[Bilateral papilledema secondary to intracranial hypertension in an adolescent girl].
Papilledema is a fluid and/or axonal swelling of the optic nerve head due to a blockage of axoplasmic flow at the level of the cribriform plate. We report the case of a 17-year old adolescent girl with bilateral papilledema secondary to idiopathic intracranial hypertension.


Children's Experiences of Completing a Computer-Based Violence Survey: Finnish Child Victim Survey Revisited.
The involvement of children as research subjects requires special considerations with regard to research practices and ethics. This is especially true concerning sensitive research topics such as sexual victimization. Prior research suggests that reflecting these experiences in a survey can cause negative feelings in child participants, although posing only a minimal to moderate risk. Analyzing only predefined, often negative feelings related to answering a sexual victimization survey has dominated the existing literature. In this article children's free-text comments about answering a victimization survey and experiences of sexual victimization are analyzed together to evaluate the effects of research participation in relation to this sensitive issue. Altogether 11,364 children, aged 11-12 and 15-16, participated in the Finnish Child Victim Survey in 2013. Of these, 69% (7,852) reflected on their feelings about answering the survey. Results indicate that both clearly negative and positive feelings are more prevalent among victimized children compared to their nonvictimized peers. Characteristics unique to sexual victimization as well as differences related to gender and age are also discussed. The study contributes to the important yet contradictory field of studying the effects of research participation on children.


The effects of forskolin on cyclic AMP, intraocular pressure and aqueous humor formation in rabbits.
Forskolin was used to study cyclic AMP-mediated regulation of aqueous humor dynamics in rabbits. Crystalline forskolin was solubilized in oil and its pharmacological effects were studied both in vitro and following topical ocular administration. In vitro, using cultured corneal epithelial cells, forskolin rapidly stimulated cyclic AMP production and in vivo increased cyclic AMP concentration in the aqueous humor 10-fold following topical administration. The effect of topical forskolin on intraocular pressure and aqueous humor formation was determined in vivo using pneumatonometry and fluorophotometry, respectively. Forskolin caused a prolonged reduction of intraocular pressure and decreased aqueous humor formation. The ability of forskolin to potentiate the ocular hypotensive effect of epinephrine was investigated. Forskolin in combination with epinephrine caused a decrease in intraocular pressure of longer duration than either 0.1% epinephrine or 1% forskolin administered separately. Forskolin caused a small but significant increase in the permeability of the blood-aqueous barrier at the time of maximal intraocular pressure reduction. This effect on the blood-aqueous barrier may explain the inhibitory effect of forskolin on aqueous humor formation.


The orphan nuclear receptor RORα is a potential endogenous protector in renal ischemia/reperfusion injury.
Emerging evidence indicates that retinoid-related orphan receptor (ROR)α, a member of the ROR nuclear receptor subfamily, mediates key cellular adaptions to hypoxia and contributes to the pathophysiology of many disease states. However, the effects of RORα in renal ischemia/reperfusion (I/R) injury remain unclear. Wild-type (WT) C57 black 6 (C57BL/6) mice and RORα-deficient stagger [ROR(sg/sg)] mice and their WT littermates were used for in vivo studies. The renal I/R injury model was induced by bilateral renal pedicle clamping for 35 min. Human proximal tubule cell line cells were treated with hypoxia (1% oxygen) to establish the cell hypoxia/reoxygenation (H/R) model. We investigated the renal expression and biologic function of RORα, and we found that RORα was significantly down-regulated after renal I/R injury. ROR(sg/sg) mice displayed dramatically augmented renal dysfunction and morphologic damage compared with WT mice at 24 h post-I/R. Further study revealed that the detrimental effects of RORα deficiency were attributable to tubular epithelial cell apoptosis and, consequently, renal inflammation and oxidative stress. The proapoptotic effect of RORα deficiency was associated with aggravated mitochondrial dysfunction in renal tubular cells after I/R. However, pretreatment of C57BL/6 mice with the RORα agonist SR1078 ameliorated I/R-induced renal dysfunction and damage and elicited a concomitant decrease in tubular epithelial cell apoptosis. In summary, our study provides experimental evidence showing that RORα is a novel endogenous protector against renal I/R injury and that ROR-α activation is a promising therapeutic strategy for the prevention of acute kidney injury.-Cai, J., Jiao, X., Fang, Y., Yu, X., Ding, X. The orphan nuclear receptor RORα is a potential endogenous protector in renal ischemia/reperfusion injury.


Mini-review: Glucagon responses in type 1 diabetes - a matter of complexity.
In recent years the role of altered alpha cell function and glucagon secretion in type 1 diabetes has attracted scientific attention. It is well established that glucagon responses to hypoglycemia are absent in type 1 diabetes, but more uncertain whether it is intact following other physiological and metabolic stimuli compared with nondiabetic individuals. The aim of this review is to (i) summarize current knowledge on glucagon responses during hypoglycemia in normal physiology and type 1 diabetes, and (ii) review human in vivo studies investigating glucagon responses after other stimuli in individuals with type 1 diabetes and nondiabetic individuals. Available data suggest that in type 1 diabetes the absence of glucagon secretion after hypoglycemia is irreversible. This is a scenario specific to hypoglycemia, since other stimuli, including administration of amino acids, insulin withdrawal, lipopolysaccharide exposure and exercise lead to substantial glucagon responses though attenuated compared to nondiabetic individuals in head-to-head studies. The derailed glucagon secretion is not confined to hypoglycemia as individuals with type 1 diabetes, as opposed to nondiabetic individuals display glucagon hypersecretion after meals, thereby potentially contributing to insulin resistance. The complexity of these phenomena may relate to activation of distinct regulatory pathways controlling glucagon secretion i.e., intra-islet paracrine signaling, direct and autonomic nervous signaling.


4-Acetonylidene-1-ethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one.
The title compound, C(14)H(16)N(2)O(2), contains a diazepine ring, which appears in a boat conformation. An intramolecular hydrogen bond is formed between the NH group of the diazepine ring and a carbonyl O atom of one of the side chains.


One year with the COVID-19 pandemic - Lessons learnt? Intersectoral collaboration measures established during the crisis could benefit capacity and patient flow management in daily clinical practice.
The COVID-19 pandemic has changed the way hospitals work. Strategies that were detached from the boundaries of departments and responsibilities in the COVID-19 pandemic have proven themselves under extreme conditions and show a beneficial influence on patient flow and resource management as well as on the communication culture. The continuation of closer interdisciplinary and cross-sectoral co-operation in a "new clinical routine" could have a positive impact on personnel concepts, communication strategies, and the management of acute care capacities and patient pathways. The aim of the paper is to critically discuss the knowledge gained in the context of the COVID-19 pandemic from the various approaches in patient flow and capacity management as well as interdisciplinary co-operation. More recent research has evaluated patient pathway management, personnel planning and communication measures with regard to their effect and practicability for continuation in everyday clinical practice. Patient flows and acute care capacities can be more efficiently managed by continuing a culture change towards closer interdisciplinary and intersectoral co-operation and technologies that support this with telemedicine functionalities and regional healthcare data interoperability. Together with a bi-directional, more frequent and open communication and feedback culture, it could form a "new clinical routine". This paper discusses a holistic approach on the way away from silo thinking towards cross-departmental collaboration.


Routine delirium monitoring is independently associated with a reduction of hospital mortality in critically ill surgical patients: A prospective, observational cohort study.
Although delirium monitoring is recommended in international guidelines, there is lacking evidence for improved outcome due to it. We hypothesized that adherence to routine delirium monitoring would improve clinical outcome in adult critically ill patients. We present the results of a prospective, noninterventional, observational cohort study that was conducted on 2 intensive care units (ICUs) of a tertiary care medical center between July and October 2007 (International Standard Registered Clinical Trial Record identifier: 76100795). We assessed delirium-monitoring and outcome parameters on a daily basis. Besides multivariate logistic and robust linear regression to analyze the relationship between delirium monitoring and outcome, we used the doubly robust augmented inverse probability weighting method for observational data to estimate effect sizes. Of 355 screened patients, we included 185 surgical ICU patients into our final analysis, of which 87 were mechanically ventilated. We found an independent association between delirium-monitoring adherence and in-hospital mortality for ventilated patients (odds ratio, 0.973; P= .041). Estimating the effect size, delirium monitoring indicated a reduction of 22% of in-hospital mortality if conducted 50% or more of ICU days per patient. The average ICU length of stay of 46 days was estimated to be reduced by 19 days (P= .031) if patients were sufficiently monitored. Our data suggest an improved outcome for mechanically ventilated patients being screened for delirium in clinical routine.


The utility of 6-month protocol renal biopsy under modern immunosuppression.
Protocol biopsies after renal transplantation are useful in detecting subclinical rejection. In earlier studies, the incidence of subclinical rejection was high among renal transplant recipients on a cyclosporine-based immunosuppression. However, recent data show that subclinical rejection is low under tacrolimus-based immunosuppression. This study evaluates the utility of 6-month protocol biopsy in renal transplant recipients under induction with rabbit antithymocyte globulin and maintenance immunosuppression with tacrolimus, mycophenolate mofetil (MMF) and corticosteroids. 6-month protocol biopsies on 40 transplant recipients were analyzed for borderline and subclinical rejections. Allograft injury at biopsy was evaluated using the chronic allograft damage index score system (CADI) and was compared with initial scores obtained at implantation. Borderline rejection was detected in 1 out of 40 patients. No case of subclinical rejection was detected at protocol biopsy. In 31 patients with corresponding implantation biopsies, mean CADI score increased from 1.1 +/- 1.4 to 2.8 +/- 2.1 at 6 months despite stable graft function. In the subgroup of patients with a 6-month CADI score of 2 or less (n = 11), graft function remained stable at 12 months post transplant (65.3 +/- 16.9 ml/min/1.73 m2 at 6 months vs. 65.2 +/- 16.7 ml/min/1.73 m2 at 12 months, p = 0.96). In contrast, allograft function declined significantly at 12 months in those with a 6-month CADI score of > 2 (n = 20) (64.3 +/- 13.5 ml/min/1.73 m2 at 6 months vs. 51 +/- 9.8 ml/min/1.73 m2 at 12 months, p = 0.0006). While the incidence of borderline and subclinical is low under antilymphocyte antibody induction and tacrolimus-based immunosuppression, chronic allograft damage is highly prevalent at 6 months post transplantation. Our findings suggest that protocol biopsies under current immunosuppression may be more useful in the early detection of chronic allograft nephropathy (CAN).


