New pharmacotherapy for the treatment of onychomycosis: an update.
Onychomycosis is an infection of the nail plate that is an important priority area for the development of antifungal drugs. The high incidence of relapse and reinfection often makes onychomycosis a chronic condition. The current gold standard is oral therapy, but the development of effective topical agents remains a priority as they have fewer systemic interactions. This review summarizes development of antifungals from early phase development through Phase III clinical trials for onychomycosis. The oral molecules in development are azole molecules. Topical drugs in development include azoles, allylamines, benzoxaboroles and nanoemulsions. Photosensitizers for photodynamic therapy and new laser systems are also emerging therapeutic options. There is a diverse array of antifungal drugs in the early phases of development. The goals of onychomycosis therapy are a mycological cure and a normal appearing nail. The recent development of topical antifungals has been successful at improving the nail permeation and efficacy. The diversification of molecular targets is the next primary goal of antifungal development. Incomplete treatment of onychomycosis provides an environment conducive to the development of antifungal resistance. New topical agents and device-based therapies expand the therapeutic options. Combination therapy using multiple drug classes may improve the overall efficacy of antifungal treatment in onychomycosis.


TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate/Gαs signaling.
Hepatic cystogenesis in polycystic liver disease is associated with increased levels of cyclic adenosine monophosphate (cAMP) in cholangiocytes lining liver cysts. Takeda G protein receptor 5 (TGR5), a G protein-coupled bile acid receptor, is linked to cAMP and expressed in cholangiocytes. Therefore, we hypothesized that TGR5 might contribute to disease progression. We examined expression of TGR5 and Gα proteins in cultured cholangiocytes and in livers of animal models and humans with polycystic liver disease. In vitro, we assessed cholangiocyte proliferation, cAMP levels, and cyst growth in response to (1) TGR5 agonists (taurolithocholic acid, oleanolic acid [OA], and two synthetic compounds), (2) a novel TGR5 antagonist (m-tolyl 5-chloro-2-[ethylsulfonyl] pyrimidine-4-carboxylate [SBI-115]), and (3) a combination of SBI-115 and pasireotide, a somatostatin receptor analogue. In vivo, we examined hepatic cystogenesis in OA-treated polycystic kidney rats and after genetic elimination of TGR5 in double mutant TGR5-/- ;Pkhd1del2/del2 mice. Compared to control, expression of TGR5 and Gαs (but not Gαi and Gαq ) proteins was increased 2-fold to 3-fold in cystic cholangiocytes in vitro and in vivo. In vitro, TGR5 stimulation enhanced cAMP production, cell proliferation, and cyst growth by ∼40%; these effects were abolished after TGR5 reduction by short hairpin RNA. OA increased cystogenesis in polycystic kidney rats by 35%; in contrast, hepatic cystic areas were decreased by 45% in TGR5-deficient TGR5-/- ;Pkhd1del2/del2 mice. TGR5 expression and its colocalization with Gαs were increased ∼2-fold upon OA treatment. Levels of cAMP, cell proliferation, and cyst growth in vitro were decreased by ∼30% in cystic cholangiocytes after treatment with SBI-115 alone and by ∼50% when SBI-115 was combined with pasireotide. TGR5 contributes to hepatic cystogenesis by increasing cAMP and enhancing cholangiocyte proliferation; our data suggest that a TGR5 antagonist alone or concurrently with somatostatin receptor agonists represents a potential therapeutic approach in polycystic liver disease. (Hepatology 2017;66:1197-1218).


The influence of a patient-management course to dental hygiene students on the dental anxiety of their patients.
This study investigated the effect of teaching dental hygiene students a course in caregiver-patient relationships on their patients' dental anxiety, and patients' feelings toward known anxiety-provoking stimuli. The study group (twenty-five men and twenty-five women) was treated by a class of dental hygiene students following a behavioral course given after the first visit. The control group (twenty-four men, twenty-six women) was treated by another class without the intervention. Corah's Dental Anxiety Scale (DAS) and a twelve-item questionnaire identifying specific anxiety-provoking situations were completed by the patients before initial visit and after the third visit. A significant reduction in DAS within the study group was observed after the intervention. In both groups, women demonstrated higher anxiety. No significant difference was found in the twelve-item questionnaire after intervention in both groups. These findings suggest that a four-hour behavioral course to a class of dental hygiene students was an influencing factor in reducing their patients' levels of dental anxiety.


