GLOBAL SURVEY OF MITOCHONDRIAL DNA SEQUENCES IN THE THREESPINE STICKLEBACK: EVIDENCE FOR RECENT MIGRATIONS.
Phylogenetic analyses of mitochondrial DNA (mtDNA) sequences were used to assess the matriarchal genetic structure of the threespine stickleback, Gasterosteus aculeatus. A 747 base-pair (bp) fragment of the cytochrome b was sequenced from 36 individuals collected from 25 localities in Europe, North America, and Japan. Two major divergent clades were revealed: one widespread in Japan but with representatives in some Alaskan and British Columbian lakes and the other common in Europe and North America. A simple diagnostic test using the polymerase chain reaction (PCR) and a restriction enzyme was used to assay additional individuals, confirming the absence of the Japanese clade in the Atlantic basin. Geographic distribution of mtDNA variation suggests (1) a recent origin of the Atlantic populations, and (2) support for previous hypotheses about the existence of Pleistocene refugia for freshwater fishes in Alaska and British Columbia. Silent substitution rates were used to date the colonization of the Atlantic at 90,000 to 260,000 yr before present, which conflicts with earlier dates implied by the fossil record. The recent replacement of Atlantic mitochondrial lineages suggested by our data may be explained by severe reduction or extinction of northern Atlantic populations during the Pleistocene, followed by a recent reinvasion from the Pacific. With a global perspective of the distribution of genetic variation as a framework, meaningful comparisons at a smaller geographical scale will now be possible.


Effectiveness of a Theory-Based Resiliency Intervention for Nurses.
The stress level among nurses is significantly high, which negatively affects the nurses' well-being and the quality of care provided to patients. The goal of this study was to measure the impact of implementing a resiliency training program on nurses. A pretest-posttest quasi-experimental design was used to measure the impact of nurses' participation in a resiliency training program. The sample was recruited with the convenience sampling technique. Participants were allocated to groups according to their ability to attend all intervention sessions. A total of 137 participants completed all phases of the study. The study was conducted at a private hospital in Amman, Jordan. Data were collected at two time points, before the intervention and 1 week after the intervention. Analysis of covariance was used to measure differences between groups after the intervention. The results indicated that there were statistically significant differences (p < .001) in resilience and stress levels between the groups after the intervention. Nurses in the intervention group showed a significant improvement in resilience scores and a significant reduction in stress scores. [J Contin Educ Nurs. 2023;54(12):581-588.].


Substituted 9-Anthraldehydes from Dibenzocycloheptanol Epoxides via Acid-Catalyzed Epoxide Opening/Semipinacol Rearrangement.
Starting from benzaldehyde derivatives, the corresponding dibenzocycloheptenol could be prepared in five steps. Under both substrate (secondary vs tertiary alcohol and the substituents on the aromatic ring(s)) and condition control, the subsequent epoxidation and acid-catalyzed epoxide opening/semipinacol rearrangement/aromatization afforded the corresponding 9-anthraldehydes in good yields, up to 88% over two steps. The presence of the electron-withdrawing group(s) on the aromatic ring(s) suppressed the rate of the epoxidation while the subsequent semipinacol rearrangement step required heating; the presence of the electron-donating group(s), on the other hand, frequently led to the decomposition during the epoxidation. From the mechanistic studies, the semipinacol rearrangement of the epoxide could precede the ionization at the bisbenzylic position, yielding the aldehyde intermediate. The ensuing dehydrative aromatization led to the formation of 9-anthraldehyde. Conversely, nucleophilic addition to the aldehyde and dehydrative aromatization with concomitant loss of formic acid led to anthracene.


[FHIT gene is abnormal in tongue carcinoma cell line].
To study the alteration of FHIT gene in tongue carcinoma Tca8113 cell line, total RNA of Tca8113 cells was extracted. The transcript of the FHIT gene of the Tca8113 cell line was detected with nest RT-PCR, and DNA was sequenced. The result showed that abnormal transcript (about 247 bp) of FHIT gene was detected in the Tca8113 cell line. The sequence analysis of the aberrant cDNAs revealed deletions of exons 1-8. Therefore, the deletion of the FHIT gene in Tca8113 cell line might support the hypothesis that the FHIT gene alteration is involved in the development of tongue carcinoma.


Diploid porcine parthenotes produced by inhibition of first polar body extrusion during in vitro maturation of follicular oocytes.
We investigated nuclear progression and in vitro embryonic development after parthenogenetic activation of porcine oocytes exposed to cytochalasin B (CB) during in vitro maturation (IVM). Nuclear progression was similar in control oocytes and oocytes matured in the presence of 1 microg/ml CB (IVM-CB group) by 37 h IVM; at this time the proportion of oocytes that had reached or passed through the anaphase-I stage did not differ significantly between the IVM-CB and the control groups (61.3 and 69.9% respectively; P < 0.05). After IVM for 37 h, no polar body extrusion was observed in the IVM-CB group. In these oocytes, the two lumps of homologous chromosomes remained in the ooplasm after their segregation and turned into two irregular sets of condensed chromosomes. By 41 h IVM, the double sets of chromosomes had reunited in 89.5% IVM-CB oocytes and formed a single large metaphase plate, whereas 68.8% of the control oocytes had reached the metaphase-II stage by this time. When IVM-CB oocytes cultured for 46 h were stimulated with an electrical pulse and subsequently cultured for 8 h without CB, 39.0% of them extruded a polar body and 82.9% of them had a female pronucleus. Chromosome analysis revealed that the majority of oocytes that extruded a polar body were diploid in both the control and the IVM-CB groups. However, the incidence of polyploidy in the IVM-CB group was higher than that in the control group (P < 0.05). In vitro development of diploid parthenotes in the control and the IVM-CB groups was similar in terms of blastocyst formation rates (45.8 and 42.8% respectively), number of blastomeres (39.9 and 44.4 respectively), the percentage of dead cells (4.3 and 2.9% respectively), and the frequency of apoptotic cells (7.3 and 6.3% respectively). Tetraploid embryos had a lower blastocyst formation rate (25.5%) and number of cells (26.2); however, the proportion of apoptotic nuclei (7.0%) was similar to that in diploid parthenotes. These results suggest that the proportion of homozygous and heterozygous genes does not affect in vitro embryo development to the blastocyst stage.


The PIT-trap-A "model-free" bootstrap procedure for inference about regression models with discrete, multivariate responses.
Bootstrap methods are widely used in statistics, and bootstrapping of residuals can be especially useful in the regression context. However, difficulties are encountered extending residual resampling to regression settings where residuals are not identically distributed (thus not amenable to bootstrapping)-common examples including logistic or Poisson regression and generalizations to handle clustered or multivariate data, such as generalised estimating equations. We propose a bootstrap method based on probability integral transform (PIT-) residuals, which we call the PIT-trap, which assumes data come from some marginal distribution F of known parametric form. This method can be understood as a type of "model-free bootstrap", adapted to the problem of discrete and highly multivariate data. PIT-residuals have the key property that they are (asymptotically) pivotal. The PIT-trap thus inherits the key property, not afforded by any other residual resampling approach, that the marginal distribution of data can be preserved under PIT-trapping. This in turn enables the derivation of some standard bootstrap properties, including second-order correctness of pivotal PIT-trap test statistics. In multivariate data, bootstrapping rows of PIT-residuals affords the property that it preserves correlation in data without the need for it to be modelled, a key point of difference as compared to a parametric bootstrap. The proposed method is illustrated on an example involving multivariate abundance data in ecology, and demonstrated via simulation to have improved properties as compared to competing resampling methods.


Manual materials handling in simulated motion environments.
Seafaring occupations have been shown to place operators at an increased risk for injury. The purpose of this study was to understand better the demands of a moving environment on the ability of a person to perform specific lifting tasks. Subjects lifted a 15-kg load under four different lifting conditions. A 6-degree-of-freedom ship motion simulator imposed repeatable deck motions under foot while subjects executed the lifting tasks. Subjects were oriented in three different positions on the simulator floor to inflict different motion profiles. Electromyographic records of four muscles were collected bilaterally, and thoracolumbar kinematics were measured. A repeated-measures ANOVA was employed to assess trunk motions and muscle activities across lifting and motion conditions. The erector spinae muscles showed a trend toward significant differences for motion effects. Maximal sagittal velocities were significantly smaller for all motion states in comparison with the stable condition (p <or= .01), whereas maximum twisting and lateral bending velocities were higher (p <or= .05). Results suggest working in a moving environment will likely increase the operator's risk for overexertion injuries, particularly to the trunk region.


Proton beam therapy versus stereotactic body radiotherapy for hepatocellular carcinoma: practice patterns, outcomes, and the effect of biologically effective dose escalation.
Stereotactic body radiation therapy (SBRT) and proton beam therapy (PBT) generally are safe and effective for non-operative hepatocellular carcinoma (HCC). To date, data comparing the two modalities are limited. We aimed to identify the practice patterns and outcomes of nonsurgical HCC cases treated definitively with either SBRT or PBT. We queried the National Cancer Database for T1-2N0 HCC patients receiving PBT or SBRT from 2004 to 2015. Patients were excluded for any treatment other than non-palliative external beam radiotherapy. A multivariable binomial regression model identified patterns of SBRT/PBT use, and propensity-matched multivariable Cox regression assessed correlates of survival. A total of 71 patients received PBT and 918 patients received SBRT (median follow-up 45 months). SBRT was used in 1.8% of nonoperative early stage HCC cases in 2004 and 4.2% of cases in 2015, whereas PBT was used in 0.1-0.2% of cases every year. The median biologically effective dose (BED) for SBRT and PBT was 100 Gy10 and 98 Gy10, respectively (OR =0.70, P=0.17). Factors predictive of receiving PBT included: white race, higher comorbidity score, higher education, metropolitan residence, tumors >5 cm and recent treatment (all P<0.05). Both PBT (HR =0.48, 95% CI: 0.29-0.78) and BED ≥100 Gy10 (HR =0.61, 95% CI: 0.38-0.98) were independent predictors for longer survival. Although not implying causation and requiring prospective corroboration, PBT was independently associated with longer survival than SBRT, despite being delivered to HCC patients with multiple poor prognostic factors. PBT may also allow for safer BED escalation, which also independently associated with outcomes.