Effect of fungicides on growth and on DNA, RNA and protein anabolism of a Rhizobium sp.
Eleven fungicides were examined for their effect on the growth and anabolism of Rhizobium sp. in pure culture. Of these, only 4 were found to inhibit growth of rhizobia at a concentration as low as 10 micrograms/ml. Growth inhibition by these fungicides appeared to be primarily due to inhibition of respiration, although thiophanate and anilazine also affected DNA and RNA synthesis, respectively. Inhibition is, however, transitory and the bacterium has the ability to overcome this initial inhibition without mutation.


Factors affecting minimal manifestation status induction in myasthenia gravis.
Minimal manifestation status (MMS) is an important landmark in the treatment of myasthenia gravis (MG), and predictors of MMS induction have rarely been identified in previous studies. The objective of this study is to evaluate the clinical factors associated with MMS induction among patients with MG. This two-step retrospective cohort study with a single center investigated the factors that may be associated with MMS induction and retested these predictors in a test cohort. A total of 388 diagnosed MG patients who visited Xiangya Hospital between 1 July 2015 and 1 July 2019 were involved. We performed detailed chart reviews and recorded all cases achieving MMS. Demographics and clinical characteristics were also collected and their relationships to achieving MMS were investigated. MMS was achieved in 124 patients (50.2%), and the median time to achieve MMS was 26 months. Several factors were found to be associated with MMS induction in exploring cohort, including muscle-specific tyrosine-protein kinase receptor (MuSK) antibody positivity (adjusted hazard ratio, HR = 4.333, 95% confidence interval, CI: 1.862-10.082), isolated ocular involvement (adjusted HR = 1.95, 95% CI: 1.284-2.961), and low baseline quantitative myasthenia gravis score (QMG score; adjusted HR = 2.022, 95% CI: 1.086-3.764). These factors were then retested in the test cohort. Isolated ocular involvement or low baseline QMG scores were factors found to be beneficial for MMS induction were confirmed. Isolated ocular involvement and low baseline QMG score are predictors of MMS induction in MG patients.


The current unsatisfactory state of relapse prevention in schizophrenic psychoses--suggestions for improvement.
The current state of relapse prevention in schizophrenic psychoses is very unsatisfactory. Although in the form of neuroleptics a very efficient means of relapse prevention has been available for almost 40 years, approximately 50% of the schizophrenic patients still suffer a relapse within the first year after their most recent episode. Seventy percent of the hospitalized schizophrenic patients are readmissions, and the noncompliance rate for neuroleptic relapse prevention is 75%. An important factor contributing to these high rates of noncompliance and relapse seems to be the fact that, 40 years after the introduction of neuroleptics, there is still no consensus on how these drugs are to be used in relapse prevention. An inquiry among Austrian and German psychiatrists revealed unacceptably high discrepancies concerning their recommendations for indication and duration of neuroleptic relapse prevention. To overcome this unsatisfactory situation, an international consensus meeting on guidelines for neuroleptic relapse prevention was organized by the author in April 1989. Precise guidelines on indication, duration, and dosage of neuroleptic for relapse prevention that resulted from that meeting are presented.


Genistein attenuates advanced glycation end product-induced expression of fibronectin and connective tissue growth factor.
To investigate the effect of advanced glycation end products (AGEs) on the expression of connective tissue growth factor (CTGF) and fibronectin (FN) in human peritoneal mesothelial cells (HPMC). To observe the effect of genistein (Gen) on the expression of CTGF and FN in HPMC induced by AGEs. First, HPMC were stimulated with different concentrations of AGEs (0, 200, 600 and 1,000 mg/l) for 48 h; the expression of FN was detected by reverse transcription-polymerase chain reaction (RT-PCR). Second, HPMC were divided into the following groups: (1) control group, (2) AGE-treated group (600 mg/l AGEs) and (3) Gen-treated groups with 600 mg/l AGEs and 25, 50 and 100 µMGen, respectively. The expression of messenger RNA (mRNA) for FN and CTGF was measured by RT-PCR; the expression of FN and CTGF protein was detected by enzyme-linked immunosorbent assay (ELISA) after 48 h. The expression of FN mRNA in HPMC increased in a dose-dependent manner after induction with AGEs. Compared with controls, 600 mg/l AGEs markedly promoted the expression of mRNA and protein for FN and CTGF. Compared with the AGE-treated group (600 mg/l), 25, 50, and 100 µM Gen significantly inhibited the expression of mRNA and protein for FN and CTGF. AGEs can markedly increase the expression of mRNA and protein for FN and CTGF; however, Gen can inhibit the expression of FN and CTGF mRNA and protein stimulated by AGEs, which implies that Gen probably decreases the accumulation of extracellular matrix through inhibiting the expression of CTGF, and it may play a role in anti-peritoneal fibrosis.


Males with epilepsy, complete subcortical band heterotopia, and somatic mosaicism for DCX.
Subcortical band heterotopia (SBH) is seen predominantly in females, resulting from mutations in the X-linked doublecortin (DCX) gene, and can present with mild mental retardation and epilepsy. Males carrying DCX mutations usually demonstrate lissencephaly and are clinically much more severely affected. This article reports two cases of males with SBH indistinguishable from the female phenotype, both resulting from somatic mosaicism for DCX mutation.


Antibiotic resistance, virulence factors and genotyping of Uropathogenic Escherichia coli strains.
The way of treating different types of infectious diseases is really important. Using genotyping method, we can determine the genetic relatedness between the organisms with different resistance profile from different sources. The aim of this study was to determine antibiotic resistance and genotyping of uropathogenic Escherichia coli (UPEC) strains using pulsed field gel electrophoresis (PFGE). Escherichia coli (E. coli) strains were recovered from the patients with urinary tract infections (UTI) whom admitted in several major hospitals in Tehran. Antibiotic susceptibility testing was done according to CLSI guideline. The present of some virulence factor have been detected using PCR assay. Genotyping of the strains was performed by PFGE and all PFGE profiles were subjected to data processing. In total, 60 E. coli strains were subjected to the study. Most of E. coli isolates were resistant to cefepime (100%) and cephalothin (74%) and susceptible to imipenem (100%), vancomycin (100%) and doxycycline (100%). Among the UPEC isolates the prevalence of fimbriae type I (fimH), hemolysin (hlyA) and aerobactin (aer) genes were 89%, 60% and 90%, respectively. The PFGE differentiated E. coli strains into 33 different genetic clusters. Majority (30%) of them including PFGE type 11 generated 15 bands, while PFGE type 2 was the lowest (2%) prevalent group with 9 bands. The result showed that the antibiotic resistance is escalating rapidly. UPEC strains causing infections are more likely to harbor certain virulence genes. Our finding also showed E. coli strains isolated under the study were belonged to the diverse clones.


Role 1 Pediatric Trauma Care on the Israeli-Syrian Border-First Year of the Humanitarian Effort.
This article summarizes the experience with Role 1 care for 135 Syrian children who received medical care during the year 2013 as part of an ongoing humanitarian effort. The database included demographic information, point-of-injury assessment and outcome, and was analyzed using SPSS. Trauma casualties were the majority of the group (84 cases), and mostly male. Almost one-third of casualties arrived more than 6 hours after injury, and time of injury was unknown in another third. The most common mechanism of injury was shrapnel (51.2%), followed by gunshot wounds (22.6%). Gunshot wound victims were significantly older than shrapnel and artillery victims (p < 0.01, < 0.05, respectively). Only 14 cases (14.28%) underwent previous interventions in Syria. Most of the casualties (44 cases, 52.4%) underwent at least one procedure during Role 1 treatment with a high overall success rate (93.18%) that was not correlated to Advanced Life Support provider type (physician [MD], emergency medical technician-paramedic, or both). Mortality was low (3 cases). The study cohort exhibits several unique features, including a delay in arrival to medical care, paucity of prior care and information, and the specific mechanisms of injury. Our study suggests that Advanced Life Support providers do not differ significantly in Role 1 treatment choices and procedure success.


Coexistence of multiple genotypes, including newly identified genotypes, in outbreaks of gastroenteritis due to Norovirus in Japan.
Norovirus (NV) (formerly called Norwalk-like virus) is the most common cause of acute nonbacterial gastroenteritis in humans. Recently, we reported an NV genotyping scheme based on variability in the capsid N-terminal/shell (N/S) domain gene (Katayama et al., Virology 299:225-239, 2002). We found 19 genotypes, including nine of genogroup I and 10 of genogroup II. In the present study, we investigated the molecular epidemiology of NV from 66 outbreaks that occurred in Saitama Prefecture, Japan, from 1997 to 2002. We screened 416 stool specimens by a real-time reverse transcription (RT)-PCR method (Kageyama et al., J. Clin. Microbiol. 41:1548-1557, 2003) and detected 156 NV-positive specimens, from which we amplified the capsid N/S domain gene by RT-PCR and then cloned the PCR products. After sequencing these clones, we obtained 368 sequence variants (strains). By applying our classification scheme to the strains from Saitama and other published strains, we identified a total of 31 genotypes, including an additional five genotypes for genogroup I and seven for genogroup II. Of the 31 genotypes, 26 were present in the Saitama area during that time period. These results provide additional evidence for the great diversity of human NV genotypes. Specimens from all shellfish-related infections contained multiple genotypes, including several new genotypes. On the other hand, single genotypes were observed mostly in outbreaks that originated in semiclosed communities. Thus, the number of NV genotypes in each outbreak depended on the route of transmission.


Abstract of Papers Presented at the Seventy-Fifth Annual Meeting of the IAMFES.
Abstracts of most papers submitted for presentation at the 75th Annual Meeting of the IAMFES appear on this and the following pages. The complete text of some of the papers will appear in future issues of the Journal of Food Protection or Dairy and Food Sanitation.


A Multiresponsive Calix[6]arene Pseudorotaxane Empowered by Fluorophoric Dansyl Groups.
We report the synthesis and characterization, by means of NMR and UV-visible spectroscopy and electrochemical techniques, of a dansyl calix[6]arene derivative and of its pseudorotaxane complex with a bipyridinium-based axle. This novel macrocycle shows remarkable complexation ability, in analogy with parent compounds, while the dansyl moieties impart valuable features to the system. Indeed, these units: i) signal the state of the system by fluorescence; ii) can be reversibly protonated, enabling the modulation of the complexation abilities of the macrocycle; iii) participate in photoinduced electron transfer processes, which may be exploited to tune the stability of the supramolecular complex. Therefore, in this multiresponsive pseudorotaxane, the threading and de-threading motions of the molecular components can be modulated either by protonation of the calixarene host or by reduction of the bipyridinium guest, which can be accomplished both by electrochemical reduction and via photoinduced electron transfer. Overall, three orthogonal and reversible stimuli can be used to induce molecular movements of the pseudorotaxane components.