5α,6α-Epoxyphytosterols and 5α,6α-Epoxycholesterol Increase Nitrosative Stress and Inflammatory Cytokine Production in Rats on Low-Cholesterol Diet.
Oxidized cholesterol derivatives are compounds with proven atherogenic and mutagenic effects. However, little is known about the effect of oxidized plant sterol derivatives (oxyphytosterols), whose structure is similar to the one of oxycholesterols. Our previous studies indicate that they have a similar profile of action, e.g., both exacerbate disorder of lipid metabolism and oxidative stress in experimental animals. The aim of the present study was to assess the effect of epoxycholesterol and epoxyphytosterols (mainly sitosterol) on the severity of nitrosative stress and the concentration of selected proinflammatory cytokines in blood and liver tissue of rats on a low-cholesterol diet. Material and Methods. Forty-five male Wistar rats were fed with feed containing 5α,6α-epoxyphytosterols (ES group, n: 15), 5α,6α-epoxycholesterol (ECh group, n: 15), and oxysterol-free feed (C group, n: 15) for 90 days (daily dose of oxysterols: 10 mg/kg). At the end of the experiment, nitrotyrosine, TNF-α, IL-1β, IL-6, and lipid metabolism parameters were determined in blood serum. Furthermore, nitrotyrosine, TNF-α, cholesterol, and triglyceride content were determined in liver homogenates. Serum nitrotyrosine, IL-1β, and TNF-α concentrations as well as TNF-α content in the liver were significantly higher in both groups exposed to oxysterols (ECh and ES groups) as compared to the C group. The serum IL-6 level and nitrotyrosine content in the liver were significantly higher in the ECh group, as compared to the C and ES groups. There was evidence to support the dyslipidemic effect of studied compounds. The results indicate that oxidized plant sterols have a similar toxicity profile to that of oxycholesterols, including nitrosative stress induction, proinflammatory effect, and impaired lipid metabolism.


Coenzyme Q10 inhibits mitochondrial complex-1 down-regulation and nuclear factor-kappa B activation.
We have used control-homozygous weaver mutant, and -heterozygous weaver mutant mice in order to explore the basic molecular mechanism of neurodegeneration and the neuroprotective potential of coenzyme Q(10). Homozygous weaver mutant mice exhibited progressive neurodegeneration in the hippocampus, striatum, and cerebellum, and a reduction in the striatal levels of dopamine and coenzyme Qs (Q(9) and Q(10)) without any significant changes in norepinephrine and serotonin. Mitochondrial complex-1 was down regulated; whereas nuclear factor-kappa B was up regulated in homozygous weaver mutant mice. Rotenone inhibited complex-1, enhanced nuclear factor-kappa B, and caused apoptosis in human dopaminergic (SK-N-SH) neurons; whereas nuclear factor-kappa B antibody suppressed rotenone-induced apoptosis, suggesting that enhancing coenzyme Q(10) synthesis and suppressing the induction of NF-kappa B, may provide neuroprotection.


