Intramuscular diclofenac for the prevention of post-ERCP pancreatitis: a randomized trial.
Rectal nonsteroidal anti-inflammatory drugs have been shown to reduce the incidence of postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). The aim of this study was to determine whether intramuscular diclofenac reduces the risk of PEP. Patients who underwent ERCP were randomized to receive either 90 mg of diclofenac or placebo by intramuscular injection immediately after the procedure. PEP was defined as elevated serum amylase levels (at least three times the upper limit of normal 24 hours after the procedure) associated with new or worsened upper abdominal, epigastric, or back pain. In total, 380 patients were randomized, and 343 were eligible for analysis. The two groups were similar regarding clinical and demographic factors, as well as patient- and procedure-related risk factors for PEP. PEP developed in 20/170 patients (11.8 %) in the placebo group and in 22/173 patients (12.7 %) in the diclofenac group (P = 0.87). Multivariate regression analysis failed to illustrate that intramuscular diclofenac prevented PEP (odds ratio 0.79; 95 % confidence interval 0.39 - 1.25; P = 0.51). Prophylactic intramuscular diclofenac had no beneficial preventive effect on PEP.Clinicaltrials.gov NCT01717599.


STINGing Antitumor Immunity into Action.
Efforts to stimulate STING signaling, thereby turning immunologically "cold" tumors "hot" and receptive to immunotherapy, are gaining ground in the industry. To date, directly targeting the STING receptor with synthetic ligands is the main approach to have entered clinical trials, but indirect small-molecule modulators of the pathway are also being pursued.


Hippocampal Neurogenesis Reduces the Dimensionality of Sparsely Coded Representations to Enhance Memory Encoding.
Adult neurogenesis in the hippocampal dentate gyrus (DG) of mammals is known to contribute to memory encoding in many tasks. The DG also exhibits exceptionally sparse activity compared to other systems, however, whether sparseness and neurogenesis interact during memory encoding remains elusive. We implement a novel learning rule consistent with experimental findings of competition among adult-born neurons in a supervised multilayer feedforward network trained to discriminate between contexts. From this rule, the DG population partitions into neuronal ensembles each of which is biased to represent one of the contexts. This corresponds to a low dimensional representation of the contexts, whereby the fastest dimensionality reduction is achieved in sparse models. We then modify the rule, showing that equivalent representations and performance are achieved when neurons compete for synaptic stability rather than neuronal survival. Our results suggest that competition for stability in sparse models is well-suited to developing ensembles of what may be called memory engram cells.


Dose-response effects of aerobic exercise on energy compensation in postmenopausal women: combined results from two randomized controlled trials.
Despite the clear health benefits of exercise, exercised-induced weight loss is often less than expected. The term 'exercise energy compensation' is used to define the amount of weight loss below what is expected for the amount of exercise energy expenditure. We examined the dose-response effects of exercise volume on energy compensation in postmenopausal women. Data from Alberta Physical Activity and Breast Cancer Prevention (ALPHA) and Breast Cancer and Exercise Trial in Alberta (BETA) were combined for the present analysis. The ALPHA and BETA trials were two-centred, two-armed, 12-month randomized controlled trials. The ALPHA trial included 160 participants randomized to 225 min per week of aerobic exercise, and the BETA trial randomized 200 participants to each 150 and 300 min per week of aerobic exercise. All participants were aged 50-74 years, moderately inactive (<90 min per week of exercise), had no previous cancer diagnosis and a body mass index between 22 and 40 kg m-2. Energy compensation was based on changes in body composition (dual-energy X-ray absorptiometry scan) and estimated exercise energy expenditure from completed exercise volume. Associations between Δenergy intake, ΔVO2peak and Δphysical activity time with energy compensation were assessed. No differences in energy compensation were noted between interventions. However, there were large inter-individual differences in energy compensation between participants; 9.4% experienced body composition changes that were greater than expected based on exercise energy expenditure, 64% experienced some degree of energy compensation and 26.6% experienced weight gain based on exercise energy expenditure. Increases in VO2peak were associated with reductions in energy compensation (β=-3.44 ml kg-1 min-1, 95% confidence interval for β=-4.71 to -2.17 ml kg-1 min-1; P=0.0001). Large inter-individual differences in energy compensation were noted, despite no differences between activity doses. In addition, increases in VO2peak were associated with lower energy compensation. Future studies are needed to identify behavioral and metabolic factors that may contribute to this large inter-individual variability in energy compensation.


Gastric peroxidase--localization, catalytic properties and possible role in extrathyroidal thyroid hormone formation.
A highly active peroxidase (EC 22.214.171.124) has been found to be localized in the mitochondria isolated from the fundic region of mouse stomach. The stomach has also the property of concentrating iodide significantly. Evidence has been presented to show that the peroxidase is orientated outside the mitochondrial membrane. The enzyme is strongly inhibited by antithyroid drugs like methimazole and thiouracil. Azide and cyanide completely inactivate the enzyme. The activity is inhibited by SH-blocking reagents like mersalyl or p-chloromercuribenzene sulphonate, but not by N-ethyl-maleimide. The enzyme is also sensitive to the action of some proteolytic enzymes. It can catalyse the formation of mono- or diiodotyrosine from tyrosine or monoiodotyrosine as substrate, respectively. The enzyme is capable of synthesizing thyroxine and triiodothyronine on the backbone of a protein, such as thyroglobulin or albumin.


Mirror movements in normal adult subjects.
Intensity of mirror movements occurring under specific task conditions in normal adults was investigated using a finger flexion task. Subjects were asked to sustain target pressures using different fingers. Greater pressures of mirror movement were recorded when the weaker, small finger of either hand performed the task. The target pressure which subjects were asked to sustain did not influence the amount of mirror movement exhibited by either males or females, even though higher target forces required a significantly greater percentage of total finger strength. On average, males exhibited the same quantity of mirror movements as female subjects, despite the force requirements of the task representing for them a significantly smaller percentage of total finger strength. Moreover, when the right hand performed the experimental tasks, less mirror movement was exhibited than when the left hand was active. Thus, the left hand showed stronger mirror movements. The findings were consistent with previous research using children as subjects, although the nonsignificant effects of gender and pressure were unexpected and need to be examined further. It appears that, while the force requirement of the task does influence the magnitude of mirror movement, it is not the principle determinant.


A yeast artificial chromosome-splitting vector designed for precise manipulation of specific plant chromosome region.
A yeast artificial chromosome (YAC) splitting vector, pKI01, was constructed for manipulating plant chromosome fragments cloned as YACs in order to transfer specific regions of the fragments into plant cells. Vector pKI01 consists of Km(r) and ADE2 genes (selective markers for plant and yeast transformants, respectively), inverted telomeric repeats Tr and CEN4. To demonstrate the utility of pKI01, YAC CIC9e2 harboring a 590-kb fragment from Arabidopsis thaliana chromosome 5 was split into specific fragments. A 1-kb target region positioned 100 kb from the right end of the 590 kb fragment was cloned into pKI01. The resultant plasmid, pKY03, was introduced into Saccharomyces cerevisiae harboring YAC CIC9e2. The Ade+ transformants were found to contain two new YACs of 490 and 100 kb, and to lack the original 590 kb YAC, consistent with the expected splitting event. To release the desired middle region of YAC CIC9e2, two additional splitting vectors were constructed, pKY11 and pKY14. By conducting two rounds of splitting, i.e., the first round 100 kb from the right end of YAC CIC9e2 with pKY11 to generate 490 and 100 kb YACs and a second round 50 kb from the right end of the new 490 kb YAC to generate 440 and 50 kb YACs, the middle 50 kb region of a plant chromosome fragment harboring Km(r) was successfully released as a split YAC. These results indicate that YAC splitting vectors as constructed in this study are useful for generating any desired plant chromosome fragment as a YAC for eventual re-introduction into plant cells.


COINCIDENT BIOGEOGRAPHIC PATTERNS: INDO-WEST PACIFIC OCEAN.
The majority of tropical marine families demonstrate their greatest concentration of species within the relatively small East Indies Triangle. In every direction, the species diversity decreases with distance from the East Indies. Other patterns suggest that the East Indies is where the average generic age is youngest, where some historical routes of dispersal originate, where the most apomorphic species occur, where genetic diversity is the greatest, and where extinctions are likely to originate. These coincident patterns provide support for the hypothesis that the East Indies has been operating as a center of evolutionary radiation. The driving force for this dynamic system is apparently the predominance of successful speciation involving relatively large populations with higher genetic diversity. This mechanism fits the centrifugal speciation model that was proposed more than 50 years ago.


Intravascular platelet aggregation and acute respiratory insufficiency.
Respiratory effects of long-lasting episodes of intravascular platelet aggregation have been studied in cats. Animals in 1 group had the chest opened and were given mechanical ventilation with a constant tidal volume. Animals of another group were breathing spontaneously. Platelet aggregation was induced by intravenous infusion (for 1 hr) of a suspension of collagen fibrils. Such infusions caused acute respiratory distress in both groups. Severe arterial hypoxemia and rapid breathing as well as constriction of airways and lung vessels occurred. Most of these changes were reversed within 2 hr after collagen infusion had ended. Deep lung inflations markedly improved lung function. It is concluded that an acute, but reversible pulmonary insufficiency might be caused by pulmonary microembolization due to intravascular platelet aggregation. The arterial hypoxemia is suggested to be caused by disturbances in the ventilation-perfusion ratio secondary to airway constriction and closure. The present findings also imply that besides platelet aggregation, some additional factors are necessary for irreversible or progressive respiratory insufficiency to develop.


Studies on the role of cellular immunity and genetics in the etiology of rapidly progressing breast cancer in Tunisia.
It has been suggested that poussée évolutive (PEV) or rapidly progressing breast cancer (RPBC) represents a failure in the host immune system to control the proliferation of breast cancer cells. To evaluate this possibility, we have performed in vivo and in vitro assays of cellular immunity in Tunisian patients with breast cancer. Studies of delayed hypersensitivity using microbial antigens and in vitro including lymphocyte transformation tests and measurements of B and T cells indicated that RPBC patients had an immune response comparable to that of breast cancer patients without evidence of rapid progression. Normal Tunisians were more immunocompetent, however, an appeared to have a higher level of immune activity than normal individuals in the United States. In a second, independent series, an increased frequency of blood group A was found in RPBC patients, suggesting a genetic predisposition to this form of breast cancer. However HLA typing for A, B and DRW antigens revealed no specific RPBC-associated HLA antigen. Our studies clearly demonstrate that RPBC, or PEV, is not a reflection of immunodeficiency.