CU(II)-catalyzed oxidation of Alzheimer's disease beta-amyloid peptide and related sequences: remarkably different selectivities of neurotoxic betaAP1-40 and non-toxic betaAP40-1.
We investigated the CuII-catalyzed oxidation of beta-amyloid peptides betaAP10-20 and betaAP40-1 by tandem mass spectrometry and compared oxidation yields and selectivities to those for betaAP1-16, betaAP1-28 and betaAP1-40, which were obtained earlier (26). While betaAP1-16, betaAP1-28 and betaAP1-40 showed an almost exclusive oxidation of His residues to 2-oxo-histidine, the selectivity pattern is changed for betaAP10-20,which shows oxidation of His but also hydroxylation of Tyr and Phe. In contrast to betaAP1-40, the reverse sequence betaAP40-1 shows a strong selectivity for the hydroxylation of Tyr31 while only negligible His oxidation is observed at early time points. These selectivity patterns show the importance of the geometry of the metal-binding site for peptide/protein oxidation. The significantly different characteristic of betaAP1-40 and betaAP40-1 with regard to metal catalyzed processes may be related to the differences in the neurotoxic properties of these sequences.


D-JNK signaling in visceral muscle cells controls the laterality of the Drosophila gut.
Although bilateral animals appear to have left-right (LR) symmetry from the outside, their internal organs often show directional and stereotypical LR asymmetry. The mechanisms by which the LR axis is established in vertebrates have been extensively studied. However, how each organ develops its LR asymmetric morphology with respect to the LR axis is still unclear. Here, we showed that Drosophila Jun N-terminal kinase (D-JNK) signaling is involved in the LR asymmetric looping of the anterior-midgut (AMG) in Drosophila. Mutant embryos of puckered (puc), which encodes a D-JNK phosphatase, showed random laterality of the AMG. Directional LR looping of the AMG required D-JNK signaling to be down-regulated by puc in the trunk visceral mesoderm. Not only the down-regulation, but also the activation of D-JNK signaling was required for the LR asymmetric looping. We also found that the LR asymmetric cell rearrangement in the circular visceral muscle (CVM) was regulated by D-JNK signaling and required for the LR asymmetric looping of the AMG. Rac1, a Rho family small GTPase, augmented D-JNK signaling in this process. Our results also suggest that a basic mechanism for eliciting LR asymmetric gut looping may be conserved between vertebrates and invertebrates.


Enriching Diet with n-3 PUFAs to Help Prevent Cardiovascular Diseases in Healthy Adults: Results from Clinical Trials.
Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are believed to be important for cardiovascular health. Many investigations have been carried out in an attempt to examine the effect of n-3 PUFAs intake, in the form of supplementation or fortified foods, for the management of cardiovascular disease (CVD) and risk factors for CVD, whereas less is known about the effect on healthy individuals. The present study reviews the available literature in order to examine the relationship between n-3 PUFAs intake, either via supplementation or enriched food, and the prevention of CVD among healthy adults. Interventional clinical trials on subjects aged >18 years old with none of the established risk factors for CVD have been considered for review. n-3 PUFAs supplementation or enriched food may positively regulate triglycerides and some lipoprotein subsets, as well as several vascular and coagulation parameters, even in healthy patients, presenting no risk factors for CVD, suggesting a protective effect. Diet enrichment with omega-3 is likely to be useful in helping to lower the risk of developing CVD in healthy individuals, but still offers no strong evidence of a tangible benefit on a population level. Additional studies are needed to determine the optimal daily intake, especially to prevent the unfavorable effects of PUFAs over-consumption.


Further possible mechanisms of dipeptidyl peptidase-4 inhibitors to decrease blood glucose in subjects with type 2 diabetes.
Recently, dipeptidyl peptidase-4 (DPP-4) inhibitors have been launched into clinical use for type 2 diabetes in Japan. Shortly after its use, several cases have been reported, in which the co-administration of DPP-4 inhibitors with sulfonylureas caused severe hyperglycemia in Japan. Additionally, the efficacy to improve glycemic control was greater than expected. Taken together, it is suggested that DPP-4 inhibitors may have other action mechanisms than to stimulate insulin secretion in glucose-dependent manner. I present here several possible mechanisms of DPP-4 inhibitors to reduce blood glucose in type 2 diabetes; first, to inhibit glucagon secretion, second, to stimulate glucose-dependent insulinotropic peptide (GIP) secretion, which may regain its action to stimulate insulin secretion when hyperglycemia has been improved, third, to recover the response to sulfonylureas by restoring pancreatic ATP levels, fourth, to stimulate glucagon-like peptide 1 (GLP-1 ) secretion directly from the intestine, and finally to inhibit the action of DPP-4 as an adipokine.


Population Pharmacokinetics of High-Dose Tigecycline in Patients with Sepsis or Septic Shock.
Tigecycline is a glycylcycline often used in critically ill patients as the antibiotic of last resort. The pharmacokinetics (PK) of tigecycline in intensive care unit (ICU) patients can be affected by severe pathophysiological changes so that standard dosing might not be adequate. The aim of this study was to describe population PK of high-dose tigecycline in patients with sepsis or septic shock and evaluate the relationship between individual PK parameters and patient covariates. The study population consisted of 37 adult ICU patients receiving a 200-mg loading dose of tigecycline followed by multiple doses of 100 mg every 12 h. Blood samples were collected at 0.5, 2, 4, 8, and 12 h after dose administration. A two-compartment model with interindividual (IIV) and interoccasion (IOV) variability in PK parameters was used to describe the concentration-time course of tigecycline. The estimated values of mean population PK parameters were 22.1 liters/h and 69.4 liters/h for elimination and intercompartmental clearance, respectively, and 162 liters and 87.9 liters for volume of the central and peripheral compartment, respectively. The IIV and IOV in clearance were less than 20%. The estimated values of distribution volumes were different from previously published values, which might be due to pathophysiological changes in ICU patients. No systematic relationship between individual PK parameters and patient covariates was found. The developed model does not show evidence that individual tigecycline dosing adjustment based on patient covariates is necessary to obtain the same target concentration in patients with sepsis or septic shock. Dosing adjustments should be based on the pathogens, their susceptibility, and PK targets.


Stem cell transplantation for autoimmune diseases.
Hematopoietic stem cell transplantation is an increasingly used therapy for treatment of autoimmune diseases and severe immune-mediated disorders. We address some general concepts and principles in the development of hematopoietic stem cell transplantation in order to understand the principles and design of safe autologous and allogeneic transplant regimens for these unique diseases.


[MINI-PERCUTANEOUS NEPHROLITHOTRIPSY – OUR FIRST EXPERIENCE].
Urolithiasis is a significant problem in the developed countries due to the increased number of patients with stones. Just a few decades ago open surgery was the only surgical treatment which is today, in most cases, replaced with minimally-invasive methods. One of these new methods is mini-percutaneous nephrolihotripsy. We present four patients in whom mini-percutaneous nephrolithotripsy was performed. In all patients the stone was located in the renal pelvis. In three patients the stone was in the native kidney and in one in the transplanted kidney. In all patients laser lithotripsy was successfully performed. On the control x-ray the residual fragments were not found in any patients. Mini-percutaneous nephrolithotripsy is a minimally-invasive method which is successfull in the treatment of nephfrolithiasis in native and transplanted kidneys.


[Acromegaly in the differential diagnosis of hearing loss].
Acromegaly is a multifactorial neuroendocrine disease caused by hyperproduction of growth hormone (GH). In more than 95% of cases the reason of acromegaly the GH-secreting pituitary adenoma. In patients with this neuroendocrine disease, a slowly developing complex of symptom can manifest with concomitant pathological conditions, including auditory function disordersDiagnostic difficulties of acromegaly at the ambulatory stage determine the importance of doctor`s awareness in different medical specialties.Here we demonstrate a clinical case of the improvement of the auditory function due to combined surgical and medical treatment of a patient with the pituitary macroadenoma, acromegaly and hearing loss.Anamnesis features: a patient with an active stage of acromegaly and a pituitary macroadenoma measuring 57x35x32 mm with ante-, supra-, infra-, parasellar spread, (Knosp III(D), Knosp IV(S) noted a violation of auditory function. She was consulted by an otolaryngologist, sensorineural hearing loss on the right of the 3rd degree was diagnosed, on the left of the 1st degree. The patient underwent surgical treatment of pituitary adenoma, noted a significant improvement in auditory function in the early postoperative period. Six months later, repeated audiometry was performed, marked regression of hearing damage was noted.The case described by us indicates the reversibility of a rare complication of acromegaly - hearing loss and the importance of an interdisciplinary approach in the management of patients with this pathology.


Thermopower evidence for an abrupt Fermi surface change at the quantum critical point of YbRh2Si2.
We present low-temperature thermopower results, S(T), on the heavy-fermion compound YbRh2Si2 in the vicinity of its field-induced quantum critical point (QCP). At B=0, a logarithmic increase of -S(T)/T between 1 and 0.1 K reveals strong non-Fermi-liquid behavior. A pronounced downturn of -S(T)/T below T{max}=0.1 K and a sign change from negative to positive S(T) values at T{0} approximately 30 mK are observed on the low-field side of the Kondo breakdown crossover line T{*}(B). In the field-induced, heavy Landau-Fermi-liquid regime, S(T)/T assumes constant, negative values below T{LFL}. A pronounced crossover in the -S(B)/T isotherms at T{*}(B) sharpens with decreasing T and seems to evolve toward a steplike function for T-->0. This is attributed to an abrupt change of the Fermi volume upon crossing the unconventional QCP of YbRh2Si2.


[Social functioning of schizophrenic patients after 15 years from the first hospitalization (Part II -- the evaluation of needs for community care)].
The description of the studied group was given in the first part of the paper. Some of the factors having been present at the first hospitalization were found to be important for the patients' functioning 15 years later. On the basis of the collected regarding data 85 patients, significant coincidence has been found between more intensive use of extramural services, more frequent and longer hospitalizations, and worse social functioning during 15 years' period in individual cases. The conclusion has been assumed that there exists obvious need for more intensive community care for such patients. On the basis of 0.15% morbidity index the number of schizophrenics needing social support, sheltered accommodation and sheltered working conditions were estimated. According to the Mental Health Care Act of 1994 such services have to be organized within social care system.