[Reccurent tibial osteomyelitis after the segmental bone transport: a radical interdisciplinary treatment].
Long-term or recurrent osteomyelitis results in the deterioration of soft tissue quality at the site of an infectious process. An insufficient perfusion of the scar tissue contributes to difficult treatment of osteomyelitis. A local transpositional or free muscle flap used to replace the vulnerable scar tissue will enhance perfusion of the affected bone and will help to control osteomyelitis. The authors present the case of a patient who had been treated by bone transport for a 14-cm-long segmental defect of the tibia after post-traumatic osteomyelitis. Recurrent osteomyelitis was found nine years after the primary surgery. The whole tibial cavity was opened leaving a 12-mm-wide trepanation opening, and debridement of all necrotic and inflammatory tissue including dystrophic skin was performed. The Orr technique was used for further treatment. There was no relapse and granulation tissue samples repeatedly gave negative culture results. Therefore, at the second stage, the soft tissue defect was covered with a free latissimus dorsi muscle flap. Anastomoses to the recipient vessels were technically difficult to carry out in the tissue greatly affected by previous chronic inflammation. Ten days after the surgery the patient was allowed to stand and walk, full weight-bearing was allowed at 2 months post-operatively when the flap was completely integrated. At 6-year follow-up the extremity was fully weight-bearing, with no recurrence of infection, and the patient was satisfied with the outcome. The authors regard this interdisciplinary management (extensive bone and soft tissue debridement, free muscle flap transfer) as a method indicated for the treatment of recurrent tibial osteomyelitis.


Protein coding gene CRNKL1 as a potential prognostic biomarker in esophageal adenocarcinoma.
Esophageal adenocarcinoma (EAC) is one of the most aggressive gastroesophageal cancers. PTGS2, EGFR, ERBB2 and TP53 are the traditional EAC prognostic biomarkers, but they are still limited in their ability to effectively predict the overall survival. To identify an improved biomarker for predicting the prognosis of EAC by using the expression profile. Differential co-expression analysis and differential expression analysis were performed to identify the related genes of EAC. The 5-fold cross-validation was used to select a prognostic biomarker from the 532 EAC related genes. CRNKL1 was identified as a prognostic biomarker to predict the survival of EAC patients. It could significantly stratify EAC patients into high-risk and low-risk groups and was much better than the traditional biomarkers. Furthermore, ROC curve also verified that CRNKL1 with the highest area under the curve (AUC), reaching a sensitivity of 83.33% and a specificity of 78.57%. Our research proposed that CRNKL1 might be a novel prognostic biomarker with better predictive ability by comparing with the traditional biomarkers, which provided a preferable opportunity in the clinical applications of EAC.


Connecting public health and clinical information systems by using a standardized methodology.
To meet the challenge for efficient, high quality and sustainable care, health systems in developed and increasingly in developing countries require extended communication and cooperation between all principals involved in citizen's care. The challenge also concerns supporting information systems, which demand interoperation with public health, bioinformatics, genomics, administrative, governmental, and other sources of data. The paper describes an architecture development methodology for modeling the integration between clinical and public health information systems that harmonizes existent standardized modeling approaches and integrates HL7 domain knowledge. An integration-architecture for information sharing between public health surveillance and clinical information systems is derived demonstrating the feasibility of the proposed methodology. Predominantly, a harmonized process for analysis, design, implementation and maintenance of semantically interoperable information systems based on formal grammars is discussed in some detail.


The topoisomerase I gene from Ustilago maydis: sequence, disruption and mutant phenotype.
The Ustilago maydis genomic TOP1 gene encoding DNA topoisomerase I was cloned by amplifying a gene fragment using the polymerase chain reaction, and using this fragment to search a genomic DNA library by hybridization. The predicted peptide sequence exhibited 30-40% identity to other eukaryotic TOP1 genes, yet differed in several features. First, an unusually long acidic region was identified near the amino terminus (28/29 residues are acidic), which resembles other nucleolar peptide motifs. Second, an atypical carboxy-terminal 'tail', absent in other TOP1 genes, followed the active site tyrosine residue. A top1 gene disruption mutant was constructed by replacing the genomic TOP1 gene, with a top1::HygR null allele. This mutant lost the abundant topoisomerase I activity evident in wild-type U.maydis, and displayed a subtle coloration phenotype evident during cell senescence.