Seedling growth responses to phosphorus reflect adult distribution patterns of tropical trees.
Soils influence tropical forest composition at regional scales. In Panama, data on tree communities and underlying soils indicate that species frequently show distributional associations to soil phosphorus. To understand how these associations arise, we combined a pot experiment to measure seedling responses of 15 pioneer species to phosphorus addition with an analysis of the phylogenetic structure of phosphorus associations of the entire tree community. Growth responses of pioneers to phosphorus addition revealed a clear tradeoff: species from high-phosphorus sites grew fastest in the phosphorus-addition treatment, while species from low-phosphorus sites grew fastest in the low-phosphorus treatment. Traits associated with growth performance remain unclear: biomass allocation, phosphatase activity and phosphorus-use efficiency did not correlate with phosphorus associations; however, phosphatase activity was most strongly down-regulated in response to phosphorus addition in species from high-phosphorus sites. Phylogenetic analysis indicated that pioneers occur more frequently in clades where phosphorus associations are overdispersed as compared with the overall tree community, suggesting that selection on phosphorus acquisition and use may be strongest for pioneer species with high phosphorus demand. Our results show that phosphorus-dependent growth rates provide an additional explanation for the regional distribution of tree species in Panama, and possibly elsewhere.


Transglutaminase-catalyzed incorporation of polyamines masks the DNA-binding region of the transcription factor Relish.
In Drosophila, the final immune deficiency (IMD) pathway-dependent signal is transmitted through proteolytic conversion of the nuclear factor-κB (NF-κB)-like transcription factor Relish to the active N-terminal fragment Relish-N. Relish-N is then translocated from the cytosol into the nucleus for the expression of IMD-controlled genes. We previously demonstrated that transglutaminase (TG) suppresses the IMD pathway by polymerizing Relish-N to inhibit its nuclear translocation. Conversely, we also demonstrated that orally ingested synthetic amines, such as monodansylcadaverine (DCA) and biotin-labeled pentylamine, are TG-dependently incorporated into Relish-N, causing the nuclear translocation of modified Relish-N in gut epithelial cells. It remains unclear, however, whether polyamine-containing Relish-N retains transcriptional activity. Here, we used mass spectrometry analysis of a recombinant Relish-N modified with DCA by TG activity after proteolytic digestion and show that the DCA-modified Gln residues are located in the DNA-binding region of Relish-N. TG-catalyzed DCA incorporation inhibited binding of Relish-N to the Rel-responsive element in the NF-κB-binding DNA sequence. Subcellular fractionation of TG-expressing Drosophila S2 cells indicated that TG was localized in both the cytosol and nucleus. Of note, natural polyamines, including spermidine and spermine, competitively inhibited TG-dependent DCA incorporation into Relish-N. Moreover, in vivo experiments demonstrated that Relish-N was modified by spermine and that this modification reduced transcription of IMD pathway-controlled cecropin A1 and diptericin genes. These findings suggest that intracellular TG regulates Relish-N-mediated transcriptional activity by incorporating polyamines into Relish-N and via protein-protein cross-linking.


[Study on attenuate and synergistic mechanism between aconiti lateralis praeparata radix and glycyrrhizae radix for toxicity reduction based on metabonomic of MI-RI mouse cardiomyocytes].
Sini decoction (SND), a classical traditional Chinese medicine emergency formula recorded in Shanghan Lun (Treatise on Febrile Diseases), which is composed of Aconiti Lateralis Preparata Radix, Glycyrrhizae Preparata Radix and Zingiberis Rhizoma. Modern clinical and pharmacological researches have shown that SND can protect the myocardium effectively during myocardial ischemia reperfusion injury (MI-RI). A myocardial ischemia reperfusion injury model of H9c2 cardiomyocytes in vitro has been established. Four groups, control group, MI-RI Model group, SND group and SND without Glycyrrhizae Radix group, were arranged. The livability, the level of LDH and CK activity in H9c2 cardiomyocytes in different groups were tested. By combining with principal components analysis (PCA), partial least squares discriminant analysis (PLS-DA), orthogonal partial least squares projection of latent structures-discriminant analysis (OPLS-DA), 17 biomarkers in extracellular fluid were identified and 15 of them were related to the pathway of biological processes. The results showed that the attenuate and synergistic mechanism between Aconiti Lateralis Praeparata Radix and Glycyrrhizae Radix for toxicity reduction was related with the glycolysis, lipid metabolism, citrate cycle and nitrogen metabolism of amino acids metabolism. The study proved the effect on H9c2 cardiomyocyte treated by MI-RI injury both SND group and SND without Glycyrrhizae Radix group, and compared with the SND without Glycyrrhizae Radix, the protective effect of myocardial ischemia reperfusion injury model of H9c2 cardiomyocyte from SND was stronger.


Factors influencing results for thyroxine concentration in blood, as measured in paper filter spots in a screening program for neonatal hypothyroidism.
To reduce the number of false-positives in our screening program for neonatal hypothyroidism, we investigated the effect of age, body weight, and interval between sampling and analysis on results for filter paper spot thyroxine determination. The statistical analysis included an analysis of covariance. The age of the infant did not influence the results, the interval influenced them minimally, but weight did require a correction factor of about 0.16 ng/kg below the mean weight. This correction factor should reduce our false-positives from 0.75% to 0.60%. Furthermore, because all hypothyroid infants had results that fell more than 2.8 SD below the geometric mean, we intend to measure thyrotropin concentrations in the blood eluate of all the spots with a thyroxine concentration below that cut-off point.


Adnexal tumor and a pigmented nevoid lesion in a benign cystic ovarian teratoma.
We describe a case of an unusual adnexal lesion and concurrent collections of dendritic melanocytes of the type occurring in a blue nevus in a mature cystic teratoma of the ovary. To our knowledge, there have been no previous reports of benign skin adnexal tumors in an ovarian dermoid cyst. This rarity would indicate that the cutaneous adnexal tissue in a benign teratoma is not unduly prone to undergo further more-specialized secondary tumorigenesis. The combination of the three benign lesions is therefore probably purely coincidental.


The Impact of Educational Attainment and Income on Long-Term Care for Persons with Alzheimer's Disease and Other Dementias: A Swedish Nationwide Study.
Long-term care improves independence and quality of life of persons with dementia (PWD). The influence of socioeconomic status on access to long-term care was understudied. To explore the socioeconomic disparity in long-term care for PWD. This registry-based study included 14,786 PWD, registered in the Swedish registry for cognitive and dementia disorders (2014-2016). Education and income, two traditional socioeconomic indicators, were the main exposure. Outcomes were any kind of long-term care, specific types of long-term care (home care, institutional care), and the monthly average hours of home care. The association between outcomes and socioeconomic status was examined with zero-inflated negative binomial regression and binary logistic regression. PWD with compulsory education had lower likelihood of receiving any kind of long-term care (OR 0.80, 95% CI 0.68-0.93), or home care (OR 0.83, 95% CI 0.70-0.97), compared to individuals with university degrees. Their monthly average hours of home care were 0.70 times (95% CI 0.59-0.82) lower than those of persons with university degrees. There was no significant association between education and the receipt of institutional care. Stratifying on persons with Alzheimer's disease showed significant association between lower education and any kind of long-term care, and between income and the hours of home care. Socioeconomic inequalities in long-term care existed in this study population. Lower-educated PWD were less likely to acquire general long-term care, home care and had lower hours of home care, compared to their higher-educated counterparts. Income was not significantly associated with the receipt of long-term care.


Resting energy expenditure measured by indirect calorimetry in mechanically ventilated patients during ICU stay and post-ICU hospitalization: A prospective observational study.
The metabolic course during and after critical illness is unclear. We performed repeated indirect calorimetry (IC) measurements during ICU- and post-ICU hospitalization to determine resting energy expenditure (REE). Prospective observational design. In ventilated ICU patients, IC measurements were performed every three days until hospital discharge. Measured REE as predicted by the Harris-Benedict equation (HBE-REE) and 25 kcal/adjusted body weight/day (25-REE) were compared. In 56 patients (38% females, 71[13]years, BMI 29(27;31)kg/m2), 189 ICU IC measurements were performed. Measured REE did not differ from HBE-REE at ICU admission, but was lower than 25-REE. Measured REE was increased compared to baseline on ICU-admission-day four (29(29-30)kcal/kg/day; mean difference 3.1(1.4-4.9)kcal/kg/day, p < 0.001) and thereafter during ICU admission. During post-ICU ward stay, 44 measurements were performed in 23 patients, showing a higher mean REE than during ICU stay (33(31-35)kcal/kg/day; mean difference 2.6(1.2-3.9)kcal/kg/day, p < 0.001). The REE in the ICU and ward was >110% of HBE-REE from day four onwards. Critically ill mechanically ventilated patients were shown to have a resting energy expenditure (REE) > 110% of predicted REE on ICU admission day four and thereafter. Indirect calorimetry measurements suggest that the mean energy requirements during post-ICU hospitalization are higher than those in the ICU.


Time estimation in Parkinson's disease and degenerative cerebellar disease.
With functional MRI, we recently identified fronto-cerebellar activations in predicting time to reach a target and basal ganglia activation in velocity estimation, that is, small interval assessment. We now tested these functions in patients with Parkinson's disease (PD) and degenerative cerebellar ataxia. They watched a ball that repeatedly appeared, moved, and disappeared. Velocity, stop locations, and predicted target locations as well as time to reach a target were indicated. Compared with controls, PD patients showed impaired velocity estimation (momentary mode) whereas temporal prediction was selectively impaired in cerebellar ataxia patients. The latter highlights feed-forward processing within fronto-cerebellar circuitry. Impaired velocity estimation in PD fits the concept of a basal ganglia clock function.


Evidence of a new leukemia inhibitory factor-associated genetic marker for litter size in a synthetic pig line.
The association of a diallelic polymorphism in the leukemia inhibitory factor (LIF) gene with reproductive, growth, and carcass traits was studied in a German synthetic pig line. The diallelic SNP has been located in the 3'-untranslated region of the third exon of the porcine LIF gene. Information on 955 litter records from 273 genotyped sows was used in the analyses with respect to the number of piglets born alive. To identify possible pleiotropic marker effects, the growth and carcass traits ADG and backfat thickness were tested for associations with the SNP within the LIF gene in this population. At the LIF locus, the allele frequencies were 0.27 for the A allele and 0.73 for the B allele. There was an indication of an additive effect on the number of piglets born alive, and a significant dominance effect of the B allele was observed for first, second, and third to 10th parities (P = 0.044). The dominance effect for the first parity amounted to -0.73 +/- 0.36 (P = 0.047). No associations were detected between the marker alleles and the growth and carcass traits.