A Nap But Not Rest or Activity Consolidates Language Learning.
Recent evidence suggests that a period of sleep after a motor learning task is a relevant factor for memory consolidation. However, it is yet open whether this also holds true for language-related learning. Therefore, the present study compared the short- and long-term effects of a daytime nap, rest, or an activity task after vocabulary learning on learning outcome. Thirty healthy subjects were divided into three treatment groups. Each group received a pseudo-word learning task in which pictures of monsters were associated with unique pseudo-word names. At the end of the learning block a first test was administered. Then, one group went for a 90-min nap, one for a waking rest period, and one for a resting session with interfering activity at the end during which a new set of monster names was to be learned. After this block, all groups performed a first re-test of the names that they initially learned. On the morning of the following day, a second re-test was administered to all groups. The nap group showed significant improvement from test to re-test and a stable performance onto the second re-test. In contrast, the rest and the interference groups showed decline in performance from test to re-test, with persistently low performance at re-test 2. The 3 (GROUP) × 3 (TIME) ANOVA revealed a significant interaction, indicating that the type of activity (nap/rest/interfering action) after initial learning actually had an influence on the memory outcome. These data are discussed with respect to translation to clinical settings with suggestions for improvement of intervention outcome after speech-language therapy if it is followed by a nap rather than interfering activity.


Ultrasonographic and computed tomographic features of rice bodies in an Arabian horse with atlantal bursitis.
A 19-year-old castrated Arabian male horse presented for evaluation of a firm mass at the dorsal cervical region. Ultrasonography and computed tomography revealed multiple well defined fusiform structures within the atlantal bursa. Multiple glossy smooth, white to yellowish, flattened fusiform structures were removed surgically. These structures were composed of dense fibrin with some leukocytes and red blood cells. The imaging and histopathological features of these structures were similar to chronic 'rice bodies' reported in humans with bursitis or tenosynovitis. This is the first veterinary report describing the imaging features of 'rice bodies' in a horse with atlantal bursitis.


Potent neutralization of botulinum neurotoxin by recombinant oligoclonal antibody.
The botulinum neurotoxins (BoNTs) cause the paralytic human disease botulism and are one of the highest-risk threat agents for bioterrorism. To generate a pharmaceutical to prevent or treat botulism, monoclonal antibodies (mAbs) were generated by phage display and evaluated for neutralization of BoNT serotype A (BoNT/A) in vivo. Although no single mAb significantly neutralized toxin, a combination of three mAbs (oligoclonal Ab) neutralized 450,000 50% lethal doses of BoNT/A, a potency 90 times greater than human hyperimmune globulin. The potency of oligoclonal Ab was primarily due to a large increase in functional Ab binding affinity. The results indicate that the potency of the polyclonal humoral immune response can be deconvoluted to a few mAbs binding nonoverlapping epitopes, providing a route to drugs for preventing and treating botulism and diseases caused by other pathogens and biologic threat agents.


Crying vital capacity. Measurement of neonatal lung function.
Serial measurements of crying vital capacity (CVC), expressed as ml/cm chest circumference, were made by reverse plethysmography during the first 2 weeks of life. Clinically normal babies born at term by elective caesarean section had a smaller mean CVC in the first 2 weeks of life compared with clinically normal term babies born vaginally. In contrast, no significant difference was shown between the mean CVC in term babies born vaginally and those born by urgent caesarean section. Clinically normal term babies born by caesarean section (elective and urgent) had a smaller mean percentage rise of CVC in the first 24 hours of life and a significant delayed rise of CVC from 24-48 hours compared with those born vaginally. Clinically normal preterm babies born vaginally had a smaller mean CVC in the first 2 weeks of life compared with term babies born vaginally, and were characterized by a significant rise of CVC from 5-10 days. Babies with hyaline membrane disease (HMD) had a smaller CVC in the first 2 weeks of life compared with clinically normal preterm babies. Babies of various gestational ages with transient tachypnoea (TT) had a smaller mean CVC in the first 2 weeks of life compared with clinically normal term babies, but a similar mean CVC in the first 72 hours of life compared with clinically normal preterm babies. At each postnatal age the mean CVC of babies with HMD was less than the corresponding mean in babies with TT. All babies with TT had a rise in CVC from 24-48 hours, whereas CVC fell in all babies with HMD except one during this period. CVC is a simple, safe, rapid, and noninvasive test of neonatal lung function, and is a valuable aid to other methods of assessing pulmonary function in the neonate with respiratory distress.


Unified Thermodynamic Uncertainty Relations in Linear Response.
Thermodynamic uncertainty relations (TURs) are recently established relations between the relative uncertainty of time-integrated currents and entropy production in nonequilibrium systems. For small perturbations away from equilibrium, linear response (LR) theory provides the natural framework to study generic nonequilibrium processes. Here, we use LR to derive TURs in a straightforward and unified way. Our approach allows us to generalize TURs to systems without local time-reversal symmetry, including, e.g., ballistic transport and periodically driven classical and quantum systems. We find that, for broken time reversal, the bounds on the relative uncertainty are controlled both by dissipation and by a parameter encoding the asymmetry of the Onsager matrix. We illustrate our results with an example from mesoscopic physics. We also extend our approach beyond linear response: for Markovian dynamics, it reveals a connection between the TUR and current fluctuation theorems.


Prevalence and risk factors of myopia in adult Korean population: Korea national health and nutrition examination survey 2013-2014 (KNHANES VI).
To evaluate the prevalence and risk factors of myopia in adult Korean population. Population-based cross-sectional data of 3,398 subjects aged 19 to 49 years was obtained using the Korea National Health and Nutrition Examination Survey 2013-2014 (KNHANES VI). Data, including refractive errors and potential risk factors were analyzed. The prevalence and risk factors of myopia, low myopia, and high myopia-defined as a spherical equivalent (SEQ) ≤ -0.5 diopters (D), -6.0 D < SEQ <-0.5 D, and SEQ ≤ -6.0 D, respectively-were evaluated. The prevalence of myopia and high myopia were 70.6 (standard error (SE), ±1.1)% and 8.0 (SE, ±0.6)%, respectively. In multivariable analysis, younger age, higher education (≥12 years), parental myopia, lower serum 25-hydroxyvitamin D (25(OH)D) concentration (<9 ng/mL), longer time spent on near work (≥3 hours/day), and higher white blood cell (WBC) count (5-8.9 x 103) were associated with increased prevalence of both myopia and high myopia. Serum 25(OH)D concentration of ≥ 9 ng/ml was significantly associated with decreased prevalence of high myopia in participants with near work of ≥3 hours/day, although the effect was not significant in myopia and low myopia. The prevalence of myopia and high myopia in Korean adults was substantially high, which increased with decreasing age. In addition to parental myopia, the serum 25(OH)D concentration, near work and inflammation reflected by WBC counts may be associated with myopia.


Design and analysis of a clinical trial using previous trials as historical control.
For single arm trials, a treatment is evaluated by comparing an outcome estimate to historically reported outcome estimates. Such a historically controlled trial is often analyzed as if the estimates from previous trials were known without variation and there is no trial-to-trial variation in their estimands. We develop a test of treatment efficacy and sample size calculation for historically controlled trials that considers these sources of variation. We fit a Bayesian hierarchical model, providing a sample from the posterior predictive distribution of the outcome estimand of a new trial, which, along with the standard error of the estimate, can be used to calculate the probability that the estimate exceeds a threshold. We then calculate criteria for statistical significance as a function of the standard error of the new trial and calculate sample size as a function of difference to be detected. We apply these methods to clinical trials for amyotrophic lateral sclerosis using data from the placebo groups of 16 trials. We find that when attempting to detect the small to moderate effect sizes usually assumed in amyotrophic lateral sclerosis clinical trials, historically controlled trials would require a greater total number of patients than concurrently controlled trials, and only when an effect size is extraordinarily large is a historically controlled trial a reasonable alternative. We also show that utilizing patient level data for the prognostic covariates can reduce the sample size required for a historically controlled trial. This article quantifies when historically controlled trials would not provide any sample size advantage, despite dispensing with a control group.


The design, synthesis, and antioxidant activity of amphiphilic oximes and amidoximes.
New amphiphilic benzamidoxime, benzoxime, and aliphatic oxime derivatives of glycolipid mimetics were synthesized. The total antioxidant capacity of these amphiphilic derivatives was evaluated using DPPH assay. The observed antioxidant activity was the highest for benzamidoxime derivatives and glycolipid mimetics with two oxime functionalities, followed by benzoxime derivatives, glycolipid mimetics with one oxime group, and dimers of oxime. Due to their amphiphilic structure, which was a guidance for compound design and synthesis, these novel amphiphilic compounds can be proposed as potential antioxidants for tackling oxidative processes in two-phase systems, either biological (cell membranes) or artificial (emulsions).


Studies on the interaction between grape-associated filamentous fungi on a synthetic medium.
Eleven fungi isolated from grapes and sun-dried grapes (Alternaria alternata, Cladosporium herbarum, Eurotium amstelodami, Penicillium janthinellum, P. decumbens, Trichoderma harzianum, Candida sp., Aspergillus carbonarius OTA-negative, A. carbonarius OTA-positive, A. niger var. niger. and A. japonicus var. aculeatus), were grown in SNM medium at different water activities (0.82-0.97) and temperature (20-40 degrees C) levels for 18 days. Pairs of one Aspergillus faced with one non-Aspergillus were grown at 0.87-0.97 a(w) and at 20 and 30 degrees C. In single cultures, daily radii were recorded. In paired cultures radii were recorded and each A. section Nigri isolate was given a dominance score. At high temperatures and low water activities, Penicillium isolates, E. amstelodami and A. niger var. niger showed higher growth rates, while T. harzianum only grew well at the highest water activity. In addition, A. section Nigri was dominant in most paired assays, being only surpassed by T. harzianum at 0.97 a(w) and 20 degrees C. Thus, prevalence of A. section Nigri in sun-dried grapes can be explained by its adaptation to environmental conditions of sun-drying, and by its capability to dominate other fungal species when coming into contact with them.


