion. This requires activation of the epidermal growth factor receptor (EGFR), Src kinase and the extracellular signal-regulated kinases MEK and ERK. Here, we have determined if the ADPKD phenotype obtained in mouse cortical collecting duct cells by stable overexpression of the C-terminal domain of polycystin-1 (PC-1 C-tail) also elicits the ADPKD-like response to ouabain in the cells. M-1 C20 cells expressing the PC-1 C-tail and M-1 C17 cells lacking expression of this construct were treated with physiological concentrations of ouabain, and cell proliferation, activation of the EGFR-Src-MEK-ERK pathway, forskolin-induced transepithelial Cl(-) secretion and the sensitivity of Na,K-ATPase to ouabain were explored. M-1 C20 cells responded to ouabain with increased cell proliferation and ERK phosphorylation. Ouabain also augmented forskolin-induced and cystic fibrosis transmembrane conductance regulator-mediated apical secretion of Cl(-) in M-1 C20 cells. These effects required activation of EGFR, Src and MEK. In contrast, ouabain had no significant effects on M-1 C17 cells. Interestingly, approximately 20% of the Na,K-ATPase from M-1 C20 cells presented an abnormally increased sensitivity to ouabain. Overexpression of PC-1 C-tail in M-1 C20 cells is associated with an ouabain-sensitive phenotype and an increased ability of the cells to proliferate and secrete anions upon ouabain stimulation. This phenotype mimics the ouabain sensitivity of ADPKD cells and may help promote their cystogenic potential.


Enhancing photo-induced ultrafast charge transfer across heterojunctions of CdS and laser-sintered TiO2 nanocrystals.
Enhancing the charge transfer process in nanocrystal sensitized solar cells is vital for the improvement of their performance. In this work we show a means of increasing photo-induced ultrafast charge transfer in successive ionic layer adsorption and reaction (SILAR) CdS-TiO2 nanocrystal heterojunctions using pulsed laser sintering of TiO2 nanocrystals. The enhanced charge transfer was attributed to both morphological and phase transformations. At sufficiently high laser fluences, volumetrically larger porous networks of the metal oxide were obtained, thus increasing the density of electron accepting states. Laser sintering also resulted in varying degrees of anatase to rutile phase transformation of the TiO2, producing thermodynamically more favorable conditions for charge transfer by increasing the change in free energy between the CdS donor and TiO2 acceptor states. Finally, we report aspects of apparent hot electron transfer as a result of the SILAR process which allows CdS to be directly adsorbed to the TiO2 surface.