SMG-BERT: integrating stereoscopic information and chemical representation for molecular property prediction.
Molecular property prediction is a crucial task in various fields and has recently garnered significant attention. To achieve accurate and fast prediction of molecular properties, machine learning (ML) models have been widely employed due to their superior performance compared to traditional methods by trial and error. However, most of the existing ML models that do not incorporate 3D molecular information are still in need of improvement, as they are mostly poor at differentiating stereoisomers of certain types, particularly chiral ones. Also,routine featurization methods using only incomplete features are hard to obtain explicable molecular representations. In this paper, we propose the Stereo Molecular Graph BERT (SMG-BERT) by integrating the 3D space geometric parameters, 2D topological information, and 1D SMILES string into the self-attention-based BERT model. In addition, nuclear magnetic resonance (NMR) spectroscopy results and bond dissociation energy (BDE) are integrated as extra atomic and bond features to improve the model's performance and interpretability analysis. The comprehensive integration of 1D, 2D, and 3D information could establish a unified and unambiguous molecular characterization system to distinguish conformations, such as chiral molecules. Intuitively integrated chemical information enables the model to possess interpretability that is consistent with chemical logic. Experimental results on 12 benchmark molecular datasets show that SMG-BERT consistently outperforms existing methods. At the same time, the experimental results demonstrate that SMG-BERT is generalizable and reliable.


Fasting to enhance Cancer treatment in models: the next steps.
Short-term fasting (STF) is a technique to reduce nutrient intake for a specific period. Since metabolism plays a pivotal role in tumor progression, it can be hypothesized that STF can improve the efficacy of chemotherapy. Recent studies have demonstrated the efficacy of STF in cell and animal tumor models. However, large-scale clinical trials must be conducted to verify the safety and effectiveness of these diets. In this review, we re-examine the concept of how metabolism affects pathophysiological pathways. Next, we provided a comprehensive discussion of the specific mechanisms of STF on tumor progression, derived through studies carried out with tumor models. There are currently at least four active clinical trials on fasting and cancer treatment. Based on these studies, we highlight the potential caveats of fasting in clinical applications, including the onset of metabolic syndrome and other metabolic complications during chemotherapy, with a particular focus on the regulation of the epithelial to mesenchymal pathway and cancer heterogeneity. We further discuss the advantages and disadvantages of the current state-of-art tumor models for assessing the impact of STF on cancer treatment. Finally, we explored upcoming fasting strategies that could complement existing chemotherapy and immunotherapy strategies to enable personalized medicine. Overall, these studies have the potential for breakthroughs in cancer management.


Sites of action of arginine vasotocin in the nephron of the bullfrog kidney.
The nature and location of arginine vasotocin (AVT) V2-type receptors in the bullfrog kidney with respect to cellular 3',5'-cyclic monophosphate (cAMP) production in response to AVT were studied in microdissected segments of the nephron and urinary bladder. The basal levels of cAMP were similar in renal corpuscles, proximal, distal convoluted, and connecting tubules, and urinary bladder of normal bullfrogs. A marked dose-dependent increase in cAMP production by AVT occurred in preparations from both the connecting tubule and the urinary bladder. The minimum effective and half-maximal concentrations of AVT on the connecting tubule were about 100 nM and 2 microM, respectively. No activation by AVT was observed in renal corpuscles and proximal tubules. These results suggest that V2-type AVT receptors exist in the connecting tubule of the nephron and the urinary bladder. The lack of hormonal activation of cAMP production observed in some tissues may reflect either the total absence or the presence of minor amounts of hormonal receptors associated with the cAMP-generating system in bullfrog nephron segments.


Spironolactone is an antagonist of NRG1-ERBB4 signaling and schizophrenia-relevant endophenotypes in mice.
Enhanced NRG1-ERBB4 signaling is a risk pathway in schizophrenia, and corresponding mouse models display several endophenotypes of the disease. Nonetheless, pathway-directed treatment strategies with clinically applicable compounds have not been identified. Here, we applied a cell-based assay using the split TEV technology to screen a library of clinically applicable compounds to identify modulators of NRG1-ERBB4 signaling for repurposing. We recovered spironolactone, known as antagonist of corticosteroids, as an inhibitor of the ERBB4 receptor and tested it in pharmacological and biochemical assays to assess secondary compound actions. Transgenic mice overexpressing Nrg1 type III display cortical Erbb4 hyperphosphorylation, a condition observed in postmortem brains from schizophrenia patients. Spironolactone treatment reverted hyperphosphorylation of activated Erbb4 in these mice. In behavioral tests, spironolactone treatment of Nrg1 type III transgenic mice ameliorated schizophrenia-relevant behavioral endophenotypes, such as reduced sensorimotor gating, hyperactivity, and impaired working memory. Moreover, spironolactone increases spontaneous inhibitory postsynaptic currents in cortical slices supporting an ERBB4-mediated mode-of-action. Our findings suggest that spironolactone, a clinically safe drug, provides an opportunity for new treatment options for schizophrenia.


Hypocalcemic generalised seizures as a manifestation of iatrogenic hypoparathyroidism months to years after thyroid surgery.
Hypoparathyroidism is a relatively common side effect of a thyroidectomy and leads to hypocalcemia. Carpopedal spasm and tetany are typical manifestations and usually occur within weeks after surgery. The first signs can be less typical and include movement disorders such as chorea, as well as symptoms of increased intracranial pressure or epileptic seizures. We describe two cases with generalised tonic-clonic seizures as the first manifestation of postoperative hypoparathyroidism, appearing months and years after thyroidectomy. Iatrogenic hypoparathyroidism needs to be considered in the differential diagnosis of adult-onset, generalised, tonic-clonic seizures even if the thyroidectomy was performed years earlier.


Second-harmonic generation from metal nanoparticles: resonance enhancement versus particle geometry.
We demonstrate that optical second-harmonic generation (SHG) from arrays of noncentrosymmetric gold nanoparticles depends essentially on particle geometry. We prepare nanoparticles with different geometrical shapes (L and T) but similar wavelengths for the polarization-dependent plasmon resonances. In contrast to recent interpretations emphasizing resonances at the fundamental frequency, the T shape leads to stronger SHG when only one, instead of both, polarization component of the fundamental field is resonant. This is explained by the character of plasmon oscillations supported by the two shapes. Our numerical simulations for both linear and second-order responses display unprecedented agreement with measurements.


Calculation of incubation period and serial interval from multiple outbreaks of Marburg virus disease.
Marburg viruses have been responsible for a number of outbreaks throughout sub-Saharan Africa, as well as a number of laboratory infections. Despite many years of experience with the viruses, little is known about several important epidemiologic parameters relating to the development of Marburg virus disease. The analysis uses pooled data from all Marburg cases between 1967 and 2008 to develop estimates for the incubation period and the clinical onset serial interval (COSI). Data were obtained from original outbreak investigation forms (n=406) and from published data (n=45). Incubation periods were calculated for person-to-person exposure, for laboratory-acquired infections, and for presumed zoonotic exposures. Similar analysis was conducted for COSI, using only cases with unambiguous person-to-person transmission where both the primary and the secondary case patients had well-defined illness onsets. Seventy-six cases were retained for the incubation period analysis. Incubation periods ranged from a minimum of 2 days in the case of two laboratory workers to a maximum of at least 26 days for a person-to-person household transmission. Thirty-eight cases were retained for COSI analysis. The median COSI was 11 days, with an interquartile range of 8 to 15. This study extends the maximum known incubation period of Marburg virus disease to 26 days. The analysis was severely hampered by a lack of completeness in epidemiologic data. It is necessary to prioritize obtaining more accurate epidemiologic data in future outbreaks; greater use of COSI may facilitate an improved understanding of outbreak dynamics in Marburg and other diseases.


Social and economic impact of childhood asthma.
In order to assess the social, educational and economic impact in children with asthma and their families, we studied 162 children with bronchial asthma. The patients and their parents were interviewed to assess the restriction on various activities of the child and family, the impact on schooling and expenditure on therapy. One hundred and forty one (87%) children had either mild or moderate persistent asthma. Nearly two thirds of children had some restriction placed on their play activities because of asthma. Restrictions on other physical activities and social activities were reported in half the children. Children had absented from school for a median of 4 days in preceding 6 months. All these restrictions were more common in children with more severe disease and/or poor control of symptoms. The median monthly expenditure on child's medication was Rs. 333, i.e., about one third of monthly per capita income. Childhood asthma has significant adverse impact on child's daily activities, schooling, and family life and finances.


Considerations for the use of qualitative methodologies in genetic counseling research.
An abundance of qualitative research is being conducted within the genetic counseling field. As this area of research expands, many within our community are "learning through doing", an approach which is practical, but may lack theoretical grounding. This can result in study outputs that do not have the sort of utility for informing clinical practice that is the hallmark of excellent clinical qualitative research. Furthermore, our alignment as a discipline within the health sciences, which still tends to favor quantitative approaches, means that we may often be obliged to justify the use of qualitative methodologies, especially when we intend to use the findings for informing clinical practice. We aim to address these issues by providing guidance about how we, individually and collectively, might think about what excellent qualitative research can look like in our field. In addition to providing information and resources about current best-practices, we discuss how quality can be ensured and evaluated. We seek to legitimize the idea of developing a philosophy of research in pursuit of establishing genetic counseling as an academic discipline. We argue that the principles, ethics, values, and practices of genetic counseling are sufficiently unique that establishing a discipline-specific qualitative research framework is not only warranted, but essential. Ultimately, we hope that this paper can serve as a launching point from which additional discussion about qualitative research can emanate as we strive towards the elevation of this form of inquiry in our field.


Effusive-constrictive pericarditis in the absence of overt pericardial disease on multiple imaging modalities.
Effusive-constrictive pericarditis (ECP) is a rare condition that may prove fatal without appropriate treatment. In ECP, there is concomitant existence of a pericardial effusion and CP, that together lead to impaired cardiac filling. Therapeutic pericardiocentesis only addresses part of the problem; surgical pericardiectomy may be required to relieve the constrictive element. Imaging in ECP characteristically demonstrates calcification or thickening of the pericardium. The authors describe a case of ECP were a number of imaging modalities (including echocardiography, cardiac magnetic resonance and CT) did not identify overt pericardial disease. The patient underwent surgical pericardiectomy that led to a rapid resolution of symptoms and full recovery. Histopathological analysis of the pericardial biopsy indicated a non-specific pericardial fibrosis, in keeping with the final diagnosis of ECP.