Spastic dysphonia and essential (voice) tremor treated with primidone.
Primidone has been reported to be effective in reducing tremor in patients with benign essential tremor. There is at least one report that suggests that the medication may reduce voice tremor, a frequent component of the essential tremor syndrome. Three patients with spastic dysphonia of essential (voice) tremor and one with more typical essential (voice) tremor were treated with primidone and experienced no alleviation in the voice signs. The side effects experienced by all patients were consistent with those noted in previous reports. Primidone does not seem to be effective in treating essential voice tremor or spastic dysphonia of essential voice tremor.


Intracranial electroencephalography features of young and old mice under midazolam administration.
Understanding the electroencephalography features of young and old patients treated with anesthetic drugs is important to allow accurate drug use in elderly patients. This study aimed to monitor the intracranial electroencephalography (in the cortex and hippocampus) in free-moving young and old mice under midazolam administration. Behavioral assessment revealed that compared with young mice, old mice had a longer immobility time with a similar midazolam dose. In both young and old mice, midazolam significantly suppressed the total, δ (0.5-4 Hz), θ (4-8 Hz), and α (8-12 Hz) power, and thus induced an increase in the relative β (12-30 Hz) and γ (30-140 Hz) power. Age had a main effect on the γ frequency; specifically, under normal conditions, old mice had a lower γ power than young mice. After midazolam administration, the relative power of high γ frequency (50-140 Hz) remained lower in old mice than in young mice. Our findings suggest that a lower γ power is indicative of an aging brain.


Empathy With Patients and Post-Traumatic Stress Response in Verbally Abused Healthcare Workers.
The current study examined the differential empathic capacity, post-traumatic symptoms, and coping strategies in healthcare workers (HCWs) according to the exposure of verbal or physical workplace violence (WPV). Using online survey, a total of 422 HCWs employed at a training general hospital of South Korea participated and completed self-reporting questionnaires including the WPV questionnaire with coping strategy, the Jefferson Scale of Physician Empathy. Those who experienced either only verbal violence or both physical and verbal violence had lower Jefferson Scale of Physician Empathy scores (p<0.05). Posttraumatic stress symptom severity was higher among people who experienced verbal violence than physical violence. HCWs' exposure to verbal violence was associated with severe posttraumatic symptoms and a low level of empathy with patients (p<0.05). More than half of the victims of verbal violence responded that they did not take any action, receive organizational protection, or peer support, while most physically-abused HCWs received institutional intervention or help from others. Our findings highlight the critical importance of reducing verbal violence, which may represent a larger psychological burden compared to physical violence, by actively implementing effective strategies and policies at the institutional level.


The fission yeast meiotic checkpoint kinase Mek1 regulates nuclear localization of Cdc25 by phosphorylation.
In eukaryotic cells, fidelity in transmission of genetic information during cell division is ensured by the action of cell cycle checkpoints. Checkpoints are surveillance mechanisms that arrest or delay cell cycle progression when critical cellular processes are defective or when the genome is damaged. During meiosis, the so-called meiotic recombination checkpoint blocks entry into meiosis I until recombination has been completed, thus avoiding aberrant chromosome segregation and the formation of aneuploid gametes. One of the key components of the meiotic recombination checkpoint is the meiosis-specific Mek1 kinase, which belongs to the family of Rad53/Cds1/Chk2 checkpoint kinases containing forkhead-associated domains. In fission yeast, several lines of evidence suggest that Mek1 targets the critical cell cycle regulator Cdc25 to delay meiotic cell cycle progression. Here, we investigate in more detail the molecular mechanism of action of the fission yeast Mek1 protein. We demonstrate that Mek1 acts independently of Cds1 to phosphorylate Cdc25, and this phosphorylation is required to trigger cell cycle arrest. Using ectopic overexpression of mek1(+) as a tool to induce in vivo activation of Mek1, we find that Mek1 promotes cytoplasmic accumulation of Cdc25 and results in prolonged phosphorylation of Cdc2 at tyrosine 15. We propose that at least one of the mechanisms contributing to the cell cycle delay when the meiotic recombination checkpoint is activated in fission yeast is the nuclear exclusion of the Cdc25 phosphatase by Mek1-dependent phosphorylation.


Extremity trauma research in the United States Army.
Extremity wounds compose the burden of injury in the global war on terrorism, and there is a great need for research to improve the treatment of soldiers who incur these devastating injuries. The mission of the United States Army Institute of Surgical Research is to conduct combat casualty care research in several areas, including explosive injury mechanisms, field tourniquet use, external fixator pin coating, wound irrigation optimization, antibiotic-impregnated bone graft substitutes, segmental muscle defects, and outcomes research. Future research directions include development of bone and soft-tissue regenerative technologies, prevention and treatment of heterotopic ossification, and bacteriology of unique pathogens.


Ectopic foci do not co-locate with ventricular epicardial stretch during early acute regional ischemia in isolated pig hearts.
Ectopic activation during early acute regional ischemia may initiate fatal reentrant arrhythmias. However, the origin of this ectopy remains poorly understood. Studies suggest that systolic stretch arising from dyskinesia in ischemic tissue may cause ectopic depolarization due to cardiac mechanosensitivity. The aim of this study was to investigate the link between mechanical stretch and ectopic electrical activation during early acute regional ischemia. We used a recently developed optical mapping technique capable of simultaneous imaging of mechanical deformation and electrical activation in isolated hearts. Eight domestic swine hearts were prepared in left ventricular working mode (LVW), in which the left ventricle was loaded and contracting. In an additional eight non-working (NW) hearts, contraction was pharmacologically suppressed with blebbistatin and the left ventricle was not loaded. In both groups, the left anterior descending coronary artery was tied below the first diagonal branch. Positive mechanical stretch (bulging) during systole was observed in the ischemic zones of LVW, but not NW, hearts. During ischemia phase 1a (0-15 min post-occlusion), LVW hearts had more ectopic beats than NW hearts (median: 19, interquartile range: 10-28 vs. median: 2, interquartile range: 1-6; p = 0.02); but the difference during phase 1b (15-60 min post-occlusion) was not significant (median: 27, interquartile range: 22-42 vs. median: 16, interquartile range: 12-31; p = 0.37). Ectopic beats arose preferentially from the ischemic border zone in both groups (p < 0.01). In LVW hearts, local mechanical stretch was only occasionally co-located with ectopic foci (9 of 69 ectopic beats). Despite the higher rate of ectopy observed in LVW hearts during ischemia phase 1a, the ectopic beats generally did not arise by the hypothesized mechanism in which ectopic foci are generated by co-local epicardial mechanical stretch.


Perinatal Outcomes of Non-Primary Maternal Cytomegalovirus Infection: A 15-Year Experience.
To evaluate perinatal outcomes in case of non-primary maternal cytomegalovirus (CMV) infection. We performed a retrospective cohort study of pregnant women with active CMV infection referred to our unit over a 15-year period (January 2000 to December 2014). Non-primary infection was diagnosed on the basis of the results of confirmatory serological and virological tests (avidity test, immunoblotting, real-time PCR-DNA). The vertical transmission rate and the percentage of symptomatic congenital infection were determined in this group of patients. A total of 205 pregnant women were enrolled. Congenital infection occurred in 7 (3.4%) fetuses/neonates. Symptomatic disease was present at birth in 3 of the 7 congenitally infected neonates (1.5%). Two out of 3 symptomatic newborns presented a pathologic second-trimester ultrasound scan. Maternal immunity offers substantial protection against intrauterine transmission of CMV infection, but not against disease once the fetus is infected.


Does temperament moderate treatment response in adolescent substance use disorders?
To assess whether temperament moderates response to treatment for substance use disorders (SUD), n = 88 consecutively referred adolescents with SUD were randomized to cognitive- behavioral (CBT) or psychoeducational (PET) therapies. Principal components analyses reduced the 10-attribute Dimensions of Temperament Revised (DOTS-R) to three factors (Rhythmicity, Activity/Flexibility, and Mood/Sociability). Three response domains (Alcohol Use, Other Substance Use, and Psychological Function) from the Teen Addiction Severity Index (T-ASI) were assessed at baseline and at 3-month post-treatment completion. There was a significant moderator effect on Treatment only for Rhythmicity on T-ASI Alcohol and Psychological domains. For Alcohol use, for youth with poor levels of Rhythmicity, only PET effected significant improvement, whereas for youth with good levels of Rhythmicity, no treatment differences emerged. For Psychological function, for youth with good levels of Rhythmicity, only CBT effected significant improvement, whereas for youth with poor levels of Rhythmicity, no treatment differences emerged. Implications of these findings are discussed.


Severity of bipolar disorder is associated with impairment of response inhibition.
Pathological impulsivity in bipolar disorder could be related to deficiencies in mechanisms involved in attention or response inhibition. We investigated these mechanisms in subjects with bipolar disorder and examined relationships to severity of course of illness, use of medication, affective state, age, education, and gender. We measured two complementary aspects of response inhibition: attention-based and reward-based. Subjects with bipolar disorder (n=112) and healthy controls (n=71) were recruited from the community. Diagnoses were rendered using the SCID for DSMIV. Impulsivity-related measures included the Immediate Memory Task (IMT), a form of the Continuous Performance Task, and the Single Key Impulsivity Paradigm (SKIP), an operant procedure measuring ability to delay responding for a reward. Subjects with bipolar disorder had fewer correct detections (Effect Size (ES)=0.5), prolonged reaction times (ES=0.88), and decreased discriminability (ES=0.57) on the IMT compared to controls. History of frequent episodes, substance use disorders, or suicide attempts predicted faster reaction times, especially to a commission error. Subjects with bipolar disorder who also met criteria for an Axis II disorder had fewer correct detections, more commission errors relative to correct detections, and poorer discriminability on the IMT than other subjects with bipolar disorder. Subjects with bipolar disorder made more responses on the SKIP than did controls (ES=0.5), with a shorter maximum delay (ES=0.62), consistent with inability to delay reward. Probit analysis showed that faster reaction time to a commission error on the IMT was associated with history of substance use disorder, suicide attempt, or many previous episodes. Effects of medication or affective state did not account for these differences. Bipolar disorder was associated with impairment in attention and response inhibition, encompassing impaired inhibition of rapid responses and an inability to delay reward, and resulting in impulsivity. Response inhibition mechanisms are impaired further in subjects with more severe complications of illness.