Pathways between marriage and parenting for wives and husbands: the role of coparenting.
As family systems research has expanded, so have investigations into how marital partners coparent together. Although coparenting research has increasingly found support for the influential role of coparenting on both marital relationships and parenting practices, coparenting has traditionally been investigated as part of an indirect system which begins with marital health, is mediated by coparenting processes, and then culminates in each partner's parenting. The field has not tested how this traditional model compares with the equally plausible alternative model, in which coparenting simultaneously predicts both marital relationships and parenting practices. Furthermore, statistical and practical limitations have typically resulted in only one parent being analyzed in these models. This study used model-fitting analyses to include both wives and husbands in a test of these two alternative models of the role of coparenting in the family system. Our data suggested that both the traditional indirect model (marital health to coparenting to parenting practices), and the alternative predictor model where coparenting alliance directly and simultaneously predicts marital health and parenting practices, fit for both spouses. This suggests that dynamic and multiple roles may be played by coparenting in the overall family system, and raises important practical implications for family clinicians.


Tumefactive demyelination: updated perspectives on diagnosis and management.
Tumefactive demyelination (TD) can be a challenging scenario for clinicians due to difficulties distinguishing it from other conditions, such as neoplasm or infection; or with managing the consequences of acute lesions, and then deciding upon the most appropriate longer term treatment strategy. The authors review the literature regarding TD covering its clinic-radiological features, association with multiple sclerosis (MS), and its differential diagnosis with other neuroinflammatory and non-inflammatory mimicking disorders with an emphasis on atypical forms of demyelination including acute disseminated encephalomyelitis (ADEM), MOG antibody-associated demyelination (MOGAD) and neuromyelitis spectrum disorders (NMOSD). We also review the latest in the acute and long-term treatment of TD. It is important that the underlying cause of TD be determined whenever possible to guide the management approach which differs between different demyelinating and other inflammatory conditions. Improved neuroimaging and advances in serum and CSF biomarkers should one day allow early and accurate diagnosis of TD leading to better outcomes for patients.


Strategies for manipulating the relative concentration of recombinant rotavirus structural proteins during simultaneous production by insect cells.
Adequate production strategies of virus-like particles are among the challenges that must be addressed before such complex multimeric structures find practical applications as vaccines. Attainment of the correct stoichiometric relation between proteins that constitute virus-like particles should result in an increased productivity by maximizing the concentration of assembled proteins and preventing the accumulation of waste monomers. In this work, strategies for manipulating the relative concentration between two of the structural proteins that constitute rotavirus-like particles (VP2 and VP6) were explored using the insect cell baculovirus expression vector system. It was shown that multiplicity of infection is a useful tool for manipulating protein production rates and maximum concentrations in cultures expressing one or two recombinant proteins. Thus, multiplicity of infection can be employed for improving production of rotavirus-like particles. VP2 and VP6 production rates obtained during individual infections remained unchanged when both were simultaneously produced, indicating that such rates can be utilized for estimating protein concentrations during coexpression. Manipulation of the time of infection between the two recombinant baculoviruses, proposed here for the first time, also proved to be effective for controlling the relative protein concentrations. The use of such sequential infections constituted an effective production alternative that does not require high amounts of virus stocks and is easy to implement. In addition to VP2 and VP6, kinetic parameters for the individual production of the other two proteins (VP4 and VP7) that constitute rotavirus-like particles were also obtained.


BioDKG-DDI: predicting drug-drug interactions based on drug knowledge graph fusing biochemical information.
The way of co-administration of drugs is a sensible strategy for treating complex diseases efficiently. Because of existing massive unknown interactions among drugs, predicting potential adverse drug-drug interactions (DDIs) accurately is promotive to prevent unanticipated interactions, which may cause significant harm to patients. Currently, numerous computational studies are focusing on potential DDIs prediction on account of traditional experiments in wet lab being time-consuming, labor-consuming, costly and inaccurate. These approaches performed well; however, many approaches did not consider multi-scale features and have the limitation that they cannot predict interactions among novel drugs. In this paper, we proposed a model of BioDKG-DDI, which integrates multi-feature with biochemical information to predict potential DDIs through an attention machine with superior performance. Molecular structure features, representation of drug global association using drug knowledge graph (DKG) and drug functional similarity features are fused by attention machine and predicted through deep neural network. A novel negative selecting method is proposed to certify the robustness and stability of our method. Then, three datasets with different sizes are used to test BioDKG-DDI. Furthermore, the comparison experiments and case studies can demonstrate the reliability of our method. Upon our finding, BioDKG-DDI is a robust, yet simple method and can be used as a benefic supplement to the experimental process.


Does the McRoberts' manoeuvre need to start with thigh abduction? An innovative biomechanical study.
Guidelines and description about the achievement of the McRoberts manoeuvre are discordant, particularly concerning the need for abduction before the beginning of the manoeuvre. We sought to compare the biomechanical efficiency of the McRoberts' manoeuvre, with and without thigh abduction. In a postural comparative study, twenty-three gravidas > 32 weeks of gestational age and not in labour were assessed during three repetitions of two McRoberts' manoeuvre that differed in terms of starting position. For the (i) McRoberts, the legs were initially placed in stirrups; for the (m) McRoberts, the legs were resting on the bed, with thighs in wide abduction. For each manoeuvre, flexion of the plane of the external conjugate of the pelvis on the spine (ANGce), hip flexion and abduction, were assessed using an optoelectronic motion capture system. Lumbar curve were assessed with Epionics Spine® system. Temporal parameters including movement duration or acceleration of the external conjugate were also computed. All values obtained for the two types of manoeuvres were compared using a Wilcoxon matched-pairs signed-ranks test. The significance level was defined as p < 0.05. The starting position of McRoberts' otherwise had no effect on the maximum ANGce (p = 0.199), the minimal lordosis of the lumbar curve (p = 0.474), or the maximal hip flexion (p = 0.057). The other parameters were not statistically different according to the starting position (p > 0.005). Regardless of the starting position, the McRoberts' manoeuvre allows ascension of the pubic symphysis and reduction of the lumbar lordosis. This results imply that the McRoberts' manoeuvre could be performed with the legs initially placed in the stirrups.


Propofol Regulates Neural Stem Cell Proliferation and Differentiation via Calmodulin-Dependent Protein Kinase II/AMPK/ATF5 Signaling Axis.
Propofol can cause degeneration of developing brain cells and subsequent long-term learning or memory impairment. However, at the early stage of embryonic development, the molecular mechanism of propofol-induced inhibition in neural stem cells (NSCs) neurogenesis is still unclear. The aim of this study was to determine the role of propofol in NSCs neurogenesis and, more importantly, to explore the underlying mechanism. First, a single intraperitoneal injection of propofol was performed in pregnant mice, and 6 hours after administration of propofol, the hippocampus RNA and the protein of the embryos' brains was extracted to analyze the expression of neuron-specific markers. Second, the primary NSCs were isolated from the hippocampus of mouse embryonic brain and then treated with propofol for cell viability, immunostaining, and transwell assays; more importantly, we performed RNA sequencing (RNA-seq) and q-reverse transcription polymerase chain reaction assays to identify genes regulated by propofol; the Western blot, small interfering RNA (SiRNA), and luciferase reporter assays were used to study the effects of propofol on calmodulin-dependent protein kinase (CaMk) II/5' adenosine monophosphate-activated protein kinase (AMPK)/activating transcription factor 5 (ATF5) signaling pathway. Our results indicated that propofol treatment could inhibit the proliferation, migration, and differentiation of NSCs. The results of RNA-seq assays showed that propofol treatment resulted in downregulation of a group of Ca-dependent genes. The following mechanism studies showed that propofol regulates the proliferation, differentiation, and migration of NSCs through the CaMkII/phosphorylation of serine at amino acid position 485 (pS485)/AMPK/ATF5 signaling pathway. The results from study demonstrated that propofol inhibits the proliferation, differentiation, and migration of NSCs, and these effects are partially mediated by CaMkII/pS485/AMPK/ATF5 signaling pathway.


Architectural and histochemical analysis of the biceps brachii muscle of the horse.
The biceps brachii of horses is a complex muscle subdivided into two heads which may subserve distinct functions. The lateral head contains a large percentage of type I myofibers. This region is largely composed of short fibers (5-7 mm long) arranged in a pinnate fashion and heavily invested with connective tissue. The medial head contains fewer type I fibers and is composed of relatively longer myofibers (15-20 mm long), also arranged in a pinnate fashion but less heavily invested with connective tissue. It is hypothesized that the lateral muscle head of biceps brachii contributes to the postural role of the muscle in the forelimb passive stay apparatus. The medial head, with its longer fibers and generally fast fiber population may be most important during dynamic activity such as walking, trotting and running.


A simple, practical model for reducing alloimmunization in patients with sickle cell disease.
Patients with sickle cell disease (SCD) form immune alloantibodies more frequently than other transfused populations because red cells (RBCs) from white donors (with a higher incidence of certain Rh, Duffy, Kell, and Kidd blood group antigens) are transfused to black patients often lacking these antigens. We propose a model to reduce alloimmunization in patients with SCD by providing them with blood from only black random donors. Rationale is shown by examining calculations based on the phenotype E-, C-, Fy(a-), K-, and Jk(b-). There is a 7% probability that this phenotype belongs to a white donor, while there is a 93% probability that this phenotype belongs to a black donor. The probability of selecting blood from a black donor identical with the above phenotype for black recipients from an all black population and from a typical urban blood inventory population (90% white, 10% black) is 1/4 and 1/33, respectively. Therefore, an 8-fold greater chance of selecting antigen non-identical blood occurs if blood is obtained from a typical urban donor population as compared to a black population. Based on these calculations, alloimmunization can be reduced prospectively in patients with SCD by meeting their transfusion requirements with blood selected from random black blood donors.