Falls among elderly and its relation with their health problems and surrounding environmental factors in Riyadh.
Falls among the elderly are one of the major causes of morbidity and mortality worldwide. They constitute the second leading cause of unintentional deaths after road-traffic accidents. The aim of the study was to estimate the prevalence of falls among the elderly and to investigate the factors that contribute to this phenomenon. A cross-sectional analytical study was conducted in the elderly, over the age of 60, in Riyadh. The sample under scrutiny was estimated to be 357 in total. A pilot study was conducted among 15 subjects. Two questionnaires were used for the interviews which were translated into Arabic using the "Morse Fall Scale." The questionnaires assessed: the participants' previous history of falls, whether a secondary diagnosis had been obtained, whether any ambulatory aids had been used or whether an IV connection had been fitted during convalescence. They also inquired if any gait/transferring device had been used to assist the patient at any time. Out of 357 participants, 206 (57.7%) had a history of falls. Study found an association between the number of falls recorded, the age of the participants, and whether the participant was female. Furthermore, there were statistically significant associations between the history of falls and a condition of impaired health. The results also showed that environmental hazards play a significant role in the occurrence of falls with P ≤ 0.001, in which 103 (81.7%) of the individuals who were exposed to environmental hazards revealed a history of falls. Falls among the elderly are common. Significantly, if the health of the individuals is impaired, and there are contiguous environmental risk factors, these elements combine to play a part in the occurrence of such falls. There is, therefore, a need to design and develop a health awareness program to prevent such problems in the elderly.


Fullerite crystal thermodynamic characteristics and the law of corresponding states.
The existence of single-wall carbon nanotubes in organic solvents in the form of clusters is discussed. A theory is developed based on a bundlet model, which enables describing the cluster-size distribution function. Comparison of calculated solubilities with experiments would permit obtaining energetic parameters, characterizing the interaction of a nanotube with its surrounding. Fullerenes and nanotubes are objects whose behaviour in many physical situations is characterized by peculiarities, which show up in that these systems represent the only soluble forms of carbon, what is related to their molecular structures. The fullerene molecule is a virtually uniform closed spherical-spheroidal surface and a nanotube is a smooth cylindrical unit. Both structures give rise to weak interactions between the neighbouring units in a crystal and promote their interaction with solvent molecules. The phenomena have a unified explanation in the bundlet model, in which the free energy of a nanotube in a cluster is combined from two components: a volume one proportional to the number of molecules n in a cluster and a surface one proportional to n1/2. Growth mechanisms of fractal clusters in fullerene solutions are analyzed along with similarity laws, determining the thermodynamic characteristics of fullerite crystals. In accordance with the similarity laws, the dimensionless Debye temperatures theta0 for all crystals belonging to the considered class should be close. Temperatures theta0 are determined by a similarity relation from experimental and estimated data. Fullerite theta0 is twice that for inert-gas crystals because, near the Debye point, the fullerite crystal is orientationally ordered so that its structure is dissimilar to face-centred cubic. A fullerene molecule whose thermal rotation is frozen cannot be considered as a spherically symmetric particle. The fulfilment of the similarity laws, which are valuable for particles with spherically symmetric interaction potential, would hardly be expected.


Pericardial Agenesis as a Rather Unusual Cause of Palpitations: We Only See What we Know.
Cardiac palpitations secondary to ventricular ectopic beats are a frequent clinical indication for a cardiac magnetic resonance (CMR) scan. CMR has already demonstrated its additive diagnostic value in patients with frequent arrhythmias even when echocardiogram appears normal. Hereby, we describe a case of a middle-aged male patient referred to our laboratory because of frequent ventricular ectopic beats and an inconclusive echocardiogram due to an extremely poor acoustic window. A diagnosis of pericardial agenesis (PA) was made explaining patient symptoms and arrhythmias previously detected. Furthermore, at the case report description, PA prevalence, associated cardiac pathologies, and novel CMR diagnostic criteria are being described.


Purification and separation of subsets of human Ia molecules by papain digestion.
Papain digestion of human Ia(-like) molecules was performed under various conditions using 125I-labelled preparation of non-ionic-detergent-solubilized Ia antigens of Daudi cells. The products were examined for their allospecificities by a direct binding reaction with human Ia alloantisera. The Daudi Ia preparation is known to contain Ia molecules of DRw6 specificity, an HLA-DR specificity and also Ia molecules of DC1 specificity, a putative non-HLA-DR specificity. Limited papain digestion cleaved off the hydrophobic portion of human Ia molecules and gave smaller sized Ia products. The cleavage did not affect the Ia alloantigenic determinants and occurred much more readily with molecules of DC1 specificity than with molecules of DRw6 specificity. As a consequence, limited papain digestion of the Daudi Ia pool yielded an Ia preparation with DRw6 specificity but lacking DC1 specificity and another Ia preparation which was enriched in DC1 specificity. The limited papain digestion of the Daudi Ia pool followed by gel filtration and LcH affinity chromatography also produced Ia REPARATIONS OF HIGH PURITY. Extensive papain digestion damaged the Ia alloantigenic determinants but the DC1 determinant was much more resistant than the DRw6 determinant. Thus extensive papain digestion yielded an Ia preparation which was relatively rich in DC1 specificity and essentially devoid of DRw6 specificity.


Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders.
Biallelic variants in PUS3 have recently been recognized as a rare cause of neurodevelopmental disorders. Pseudouridine synthase-3 encoded by PUS3 is an enzyme important for modification of various RNAs, including transfer RNA (tRNA). Here we present the clinical and genetic features of 21 individuals with biallelic PUS3 variants: seven new and 14 previously reported individuals, where clinical features of two were updated. The clinical and genetic information were collected through collaborations or by literature search. All individuals were characterized by the local clinicians and the gene variants were identified by next generation sequencing (NGS) based methodologies. The clinical picture was dominated by global developmental delay, epilepsy, hypotonia and microcephaly. Gray sclera, which has previously been suggested to be a characteristic feature of PUS3-associated phenotypes, was reported in only seven individuals. The patients had some dysmorphic facial features, but a recognizable gestalt was not observed. In conclusion, homozygous and compound heterozygous PUS3 variants lead to a rare neurodevelopmental disorder. Further functional studies are necessary to understand involvement of PUS3 and tRNA biogenesis in normal and abnormal brain development.


Minimally invasive parathyroid surgery in 103 patients with local/regional anesthesia, without exclusion criteria.
Parathyroid surgery for sporadic primary hyperparathyroidism (pHPT) can be accomplished with local/regional anesthesia and intraoperative monitoring of intact parathyroid hormone without exclusion criteria through a 1.0- to 1.25-inch (2.5- to 3.2-cm) incision (MIPL) in a high proportion of patients. One hundred thirty-one consecutive patients with pHPT were offered MIPL. One hundred three patients elected to have this procedure. Patients were not excluded because of inadequate localization, previous parathyroid surgery, or need for concomitant thyroid surgery. Preoperative localization with ultrasound and/or sestamibi-single photon emission computed tomography scan was done in all patients. Almost all patients had intraoperative monitoring of intact parathyroid hormone (IMPTH). MIPL was accomplished in 89 of these 103 patients (86.4%), but 14 required conversion to general anesthesia. The main reasons for conversion were concomitant thyroid surgery, no positive preoperative localization, and previous parathyroid surgery. This procedure was accomplished in 13 patients requiring a bilateral procedure, 5 patients requiring thyroid surgery, 4 patients with no positive preoperative localization, and in 3 patients with previous parathyroid surgery. The complications of MIPL were comparable to the traditional bilateral exploration with general anesthesia. No patient experienced permanent hypoparathyroidism or postoperative bleeding. Two patients had transient recurrent laryngeal nerve paresis, and surgery failed to correct hypercalcemia in 5 (4.9%) of the patients. There appears to be less need for antiemetic medication in the MIPL patients compared with patients who had general anesthesia. Parathyroid surgery for sporadic pHPT can be accomplished through a 1.0- to 1.25-inch (2.5- to 3.2-cm) incision with local/regional anesthesia, without exclusion criteria. Accurate preoperative localization, particularly localization to the same site by both ultrasound and 99mTc-sestamibi scan, and IMPTH can limit the surgery to a unilateral approach. One should be cautious in proceeding with MIPL in patients with need for concomitant thyroid surgery, no preoperative localization, or previous parathyroid surgery.


Sentinel Lymph Node Biopsy Using Preoperative Computed Tomographic Lymphography and Intraoperative Indocyanine Green Fluorescence Imaging in Patients With Localized Tongue Cancer.
The indocyanine green method alone is unsuitable for sentinel lymph node biopsy in patients with oral cancer because of poor transcutaneous identification of the fluorescent signal through the platysma and sternocleidomastoid muscles. To assess the utility of a novel sentinel lymph node biopsy technique using preoperative computed tomographic (CT) lymphography followed by the intraoperative indocyanine green fluorescence method. In this prospective study performed at Akita University Hospital, Akita, Japan, participants comprised 18 patients with previously untreated cN0 tongue cancer (squamous cell carcinoma) were enrolled from November 2012 to November 2016. Median observer period was 38 (range, 14-62) months. Analysis was completed between January 10 and March 10, 2018. For preoperative sentinel lymph node mapping, CT lymphography was performed the day before sentinel lymph node biopsy. For sentinel lymph node biopsy, a minimum skin incision was made according to the predetermined location of sentinel lymph nodes. Sentinel lymph nodes were excised under indocyanine green fluorescence guidance. Identification rate of preoperative sentinel lymph node mapping by CT lymphography and the number of sentinel lymph node successfully identified by the intraoperative indocyanine green fluorescence method. Among 18 patients (8 men, 10 women; median age, 65.5 [range, 40-83] years), sentinel lymph nodes could be mapped by preoperative CT lymphography in 16 patients (89%). At least 1 sentinel lymph node was successfully identified and excised in each of these 16 patients using intraoperative indocyanine green fluorescence. Among the 16 patients in whom sentinel lymph nodes were excised, metastases to sentinel lymph nodes were found in 5 patients (31%). The novel sentinel lymph node biopsy technique of preoperative CT lymphography mapping with intraoperative indocyanine green fluorescence has a high potential for identifying sentinel lymph nodes in patients with cN0 tongue cancer. Because the intraoperative indocyanine green method alone cannot identify sentinel lymph nodes in the neck region, this combined method has clinical potential as a sentinel lymph node biopsy technique that does not require radioisotopes.