[Prognostic factors uterine corpus cancer].
The accumulated clinico-pathological dates and recent molecular biological studies have identified several prognostic factors for endometrial cancers. FIGO staging has taken into consideration of the tumor expansion and is the most important predictor in evaluating patient outcome. Characteristics of tumor biology, such as morphology of tumor and depth of invasion are also important prognostic considerations. Molecular markers indicating genetic/molecular events in cancer biology appear to be the 3rd predictors in estimating the prognosis. Finally, treatment of uterine corpus cancer can be directly related to prognosis. Postoperative chemotherapy is gradually taking precedence over irradiation in considering evidence-based medicine.


Effect of age on survival in acute leukemia. 1950-1990.
Four decades ago, survival of patients with acute leukemia was brief at any age. Since 1950, survival of children has increased remarkably but has changed little for the elderly. The nature and magnitude of this age difference in survival are not understood. Median survival was determined in 2364 Kansas residents diagnosed with acute leukemia from 1947 until 1990. Of this number, 1032 had acute lymphocytic leukemia and 1227 had acute myelocytic leukemia diagnosed between 1950 and 1989. These patients were stratified by age and decade of diagnosis. Survival was computed by life-table analysis with significance determined by log-rank, Wilcoxon, and Fisher exact tests. During the 40 years of the study, highly significant increases occurred in median survivals for all groups with either acute lymphocytic leukemia or acute myelocytic leukemia occurring in patients younger than 60 years of age (P < 0.0001 for some age groups), but no significant increases for those 61 to 80 years of age and those 81 years of age and older. Viewed in another dimension, for each decade from the 1960s to the present in acute lymphocytic leukemia and from the 1970s to the present in acute myelocytic leukemia, age at diagnosis was inversely correlated with median survival in a highly significant manner (P < 0.001). Increasing age is inversely related to survival in patients with acute leukemia. The lack of significant improvement in median survival in the last 40 years for those older than 60 years of age stands in stark contrast to the remarkable improvement for younger patients. Acute leukemia in older patients demands new and probably different therapeutic strategies.


Non-traditional drug targets: high risk, high reward.
Genomics and proteomics have unveiled a plethora of protein-protein interactions that may control cellular processes involved in disease development. Many of these interactions involve non-traditional candidate targets (i.e., neither enzymes nor cell surface receptors/channels). To date, non-traditional targets have largely been ignored by the pharmaceutical industry or have failed to lead to drugs. This review focuses on the use of transdominant genetically encoded agents and specialized small-molecule drugs to explore this void.


IL25 Enhanced Colitis-Associated Tumorigenesis in Mice by Upregulating Transcription Factor GLI1.
Interleukin-25 (IL17E/IL25) plays a critical role in colitis and intestinal homeostasis. However, the expression and biological role of IL25 in colorectal cancer is not properly understood. In this study, we show that IL25 is mainly expressed by cancer stem cells in the colorectal cancer microenvironment. Genetic deletion of IL25 inhibited tumor formation and growth and prolonged survival in AOM/DSS-treated mice. IL25 stimulated cancer organoid and cancer cells sphere formation and prevented the tumor from chemotherapy-induced apoptosis. Mechanistically, IL25 upregulated stem cell genes LGR5, CD133, and ABC transporters via activating the Hedgehog signaling pathway. IL25 inhibited phosphorylation of AMPK and promoted GLI1 accumulation to maintain cancer stem cells. Moreover, IL25 expression was associated with poor survival in patients with metastatic colorectal cancer. Taken together, our work reveals an immune-associated mechanism that intrinsically confers cancer cell stemness properties. Our results first demonstrated that IL25, as a new potent endogenous Hedgehog pathway agonist, could be an important prognostic factor and therapeutic target for CRC.


Effects of Older Donor Age and Cold Ischemic Time on Long-Term Outcomes of Heart Transplantation.
Using older donor hearts in cardiac transplantation may lead to inferior outcomes: older donors have more comorbidities that reduce graft quality, including coronary artery disease, hypertension, diabetes mellitus, and dyslipidemia. Shorter cold ischemic times might overcome the detrimental effect of older donor age. We examined the relationship between donor allograft age and cold ischemic time on the long-term outcomes of heart transplant recipients. rom 1994 through 2010, surgeons at our hospital performed 745 heart transplantations. We retrospectively classified these cases by donor ages of <50 years (younger) and ≥50 years (older), then by cold ischemic times of <120 min (short), 120 to 240 min (intermediate), and >240 min (long). Endpoints included recipient and graft survival, and freedom from cardiac allograft vasculopathy, nonfatal major adverse cardiac events, and rejection. For intermediate ischemic times, the 5-year recipient survival rate was lower when donors were older (70% vs 82.6%; P=0.02). This was also true for long ischemic times (69.8% vs 87.6%; P=0.09). For short ischemic times, we found no difference in 5-year recipient or graft survival rates (80% older vs 85.6% younger; P=0.79), in freedom from nonfatal major adverse cardiac events (83.3% vs 91.5%; P=0.46), or in freedom from cardiac allograft vasculopathy (50% vs 70.6%; P=0.66). Rejection rates were mostly similar. Long-term graft survival in heart transplantation patients with older donor allografts may improve when cold ischemic times are shorter.


Reciprocal regulation of Abl kinase by Crk Y251 and Abi1 controls invasive phenotypes in glioblastoma.
Crk is the prototypical member of a class of Src homology 2 (SH2) and Src homology 3 (SH3) domain-containing adaptor proteins that positively regulate cell motility via the activation of Rac1 and, in certain tumor types such as GBM, can promote cell invasion and metastasis by mechanisms that are not well understood. Here we demonstrate that Crk, via its phosphorylation at Tyr251, promotes invasive behavior of tumor cells, is a prominent feature in GBM, and correlating with aggressive glioma grade IV staging and overall poor survival outcomes. At the molecular level, Tyr251 phosphorylation of Crk is negatively regulated by Abi1, which competes for Crk binding to Abl and attenuates Abl transactivation. Together, these results show that Crk and Abi1 have reciprocal biological effects and act as a molecular rheostat to control Abl activation and cell invasion. Finally, these data suggest that Crk Tyr251 phosphorylation regulate invasive cell phenotypes and may serve as a biomarker for aggressive GBM.


Computing conformational free energy by deactivated morphing.
Despite the significant advances in free-energy computations for biomolecules, there exists no general method to evaluate the free-energy difference between two conformations of a macromolecule that differ significantly from each other. A crucial ingredient of such a method is the ability to find a path between different conformations that allows an efficient computation of the free energy. In this paper, we introduce a method called "deactivated morphing," in which one conformation is morphed into another after the internal interactions are completely turned off. An important feature of this method is the (shameless) use of nonphysical paths, which makes the method robustly applicable to conformational changes of arbitrary complexity.


Local suture ligation-assisted percutaneous sclerotherapy for Kasabach-Merritt phenomenon-associated kaposiform haemangioendothelioma.
Kaposiform haemangioendotheliomas (KHEs) complicated by the Kasabach-Merritt phenomenon (KMP) are rare and severe neoplastic lesions often associated with locally aggressive disease, consumption coagulopathy and high mortality rates. Current regimens have yet to achieve a satisfactory therapeutic effect. Thus, an effective and minimally invasive approach for treating complex KHE/KMP cases is necessary for clinical management. The present case series describes patients with KHE/KMP who underwent local suture ligation-assisted percutaneous sclerotherapy to minimise surgical trauma and ensure effective treatment. Between September 2015 and September 2017, 3 consecutive patients with KHE/KMP underwent staged local suture ligation-assisted percutaneous sclerotherapy. Of these patients, 2 presented with medical histories of corticosteroid treatment with unsatisfactory outcomes. The patients underwent a stepwise synthetic serial therapy programme consisting of percutaneous sclerotherapy and adjunctive pharmacotherapy accompanied by a suture ligation procedure. Clinical, radiological, pathological and laboratory data were analysed to evaluate the outcomes of the therapy. All patients were successfully managed with the proposed procedure. Significant relief of clinical symptoms and improvements in haematological indicators were achieved. No recurrence or complications were observed during regular follow-up (4, 19 and 28 months). In conclusion, local suture ligation-assisted percutaneous sclerotherapy was demonstrated to be a safe and effective treatment for KHE/KMP, being minimally invasive, involving simple manipulation and providing a clear treatment benefit in certain cases. Further studies involving larger sample sizes are required to thoroughly evaluate the procedure, which can potentially be used as a novel therapeutic option for KHE/KMP treatment.


Exposure of workers to mites in Finnish groceries.
We assessed the mite exposure of workers in Finnish groceries by collecting samples of settled dust in 5 different grocerys. Mites were counted and identified microscopically. Mite allergen (Der p 1 and Der f 1) content of dust was analyzed with 2-site ELISA. Mites were found in 20-100 % of the samples, both from storage and salesrooms. Seven samples (8 %) contained more than 100 mites per gram dust and 3 additional samples (6 %) more than 500 mites per gram dust, the suggested limits for mite sensitization and acute allergic symptoms, respectively. Most of the mites were storage mites belonging to Astigmata (Acaridae, Glycyphagidae) or Prostigmata (tarsonemids). House dust mites were found only occasionally. One dust sample out of 15 contained Der p 1, and none contained Der f 1.


Difference in cochlear efferent activity between musicians and non-musicians.
The present study aimed to confirm and extend the finding, suggested by the results of a previous study, of different auditory neural efferent functioning in musicians compared with non-musicians. The activity of the medial olivocochlear bundle (MOCB), an auditory efferent subsystem, was measured through the contralaterally induced attenuation of the amplitude of evoked otoacoustic emissions (EOAEs) in two groups, one of musicians and one of non-musicians, paired for age and sex. The results indicated a statistically significant difference between the two groups, with the musicians showing greater amplitude reduction upon contralateral noise stimulation than non-musicians (U-test, U = 204, p < 0.025, n = 32). These results indicate greater MOCB activity in musicians than in non-musicians. The possible origins and implications of this finding are discussed.


Rapid Healing of a Spontaneous Coronary Artery Dissection Detected by Computed Tomography Angiography.
Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome and little is known about characteristics, treatment, and follow-up of patients with SCAD. Computed tomography angiography (CTA) plays an important role in the diagnosis and management of SCAD. Herein, we describe a case of a patient with SCAD who underwent successful conservative management, and in whom CTA was able to detect rapid healing of the dissection, 4.5 hours post-dissection.