Apoptotic cell death induced by intracellular proteolysis.
To mimic the injection of granzymes into target cells by cytotoxic lymphocytes or the activation of endogenous proteases in programmed cell death, the proteases chymotrypsin, proteinase K, or trypsin were loaded into the cytoplasm of several different cell types using the osmotic lysis of pinosomes technique. Internalization of these proteases caused cell lysis within several hours, accompanied by extensive nuclear damage in most but not all combinations of target cells and proteases. This nuclear damage, quantitated by DNA release from nuclei, was associated with apoptotic features including DNA fragmentation into nucleosomal ladders, chromatin condensation, nuclear fragmentation, and membrane blebbing. Agents reported to block programmed cell death, including aurintricarboxylic acid, inhibitors of energy metabolism, and protein or RNA synthesis, failed to block this protease-induced death, although some inhibited nuclear damage. In separate experiments, introduction of staphylococcal nuclease into cells led to near complete (at least 75% of total) nucleosomal DNA fragmentation within 6 to 8 h. Condensation of chromatin did not accompany this fragmentation to the same extent, and there was approximately a 10-h lag between half-maximal DNA fragmentation and 50% loss of membrane integrity. The results suggest that activation of intracellular proteases during cell death by any molecular pathway could give rise to apoptotic morphology and DNA fragmentation.


[The bone-vasculature-axis interaction: new insights into the pathogenesis of vascular calcification.].
It is commonly accepted that the first cause of morbidity and mortality in chronic kidney disease (CKD) is the cardiovascular (CV) disease, in which vascular calcification (VC) plays a central pathogenetic role. In CKD population, mineral metabolism disorders have been recently investigated not only as key factors on renal osteodystrophy but also as inducing players on extra-skeletal calcification. Clearly, either high phosphate (P) or high calcium (Ca) concentration induce vascular smooth muscle cells mineralization in vitro studies. In fact, VC is induced by a cell-mediated process, which actively accompanies the traditional and passive Ca-P deposition in arterial walls. Interestingly, lack of inhibitory proteins, such as fetuin-A (alpha2-HS glycoprotein, AHSG), matrix GLA protein (MGP), osteoprotegerin (OPG), and bone morphogenetic protein 7 (BMP-7) are the regulatory key factors in preventing VC in uremic conditions.


Cloning and sequencing of the URA3 gene of Kluyveromyces marxianus CBS 6556.
The URA3 gene, coding for orotidine-5'-phosphate decarboxylase, from Kluyveromyces marxianus CBS 6556, was isolated from a genomic DNA library. The K. marxianus URA3 gene encodes a protein of 267 amino acids with a calculated molecular weight of 29.3 kDa. Comparison of the K. marxianus protein with the corresponding enzymes of Saccharomyces cerevisiae and Kluyveromyces lactis showed amino acid sequence identities of 81% and 88%, respectively. Using contour-clamped homogenous electric field gel electrophoresis, the genomic copy was found to be located on chromosome VI. We have used the cloned gene for the construction of a K. marxianus leu2 mutant. This mutant contains no heterologous sequences, which is essential to make it acceptable for application in the food industry.


The effects of environmental enrichment and transport stress on the weights of lymphoid organs, cell-mediated immune response, heterophil functions and antibody production in laying hens.
The effects of environmental enrichment and transport stress on the immune system were investigated in laying hens. A total of 48 1-day-old chickens were used, half of the chickens were reared in conventional cages (RCC) and the rest in enriched cages (REC). Transport stress was applied in the 17th week. Liver weight decreased, spleen and bursa of Fabricius weights, white blood cell count, CD4+ and CD8+ cell proportions increased due to the transport. Environmental enrichment significantly increased antibody production and tended to increase monocyte percentage and CD8+ cell proportion. The effect of transport on, heterophil (H) and lymphocyte (L) percentages was not significant in RCC chickens. While heterophil percentage and H:L ratio increased, lymphocyte percentage decreased in REC chickens subjected to transport. Transport stress increased heterophil functions both in REC and RCC chickens, but the increase was higher in REC hens than in RCC hens. In conclusion, although environmental enrichment did not neutralize the effect of transport on lymphoid organs, it activated the non-specific immune system, cellular and the humoral branches of the specific immune system by increasing heterophil functions, CD8+ cells and antibody production, respectively. Therefore, environmental enrichment suggested for improving animal welfare may also be beneficial to improve the immune system of birds exposed to stress.


Academic health center teaching hospitals in transition: a perspective from the field.
A study of 11 Academic Health Center Teaching Hospitals (ATHs) in 11 states found that cost reduction programs, internal reorganizations, reengineering, benchmarking, and broadened entrepreneurial activity were prominent among the strategic initiatives reported in dealing with an increasingly turbulent environment. Although none of the ATHs had experienced negative net margins, we conclude that today's competitive healthcare system requires ATHs be reimbursed separately for their educational and other societally related costs to assist them in competing on a level playing fields.


Experimental evaluation of cryopreservative solutions to maintain in vitro and in vivo infectivity of P. berghei sporozoites.
The rodent malaria parasite Plasmodium berghei is an excellent model organism for laboratory-based experimental evaluation of anti-malarial therapeutics prior to studies with human malaria parasites. The rodent model is especially important for evaluation of pre-erythrocytic (PE) stage therapies, especially as current efforts to develop new PE vaccines and drugs is limited by access to P. falciparum and P. vivax sporozoites. Developing a more effective method for cryopreservation of sporozoites would help improve access to sporozoites for laboratories lacking suitable insectary facilities. In this study, P. berghei GFP-expressing sporozoites were purified from infected mosquitoes by manual dissection of salivary glands and different commercially-available, serum-free cryopreservative solutions were evaluated for efficient cryopreservation of the sporozoites. The cryopreservative solutions evaluated included CryoStor CS2, CryoSolutions DX5, CryoSolutions MC, Hestar 200, Voluven, Hetastarch, and Glycerolyte 57. The viability of fresh and post-thaw cryopreserved sporozoites was determined as a function of the relative sporozoite infectivity by infecting HC-04 cells in vitro, monitoring invasion and growth and development of liver stage parasites. Flow cytometer-based counting provided unbiased and fast quantitative assessment of parasite in vitro infection in infected HC-04 and in vivo infectivity was validated by injecting sporozoites IV into mice. CryoStor CS2 delivered the highest post-thaw recovery and infectivity of cryopreserved sporozoites. Sporozoites cryopreserved in CryoStor CS2 achieved 38% complete development of hepatic stages in HC-04 and 100% infectivity in mice. The cryopreservation method described here demonstrates a viable alternative for fresh Plasmodium sporozoites. The use of cryopreserved sporozoites should facilitate greater access to sporozoites for chemotherapeutic and vaccine research.


Proteomic analysis of head kidney tissue from high and low susceptibility families of channel catfish following challenge with Edwardsiella ictaluri.
A study was performed to compare proteomic profiles of channel catfish from families with high and low susceptibility to Edwardsiella ictaluri following an immersion challenge. Total protein was isolated from head kidney samples, collected at 2 and 6h postexposure, and analyzed by 2-D-gel electrophoresis coupled with peptide mass fingerprint analysis by matrix-assisted laser desorption/ionization and time of flight tandem mass spectrometry. Comparisons were made between proteomic profiles from infected and uninfected fish from high and low susceptibility families. Heat shock protein 90-beta, from the high susceptibility infected family, and fructose-1,6-bisphosphatase 1-like protein, from the low susceptibility infected family, were identified at 2h postexposure. Rab-11-like protein (low susceptibility infected family), tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon (low susceptibility infected family), glyceraldehyde-3-phosphate dehydrogenase (high susceptibility infected family), and ATP synthase beta subunit (low susceptibility uninfected family) were identified at 6h postexposure. Four proteins, heat shock protein 90-beta, Rab-11, tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon, and glyceraldehyde-3-phosphate dehydrogenase, have activities involved in macrophage function or cellular stress responses, while the other two have functions associated with cellular energy production and metabolism. These results demonstrate the potential for use of proteomic techniques in channel catfish research.


Protective Effect of Amaranthus cruentus L. Seed Oil on UVA-Radiation-Induced Apoptosis in Human Skin Fibroblasts.
Since the exposure of fibroblasts to prolonged UVA radiation induces oxidative stress and apoptosis, there is a need for effective skin protection compounds with cytoprotective and antioxidant properties. One of their sources is Amaranthus cruentus L. seed oil (AmO), which is rich in unsaturated fatty acids, squalene, vitamin E derivatives and phytosterols. The aim of this study was to evaluate whether AmO evokes a protective effect on the apoptosis induced by UVA radiation in human skin fibroblasts. UVA radiation at an applied dose of 10 J/cm2 caused a significant reduction in the survival of human skin fibroblasts and directed them into the apoptosis pathway. Increased expression of p53, caspase-3, caspase-9 and PARP proteins in UVA-treated fibroblasts suggests the intrinsic mechanism of apoptosis. Application of the oil at 0.1% and 0.15% concentrations to UVA-treated cells decreased the expression of these proteins, which was accompanied by increased cell survival. Similarly, the UVA-dependent decrease in the expression of p-Akt and mTOR proteins was restored under the effect of the studied oil. The molecular mechanism of this phenomenon was related to the stimulation of antioxidant processes through the activation of Nrf2. This suggests that AmO stimulated the antioxidant system in fibroblasts, preventing the effects of UVA-induced oxidative stress, which may lead to pharmaceutical and cosmetological applications as a sun-protective substance.


Efficacy of Combined Antigravity Treadmill and Conventional Rehabilitation After Hip Fracture in Patients With Sarcopenia.
To compare long-term effects of antigravity treadmill (AGT) combined with conventional rehabilitation (CR) and CR after hip fracture in patients with sarcopenia. Forty-five patients were randomly allocated to AGT combined with CR (experimental group) or CR (control group) for 10 consecutive working days. Participants were evaluated prior to treatment, 3 weeks, 3 months, and 6 months after treatment. Outcome measurement included Koval walking ability scores functional ambulatory category (FAC), Berg Balance Scale (BBS), Korean version of Mini-Mental State Examination, Euro Quality of Life Questionnaire Five-Dimensional Classification, Korean version of modified Barthel index, and grip strength. At 3 weeks and 3 months, the comparison of change scores in KOVAL between two groups revealed difference of 0.84 (95% CI: -1.19, -0.49; p for trend = .000) and 1.21 (95% CI: -2.05, -0.36; p for trend = .006), respectively. At 3 weeks, comparison of change score in FAC between two groups revealed a difference of 0.73 (95% CI: 0.28, 1.19; p for trend = .003). The comparison of change scores between two groups also showed a difference in the 6 months in KOVAL and in the 3 and 6 months in FAC. The comparison of changes in scores in BBS between two groups revealed difference of 11.63 (95% CI: 5.85, 17.40; p for trend = .001), 9.00 (95% CI: 2.28, 15.71; p for trend = .006), and 11.05 (95% CI: 3.62, 18.48; p for trend = .006), respectively, at each follow-up. Both groups were improved after intervention. As additional benefits were evident among those who carried out AGT, it may be appropriate for patients with sarcopenia after hip fracture surgery.