Psychoactive substances in natural and unnatural deaths in Norway and Sweden - a study on victims of suicide and accidents compared with natural deaths in psychiatric patients.
The extent of post-mortem detection of specific psychoactive drugs may differ between countries, and may greatly influence the national death register's classification of manner and cause of death. The main objective of the present study was to analyse the magnitude and pattern of post-mortem detection of various psychoactive substances by the manner of death (suicide, accidental, undetermined and natural death with a psychiatric diagnosis) in Norway and Sweden. The Cause of Death Registers in Norway and Sweden provided data on 600 deaths in 2008 from each country, of which 200 were registered as suicides, 200 as accidents or undetermined manner of death and 200 as natural deaths in individuals with a diagnosis of mental disorder as the underlying cause of death. We examined death certificates and forensic reports including toxicological analyses. The detection of psychoactive substances was commonly reported in suicides (66 and 74% in Norway and Sweden respectively), accidents (85 and 66%), undetermined manner of deaths (80% in the Swedish dataset) and in natural deaths with a psychiatric diagnosis (50 and 53%). Ethanol was the most commonly reported substance in the three manners of death, except from opioids being more common in accidental deaths in the Norwegian dataset. In cases of suicide by poisoning, benzodiazepines and z-drugs were the most common substances in both countries. Heroin or morphine was the most commonly reported substance in cases of accidental death by poisoning in the Norwegian dataset, while other opioids dominated the Swedish dataset. Anti-depressants were found in 22% of the suicide cases in the Norwegian dataset and in 29% of suicide cases in the Swedish dataset. Psychoactive substances were detected in 66 and 74% of suicides and in 85 and 66% of accidental deaths in the Norwegian and Swedish datasets, respectively. Apart from a higher detection rate of heroin in deaths by accident in Norway than in Sweden, the pattern of detected psychoactive substances was similar in the two countries. Assessment of a suicidal motive may be hampered by the common use of psychoactive substances in suicide victims.


Iodine-131 therapy for hyperthyroidism prescribed by endocrinologist - our preliminary experience.
Radioiodine (I-131) is a useful therapeutic modality of hyperthyroidism when medical therapy fails. Traditionally, the nuclear physicians undertake the prescription of I-131 therapy. However, endocrinologists are increasingly being recognized for their competence in prescribing individualized doses of I-131 for the treatment of various thyroid disorders. In this pilot prospective study, we collaborated with our nuclear medicine colleagues to determine the outcomes of 80 patients with hyperthyroidism who underwent I-131 ablation as prescribed by the endocrinologist. Doses administered were based primarily on thyroid volume with adjustments contingent on adverse factors, and fixed assumptions on target absorbed dose (R) and uptake (U) were used. Seventy-three had Graves' disease (GD) and seven had toxic nodular goitre (TNG) or toxic adenomas (AFTN). Therapeutic success was defined as achievement of hypothyroidism or euthyroidism. 95.9 percent (70 of 73) of GD patients and 85.7 percent (6 of 7) of those with TNG/AFTN achieved successful outcomes after a single dose of endocrinologist-directed I-131 therapy. More than 50 percent of patients became hypothyroid by three months and about two-thirds became hypothyroid by six months post I-131 therapy. Our results indicate that the success rate of endocrinologist-directed I-131 therapy exceeds 95 percent with a single dose and compares favourably with nuclear physician-directed therapy outcomes.


Noninvasive prenatal testing/noninvasive prenatal diagnosis: the position of the National Society of Genetic Counselors.
The 1997 discovery of free fetal DNA in maternal plasma launched clinical researchers' efforts to establish a reliable method for non-invasive prenatal testing for fetal genetic conditions. Various methods, including, but not limited to, massively parallel sequencing (MPS) and selective analysis of cell-free fetal DNA in maternal plasma, have recently been developed as highly sensitive and specific noninvasive screening tools for common fetal chromosome aneuploidies. Incorporating these new noninvasive technologies into clinical practice will impact the current prenatal screening paradigm for fetal aneuploidy, in which genetic counseling plays an integral role. The National Society of Genetic Counselors (NSGC) currently supports Noninvasive Prenatal Testing/Noninvasive Prenatal Diagnosis (NIPT/NIPD) as an option for patients whose pregnancies are considered to be at an increased risk for certain chromosome abnormalities. NSGC urges that NIPT/NIPD only be offered in the context of informed consent, education, and counseling by a qualified provider, such as a certified genetic counselor. Patients whose NIPT/NIPD results are abnormal, or who have other factors suggestive of a chromosome abnormality, should receive genetic counseling and be given the option of standard confirmatory diagnostic testing.


Coexistence of KRAS and BRAF Mutations in Colorectal Cancer: A Case Report Supporting The Concept of Tumoral Heterogeneity.
The detection of KRAS and BRAF mutations is a crucial step for the correct therapeutic approach and predicting the epidermal growth factor receptor (EGFR)-targeted therapy resistance of colorectal carcinomas. The concomitant KRAS and BRAF mutations occur rarely in the colorectal cancers (CRCs) with the prevalence of less than 0.001% of the cases. In patients with KRAS-mutant tumors, BRAF mutations should not regularly be tested unless the patient is participating in a clinical trial enriching for the presence of KRAS or BRAF-mutated tumor. The current report demonstrates a case with advanced adenocarcinoma of the colon showing the coexistence of KRAS and BRAF mutations and may have profound clinical implications for disease progression and therapeutic responses.


The cost of head trauma in Olmsted County, Minnesota, 1970-74.
A study of the total cost of head injury in Olmsted County, Minnesota, with the costs projected to the United States population, revealed that the annual cost for head trauma in the US can be estimated at approximately +12.5 billion using a 6 per cent discount rate. The nonmedical costs accounted for more than 92 per cent (+11.5 billion) of the total cost, while direct medical costs amounted to +1.0 billion.


Single line-of-sight dual energy backlighter for mix width experiments.
We present a diagnostic technique used to spatially multiplex two x-ray radiographs of an object onto a detector along a single line-of-sight. This technique uses a thin, <2 μm, cosputtered backlighter target to simultaneously produce both Ni and Zn Heα emission. A Ni picket fence filter, 500 μm wide bars and troughs, is then placed in front of the detector to pass only the Ni Heα emission in the bar region and both energies in the trough region thereby spatially multiplexing the two radiographs on a single image. Initial experimental results testing the backlighter spectrum are presented along with simulated images showing the calculated radiographic images though the nickel picket fence filter which are used to measure the mix width in an accelerated nickel foam.


Correction: Preparation of hexagonal GeO2 particles with particle size and crystallinity controlled by peptides, silk and silk-peptide chimeras.
Correction for 'Preparation of hexagonal GeO2 particles with particle size and crystallinity controlled by peptides, silk and silk-peptide chimeras' by Estefania Boix et al., Dalton Trans., 2014, 43, 16902-16910.


The Flower-Infecting Fungus Ustilaginoidea virens Subverts Plant Immunity by Secreting a Chitin-Binding Protein.
Ustilaginoidea virens is a biotrophic fungal pathogen specifically colonizing rice floral organ and causes false smut disease of rice. This disease has emerged as a serious problem that hinders the application of high-yield rice cultivars, by reducing grain yield and quality as well as introducing mycotoxins. However, the pathogenic mechanisms of U. virens are still enigmatic. Here we demonstrate that U. virens employs a secreted protein UvCBP1 to manipulate plant immunity. In planta expression of UvCBP1 led to compromised chitin-induced defense responses in Arabidopsis and rice, including burst of reactive oxygen species (ROS), callose deposition, and expression of defense-related genes. In vitro-purified UvCBP1 protein competes with rice chitin receptor OsCEBiP to bind to free chitin, thus impairing chitin-triggered rice immunity. Moreover, UvCBP1 could significantly promote infection of U. virens in rice flowers. Our results uncover a mechanism of a floral fungus suppressing plant immunity and pinpoint a universal role of chitin-battlefield during plant-fungi interactions.


Comprehensiveness of HIV care provided at global HIV treatment sites in the IeDEA consortium: 2009 and 2014.
An important determinant of the effectiveness of HIV treatment programs is the capacity of sites to implement recommended services and identify systematic changes needed to ensure that invested resources translate into improved patient outcomes. We conducted a survey in 2014 of HIV care and treatment sites in the seven regions of the International epidemiologic Database to Evaluate AIDS (IeDEA) Consortium to evaluate facility characteristics, HIV prevention, care and treatment services provided, laboratory capacity, and trends in the comprehensiveness of care compared to data obtained in the 2009 baseline survey. Clinical staff from 262 treatment sites in 45 countries in IeDEA completed a site survey from September 2014 to January 2015, including Asia-Pacific with Australia (n = 50), Latin America and the Caribbean (n = 11), North America (n = 45), Central Africa (n = 17), East Africa (n = 36), Southern Africa (n = 87), and West Africa (n = 16). For the 55 sites with complete data from both the 2009 and 2014 survey, we evaluated change in comprehensiveness of care. The majority of the 262 sites (61%) offered seven essential services (ART adherence, nutritional support, PMTCT, CD4+ cell count testing, tuberculosis screening, HIV prevention, and outreach). Sites that were publicly funded (64%), cared for adults and children (68%), low or middle Human Development Index (HDI) rank (68%, 68%), and received PEPFAR support (71%) were most often fully comprehensive. CD4+ cell count testing was universally available (98%) but only 62% of clinics offered it onsite. Approximately two-thirds (69%) of sites reported routine viral load testing (44-100%), with 39% having it onsite. Laboratory capacity to monitor antiretroviral-related toxicity and diagnose opportunistic infections varied widely by testing modality and region. In the subgroup of 55 sites with two surveys, comprehensiveness of services provided significantly increased across all regions from 2009 to 2014 (5.7 to 6.5, p < 0.001). The availability of viral load monitoring remains suboptimal and should be a focus for site capacity, particularly in East and Southern Africa, where the majority of those initiating on ART reside. However, the comprehensiveness of care provided increased over the past 5 years and was related to type of funding received (publicly funded and PEPFAR supported).


[The cartilage conserving concept of surgical tracheostomy].
Most techniques of tracheostomy include a resection or at least incision of the cartilage himself. This may result in local tracheomalacia and chondritis. We performed 48 tracheotomies (173 cases were totally performed in our in 2002 excluding laryngectomie patients) in with horizontal incision between 2 (nd) and 3 (rd) ring sparing all cartilage. The detailed technique is described and the (endoscopic controlled) follow-up data showed no complications. We called this techniques the visor-tracheostomy. It is shown, that a modified concept of conservating cartilage while doing tracheostomy is easy to perform without any increasing in time and costs. The most important thing is to choose the right incision range. It seems to us, that healing of these tracheotomies is better and secondary complications as stenosis of trachea should be less instead of the cases where Björk-flaps or simply local resection were performed.