Application of low dose rate pulsed fluoroscopy in cardiac pacing and electrophysiology: patient dose and image quality implications.
The performance of a low dose rate pulsed fluoroscopy option and its successful application to cardiac pacing and electrophysiology is reported. Low dose rate 6.25 frames per second pulsed fluoroscopy was made available in two catheter laboratories at a specialist cardiac centre in February 2003, and was adopted as the standard imaging technique for cardiac pacing procedures. The image quality was found to be considerably poorer than conventional modern units, being very similar to that which would have been accepted as adequate performance 20 years ago, but at less than one-tenth of the dose rate. No problems with the clinical acceptance of this imaging mode for cardiac pacing and electrophysiology have been reported. The already low median patient dose-area product for pacing at this cardiac centre was further reduced by 50% with the introduction of this fluoroscopy option.


Planning genetic studies in human stroke: sample size estimates based on family history data.
Identification of stroke risk genes in humans has relied on case-control methods to determine the association between candidate genes and disease. Alternative approaches include linkage analysis using affected sibling pairs, transmission disequilibrium testing (TDT), and sibling TDT (S-TDT). Despite theoretical benefits, the feasibility of these methods in stroke remains unknown. Family history was determined in 727 patients with ischemic stroke and 623 control subjects. These data were used to estimate the number of stroke patients required for the different study designs. A family history of any stroke occurring at < or =65 years was an independent risk factor for ischemic stroke at all ages (OR 1.47, 95% CI 1.02 to 2.12, p = 0.04) and a stronger risk factor for young (< or =65 years) ischemic stroke (OR 2.25, 95% CI 1.43 to 3.55, p < 0.0001). For early-onset ischemic stroke, the sibling risk ratio was estimated to be 3.08. Assuming three major stroke loci, collection of 953 affected sibling pairs (both < or =65 years) would be needed for a linkage study, and 115,472 ischemic stroke patients would have to be screened to achieve this sample size from the authors' population. The predicted sample sizes for association studies to detect a gene conferring an OR of 2.0 were case-control methodology (414), TDT (414), and S-TDT (617), which would require screening of 820, 31,680, and 3,062 cases. Alternative genetic approaches are feasible, but TDT and linkage studies using the affected sib-pair methodology may require large multicenter collaborations. S-TDT approaches appear more practical. These estimates will aid in planning of such studies.


In Silico Prediction of Mechanism of Action for Cancer Therapeutics.
Cancer is currently the second leading cause of death in the U.S. and is projected to become the principal cause in the near future. While radiation and surgery are common cancer treatment methods, chemotherapy remains a key treatment option, offering distinct advantages over other therapy options, especially in the management of metastasized tumors. Understanding the mechanism of action (MoA) of current and newly developed drugs is crucial to ongoing drug development research. Foreknowledge of how a candidate drug works can yield a wealth of information, including which cancers a drug may treat more effectively based on the susceptibility of the cancer to drugs with the same MoA. Previous studies concerning prediction of MoA have relied on costly experimental measurements as input for their predictions. We have developed an a priori quantitative structure-activity relationship (QSAR) for the in silico prediction of MoA without the need for experimental measurements. This model enables us to relate structural features of a chemical to its efficacy with a predictive accuracy of over 80 %, thus identifying the MoA of a candidate drug without costly, time-consuming experimental tests.


Babesia canis spp. in dogs in Baghdad Province, Iraq: First molecular identification and clinical and epidemiological study.
The aim of this study was to investigate babesiosis in dogs of different breeds and ages and of both sexes in Baghdad Province by molecular detection of Babesia canis using conventional polymerase chain reaction (PCR) and sequencing followed by phylogenetic analyses. Blood samples were collected from 310 dogs of different ages and breeds, and of both sexes in different areas of Baghdad Province from December 2018 to September 2019; during clinical examinations, body temperature, pulse, respiratory rate, and signs of diseases were recorded. PCR was used to amplify a specific 450-bp fragment of the 18S rRNA gene of B. canis. PCR products were sequenced, and MEGA 6.0 software was used for analysis. Chi-square and odds ratio tests were used to investigate the prevalence and risk factors of babesiosis. Clinical signs of babesiosis included paleness or icterus of the mucus membranes, tick infestation, and febrile illness during the acute and subacute phase. The prevalence of infection with B. canis was 5.1%, with the higher prevalence in male dogs and in dogs <3 years of age. Huskies were more likely to be infected than other dogs. Infection prevalence was highest in April and June and was higher in spring and summer than in winter. Using sequence data, 14 isolates of Babesia canis canis and one isolate of each Babesia canis rossi and Babesia canis vogeli were identified. Phylogenetic analyses of B. canis canis revealed that three shared clades and several isolated lineages were similar to other isolates (97-99% similarity), whereas B. canis vogeli and B. canis rossi showed similarities of 98% and 99% with isolates from other geographical regions. This study provides the first molecular record and phylogenic analysis of B. canis in dogs in Iraq, and it will be valuable for confirming clinical signs and studying epidemiological risk factors of babesiosis in dogs.


Effects of ibuprofen lysinate and acetylsalicylic acid on gastric and duodenal mucosa. Randomized single-blind placebo-controlled endoscopic study in healthy volunteers.
Acetylsalicylic acid (ASA, CAS 50-78-2) and ibuprofen (IB) are commonly used over-the-counter drugs for short-term treatment of pain of different origin. Ibuprofen lysinate (IBL, CAS 57469-76-8) is a water soluble form of ibuprofen for rapid absorption. This single blind, randomized, controlled study compared the incidence and severity of irritation of gastric and duodenal mucosa in normal healthy subjects (n = 45) following administration of IBL (Dolormin) 800 mg/d, ASA 2000 mg/d or placebo for 3 consecutive days. Gastric and duodenal mucosal injury were assessed endoscopically using a severity scale of 0-4 for mucosal erosions and mucosal hemorrhages. Mean gastric hemorrhage and erosion scores for ASA and IBL were significantly higher than those for placebo. In addition, ASA was found to be significantly more irritating to gastric mucosa than IBL, in both the incidence and severity of gastric erosions. No duodenal hemorrhages were detected in this study. The incidence of duodenal erosions was significantly higher in the ASA group (64%) than in both the IBL (6%) and placebo groups (0%) which were not significantly different. Only one subject (in the placebo group) reported an adverse experience (mild headache) during the study. The data suggest that both active treatments are more injurious to the gastric mucosa than placebo when given for 3 days to normal healthy volunteers, but that IBL 800 mg/d is significantly less injurious to the gastric and duodenal mucosa than ASA 2000 mg/d.


Intranasal Midazolam versus Rectal Diazepam for the Management of Canine Status Epilepticus: A Multicenter Randomized Parallel-Group Clinical Trial.
Intranasal administration of benzodiazepines has shown superiority over rectal administration for terminating emergency epileptic seizures in human trials. No such clinical trials have been performed in dogs. To evaluate the clinical efficacy of intranasal midazolam (IN-MDZ), via a mucosal atomization device, as a first-line management option for canine status epilepticus and compare it to rectal administration of diazepam (R-DZP) for controlling status epilepticus before intravenous access is available. Client-owned dogs with idiopathic or structural epilepsy manifesting status epilepticus within a hospital environment were used. Dogs were randomly allocated to treatment with IN-MDZ (n = 20) or R-DZP (n = 15). Randomized parallel-group clinical trial. Seizure cessation time and adverse effects were recorded. For each dog, treatment was considered successful if the seizure ceased within 5 minutes and did not recur within 10 minutes after administration. The 95% confidence interval was used to detect the true population of dogs that were successfully treated. The Fisher's 2-tailed exact test was used to compare the 2 groups, and the results were considered statistically significant if P < .05. IN-MDZ and R-DZP terminated status epilepticus in 70% (14/20) and 20% (3/15) of cases, respectively (P = .0059). All dogs showed sedation and ataxia. IN-MDZ is a quick, safe and effective first-line medication for controlling status epilepticus in dogs and appears superior to R-DZP. IN-MDZ might be a valuable treatment option when intravenous access is not available and for treatment of status epilepticus in dogs at home.


The level of telomere dysfunction determines the efficacy of telomerase-based therapeutics in a lung cancer cell line.
Telomerase is the ribonucleoprotein enzyme that maintains telomeres of eukaryotic chromosomes. Activation of telomerase is a common feature of the majority of human cancers, and inhibition of this enzyme has been proposed as a novel target for cancer therapeutics. Here, we investigated the effects of telomerase inhibition in the non-small cell lung cancer cell line NCI-H460, using a genetic approach by ectopic expression of dominant-negative (DN)-hTERT. Five clones were selected in which telomerase activity was completely abolished. As a result, telomere erosion was observed leading to proliferation arrest after a lag period of 20-28 population doublings. Although overall telomere length was similar between the different clones as measured by quantitative fluorescence in situ hybridization (Q-FISH), striking differences were found in telomere length of individual chromosomes. In particular, lack of individual telomeres and formation of end-to-end fusions were variable. Interestingly, this level of individual telomere dysfunction was positively correlated with the remaining life span of the different clones in vitro. In addition, the amount of telomere dysfunction induced by DN-hTERT was twice as high compared to the small molecule telomerase inhibitor BIBR1532, which induced growth arrest after >100 population doublings. Thus, pharmacological strategies that aim at inhibition of telomerase in cancer cells should take into account that not only overall telomere shortening, but rapid induction of a high level telomere dysfunction appears to be the crucial surrogate parameter for the development of future telomerase-based therapeutics.


A Pyrrole-Imidazole Polyamide Is Active against Enzalutamide-Resistant Prostate Cancer.
The LREX' prostate cancer model is resistant to the antiandrogen enzalutamide via activation of an alternative nuclear hormone receptor, glucocorticoid receptor (GR), which has similar DNA-binding specificity to the androgen receptor (AR). Small molecules that target DNA to interfere with protein-DNA interactions may retain activity against enzalutamide-resistant prostate cancers where ligand-binding domain antagonists are ineffective. We reported previously that a pyrrole-imidazole (Py-Im) polyamide designed to bind the consensus androgen response element half-site has antitumor activity against hormone-sensitive prostate cancer. In enzalutamide-resistant LREX' cells, Py-Im polyamide interfered with both AR- and GR-driven gene expression, whereas enzalutamide interfered with only that of AR. Genomic analyses indicated immediate interference with the AR transcriptional pathway. Long-term treatment with Py-Im polyamide demonstrated a global decrease in RNA levels consistent with inhibition of transcription. The polyamide was active against two enzalutamide-resistant xenografts with minimal toxicity. Overall, our results identify Py-Im polyamide as a promising therapeutic strategy in enzalutamide-resistant prostate cancer. Cancer Res; 77(9); 2207-12. ©2017 AACR.