Wickerhamomyces tratensis sp. nov. and Candida namnaoensis sp. nov., two novel ascomycetous yeast species in the Wickerhamomyces clade found in Thailand.
Two closely related yeast strains, ST-382 and ST-392, isolated in Thailand showed intermediate relatedness in the DNA-DNA hybridization experiment suggesting that the two strains represent closely related distinct species. In the tree based on the D1/D2 domain sequences of the large subunit rRNA gene, the two strains are located in a subclade in the Wickerhamomyces clade with high bootstrap support. In the D1/D2 domain, the two strains differed by two nucleotides and are assumed to be very closely related. Strain ST-392(T) (=BCC 15102(T) = NBRC 107799(T) = CBS 12176(T) forming hat-shaped ascospores is described as Wickerhamomyces tratensis sp. nov. and strain ST-382(T) (= BCC 15093(T) = NBRC 107800(T) = CBS 12175(T) is described as Candida namnaoensis sp. nov. because ascospores are not found in this strain. In phenotypic characteristics, W. tratensis and C. namnaoensis are discriminated by the ability of alcoholic fermentation and the assimilation of galactose, D-xylose and D-gluconic acid.


Responsiveness and Convergent Validity of a New Patient-Reported Outcome Measure for Chronic Rhinosinusitis (CRS-PRO).
The CRS-PRO is a new patient-reported outcome measure (PROM) for chronic rhinosinusitis (CRS) that was developed using extensive patient input per Food and Drug Administration guidance on PROMs acceptable for use as end points in clinical trials. To assess the responsiveness and convergent validity of the CRS-PRO following standard-of-care medical therapy. This was a prospective study of 51 patients (21 with nasal polyps and 30 without) with newly diagnosed CRS or having an acute CRS exacerbation who were initiated on appropriate medical therapy. At the baseline visit each patient completed the CRS-PRO questionnaire, the 22-item Sino-Nasal Outcome Test, the EuroQol 5-dimensional questionnaire, and 4 Patient-Reported Outcome Measure Information System short forms along with objective testing including endoscopic and radiographic scores, smell discrimination, and nasal inspiratory flow testing. This same battery of questionnaires and testing was administered at a follow-up visit 4 to 8 weeks later. We verified that shortening the 21-item CRS-PRO to 12 items as previously described maintains its psychometric properties. The 12-item CRS-PRO was responsive with a large effect size (Cohen's d, 0.94) comparable to the longer 22-item Sino-Nasal Outcome Test (Cohen's d, 0.93). The instrument was slightly more responsive to medically treated patients with CRS without nasal polyps compared with patients with CRS with nasal polyps (Cohen's d, 1.1 vs 0.89, respectively). The change in 12-item CRS-PRO total score has moderate correlation with change in Lund-Mackay computed tomography scores. The CRS-PRO is a 12-item rigorously developed, responsive, and valid PROM that was developed using extensive input from patients with current definitions of CRS, including its 2 major phenotypes.


Neurological complications in herpes zoster.
This paper discusses the complications associated with herpes zoster, with emphasis on its neurological manifestations. These complications, which are particularly prevalent in elderly and immunodeficient patients, include focal muscle paralysis, contralateral hemiplegia, myelitis, cranial nerve palsies and meningoencephalitis. A causative relationship with herpes zoster in many of these syndromes is probably more common than previously suspected due to difficulties in diagnosis and lack of awareness among clinicians. Zoster sine herpete-- reactivation of varicella zoster virus without rash--is associated with a spectrum of neurological disease and, for obvious reasons, is particularly difficult to diagnose. The polymerase chain reaction could be a valuable tool in overcoming these diagnostic problems, especially in patients without characteristic eruptions, allowing the early initiation of effective antiviral therapy.


Clinical value of CT-derived simulations of transcatheter-aortic-valve-implantation in challenging anatomies the PRECISE-TAVI trial.
Preprocedural computed tomography planning improves procedural safety and efficacy of transcatheter aortic valve implantation (TAVI). However, contemporary imaging modalities do not account for device-host interactions. This study evaluates the value of preprocedural computer simulation with FEops HEARTguideTM on overall device success in patients with challenging anatomies undergoing TAVI with a contemporary self-expanding supra-annular transcatheter heart valve. This prospective multicenter observational study included patients with a challenging anatomy defined as bicuspid aortic valve, small annulus or severely calcified aortic valve. We compared the heart team's transcatheter heart valve (THV) planning decision based on (1) conventional multislice computed tomography (MSCT) and (2) MSCT imaging with FEops HEARTguideTM simulations. Clinical outcomes and THV performance were followed up to 30 days. A total of 77 patients were included (median age 79.9 years (IQR 74.2-83.8), 42% male). In 35% of the patients, preprocedural planning changed after FEops HEARTguideTM simulations (change in valve size selection [12%] or target implantation height [23%]). A new permanent pacemaker implantation (PPI) was implanted in 13% and >trace paravalvular leakage (PVL) occurred in 28.5%. The contact pressure index (i.e., simulation output indicating the risk of conduction abnormalities) was significantly higher in patients with a new PPI, compared to those without (16.0% [25th-75th percentile 12.0-21.0] vs. 3.5% [25th-75th percentile 0-11.3], p < 0.01) The predicted PVL was 5.7 mL/s (25th-75th percentile 1.3-11.1) in patients with none-trace PVL, 12.7 (25th-75th percentile 5.5-19.1) in mild PVL and 17.7 (25th-75th percentile 3.6-19.4) in moderate PVL (p = 0.04). FEops HEARTguideTM simulations may provide enhanced insights in the risk for PVL or PPI after TAVI with a self-expanding supra-annular THV in complex anatomies.


[Long-term experience of immediate implant loading using DenTi implants. Part 1. Material, methods and experience in immediate loading of DenTi implants].
Immediate loading of dental implants have been widely used to retain and support crossarch partial dentures. Normally 3-6 months after implantation complete osseointegration is established, this period may be shortened with immediate loading of implants. The purpose of this study was to evaluate the factors that may influence the long-term success of immediate implant loading. The immediate loading technique with DenTi implants was introduced 12 years ago, and during this period the clinical results have been followed up on 257 DenTi implants in 83 patients. 62 patients and with 263 implants placed with submerged technique were recruited into the control group. The retrospective long-term follow-up examination has revealed that the success rate of DenTi implants with traditional two stage surgery was 97.4%. The success rate of DenTi implants with immediate loading was 95.71%. According to the date of the success rata and prognosis of immediate loaded implants are comparable to the traditional two stage submerged implants.


Interaction between Single Nucleotide Polymorphism and Urinary Sodium, Potassium, and Sodium-Potassium Ratio on the Risk of Hypertension in Korean Adults.
Hypertension is a complex disease explained with diverse factors including environmental factors and genetic factors. The objectives of this study were to determine the interaction effects between gene variants and 24 h estimated urinary sodium and potassium excretion and sodium-potassium excretion ratios on the risk of hypertension. A total of 8839 participants were included in the genome-wide association study (GWAS) to find genetic factors associated with hypertension. Tanaka and Kawasaki formulas were applied to estimate 24 h urinary sodium and potassium excretion. A total of 4414 participants were included in interaction analyses to identify the interaction effects of gene variants according to 24 h estimated urinary factors on the risk of hypertension. CSK rs1378942 and CSK-MIR4513 rs3784789 were significantly modified by urinary sodium-potassium excretion ratio. In addition, MKLN rs1643270 with urinary potassium excretion, LOC101929750 rs7554672 with urinary sodium and potassium excretion, and TENM4 rs10466739 with urinary sodium-potassium excretion ratio showed significant interaction effects. The present study results indicated that the mutant alleles of CSK rs1378942 and CSK-MIR4513 rs3784789 had the strongest protective effects against hypertension in the middle group of 24 h estimated urinary sodium-potassium excretion ratio. Further studies are needed to replicate these analyses in other populations.


Characterizing nanoscale changes in the activity of VEGFR-2 on glioma microvascular endothelial cell membranes using atomic force microscopy.
The aim of the current study was to demonstrate the distribution of VEGFR-2 on glioma microvascular endothelial cells on a nanoscale and investigate changes in VEGFR-2 activity following treatment with the VEGFR-2 inhibitor and agonist sorafenib and bradykinin, respectively. Three groups were evaluated in this study: Control glioma microvascular endothelial cells, sorafenib-treated glioma microvascular endothelial cells and bradykinin-treated glioma microvascular endothelial cells. Changes in the activity of VEGFR-2 on the glioma microvascular endothelial cell membranes following treatment with sorafenib and bradykinin were characterized by atomic force microscopy (AFM). Colloidal gold-labeled immune complexes and AFM were used to visualize the distribution of VEGFR-2 on the cell membranes. In the control group, VEGFR-2, which was observed as numerous globular structures, was evenly distributed on the cell surface membranes. The majority of the receptors were active. In the sorafenib group, only a few globular structures were observed on the cell membranes, with a density significantly lower than that in the control group (P<0.01). Furthermore, compared with the control group, fewer of the receptors were active. In the bradykinin group, numerous globular structures were densely distributed on the cell membranes, with a density significantly higher than that in the control group (P<0.01). The distribution and activity of VEGFR-2 on glioma microvascular endothelial cell membranes treated with sorafenib and bradykinin suggested that the activity of VEGFR-2 could be regulated by its inhibitor or agonist.


[Effect of nucleolin silencing on differentiation of rat neural stem cells in vitro and the molecular mechanism].
To investigate the effect of nucleolin silencing on the differentiation of rat neural stem cells (NSCs) and the role of Wnt signaling pathway in mediating such effect. Adenovirus vectors expressing small interfering RNA (siRNA) against nucleolin were constructed, verified, and packaged in HEK293A cells. The adenovirus was then transfected into NSCs isolated from neonatal SD rats and the differentiation of the NSCs was examined by detecting the expressions of neuron specific encloase (NSE) and glial fibrillary acidic protein (GFAP) using immunocytochemistry. The expressions of nucleolin, nestin, Wnt3, and β-catenin in the cells were determined with Western blotting. Restriction endonuclease and sequencing analysis verified successful construction of the adenoviral vector expressing nucleolin siRNA (nucleolin-siRNA2). Infection of rat NSCs with nucleolin-siRNA2 significantly lowered nucleolin protein expression as compared with that in negative and blank control groups (P<0.05). The percentages of NSE-positive cells and GFAP-positive cells were significantly higher in NSCs infected with nucleolin-siRNA (P<0.01); the infection also resulted in obviously lowered expression of nestin protein and increased expressions of Wnt3 protein and β-catenin nucleoprotein in the cells. Nucleolin silencing by adenovirus-mediated RNA interference induces the differentiation of NSCs into neurons and astrocytes, which is related with the activation of Wnt signaling pathway.