Effectiveness and safety of bifidobacteria and berberine in people with hyperglycemia: study protocol for a randomized controlled trial.
Berberine is one of the most important examples of a Chinese traditional medicine that has hypoglycemic effects but there have been no randomized controlled trials of the drug in a larger sample. In addition, the use of probiotic biotherapy to maintain an appropriate intestinal flora may represent an effective early intervention for hyperglycemia. Unfortunately, there has been a shortage of relevant research on this possibility at the population level. This study was designed to determine the hypoglycemic effect and safety of both bifidobacteria and berberine administration to newly diagnosed patients with pre-diabetes or diabetes mellitus. This is a multicenter, double-blind, randomized, and parallel-controlled study that includes a run-in period of 2 weeks and a treatment period of 16 weeks, which will be conducted between June 2015 and October 2018. The 300 randomized patients will be assigned to the following four groups for 16 weeks' treatment: Bifidobacterium, berberine, Bifidobacterium combined berberine, and placebo control groups. The primary outcome is the absolute value of fasting plasma glucose compared with baseline after 16 weeks of treatment. This is the first randomized controlled trial to determine the hypoglycemic effect and safety of both bifidobacteria and berberine administration to newly diagnosed patients with pre-diabetes or diabetes mellitus. It may provide support for the use of berberine and bifidobacteria in the treatment of diabetes. ClinicalTrials.gov, ID: NCT03330184 . Retrospectively registered on 18 October 2017.


Identification of circulating monocytes as producers of tuberculosis disease biomarker C1q.
Tuberculosis (TB) is a prevalent disease causing an estimated 1.6 million deaths and 10.6 million new cases annually. Discriminating TB disease from differential diagnoses can be complex, particularly in the field. Increased levels of complement component C1q in serum have been identified as a specific and accessible biomarker for TB disease but the source of C1q in circulation has not been identified. Here, data and samples previously collected from human cohorts, a clinical trial and a non-human primate study were used to identify cells producing C1q in circulation. Cell subset frequencies were correlated with serum C1q levels and combined with single cell RNA sequencing and flow cytometry analyses. This identified monocytes as C1q producers in circulation, with a pronounced expression of C1q in classical and intermediate monocytes and variable expression in non-classical monocytes.


Aromatic C-H Bond Functionalization Induced by Electrochemically in Situ Generated Tris(p-bromophenyl)aminium Radical Cation: Cationic Chain Reactions of Electron-Rich Aromatics with Enamides.
An effective Friedel-Crafts alkylation reaction of electron-rich aromatics with N-vinylamides, induced by electrochemically in situ-generated TBPA radical cation, has been developed; the resulting adducts are produced in good to excellent yields. In the "ex-cell" type electrolysis, TBPA is transformed to its oxidized form in situ and subsequently employed as an electron transfer reagent to initiate a cationic chain reaction. An easily recoverable and reusable polymeric ionic liquid-carbon black (PIL-CB) composite was also utilized as a supporting electrolyte for the electrochemical generation of TBPA cation radical, without sacrificing efficiency or stability after four electrolyses. Cyclic voltammetry analysis and the results of control experiments demonstrate that the reaction of electron-rich aromatics and N-vinylamides occurs via a cationic chain reaction, which takes place though an oxidative activation of a C-H bond of electron-rich aromatics instead of oxidation of the N-vinylamide as previously assumed.


[Staging of adenocarcinoma of the kidney--CT largely replaces catheter angiography].
In renal adenocarcinoma (hypernephroma) CT as a rule provides the same information as angiography. Our experience is based on a collection of 61 tumour cases, divided in stages according to the TNM system. In retrospect, 39 of our own cases were investigated by CT as well as by angiography; the accuracy of both methods was tested on 33 operative findings. Prospectively 22 cases were examined by CT only and results controlled via 20 operative findings. CT is superior in the T and N stages. Usually demonstration of vein invasion is as good in CT as in catheter angiography. Metastases in the adrenals and the liver are vasible in CT. Seen from the point of view of a "non-touch procedure" (particularly to be demanded with a tumour metastasising as early as this!) the non-invasive method of CT proves especially suitable. We use CT primarily in all cases of suspicion. In singular cases CT is supplemented by further angiographic investigations, e.g. cavography. Exceptions to the topical proceedings mentioned above are a suspected tumour in a solitary kidney, and bilateral tumours. Such cases should be investigated by catheter angiography following i.v. urography and/or sonography.


Influence of the exchange screening parameter on the performance of screened hybrid functionals.
This work reexamines the effect of the exchange screening parameter omega on the performance of the Heyd-Scuseria-Ernzerhof (HSE) screened hybrid functional. We show that variation of the screening parameter influences solid band gaps the most. Other properties such as molecular thermochemistry or lattice constants of solids change little with omega. We recommend a new version of HSE with the screening parameter omega=0.11 bohr(-1) for further use. Compared to the original implementation, the new parametrization yields better thermochemical results and preserves the good accuracy for band gaps and lattice constants in solids.


Causes of death in patients with COPD and chronic respiratory failure.
Although the factors associated with mortality, such as forced expiratory volume in one second (FEV1), arterial oxygen tension (Pa,O2) and pulmonary arterial pressure, have been well described, there is limited information on the circumstances of death in patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the causes and circumstances of death in patients with COPD and chronic respiratory failure (Pa,O2 < 8.0 kPa (60 mmHg) breathing air), treated with long-term oxygen therapy (LTOT). Ten European centres participated in the study and data were collected from patients both during a period of clinical stability and at the time of death. Of the 215 patients evaluated (161 males and 54 females; aged 66 +/- 10 yrs), the major causes of death were: acute on chronic respiratory failure (38%); heart failure (13%); pulmonary infection (11%); pulmonary embolism (10%); cardiac arrhythmia (8%); and lung cancer (7%). Seventy five percent of patients died in hospital. There was no difference in the number of patients who died in the morning, afternoon and night hours. Twenty percent of the total died during sleep and in 26% death was unexpected. A lower arterial carbon dioxide tension (Pa,CO2), less oxygen usage per 24 h, and increased incidence of arrhythmias were seen in those patients who died suddenly. Drug therapy was not related to unexpected death. The majority of patients with chronic obstructive pulmonary disease on long-term oxygen therapy died from chronic or acute on chronic respiratory failure. Prevention and treatment of respiratory failure in patients with chronic obstructive pulmonary disease is likely to have the greatest impact in reducing mortality.


[The problem of glaucoma in Africa--progress report from Cameroon].
Glaucoma is one of the most common causes of blindness in the world. This aspect is well known for the developed countries, however in Africa blindness mainly occurs due to cataract, trachoma and onchocercosis. Glaucoma is not mentioned enough. Patients present with severe findings after a long-lasting history of disease. In our project experienced surgeons and young medical doctors have been practising regularly in Cameroon since 2001. By means of support from the "Komitee zur Verhütung von Blindheit" and medical industries we keep in contact with a local ophthalmologist. During the consultation of hundreds of patients we have often seen highly advanced glaucoma cases. The medical therapy of glaucoma and also the surgical procedures are limited -- modern antiglaucomatosa are not available. We achieved sufficient regulation of intraocular pressure after trabeculectomy with or without cataract surgery in many cases. The success rate was decreased by severe scar reactions especially in young black people. In advanced glaucoma cases and oculus ultimus we also used the old techniques of iridencleisis. There was a good postoperative regulation of eye pressure, but sometimes we saw a giant filtering bleb after this iris-mutilating procedure. Glaucoma is a very complex problem, also in Cameroon. Although the diagnostic possibilities are limited, the therapeutic spectrum is differentiated. The introduction of a robust laser for cyclophotocoagulation would be a useful alternative.


Evaluation of gene-drug common module identification methods using pharmacogenomics data.
Accurately identifying the interactions between genomic factors and the response of cancer drugs plays important roles in drug discovery, drug repositioning and cancer treatment. A number of studies revealed that interactions between genes and drugs were 'many-genes-to-many drugs' interactions, i.e. common modules, opposed to 'one-gene-to-one-drug' interactions. Such modules fully explain the interactions between complex biological regulatory mechanisms and cancer drugs. However, strategies for effectively and robustly identifying the underlying common modules among pharmacogenomics data remain to be improved. In this paper, we aim to provide a detailed evaluation of three categories of state-of-the-art common module identification techniques from a machine learning perspective, including non-negative matrix factorization (NMF), partial least squares (PLS) and network analyses. We first evaluate the performance of six methods, namely SNMNMF, NetNMF, SNPLS, O2PLS, NSBM and HOGMMNC, using two series of simulated data sets with different noise levels and outlier ratios. Then, we conduct experiments using a real world data set of 2091 genes and 101 drugs in 392 cancer cell lines and compare the real experimental results from the aspect of biological process term enrichment, gene-drug and drug-drug interactions. Finally, we present interesting findings from our evaluation study and discuss the advantages and drawbacks of each method. Supplementary information: Supplementary file is available at Briefings in Bioinformatics online.


Effects of Population Weighting on PM10 Concentration Estimation.
Particulate matter with an aerodynamic diameter of 10 μm or less (PM10) pollution poses a considerable threat to human health, and the first step in quantifying health impacts of human exposure to PM10 pollution is exposure assessment. Population-weighted exposure level (PWEL) estimation is one of the methods that provide a more refined exposure assessment as it includes the spatiotemporal distribution of the population into the pollution concentration estimation. This study assessed the population weighting effects on the estimated PM10 concentrations in Malaysia for years 2000, 2008, and 2013. Estimated PM10 annual mean concentrations with a spatial resolution of 5 kilometres retrieved from satellite data and population count obtained from the Gridded Population of the World version 4 (GPWv4) from the Centre for International Earth Science Information Network (CIESIN) were overlaid to generate the PWEL of PM10 for each state. The calculated PWEL of PM10 concentrations were then classified based on the World Health Organization (WHO) and the national Air Quality Guidelines (AQG) and interim targets (IT) for comparison. Results revealed that the annual mean PM10 concentrations in Malaysia ranged from 31 to 73 µg/m3 but became generally lower, ranging from 20 to 72 µg/m3 after population weighting, suggesting that the PM10 population exposure in Malaysia might have been overestimated. PWEL of PM10 distribution showed that the majority of the population lived in areas that complied with the national AQG, but were vulnerable to exposure level 3 according to the WHO AQG and IT, indicating that the population was nevertheless potentially exposed to significant health effects from long-term exposure to PM10 pollution.