Chronic low dose cyclophosphamide treatment of adult male rats: effect on fertility, pregnancy outcome and progeny.
Cyclophosphamide is an anticancer and immunosuppressive agent commonly used in men of reproductive age. The relationship between the effects of paternal cyclophosphamide treatment on the male reproductive system and the pregnancy outcome is unknown. To study this relationship, adult male Sprague-Dawley rats were administered saline or cyclophosphamide (1.4, 3.4, and 5.1 mg/kg) daily for 11 wk by gavage. Each male was mated weekly with two females in proestrous; 20 days later, the females were caesarean-sectioned and the number of corpora lutea, resorptions, and normal and abnormal fetuses were noted. After 11 wk of treatment, none of the drug-treated males showed any significant difference compared to controls with respect to male reproductive organ weights, serum testosterone, luteinizing hormone or follicle-stimulating hormone, epididymal sperm counts or fertility. Despite the apparent minimal effects of the treatment regimen on the male reproductive system, there were a number of effects on pregnancy outcome. There was a dose-dependent increase in preimplantation loss at 5-6 wk that was not evident at other times, a progressive dose-dependent increase in postimplantation loss starting at 2 wk, and an increase in malformed and growth-retarded fetuses at 3-4 and 7-9 wk. These results indicate that low dose chronic cyclophosphamide treatment of the male rat can affect the outcome of his progeny; such effects are seen in the absence of any apparent alteration of a number of measures of male reproductive function.


Functional Polymorphisms in BARD1 Association with Neuroblastoma in a regional Han Chinese Population.
Neuroblastoma (NB) is a sympathetic nervous system cancer for children, occupying approximately 15% of pediatric oncology deaths. BARD1, a tumor suppressor, is essential for genome stability by interaction with BRCA1. Here, we performed a systematic investigation for the association between SNPs in BARD1 and the risk of NB in Chinese population. After SNP screening in BARD1 gene, we performed case-control study of eleven selected SNPs in BARD1 with 339 NB patients and 778 cancer-free controls. The OR and 95% CI of these candidate SNPs were computed by logistic regression. After adjusted gender and age, seven out of eleven SNPs in BARD1 were significant associated with the risk of NB, including one SNP in 5'-UTR (rs17489363 G > A), two SNPs in exon (rs2229571 G > C and rs3738888 C > T), and four SNPs in intron (rs3768716 A > G, rs6435862 T > G, rs3768707 C > T and rs17487792 C > T). When stratified by the INPC, primary tumor site and the INSS, these seven SNPs were significant associated with GNB/NB, stage III/IV and adrenal origin of NB. Dual-luciferase reporter assay showed rs17489363 A allele-containing haplotypes (TAC, CAC, TAG and CAG), composed with rs34732883 T > C, and rs1129804 C > G, dramatically reduced the transcriptional activity of reporter gene. The major of our study showed that seven SNPs of BARD1 associated with increased NB risk in Chinese population, and four haplotypes could reduce transcription activity of BARD1.


[Twiddler syndrome: rare cause of definitive pacemaker dysfunction].
The authors present a case of Twiddler's syndrome, a rare complication after pacemaker implantation, first described in 1968. The article is complemented by an approach to the etiology and manifestations of this entity.


Magnetic diagnostics for equilibrium reconstructions with eddy currents on the Lithium Tokamak eXperiment.
The Lithium Tokamak eXperiment is a spherical tokamak with a close-fitting low-recycling wall composed of thin lithium layers evaporated onto a stainless steel-lined copper shell. Long-lived non-axisymmetric eddy currents are induced in the shell and vacuum vessel by transient plasma and coil currents and these eddy currents influence both the plasma and the magnetic diagnostic signals that are used as constraints for equilibrium reconstruction. A newly installed set of re-entrant magnetic diagnostics and internal saddle flux loops, compatible with high-temperatures and lithium environments, is discussed. Details of the axisymmetric (2D) and non-axisymmetric (3D) treatments of the eddy currents and the equilibrium reconstruction are presented.


JOINT IDENTIFICATION OF IMAGING AND PROTEOMICS BIOMARKERS OF ALZHEIMER'S DISEASE USING NETWORK-GUIDED SPARSE LEARNING.
Identification of biomarkers for early detection of Alzheimer's disease (AD) is an important research topic. Prior work has shown that multimodal imaging and biomarker data could provide complementary information for prediction of cognitive or AD status. However, the relationship among multiple data modalities are often ignored or oversimplified in prior studies. To address this issue, we propose a network-guided sparse learning model to embrace the complementary information and inter-relationships between modalities. We apply this model to predict cognitive outcome from imaging and proteomic data, and show that the proposed model not only outperforms traditional ones, but also yields stable multimodal biomarkers across cross-validation trials.


Electronic density response of warm dense hydrogen on the nanoscale.
The properties of hydrogen at warm dense matter (WDM) conditions are of high importance for the understanding of astrophysical objects and technological applications such as inertial confinement fusion. In this work, we present extensive ab initio path integral Monte Carlo results for the electronic properties in the Coulomb potential of a fixed ionic configuration. This gives us unique insights into the complex interplay between the electronic localization around the protons with their density response to an external harmonic perturbation. We find qualitative agreement between our simulation data and a heuristic model based on the assumption of a local uniform electron gas model, but important trends are not captured by this simplification. In addition to being interesting in their own right, we are convinced that our results will be of high value for future projects, such as the rigorous benchmarking of approximate theories for the simulation of WDM, most notably density functional theory.


Careless Responding Threatens Factorial Analytic Results and Construct Validity of Personality Measure.
The current research investigates the impact of careless responding on factorial analytic results and construct validity with real data. Results showed that inclusion of careless respondents in data analysis distorts factor loading pattern and hinders recovery of theoretical existing factors. Careless respondents also blur the distinction of theoretically distinct factors, resulting in higher inter-factor correlations. That careless responding may threaten convergent validity also receives limited support. Researchers are advised to exclude careless respondents before statistical analysis.


Bovine serum panel for evaluating foot-and-mouth disease virus nonstructural protein antibody tests.
A panel of 36 sera has been assembled from experimental cattle that had been infected by inoculation or contact exposure with 4 serotypes of foot-and-mouth disease virus (FMDV) with or without prior vaccination. Virus replication and persistence had been characterized in all of the animals. The proportion of the sera scored positive by 5 tests for antibodies to the nonstructural proteins of FMDV varied, suggesting that the panel can discriminate between the sensitivity with which such tests are able to identify infected cattle. Use of this panel will help in assessment of new tests and quality control of existing methods.


[Coronary angiography in two defined populations: Padua and Citadella].
Coronary angiography is an invasive procedure that is relatively expensive and that requires an appropriate indication. Utilization rate and the appropriateness of the use of the coronary angiography have been compared in two defined populations, namely residents from the city of Padua (group A), and subjects from the local health unit of Cittadella (group B), who underwent coronary angiography between June 1, 1992 and May 31, 1993. Appropriateness was evaluated both by comparison with the AHA/ACC guidelines and by observation of the outcome following diagnosis one year after the coronary angiogram was performed. One hundred and seventy-one patients in group A and 100 patients in group B underwent coronary angiography: both groups had similar age and sex distribution. Utilization rate was 8 per 10,000 inhabitants in group A, and 10 per 10,000 inhabitants in group B. Appropriate coronary angiography, evaluated by comparison with the AHA/ACC guidelines, was 69.9% in group A and 68% in group B. Coronary angiogram showed at least one stenosis > or = 50% in 133 patients from group A and in 66 patients from group B. These patients were followed up for at least 12 months. Of 13 deaths, 12 occurred as fatal cardiac events, while of the 147 surviving patients who had complete follow-up data, 114 (77%) improved. The outcome was measured through symptoms and stress test. In addition, subjective improvement was measured in group A using the "Nottingham Health Profile". Criteria of appropriateness for an invasive diagnostic procedure such as coronary angiography, which is a determinant "entry point" for revascularization procedures, is based on common clinical knowledge that may be evolving with time. Based on these data, it seems that the current guidelines could be modified, especially for indications within the setting of myocardial infarction.


Complete genome sequences of eight Auritidibacter ignavus strains isolated from ear infections in Germany.
Here, we present the complete genome sequences of eight Auritidibacter ignavus strains isolated from clinical samples of patients with ear infections in Bochum, Germany. The sequence information will give assistance to greater knowledge about the virulence potential of this unfamiliar putative pathogen.


Attenuated LKB1-SIK1 signaling promotes epithelial-mesenchymal transition and radioresistance of non-small cell lung cancer cells.
Radiotherapy is one of the main therapeutic approaches for non-small cell lung cancer (NSCLC). However, radioresistant cancer cells can eventually cause tumor relapse and even fatal metastasis. It is thought that radioresistance and metastasis could be potentially linked by epithelial-mesenchymal transition (EMT). In this study, we established radioresistant NSCLC cells to investigate the potential relationship among radioresistance, EMT, and enhanced metastatic potential and the underlying mechanism involving liver kinase B1 (LKB1)-Salt-inducible kinase 1 (SIK1) signaling. The radioresistant cell lines A549R and H1299R were generated by dose-gradient irradiation of the parental A549 and H1299 cells. The radioresistance/sensitivity was evaluated by Cell Counting Kit-8 assay, apoptosis analysis, and/or clonogenic cell survival assay. The EMT phenotype and the signaling change were assessed by Western blotting. The abilities of invasion and migration were evaluated by transwell assays and wound healing assays. The radioresistant cell lines A549R and H1299R displayed mesenchymal features with enhanced invasion and migration. Mechanistically, A549R and H1299R cells had attenuated LKB1-SIK1 signaling, which leaded to the up-regulation of Zinc-finger E-box-binding homeobox factor 1 (ZEB1)--a transcription factor that drives EMT. Re-expression of LKB1 in A549R cells reversed the EMT phenotype, whereas knockdown of LKB1 in H1299R cells further promoted the EMT phenotype. Moreover, re-expression of LKB1 in A549 cells increased the radiosensitivity, whereas knockdown of LKB1 in H1299 cells decreased the radiosensitivity. Our findings suggest that attenuated LKB1-SIK1 signaling promotes EMT and radioresistance of NSCLC cells, which subsequently contributes to the enhanced metastatic potential. Targeting the LKB1-SIK1-ZEB1 pathway to suppress EMT might provide therapeutic benefits.