Cortisone-induced alterations in mitochondrial function and structure.
The effects of cortisone treatment on oxygen consumption, oxidative phosphorylation, and fine structure of rat liver mitochondria have been studied. Male rats weighing 125 g were treated for 6 days with 5 mg of cortisone acetate or isotonic saline. On the 7th day, sections of liver were excised and processed for light and electron microscopy. Mitochondrial respiration and oxidative phosphorylation were studied with mitochondria isolated from these livers. Cortisone treatment is responsible for a 14-40% decrease in the amount of oxygen consumed per mg of mitochondrial protein when succinate, alpha-ketoglutarate, or beta-hydroxybutyrate are used as substrates, or with ascorbate and N,N,N(1),N(1)-tetramethyl p-phenylenediamine as electron donors. In addition, oxidative phosphorylation is uncoupled with a lowering of the P:O ratios. Randomly selected liver cells have been analyzed by quantitative morphometric techniques. The average mitochondrial volume is increased fourfold in the peripheral and midzonal regions with a commensurate decrease in the number of mitochondria per cell. These alterations are present throughout the hepatic lobule, but are most marked in midzonal cells. The total mitochondrial volume per cell and the per cent of the total cytoplasmic volume occupied by mitochondria remains relatively unaltered, as does the total amount of cristae surface per cell. While the mitochondria are enlarged, they are not "swollen." The relationships between the steroid hormone treatment and the alterations in mitochondrial function and structure are discussed.


Employment status and other predictors of mental health and cognitive functions in older Croatian workers.
The aim of this study was to examine mental health and cognitive functions in older Croatian workers (50-65 years) taking into account their employment status, self-assessed health, and a set of demographic characteristics. We analysed the data collected on 650 older workers (71 % employed) in the Wave 6 of the Survey of Health, Ageing and Retirement in Europe (SHARE). Unemployed workers reported symptoms of loneliness more often than the employed, while in rural areas unemployment was additionally associated with more pronounced symptoms of depression. Feeling of loneliness was also higher in those living without a partner in the household and in those with poorer health. In urban residents symptoms of depression were more severe in women, respondents with higher education, those living without a partner, and those who rated their health as poorer. As for cognitive functions, unemployment significantly predicted poorer subtraction in the rural subsample. Women in general showed less efficient numerical abilities. In the urban subsample poorer numerical abilities were also associated with lower education and living without a partner in the household. Better verbal recall was predicted by higher education and better self-rated memory. Higher scores in verbal fluency were predicted by urban residency and better self-rated health. Our results indicate that the protective factors for good mental health and cognitive functioning in older Croatian workers are being employed, having more education, living with a partner in the household, and being healthier. These findings stress the importance of implementing broader social policy strategies covering employment, education, and health.


Effect of neonatal phototherapy on melanocytic nevus count in children.
Melanocytic nevus is the strongest risk factor for the development of cutaneous melanoma. Fair skin and exposure to UV light, especially in childhood, are correlated with the development of childhood nevi. To assess the role of blue light neonatal phototherapy used to treat hyperbilirubinemia in nevus acquisition in childhood. Case-control prospective study. University hospital. Fifty-eight children were included in this study. Selection criteria included the following: age, 8 to 9 years; and skin type, less than IV by Fitzpatrick classification (ie, brown, always tans, rarely burns). The case group consisted of 18 children exposed to neonatal phototherapy (mostly intensive phototherapy) retrospectively found by review of consecutive neonatal medical records at Saint-Antoine Hospital, Paris, France. The control group was composed of 40 nonexposed children consecutively recruited from a public school in the same geographic area. Total body nevus count in children, phenotypic characteristics, solar exposure, and demographic data were assessed by the same dermatologist. A comparison of both groups showed that the number of nevi larger than 2 mm was significantly higher in the exposed group. The mean (SD) nevus count was 3.5 (3.05; median, 3.0) per child in the exposed group, compared with 1.45 (1.99; median, 1.0) per child in the nonexposed group (P(mean) = .02 and P(median) = .01). Multivariate analysis confirmed these results, with a statistically significant correlation with nevus count, especially with nevi 2 to 5 mm in greatest diameter. The association between neonatal phototherapy and nevus count was not significant for nevi smaller than 2 mm or larger than 5 mm. Solar exposure, especially during vacations, was strongly associated with total nevus count and all nevus sizes (2-5 mm, <2 mm, and >5 mm). At univariate analysis, hair color was significantly associated with nevus size smaller than 2 mm (P(mean) = .03). Intensive neonatal phototherapy is a strong risk factor for nevus development in childhood. While childhood development of nevi is correlated with fair skin and solar light exposure, and having many nevi is a recognized risk factor in persons with melanoma, we must be careful not to equate childhood nevi development in response to neonatal phototherapy with an individual's risk of developing melanoma. The treatment of hyperbilirubinemia remains neonatal phototherapy. Exposed children should undergo dermatologic preventive measures and surveillance for the development of melanoma.


Intestinal Epithelial Ecto-5'-Nucleotidase (CD73) Regulates Intestinal Colonization and Infection by Nontyphoidal Salmonella.
Ecto-5'-nucleotidase (CD73) is expressed abundantly on the apical surface of intestinal epithelial cells (IECs) and functions as the terminal enzyme in the generation of extracellular adenosine. Previous work demonstrated that adenosine signaling in IECs results in a number of tissue-protective effects during inflammation; however, a rationale for its apical expression has been lacking. We hypothesized that the highly polarized expression of CD73 is indicative of an important role for extracellular adenosine as a mediator of host-microbe interactions. We show that adenosine harbors bacteriostatic activity against Salmonella enterica serovar Typhimurium that is not shared by the related purine metabolite 5'-AMP, inosine, or hypoxanthine. Analysis of Salmonella colonization in IEC-specific CD73 knockout mice (CD73f/fVillinCre ) revealed a nearly 10-fold increase in colonization compared to that in controls. Despite the increased luminal colonization by Salmonella, CD73f/fVillinCre mice were protected against Salmonella colitis and showed reduced Salmonella burdens in viscera, suggesting that adenosine promotes dissemination. The knockdown of CD73 expression in cultured IECs resulted in dramatic defects in intraepithelial localization and replication as well as defective transepithelial translocation by Salmonella In conclusion, we define a novel antimicrobial activity of adenosine in the gastrointestinal tract and unveil an important role for adenosine as a regulator of host-microbe interactions. These findings have broad implications for the development of new therapeutic agents for infectious disease.


Inhibitory effect of a lipopeptide biosurfactant produced by Bacillus subtilis on planktonic and sessile cells of Trichosporon spp.
The present study aimed to investigate the inhibitory effect of a bacterial biosurfactant (TIM96) on clinical strains of Trichosporon. Additionally, the effect of TIM96 on the ergosterol content, cell membrane integrity, and the hydrophobicity of planktonic cells was assessed. The inhibitory activity of TIM96 against Trichosporon biofilms was evaluated by analyzing metabolic activity, biomass and morphology. MIC values ranged from 78.125 to 312.5 μg ml-1 for TIM96; time-kill curves revealed that the decline in the number of fungal cells started after incubation for 6 h with TIM96 at both MIC and 2×MIC. The biosurfactant reduced the cellular ergosterol content and altered the membrane permeability and the surface hydrophobicity of planktonic cells. Incubation at 10×MIC TIM96 reduced cell adhesion by up to 96.89%, thus interfering with biofilm formation. This concentration also caused up to a 99.2% reduction in the metabolic activity of mature biofilms. The results indicate potential perspectives for the development of new antifungal strategies.


Isolated liver tuberculosis abscess in a patient without immunodeficiency: A case report.
Although hepatic tuberculosis is not a rare disease entity, tubercular liver abscess (TLA) is extremely rare. It is usually associated with foci of infection either in the lung and/or gastrointestinal tract or with an immunocompromised state. An isolated or primary TLA with no evidence of tuberculosis elsewhere is even rarer. We report on a 28 year old man who developed an isolated tuberculous liver abscess not associated with lung involvement. Ultrasonography and computed tomography of the abdomen showed the abscess lesions in the liver but the diagnosis of tuberculosis was confirmed by histological examination of the wall of the abscess after surgical drainage. Although tuberculous liver abscess is very rare, it should be included in the differential diagnosis of abscess and unknown hepatic mass lesions.


Abcb7, the gene responsible for X-linked sideroblastic anemia with ataxia, is essential for hematopoiesis.
X-linked sideroblastic anemia with ataxia (XLSA/A) is a rare syndromic form of inherited sideroblastic anemia associated with spinocerebellar ataxia, and is due to mutations in the mitochondrial ATP-binding cassette transporter Abcb7. Here, we show that Abcb7 is essential for hematopoiesis and formally demonstrate that XLSA/A is due to partial loss of function mutations in Abcb7 that directly or indirectly inhibit heme biosynthesis.


Role of genetically engineered animals in future food production.
Genetically engineered (GE) animals are likely to have an important role in the future in meeting the food demand of a burgeoning global population. There have already been many notable achievements using this technology in livestock, poultry and aquatic species. In particular, the use of RNA interference (RNAi) to produce virus-resistant animals is a rapidly-developing area of research. However, despite the promise of this technology, very few GE animals have been commercialised. This review aims to provide information so that veterinarians and animal health scientists are better able to participate in the debate on GE animals.


Cytokeratin expression in chondroblastomas.
The present study is based on the histopathological and immunohistochemical examination of seven chondroblastomas, including one lung metastasis occurring 9 years after treatment. Chondroblastomas were shown to co-express vimentin, S-100 protein, neuron-specific enolase, and the epithelial markers recognized by CAM 5.2, EMA and a polyclonal cytokeratin antibody. The cytokeratins present in the tumour cells of the lung metastasis were characterized as cytokeratins 8, 18, 19 and, to a lesser extent, cytokeratin 7. The results suggest aberrant cytokeratin expression in chrondroblastomas.