EPR studies of copper(II) and cobalt(II) complexes of adriamycin.
Cu2+ and Co2+ complexes of adriamycin (ADM) in aqueous solutions have been examined using EPR spectroscopy. An appreciable amount of Cu2+ and Co2+ complexes formed in the solutions were found to be in the EPR silent associated form, where the metal ions are antiferromagnetically coupled. The associated form of the Cu2+ complex may be neither a simple dimer nor coordination polymer but aggregates of a stacked type. Formation of a complex having Cu2+-ADM stoichiometry of 1:2 was observed for the solutions containing excess of ADM as an EPR observable species. The complex having Cu2+-ADM stoichiometry of 1:1 was not observed directly by EPR, but the presence of the complex is undeniable, especially at low pH range so far as large excessive ADM is not present. The Co2+ complex of ADM observed by EPR is in the high-spin (S = 3/2) state and may have a coordination structure of tetragonal symmetry. The EPR spectra of these complexes apparently show that the Cu2+ and Co2+ ions are bound at the carbonyl and phenolate oxygen in the 1,4-dihydroxyanthraquinone moiety and the amino nitrogen in the sugar part does not seem to participate in the coordination to the metal ions.


[Expression of influenza B virus hemagglutinin and its immunogenicity determination].
Influenza B virus is one of the causes for seasonal influenza, which can account for serious illness or even death in some cases. We tested the expression of extracellular domain of hemagglutinin (HA-ecto) of influenza B viruses in mammalian cells, and then determined the immunogenicity of HA-ecto in mice. The gene sequence encoding influenza B virus HA-ecto, foldon sequence, and HIS tag was optimized and inserted into pCAGGS vector. The opening reading frame (ORF) of neuraminidase was also cloned into pCAGGS. The pCAGGS-HA-ecto and pCAGGS-NA were co-transfected into 293T cells using linear polyethylenimine. Cell supernatant after transfection was collected after 96 h, and the secreted trimmeric HA-ecto protein was purified by nickel ion affinity chromatography and size exclusion chromatography. Subsequently, the mice were immunized with HA-ecto protein, and the corresponding antibody titers were detected by ELISA and hemagglutination inhibition (HAI) assays. The results showed that soluble trimeric HA-ecto protein could be obtained using mammalian cell expression system. Moreover, trimeric HA-ecto protein, in combination with the adjuvant, induced high levels of ELISA and HAI antibodies against homogenous and heterologous antigens in mice. Thus, the soluble HA-ecto protein expressed in mammalian cells could be used as a recombinant subunit vaccine candidate for influenza B virus.


Women's perspectives on quality of maternal health care services in Malawi.
Despite promotion by many stakeholders to improve maternal health outcome in many developing countries including Malawi, many analysts agree that the utmost success in maternal health will arise if maternal health care services are an unparallel led source for women's health care solutions for any problem related to childbirth. Health advocates worldwide claim that even though maternal services are provided, women's utilization of such services has not been ascertained. The objective of this study was to explore women's perspectives on the quality of health care service delivery in Malawi. This article therefore investigates women's perspectives on the quality of maternal health care services in Malawi. We used six focus group discussions in six health facilities that were selected across Malawi. We found that erratic availability of medical resources and unethical practices among health workers adversely affected quality of maternal health care service delivery. We concluded that the expensive routine operational audits of medical resources and service delivery across health facilities are imperative if women's health outcomes are to be enhanced in Malawi.


Reducing pesticide use while preserving crop productivity and profitability on arable farms.
Achieving sustainable crop production while feeding an increasing world population is one of the most ambitious challenges of this century1. Meeting this challenge will necessarily imply a drastic reduction of adverse environmental effects arising from agricultural activities2. The reduction of pesticide use is one of the critical drivers to preserve the environment and human health. Pesticide use could be reduced through the adoption of new production strategies3-5; however, whether substantial reductions of pesticide use are possible without impacting crop productivity and profitability is debatable6-17. Here, we demonstrated that low pesticide use rarely decreases productivity and profitability in arable farms. We analysed the potential conflicts between pesticide use and productivity or profitability with data from 946 non-organic arable commercial farms showing contrasting levels of pesticide use and covering a wide range of production situations in France. We failed to detect any conflict between low pesticide use and both high productivity and high profitability in 77% of the farms. We estimated that total pesticide use could be reduced by 42% without any negative effects on both productivity and profitability in 59% of farms from our national network. This corresponded to an average reduction of 37, 47 and 60% of herbicide, fungicide and insecticide use, respectively. The potential for reducing pesticide use appeared higher in farms with currently high pesticide use than in farms with low pesticide use. Our results demonstrate that pesticide reduction is already accessible to farmers in most production situations. This would imply profound changes in market organization and trade balance.


A mechanistic basis for underyielding in phytoplankton communities.
Species richness has been shown to increase biomass production of plant communities. Such overyielding occurs when a community performs better than its component monocultures due to the complementarity or dominance effect and is mostly detected in substrate-bound plant communities (terrestrial plants or submerged macrophytes) where resource use complementarity can be enhanced due to differences in rooting architecture and depth. Here, we investigated whether these findings are generalizeable for free-floating phytoplankton with little potential for spatial differences in resource use. We performed aquatic microcosm experiments with eight phytoplankton species belonging to four functional groups to determine the manner in which species and community biovolume varies in relation to the number of functional groups and hypothesized that an increasing number of functional groups within a community promotes overyielding. Unexpectedly, we did not detect overyielding in any algal community. Instead, total community biovolume tended to decrease with an increasing number of functional groups. This underyielding was mainly caused by the negative dominance effect that originated from a trade-off between growth rate and final biovolume. In monoculture, slow-growing species built up higher biovolumes than fast-growing ones, whereas in mixture a fast-growing but low-productive species monopolized most of the nutrients and prevented competing species from developing high biovolumes expected from monocultures. Our results indicated that the magnitude of the community biovolume was largely determined by the identity of one species. Functional diversity and resource use complementarity were of minor importance among free-floating phytoplankton, possibly reflecting the lack of spatially heterogeneous resource distribution. As a consequence, biodiversity-ecosystem functioning relationships may not be easily generalizeable from substrate-bound plant to phytoplankton communities and vice versa.


Augmentation of cGMP/PKG pathway and colonic motility by hydrogen sulfide.
Hydrogen sulfide (H2S), like nitric oxide (NO), causes smooth muscle relaxation, but unlike NO, does not stimulate soluble guanylyl cyclase (sGC) activity and generate cyclic guanosine 5'-monophosphate (cGMP). The aim of this study was to investigate the interplay between NO and H2S in colonic smooth muscle. In colonic smooth muscle from rabbit, mouse, and human, l-cysteine, substrate of cystathionine-γ-lyase (CSE), or NaHS, an H2S donor, inhibited phosphodiesterase 5 (PDE5) activity and augmented the increase in cGMP levels, IP3 receptor phosphorylation at Ser1756 (measured as a proxy for PKG activation), and muscle relaxation in response to NO donor S-nitrosoglutathione (GSNO), suggesting augmentation of cGMP/PKG pathway by H2S. The inhibitory effect of l-cysteine, but not NaHS, on PDE5 activity was blocked in cells transfected with CSE siRNA or treated with CSE inhibitor d,l-propargylglycine (dl-PPG), suggesting activation of CSE and generation of H2S in response to l-cysteine. H2S levels were increased in response to l-cysteine, and the effect of l-cysteine was augmented by GSNO in a cGMP-dependent protein kinase-sensitive manner, suggesting augmentation of CSE/H2S by cGMP/PKG pathway. As a result, GSNO-induced relaxation was inhibited by dl-PPG. In flat-sheet preparation of colon, l-cysteine augmented calcitonin gene-related peptide release in response to mucosal stimulation, and in intact segments, l-cysteine increased the velocity of pellet propulsion. These results demonstrate that in colonic smooth muscle, there is a novel interplay between NO and H2S. NO generates H2S via cGMP/PKG pathway, and H2S, in turn, inhibits PDE5 activity and augments NO-induced cGMP levels. In the intact colon, H2S promotes colonic transit.NEW & NOTEWORTHY Hydrogen sulfide (H2S) and nitric oxide (NO) are important regulators of gastrointestinal motility. The studies herein provide the cross talk between NO and H2S signaling to mediate smooth muscle relaxation and colonic transit. H2S inhibits phosphodiesterase 5 activity to augment cGMP levels in response to NO, which, in turn, via cGMP/PKG pathway, generates H2S. These studies suggest that interventions targeted at restoring NO and H2S homeostasis within the smooth muscle may provide novel therapeutic approaches to mitigate motility disorders.


Metabolomic analysis of rat brain by high resolution nuclear magnetic resonance spectroscopy of tissue extracts.
Studies of gene expression on the RNA and protein levels have long been used to explore biological processes underlying disease. More recently, genomics and proteomics have been complemented by comprehensive quantitative analysis of the metabolite pool present in biological systems. This strategy, termed metabolomics, strives to provide a global characterization of the small-molecule complement involved in metabolism. While the genome and the proteome define the tasks cells can perform, the metabolome is part of the actual phenotype. Among the methods currently used in metabolomics, spectroscopic techniques are of special interest because they allow one to simultaneously analyze a large number of metabolites without prior selection for specific biochemical pathways, thus enabling a broad unbiased approach. Here, an optimized experimental protocol for metabolomic analysis by high-resolution NMR spectroscopy is presented, which is the method of choice for efficient quantification of tissue metabolites. Important strengths of this method are (i) the use of crude extracts, without the need to purify the sample and/or separate metabolites; (ii) the intrinsically quantitative nature of NMR, permitting quantitation of all metabolites represented by an NMR spectrum with one reference compound only; and (iii) the nondestructive nature of NMR enabling repeated use of the same sample for multiple measurements. The dynamic range of metabolite concentrations that can be covered is considerable due to the linear response of NMR signals, although metabolites occurring at extremely low concentrations may be difficult to detect. For the least abundant compounds, the highly sensitive mass spectrometry method may be advantageous although this technique requires more intricate sample preparation and quantification procedures than NMR spectroscopy. We present here an NMR protocol adjusted to rat brain analysis; however, the same protocol can be applied to other tissues with minor modifications.