Budget impact model in moderate-to-severe psoriasis vulgaris assessing effects of calcipotriene and betamethasone dipropionate foam on per-patient standard of care costs.
To develop a budget impact model (BIM) for estimating the financial impact of formulary adoption and uptake of calcipotriene and betamethasone dipropionate (C/BD) foam (0.005%/0.064%) on the costs of biologics for treating moderate-to-severe psoriasis vulgaris in a hypothetical US healthcare plan with 1 million members. This BIM incorporated epidemiologic data, market uptake assumptions, and drug utilization costs, simulating the treatment mix for patients who are candidates for biologics before (Scenario #1) and after (Scenario #2) the introduction of C/BD foam. Predicted outcomes were expressed in terms of the annual cost of treatment (COT) and the COT per member per month (PMPM). At year 1, C/BD foam had the lowest per-patient cost ($9,913) necessary to achieve a Psoriasis Area and Severity Index (PASI)-75 response compared with etanercept ($73,773), adalimumab ($92,871), infliximab ($34,048), ustekinumab ($83,975), secukinumab ($113,858), apremilast ($47,960), and ixekizumab ($62,707). Following addition of C/BD foam to the formulary, the annual COT for moderate-to-severe psoriasis would decrease by $36,112,572 (17.91%, from $201,621,219 to $165,508,647). The COT PMPM is expected to decrease by $3.00 (17.86%, from $16.80 to $13.80). Drug costs were based on Medi-Span reference pricing (January 21, 2016); differences in treatment costs for drug administration, laboratory monitoring, or adverse events were not accounted for. Potentially confounding were the definition of "moderate-to-severe" and the heterogeneous efficacy data. The per-patient cost for PASI-75 response at year 1 was estimated from short-term efficacy data for C/BD foam and apremilast only. The introduction of C/BD foam is expected to decrease the annual COT for moderate-to-severe psoriasis treatable with biologics by $36,112,572 for a hypothetical US healthcare plan with 1 million plan members, and to lower the COT PMPM by $3.00.


The impact of the Affordable Care Act on hospital-led community health evaluation in the U.S. Appalachian Ohio region.
In recent years, policy developments in the United States have dramatically changed how nonprofit hospitals interact with surrounding communities. However, despite the importance of these changes encoded in Internal Revenue Service regulations, little is known about how these requirements have affected how nonprofit hospitals are approaching community health evaluation. We present qualitative findings from interviews with hospital employees and consultants overseeing preliminary rounds of community health needs assessments, as required by the Affordable Care Act. The sample comes from the Appalachian region of Ohio, an area targeted because of significant health challenges. Our findings suggest that the Affordable Care Act has led hospitals to formalize their processes, focus on developing an evidence base, cultivate local partnerships, and reflect on the role of the hospital in public health.


[Stress fracture of the ribs in amateur golfers diagnosed by Tc-99m MDP scintigraphy].
Golf has become a popular sport in Taiwan recently. Some amateur golfers suffer from back or chest pain, and a few of them have stress fractures of the ribs. Six amateur golfers suffering from back pain or chest pain, all male and right-handed players, aged from 28 to 39, were included in our study. The initial chest roentgenograms, including special views focusing on ribs, were all negative. Tc-99m MDP bone scan confirmed the diagnosis of stress fractures of the ribs. The intervals between playing golf and time of diagnosis were from 1 month to 5 months. In five cases, fracture sites in the left side were prominently located in the posterior aspect, a condition which may result from traction of the serratus anterior. Three cases with fracture sites in the right side had fractures prominently located in the lateral aspect, which may result from the repercussive force produced by the clubhead hitting the ground. Tc-99m MDP bone scan, with its high sensitivity, is useful in establishing the diagnosis of stress fracture.


Cd34 and Mast Cell Analysis in Normal Oral Mucosa and Different Grades of Oral Squamous Cell Carcinoma: A Comparative Study.
Oral Squamous Cell Carcinoma (OSCC) remains a serious health problem worldwide. Prognosis of OSCC is poor and long term survival rate still remains below 50%. Angiogenesis or neovascularisation plays an important role in tumour progression and metastasis. Mast cells have been implicated in promoting tumour angiogenesis, especially of digestive tract, little is known in OSCC. To study the correlation between blood vessel density (BVD) and mast cell density (MCD) in different grades of OSCC. Thirty eight paraffin blocks of different grades of OSCC were retrieved from the department and sections were stained with CD34 followed by counterstaining with toluidine blue. The slides were then analysed using Leica Software (Version 4.5). Mean BVD and MCD were found to be increased in OSCC as compared to normal mucosa. Increase in BVD with co-current increase in MCD was also observed in different grades of OSCC. From our study, it was concluded that, mast cells play a major role in promoting tumour angiogenesis. But, as the grade of the tumour increases, other angiogenic factors may play a more significant role than mast cells in tumour progression.


Peripapillary staphyloma: clinical features and visual outcome in 19 cases.
To investigate the clinical features and visual outcome of patients with peripapillary staphyloma. The medical records of patients diagnosed as having peripapillary staphyloma at Seoul National University Children's Hospital, Seoul, Korea, between January 1, 1991, and December 31, 2003, were reviewed. Visual acuity and associated ocular and systemic abnormalities were recorded. Nineteen patients (21 eyes) with peripapillary staphyloma were included in the study. The mean age at initial examination was 21 months, and 42% (8/19) of the patients were girls. Two patients (11%) had bilateral peripapillary staphylomas. Only 2 eyes had visual acuity better than 20/200 at the last examination, and 7 eyes had severe myopia of more than -6 diopters. After occlusion therapy, 1 patient achieved a visual improvement from light perception to 20/30. Congenital cataract and persistent pupillary membrane were present in 2 eyes each at initial examination. Complications observed during the follow-up period included acquired total cataract in 2 eyes and retinal detachment in 3 eyes. Scleral encircling buckling was performed in 1 eye with retinal detachment, and subsequently the retina was reattached. Only 2 patients had accompanying systemic abnormalities. Rarely, patients with peripapillary staphyloma can achieve significant visual improvement by occlusion therapy, although visual outcome is generally poor. Because associated ocular disease and refractive errors are not infrequent, complete ophthalmic examinations and regular follow-up are necessary.


Endosome Traffic Modulates Pro-Inflammatory Signal Transduction in CD4+ T Cells-Implications for the Pathogenesis of Systemic Lupus Erythematosus.
Endocytic recycling regulates the cell surface receptor composition of the plasma membrane. The surface expression levels of the T cell receptor (TCR), in concert with signal transducing co-receptors, regulate T cell responses, such as proliferation, differentiation, and cytokine production. Altered TCR expression contributes to pro-inflammatory skewing, which is a hallmark of autoimmune diseases, such as systemic lupus erythematosus (SLE), defined by a reduced function of regulatory T cells (Tregs) and the expansion of CD4+ helper T (Th) cells. The ensuing secretion of inflammatory cytokines, such as interferon-γ and interleukin (IL)-4, IL-17, IL-21, and IL-23, trigger autoantibody production and tissue infiltration by cells of the adaptive and innate immune system that induce organ damage. Endocytic recycling influences immunological synapse formation by CD4+ T lymphocytes, signal transduction from crosslinked surface receptors through recruitment of adaptor molecules, intracellular traffic of organelles, and the generation of metabolites to support growth, cytokine production, and epigenetic control of DNA replication and gene expression in the cell nucleus. This review will delineate checkpoints of endosome traffic that can be targeted for therapeutic interventions in autoimmune and other disease conditions.


Circulating T cell profiles associate with enterotype signatures underlying hematological malignancy relapses.
Early administration of azithromycin after allogeneic hematopoietic stem cell transplantation was shown to increase the relapse of hematological malignancies. To determine the impact of azithromycin on the post-transplant gut ecosystem and its influence on relapse, we characterized overtime gut bacteriome, virome, and metabolome of 55 patients treated with azithromycin or a placebo. We describe four enterotypes and the network of associated bacteriophage species and metabolic pathways. One enterotype associates with sustained remission. One taxon from Bacteroides specifically associates with relapse, while two from Bacteroides and Prevotella correlate with complete remission. These taxa are associated with lipid, pentose, and branched-chain amino acid metabolic pathways and several bacteriophage species. Enterotypes and taxa associate with exhausted T cells and the functional status of circulating immune cells. These results illustrate how an antibiotic influences a complex network of gut bacteria, viruses, and metabolites and may promote cancer relapse through modifications of immune cells.


A genetic variant in granzyme B is associated with progression of joint destruction in rheumatoid arthritis.
Genetic factors account for an estimated 45-58% of the variance in joint destruction in rheumatoid arthritis (RA). The serine proteinase granzyme B induces target cell apoptosis, and several in vitro studies suggest that granzyme B is involved in apoptosis of chondrocytes. Serum levels of granzyme B are increased in RA and are also associated with radiographic erosions. The aim of this study was to investigate GZMB as a candidate gene accounting for the severity of joint destruction in RA. A total of 1,418 patients with 4,885 radiograph sets of the hands and feet from 4 independent cohorts were studied. First, explorative analyses were performed in 600 RA patients in the Leiden Early Arthritis Clinic cohort. Fifteen single-nucleotide polymorphisms (SNPs) tagging GZMB were tested. Significantly associated SNPs were genotyped in data sets representing patients from the Groningen, Sheffield, and Lund cohorts. In each data set, the relative increase in the annual rate of progression in the presence of a genotype was assessed. Data were summarized in a meta-analysis. The association of GZMB with the RNA expression level of the GZMB genomic region was tested by mapping expression quantitative trait loci (QTLs) on 1,469 whole blood samples. SNP rs8192916 was significantly associated with the rate of joint destruction in the first cohort and in the meta-analysis of all data sets. Patients homozygous for the minor allele of rs8192916 had a higher rate of joint destruction per year compared with other patients (P = 7.8 × 10(-4)). Expression QTL of GZMB identified higher expression in the presence of the minor allele of rs8192916 (P = 2.27 × 10(-5)). SNP rs8192916 located in GZMB is associated with the progression of joint destruction in RA as well as with RNA expression in whole blood.