A comparative study to evaluate the efficacy of platelet-rich plasma and triamcinolone to treat tennis elbow.
Lateral elbow pain is common with a population prevalence of 1%-3%. The study was a comparative trial to validate the efficacy of single injection of platelet-rich plasma (PRP) for tennis elbow as compared with single injections of triamcinolone and placebo (normal saline) over a short term period. Comparative trial with 3- and 6-month followup evaluated with visual analog scale (VAS) and facial pain scale (FPS). Our study included a total of eighty patients with unilateral or bilateral tennis elbows. The study population included patients between 20 and 40 years age group belonging to either sex with seventy unilateral and ten bilateral affections for more than 3-month duration. Patients suffering from elbow pain due to other problems or those who have received any form of injection were excluded from the study. One milliliter of 2% Xylocaine injection was given before injecting the proposed formulation under trial. VAS and FPS were used for scoring pain. Kruskal-Wallis test and Mann-Whitney U-tests were used for statistical analyses at 12 and 24 weeks. Overall, 49 females and 31 males were included with thirty elbows in each group. Both the PRP and triamcinolone groups had better pain relief at 3 and 6 months as compared to normal saline group (P < 0.05), but at 6 months followup, the PRP group had statistically significant better pain relief than triamcinolone group. In the triamcinolone group, 13 patients had injection site hypopigmentation and 3 patients had subdermal atrophy. Over a short term period, PRP gives better pain relief than triamcinolone or normal saline in tennis elbow which needs to be validated over long term period by further studies.


[A case of subcutaneous metastases from bladder cancer after radical cystouretherectomy].
A case of transitional cell carcinoma (TCC) of the bladder metastasizing subcutaneously to the right lower abdomen and to the left back approximately 2 years after radical cystouretherectomy is reported. A 65-year-old male underwent radical cystouretherectomy with the creation of ileal couduit after preoperative intraarterial chemotherapy and radiotherapy. At the out patient clinic two years postoperatively, a subcutaneous tumor was palpated in the right lower abdomen and the left back. The tumors were removed and histopathologically diagnosed as subcutaneous metastases of TCC. The patient received three courses of postoperative systemic chemotherapy. At 15 months after the last chemotherapy, the patient remains free of metastases and relapse.


[Frequent errors in planning and clinical management of tumor therapy].
Frequent and important errors in the management of cancer patients are reviewed. Mistakes can occur during diagnostic work-up, treatment planning, the actual treatment phase, evaluation of the response and of treatment-related side effects, the continuation or termination of a therapy, follow-up of the cancer patient and on several other occasions. Despite the fact that human knowledge and human actions are less than perfect, the knowledgeable and alert physician can avoid many errors in caring for cancer patients.


Comparison of Revision Rates of Anterior- and Posterior-Approach Ptosis Surgery: A Retrospective Review of 1519 Cases.
To compare revision rates for ptosis surgery between posterior-approach and anterior-approach ptosis repair techniques. This is the retrospective, consecutive cohort study. All patients undergoing ptosis surgery at a high-volume oculofacial plastic surgery practice over a 4-year period. A retrospective chart review was conducted of all patients undergoing posterior-approach and anterior-approach ptosis surgery for all etiologies of ptosis between 2011 and 2014. Etiology of ptosis, concurrent oculofacial surgeries, revision, and complications were analyzed. The main outcome measure is the ptosis revision rate. A total of 1519 patients were included in this study. The mean age was 63 ± 15.4 years. A total of 1056 (70%) of patients were female, 1451 (95%) had involutional ptosis, and 1129 (74.3%) had concurrent upper blepharoplasty. Five hundred thirteen (33.8%) underwent posterior-approach ptosis repair, and 1006 (66.2%) underwent anterior-approach ptosis repair. The degree of ptosis was greater in the anterior-approach ptosis repair group. The overall revision rate for all patients was 8.7%. Of the posterior group, 6.8% required ptosis revision; of the anterior group, 9.5% required revision surgery. The main reason for ptosis revision surgery was undercorrection of one or both eyelids. Concurrent brow lifting was associated with a decreased, but not statistically significant, rate of revision surgery. Patients who underwent unilateral ptosis surgery had a 5.1% rate of Hering's phenomenon requiring ptosis repair in the contralateral eyelid. Multivariable logistic regression for predictive factors show that, when adjusted for gender and concurrent blepharoplasty, the revision rate in anterior-approach ptosis surgery is higher than posterior-approach ptosis surgery (odds ratio = 2.08; p = 0.002). The overall revision rate in patients undergoing ptosis repair via posterior-approach or anterior-approach techniques is 8.7%. There is a statistically higher rate of revision with anterior-approach ptosis repair.


Anti-N-Methyl-D-Aspartate-Receptor Encephalitis in Young Females.
Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an immune-mediated disease commonly associated with ovarian teratoma. Anti-NMDA-receptor autoantibodies disrupt NMDA function leading to the development of psychosis, seizures and autonomic dysfunction. The treatment includes underlying tumour resection and immunosuppression. Slow recovery and unpredictable clinical course makes intensive care management of these patients challenging. We report the management of two young female patients with anti-NMDA-receptor encephalitis associated with ovarian teratoma.


[Lesions produced by radiofrequency ablation of the cavotricuspid isthmus in an experimental model].
Experimental studies have shown that deeper and wider lesions (up to 10 mm long or deep) can be safely created using an 8 mm or irrigated tip catheter for ablation to treat atrial flutter. However, potential damage to the tricuspid valve or inferior cava vein has not been systematically evaluated. The cavotricuspid isthmus was ablated in 26 pigs (body weight 26-52 kg), with a total of 187 radiofrequency pulses. Standard 4 mm, 8 mm and irrigated tip catheters were used at random. For each ablation, energy, impedance and temperature were recorded continuously. The lesions were larger with irrigated tip and 8-mm catheters than with standard ones. In 7 animals (1 with an irrigated tip, 4 with an 8-mm, and 2 with a standard tip) the tricuspid valve was damaged. The tricuspid valve was severely damaged in 3 pigs and lesions were moderate in 4. In animals with tricuspid valve lesions, maximal energy was higher (59 +/- 27 vs. 51 +/- 24 W; p=0,03) and higher temperatures were reached (63 +/- 4 vs. 55 +/- 11 degrees C; p<0.001). Low energy pulses measured before ablation were also more intense in animals in which damage was produced (0.55 +/- 0.24 vs. 0.35 +/- 0.29; p=0.001), indicating greater contact pressure. The tricuspid valve may be severely damaged during the ablation of the cavotricuspid isthmus for atrial flutter: damage was seen most often with high energy pulses and with 8-mm catheters, but can also occur with usual energy levels and standard catheters. To minimize damage this technique should not be used from the inside of the right ventricle just above the tricuspid valve.


Enzymatic Interesterification of Palm Stearin, Flaxseed Oil and Cottonseed Stearin to Produce Stable Plastic Fat with Balanced Omega-6 and Omega-3 Fatty Acids.
This study aimed to produce stable plastic fat with desired physicochemical characteristics and ω-6/ω-3 fatty acid ratio (1:1-4:1) from palm stearin (PS), flaxseed oil (FSO) and cottonseed stearin (CS) via enzymatic interesterification (EIE). For the first time, the EIE variables of the blends containing PS, FSO and CS were investigated and optimized through single-factor experiments and response surface design to achieve a high interesterification degree. The optimized enzymatic interesterification conditions were: 60°C, 6 wt% Lipase UM1, and 6 h. Lipase UM1 had a similar effect on ID values with commercial lipases. The EIE improved the compatibility of the lipid blends, with the interesterified product EIE-721 (7:2:1, PS: FSO:CS) being the best candidate base stock for shortening considering its solid fat content, desired ω-6/ω-3 fatty acid ratio, wide melting range, abundant β' form crystal, and compact microstructure. This study provides a strategy to produce balanced ω-6/ω-3 fatty acid plastic fat through enzymatic interesterification and validates the application of Lipase UM1 in the preparation of plastic fat.


Dietary protein-induced increases in urinary calcium are accompanied by similar increases in urinary nitrogen and urinary urea: a controlled clinical trial.
To determine the usefulness of urinary urea as an index of dietary protein intake, 10 postmenopausal women were enrolled in and completed a randomized, double-blind, cross-over feeding trial from September 2008 to May 2010 that compared 10 days of a 45-g whey supplement with 10 days of a 45-g maltodextrin control. Urinary nitrogen, urinary calcium, urinary urea, and bone turnover markers were measured at days 0, 7, and 10. Paired sample t tests, Pearson's correlation statistic, and simple linear regression were used to assess differences between treatments and associations among urinary metabolites. Urinary nitrogen/urinary creatinine rose from 12.3±1.7 g/g (99.6±13.8 mmol/mmol) to 16.8±2.2 g/g (135.5±17.8 mmol/mmol) with whey supplementation, but did not change with maltodextrin. Whey supplementation caused urinary calcium to rise by 4.76±1.84 mg (1.19±0.46 mmol) without a change in bone turnover markers. Because our goal was to estimate protein intake from urinary nitrogen/urinary creatinine, we used our data to develop the following equation: protein intake (g/day)=71.221+1.719×(urinary nitrogen, g)/creatinine, g) (R=0.46, R(2)=0.21). As a more rapid and less costly alternative to urinary nitrogen/urinary creatinine, we next determined whether urinary urea could predict protein intake and found that protein intake (g/day)=63.844+1.11×(urinary urea, g/creatinine, g) (R=0.58, R(2)=0.34). These data indicate that urinary urea/urinary creatinine is at least as good a marker of dietary protein intake as urinary nitrogen and is easier to quantitate in nutrition intervention trials.


Helianthus tuberosus agglutinin directly induces neutrophil migration, which can be modulated/inhibited by resident mast cells.
We investigated the effect of Helianthus tuberosus agglutinin (HTA) on neutrophil migration in vivo and in vitro. The role of resident cells in this effect was analyzed. Peritonitis was induced by injecting stimuli into rat (150-200 g) peritoneal cavities, and in vitro neutrophil chemotaxis was performed using a Boyden microchamber. HTA (80, 200, or 500 microg/mL per cavity) induced significant in vivo neutrophil migration (p < 0.05); in vitro assays showed that this lectin also induced neutrophil chemotaxis, an effect inhibited by the incubation of lectin associated with alpha-D(+)-mannose, its specific binding sugar. Depletion of the resident-cell population by peritoneal lavage did not alter HTA-induced neutrophil migration (200 microg/mL per cavity). The opposite strategy, increasing peritoneal macrophages by intraperitoneally injecting rats with thioglycollate, did not enhance the neutrophil migration produced by HTA (200 microg/mL per cavity). In addition, injection of supernatant from HTA-stimulated macrophage culture (300 microg/mL) into rat peritoneal cavities did not induce neutrophil migration. However, reduction of the peritoneal mast-cell population potentiated the neutrophil migration (p < 0.05) induced by HTA (200 microg/mL per cavity). Lectin from H. tuberosus has a direct neutrophil chemotatic effect that is modulated by mast cells.


Elevated reactive oxygen species but not glutathione regulate mercury resistance to AML-2/DX100 cells.
The multidrug resistance-associated protein (MRP1) mediates cellular efflux of various xenobiotics and cellular resistance to heavy metals. Previously we reported that MRP1 mediates resistance to mercury exposure and possible mechanism mediating MRP1 expression after mercury exposure. This study was designed to investigate the role of reactive oxygen species (ROS) and glutathione on the resistance of AML-2/DX100 cells to mercuric chloride. The MRP1 overexpressing cells (AML-2/DX100) cells showed less scavenging activity to ROS induced by mercury while no difference in the basal glutathione levels between AML-2/WT and AML-2/DX100 cells. Mercury induced the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) but not c-jun-N-terminal kinase in AML-2/DX100 cells. The specific inhibitor for p38 MAPK and ERK, and antioxidant decreased the production of MRP1 and therefore resistance of AML-2/DX100 cells against mercury exposure. These results suggest that induction of ROS and downstream p38 MAPK and ERK were involved in the resistance of cells to mercury by expression MRP1 in AML-2/DX100 cells.


Physician-assisted suicide in Alzheimer's disease.
This paper takes up the question of physician-assisted suicide (PAS) in Alzheimer's disease (AD), reviewing arguments for and against in a broad interdisciplinary context. Preemptive PAS-AD involving competent patients raises the further question of AD-euthanasia. The author concludes, after thorough assessment of the literature, that caution in moving toward AD-PAS is necessary. However, where PAS is legalized, it may be difficult to justify precluding people with AD from access.


Profile of differential promoter activity by nucleotide substitution at GWAS signals for multiple sclerosis.
This experimental study was conducted with completely randomized design. Genome-wide association studies (GWAS) have revealed a large number of genetic associations of nucleotide sequence variants with susceptibility to multiple sclerosis (MS). Nevertheless, studies to identify the functional relevance of these variants lag far behind identification of the GWAS signals. Expression quantitative trait loci (eQTLs) analysis and promoter activity analysis with the variants filtered by GWAS were conducted to identify their functional alleles and haplotypes. The promoter activity was assayed with reporter constructs containing variants at 8 MS GWAS signals resulted from 18 GWAS. The promoter activity differed by alternative sequence variants at upstream regions of the CYP24A1, CYP27B1, SYK, RAD21L1, PVR, ODF3B, and RGS14 genes (P<0.05). The transcriptional regulations of sequence variants were also found by identifications of eQTLs for their corresponding genes with lymphoblastoid cells in the current study (SYK, ODF3B, RGS14, and PVR, P<8.33×10⁻³) and with dendritic cells in a previous study (CYP27B1, P=1.84×10⁻⁶). This study identified regulatory nucleotide sequences in the promoters of the CYP24A1, CYP27B1, SYK, RAD21L1, PVR, ODF3B, and RGS14 genes, and their variants differentially affected gene expression. This might result in their associations with MS susceptibility in previous GWAS. Further functional studies are required to understand the process of transcriptional regulation of the variants identified in the current study and the mechanisms underlying susceptibility to MS.


Magnetic Resonance Imaging of Intracranial Hypotension: Diagnostic Value of Combined Qualitative Signs and Quantitative Metrics.
The aim of this study was to investigate whether the use of combination quantitative metrics (mamillopontine distance [MPD], pontomesencephalic angle, and mesencephalon anterior-posterior/medial-lateral diameter ratios) with qualitative signs (dural enhancement, subdural collections/hematoma, venous engorgement, pituitary gland enlargements, and tonsillar herniations) provides a more accurate diagnosis of intracranial hypotension (IH). The quantitative metrics and qualitative signs of 34 patients and 34 control subjects were assessed by 2 independent observers. Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic performance of quantitative metrics and qualitative signs, and for the diagnosis of IH, optimum cutoff values of quantitative metrics were found with ROC analysis. Combined ROC curve was measured for the quantitative metrics, and qualitative signs combinations in determining diagnostic accuracy and sensitivity, specificity, and positive and negative predictive values were found, and the best model combination was formed. Whereas MPD and pontomesencephalic angle were significantly lower in patients with IH when compared with the control group (P < 0.001), mesencephalon anterior-posterior/medial-lateral diameter ratio was significantly higher (P < 0.001). For qualitative signs, the highest individual distinctive power was dural enhancement with area under the ROC curve (AUC) of 0.838. For quantitative metrics, the highest individual distinctive power was MPD with AUC of 0.947. The best accuracy in the diagnosis of IH was obtained by combination of dural enhancement, venous engorgement, and MPD with an AUC of 1.00. This study showed that the combined use of dural enhancement, venous engorgement, and MPD had diagnostic accuracy of 100 % for the diagnosis of IH. Therefore, a more accurate IH diagnosis can be provided with combination of quantitative metrics with qualitative signs.


Statistical Methods for Recurrent Event Analysis in Cohort Studies of CKD.
Cardiovascular events, such as hospitalizations because of congestive heart failure, often occur repeatedly in patients with CKD. Many studies focus on analyses of the first occurrence of these events, and discard subsequent information. In this article, we review a number of statistical methods for analyzing ordered recurrent events of the same type, including Poisson regression and three commonly used survival models that are extensions of Cox proportional hazards regression. We illustrate the models by analyzing data from the Chronic Renal Insufficiency Cohort Study to identify risk factors for congestive heart failure hospitalizations in patients with CKD. We show that recurrent event analyses provide additional insights about the data compared with a standard survival analysis of time to the first event.


A review of 42 cases of intestinal pseudo-obstruction in patients with systemic lupus erythematosus based on case reports.
Intestinal pseudo-obstruction (IpsO) is considered a severe manifestation of systemic lupus erythematosus (SLE) characterized by clinical and radiological evidence of intestinal obstruction with no identifiable mechanical lesion. We performed a systematic review to document IpsO in SLE. Twenty-eight articles with 42 patients were included. The median age of onset of IpsO was 27.5 (10-57) years. The female to male ratio was 38:4. Twenty-two (52.4%) patients had IpsO as the initial presentation of their underlying lupus. Three (7.1%) patients manifested in inactive lupus. The duration of abdominal symptoms before admitted ranged from 3 days to 3 years, however most of the patients responded well to systemic corticosteroid or immunosuppressive treatment within 2 days to about 3 months. Concomitant ureterohydronephrosis was present in approximately three-fourths of the cases. More interestingly, 4 patients presented hepatobiliary dilatation without mechanical obstruction together with IPO and ureterohydronephrosis. In conclusion, IpsO is an uncommon but important manifestation of SLE. The finding of coexisting ureterohydronephrosis and hepatobiliary dilatation suggests that there may be generalized visceral muscle dysmotility. Early recognition of IpsO is necessary to institute appropriate medical treatment and to avoid inappropriate surgical intervention.


Lonicera caerulea Berry Polyphenols Extract Alleviates Exercise Fatigue in Mice by Reducing Oxidative Stress, Inflammation, Skeletal Muscle Cell Apoptosis, and by Increasing Cell Proliferation.
Exercise fatigue can exert deleterious effects on the body. This study evaluated the effects and mechanisms by which Lonicera caerulea berry polyphenols extract (LCBP) improved the treadmill endurance of mice. Comparison was performed between the effects at 25°C and low temperatures (-5°C). Energy storage, product metabolism, and other biochemical indices were determined using vitamin C (VC) as a positive control. Co-immunoprecipitation was performed to detect the interaction between different proteins. Dietary supplementation with LCBP significantly prolonged the exhaustion time during treadmill exercise by 20.4% (25 °C) and 27.4% (-5 °C). LCBP significantly regulated the expression of antioxidant and inflammatory proteins, Bcl-2 /Bax apoptosis proteins, and the PKCα -NOx2 / Nox4 pathway proteins, and activated the expression of AMPK-PGC1α -NRF1-TFAM proteins in skeletal muscle mitochondria. The gene and protein expression of miRNA-133a/IGF-1/PI3K/Akt/mTOR in skeletal muscle cells was also activated. Molecular docking confirmed that the main components of LCBP such as cyanidin-3-glucoside, catechin, and chlorogenic acid, have strong binding affinity toward AMPKα. LCBP alleviates exercise fatigue in mice by reducing oxidative stress, inflammation, and apoptosis of skeletal muscle cells, enhances mitochondrial biosynthesis and cell proliferation, reduces fatigue, and enhances performance. These effects are also significant in a low-temperature environment (Graphical Abstract). Consequently, these results provide novel insights into the anti- fatigue roles of LCBP in exercise fatigue.


Adolescent use of mobile phones for calling and for sending text messages after lights out: results from a prospective cohort study with a one-year follow-up.
To assess the prevalence of the use of mobile phones by adolescents after lights out and its relationship to tiredness levels after one year. Prospective cohort study with self-reports and follow up questionnaire after one year. Second- and fifth-year secondary school children in 15 schools in Flanders, Belgium. 1656 school children; 52.1% boys. Average age was 13.7 years (SD: 0.68) in the youngest group and 16.9 years (SD: 0.83) in the oldest group at baseline. Self-reported tiredness. Only 38% of the subjects never used their mobile phone after lights out. Multinomial logistic regression showed that using the mobile phone less than once a month increased the odds of being very tired one year later by 1.8 (95% CI 1.2-2.8). Those who used it less than once a week were 2.2 times more likely to be very tired (95% CI 1.4-3.5). Using it about once a week increased the odds by 3.3 (95% CI 1.9-5.7) and those who used it more than once a week were 5.1 times more likely to be very tired (95% CI 2.5-10.4). Overall 35% of the cases of being very tired were attributed to the use of the mobile phone. Use of the phone right after lights out increased the odds of being very tired by 2.2 (95% CI 1.4-3.4); between 00:00 and 03:00 the odds were 3.9 times higher (95% CI 2.1-7.1), and in those who used it at any time of the night the odds were 3.3 times higher (95% CI 1.8-6.0). Mobile phone use after lights out is very prevalent among adolescents. Its use is related to increased levels of tiredness. There is no safe dose and no safe time for using the mobile phone for text messaging or for calling after lights out.