Functional Role of Phospholipase D in Bone Metabolism.
Phospholipase D (PLD) proteins are major enzymes that regulate various cellular functions, such as cell growth, cell migration, membrane trafficking, and cytoskeletal dynamics. As they are responsible for such important biological functions, PLD proteins have been considered promising therapeutic targets for various diseases, including cancer and vascular and neurological diseases. Intriguingly, emerging evidence indicates that PLD1 and PLD2, 2 major mammalian PLD isoenzymes, are the key regulators of bone remodeling; this suggests that these isozymes could be used as potential therapeutic targets for bone diseases, such as osteoporosis and rheumatoid arthritis. PLD1 or PLD2 deficiency in mice can lead to decreased bone mass and dysregulated bone homeostasis. Although both mutant mice exhibit similar skeletal phenotypes, PLD1 and PLD2 play distinct and nonredundant roles in bone cell function. This review summarizes the physiological roles of PLD1 and PLD2 in bone metabolism, focusing on recent findings of the biological functions and action mechanisms of PLD1 and PLD2 in bone cells.


Sublingual immunotherapy and quality of life.
Sublingual immunotherapy (SLIT) has been shown to be a new and promising treatment for people with various allergic syndromes. Several studies have examined its efficacy. However, significantly fewer investigations have explored its specific impact on the patient's quality of life (QOL). SLIT has an excellent safety profile, superior in many ways to subcutaneous immunotherapy (SCIT). Additionally, SLIT significantly decreases the use of allergy medications, as well as decreasing the money spent on allergy symptom control. Finally, SLIT has been shown to improve the patient's QOL when compared to placebo or even second-generation antihistamines. Increasing data support the use of SLIT as a well tolerated, cost-effective, and time-efficient modality for the treatment of multiple allergic syndromes. However, additional studies are needed, particularly QOL studies which compare SLIT to the FDA-approved SCIT.


Amla (Emblica officinalis) extract is effective in preventing high fructose diet-induced insulin resistance and atherogenic dyslipidemic profile in ovariectomized female albino rats.
The aim of this study was to evaluate the effect of ovarian hormone withdrawal and a high fructose diet on the development of atherogenic dyslipidemia in rats. Because amla (Indian gooseberry) is known to possess hypolipidemic properties, its preventive effect on the above was also studied. Three-month-old female albino rats were either ovariectomized (n = 48) or sham-operated (n = 12). The study was performed in two phases: phase 1 (first 12 wk) and phase 2 (next 6 wk). The sham-operated rats were fed rodent chow in both phases (control). The ovariectomized rats were assigned to four groups: rats fed chow in both phases (O), rats fed a 60% fructose-rich diet in phase 2 alone (O + F), rats administered chow and amla extract in both phases (O + A), and rats administered chow + amla extract in phase 1 and then fed a 60% fructose-rich diet + amla extract in phase 2 (O + F + A). O + F rats developed insulin resistance and had increased triglycerides (TGs) and total cholesterol. O + A and O + F + A groups had significantly lower low-density lipoprotein cholesterol and higher high-density lipoprotein (HDL) cholesterol compared with controls. O + F + A did not develop insulin resistance and had reduced TGs compared with O + F rats. O + A and O + F + A rats showed a tremendous decrease in non-HDL cholesterol and non-HDL cholesterol/HDL cholesterol, TG/HDL cholesterol, and total cholesterol/HDL cholesterol ratios. Amla decreased low-density lipoprotein cholesterol and increased HDL cholesterol in ovariectomized rats fed chow or fructose. In ovariectomized and fructose-fed rats, it prevented insulin resistance aside from subduing the rise in TG. Amla may be explored for its use in preventing dyslipidemia in postmenopausal women.


Tumor microenvironment manipulates chemoresistance in ovarian cancer (Review).
Ovarian cancer (OC) is the leading cause of mortality among the various types of gynecological cancer, and >75% of the cases are diagnosed at a late stage. Although platinum‑based chemotherapy is able to help the majority of patients to achieve remission, the disease frequently recurs and acquires chemoresistance, resulting in high mortality rates. The complexity of OC therapy is not solely governed by the intrinsic characteristics of the OC cells (OCCs) themselves, but is also largely dependent on the dynamic communication between OCCs and various components of their surrounding microenvironment. The present review attempts to describe the mutual interplay between OCCs and their surrounding microenvironment. Tumor‑associated macrophages (TAMs) and cancer‑associated fibroblasts (CAFs) are the most abundant stromal cell types in OC. Soluble factors derived from CAFs steadily nourish both the OCCs and TAMs, facilitating their proliferation and immune evasion. ATP binding cassette transporters facilitate the extrusion of cytotoxic molecules, eventually promoting cell survival and multidrug resistance. Extracellular vesicles fulfill their role as genetic exchange vectors, transferring cargo from the donor cells to the recipient cells and propagating oncogenic signaling. A greater understanding of the vital roles of the tumor microenvironment will allow researchers to be open to the prospect of developing therapeutic approaches for combating OC chemoresistance.


Repair of aortic regurgitation due to Takayasu arteritis.
Prosthetic valve detachment after aortic valve replacement and pseudoaneurysm formation are the most important postoperative complications in patients with Takayasu arteritis with aortic regurgitation. We reviewed our experience of surgical treatment of aortic regurgitation in patients with Takayasu disease. Between November 1997 and September 2011, 11 patients (4 women and 7 men) with Takayasu arteritis with aortic regurgitation underwent surgical treatment. The age of the patients ranged from 26 to 56 years (mean, 40 ± 9 years). Primary isolated aortic valve replacement was performed in 1 patient, David procedure in 1 patient, Wheat procedure in 1 patient, Bentall procedure in 2 patients, and Cabrol procedure in 6 patients (including 2 patients who underwent primary aortic valve replacement in other hospitals before being admitted to our surgical team). There was no in-hospital death. All patients had an uneventful recovery during the postoperative course and were discharged. Prosthetic valve detachment, pseudoaneurysm formation at the suture line, and dilatation of the ascending aorta were not found in patients with composite aortic root replacement during a mean follow-up of 98 ± 45 months. One patient died during follow-up. Valve detachment after composite aortic root replacement was not observed in patients with Takayasu disease with aortic regurgitation. Satisfactory surgical outcomes were obtained using composite aortic root replacement. However, close follow-up was needed to assess the effectiveness of the Cabrol procedure in patients with Takayasu disease with aortic regurgitation.


Special at school but lonely at home: an alternative friendship group for adolescents with Down syndrome.
Friends play a significant role in mental and physical health; however, individuals with Down syndrome and other developmental disabilities, even those who are included in general education programmes, have not developed friendships as hoped. After a decade of inclusion and structured school programmes to facilitate friendships, many parents report that peer relationships end after school hours. This study compared the efficacy of school based friendship groups with a mixed age home based group. Specific methods to establish a successful friendship group are discussed. This study followed three friendship groups for five years. Two groups of six to eight general education students met with the target student twice a month during the school day; one group of mixed age participants met in the student's home. A counsellor facilitated all the groups. Parent and student concerns regarding friendships were informally assessed with interviews and observations. Observations and interviews confirmed that although peer interactions during school occurred they did not continue after school. Of the three students studied, only one had a relationship with a same-aged peer after four years of school facilitated groups. Two students had significant feelings of depression during high school. One student entered counselling. The home-based mixed age friendship group did result in significant friendships. The individual participated in two or three activities each month with friends from the group. School based friendship groups of adolescent peers were not successful in developing friendships for individuals with Down syndrome. When a multi-age group was conducted outside of the school, friendships formed and have continued for over two years. This article describes how and why parents and professionals should look beyond school based same age peer friendship groups and consider a community circle of mixed-age friends.


Evolution of closed urinary drainage systems use and associated factors in Spanish hospitals.
Although closed urinary drainage systems (CUDS) reduce the risk of catheter-associated urinary tract infection (CAUTI), open systems are still used in Spain. The object of this work was to describe the progress of CUDS use and factors associated with the drainage system type used in Spanish hospitals. The databases of the EPINE study (Study of Prevalence of Nosocomial Infections in Spain) from 1990 to 2000 were used. The EPINE study includes hospitalized patients of all ages in acute-care Spanish hospitals. Seventy-six thousand, seven hundred and eighty-eight catheterized patients were studied, and the whole database was used for the trend analysis of global hospital-acquired infection (HAI). The patient and the hospital were the two units of observation used in the analysis. Full implementation was defined as 90% CUDS use. A logistic regression model was applied to study factors influencing the use of CUDS and to determine prevalence trend. An odds ratio (OR) >1 indicates an incremental trend. The Pearson correlation coefficient between annual percentage of CUDS use and CAUTI prevalence was calculated. Variables for the year 2000 were compared using the Mann-Whitney U test between hospitals with and without full implementation. The prevalence of urinary catheterized patients in Spain increased from 12.4% in 1990 to 15.2% in 2000 (OR 1.019, 95% CI 1.016-1.021). The proportion of CUDS used increased from 50.6% in 1990 to 70% in 2000 (OR 1.1, 95% CI 1.095-1.104) and correlated with a significant decrease of UTIs (r = 0.65, P = 0.03). In 1990, 28.5% of hospitals had full implementation of CUDS and by 2000 this had risen to 40.3% (OR 1.093, 95% CI 1.06-1.127). Patients in medium (200-500 beds) and large (>500 beds) hospitals, as well as those with three of more diagnoses and two or more intrinsic risk factors had an increased probability of having a CUDS, whereas being hospitalized in areas other than intensive care, being male and less than 65 years old were associated with a lower probability of CUDS use. The median prevalence of catheterized patients in hospitals with full implementation, was significantly lower than in those without it (P = 0.049). Although CUDS use is increasing, there is still much work required to reach full implementation. Keeping CUDS for more severely ill patients may reflect a higher concern over the consequences of UTI in these patients. Nevertheless, it is necessary to change a practice that exposes patients to a known UTI risk factor and reach a consensus on indications for catheter insertion.


Facial nerve paralysis caused by tumor-forming chronic lymphatic leukemia: a case report.
A 60-year-old female with chronic lymphatic leukemia developed a complete facial paralysis. Clinical examination revealed a tumor protruding through the cranial part of the eardrum. A CT scan and biopsy specimens showed a leukemic infiltrate in the middle ear with extension to the facial canal. She was successfully treated with radiotherapy.


Tumor angiogenesis: the role of oncogenes and tumor suppressor genes.
The progressive growth of solid tumors is strictly dependent on their ability to attract new blood vessels that will supply them with oxygen and essential nutrients. Although in experimental models a number of compounds are able to elicit such angiogenesis, under normal physiological conditions new vessel growth is tightly repressed. One consequence of the cascade of oncogene activation and tumor suppressor gene loss that produces a solid tumor must be the alleviation of this normal repression. Understanding how this is achieved may help to define the functions of oncogenes and suppressor genes that are relevant to tumorigenicity and may suggest novel therapeutic strategies.