Clinical Results of Cardiac Surgery in Patients with Chronic Hepatitis C and Their Role in Risk Models: A Case-Control Study.
To evaluate the results of patients with chronic hepatitis C virus (HCV) following cardiac surgery in the TurcoSCORE (TrS) database. Sixty patients with HCV who underwent cardiac surgery between 2005 and 2016 in our clinic out of a total 8,018 patients from the TrS database were included in the study. The perioperative morbidity and mortality rates in these patients were compared with a matched cohort. The mean follow-up time was 96.6 ± 12.3 months. Hospital mortality rates (HCV group 5% vs. control group 1.7%, p = 0.61) were similar between the groups. No significant difference was found in the duration of cardiopulmonary bypass (HCV 79.1 ± 12.3 vs. control 82.6 ± 11.8, p = 0.88) and cross clamps (HCV 33.4 ± 6.9 vs control 33.8 ± 7.2 p = 0.76) between the two groups. The rate of patients who were revised due to postoperative hemorrhage was significantly higher in the HCV arm compared with the matched cohort (HCV 13.3% vs. control 1.7%, p < 0.05). Although the measured prothrombin time (PT) and international normalized ratio (INR) in the postoperative 24th hour were in normal ranges in both arms, they were significantly higher in the HCV arm (HCV 11.2 ± 1.2 vs. control 10.5 ± 0.8, p < 0.05; HCV 0.99 ± 0.06, vs. control 0.92 ± 0.03, p < 0.0001). The presence of HCV can be an important prognostic factor for morbidity in patients undergoing cardiac surgery. It can also play an important role in the risk models generated for cardiac surgery.


The prevalence of epilepsy along the Arizona-Mexico border.
This study describes the epidemiology of epilepsy on the Arizona-Mexico border. Households in Southern Arizona were identified using two strategies. County-wide random digit dialing telephone surveys were supplemented with door-to-door recruitment in three Arizona border communities. Utilizing a two-step screening process, individuals with a seizure disorder or epilepsy were identified. A consensus diagnosis was arrived at after reviewing results from the detailed interview, medical records and clinical examination. A total of 15,738 household individuals were surveyed. Two hundred and three individuals were identified as having had epilepsy at some point in their life; 25% of them were previously not diagnosed. The sex and age-adjusted prevalence estimate was 14.3 per 1000 (95% CI: 12.5-16.1) for lifetime epilepsy, and 11.8 per 1000 (CI: 10.2-13.5) for active epilepsy (seizures in the past 5 years or currently taking antiseizure medications). Non-Hispanic Whites were two times more likely to have active epilepsy than Hispanics. The majority of individuals with lifetime history of epilepsy had idiopathic or cryptogenic epilepsy; most were localization-related epilepsy although the exact location could not be determined for the majority. Although most individuals with epilepsy report receiving care from a neurology specialist, they were more likely to have visited a non-specialist in the past 3 months. The lower prevalence of epilepsy among Hispanics compared to non-Hispanics supports previous survey findings in the Southwest US and may be due to language, acculturation factors, stigma, or a reflection of the "healthy immigrant effect". The surprisingly high proportion of previously un-diagnosed individuals shows a need for further investigation as well as a need to increase community awareness.


Ultrasound degradation of xanthan polymer in aqueous solution: Its scission mechanism and the effect of NaCl incorporation.
Degradation of xanthan polymer in aqueous solution by ultrasonic irradiation was investigated. The effects of selected variables i.e. sonication intensity, irradiation time, concentration of xanthan gum and molar concentration of NaCl in solution were studied. Combined approach of full factorial design and conventional one-factor-at-a-time was applied to obtain optimum degradation at sonication power intensity of 11.5Wcm-2, irradiation time 120min and 0.1gL-1 xanthan in a salt-free solution. Molecular weight reduction of xanthan gum under sonication was described by an exponential decay function with higher rate constant for polymer degradation in the salt free solution. The limiting molecular weight where fragments no longer undergo scission was determined from the function. The incorporation of NaCl in xanthan solution resulted in a lower limiting molecular weight. The ultrasound-mediated degradation of aqueous xanthan polymer chain agreed with a random scission model. Side chain of xanthan polymer is proposed to be the primary site of scission action.


The effect of glucose-dependent insulinotropic polypeptide (GIP) variants on visceral fat accumulation in Han Chinese populations.
We aim to validate the effects of glucose-dependent insulinotropic polypeptide (GIP) on fat distribution and glucose metabolism in Han Chinese populations. We genotyped six tag single-nucleotide polymorphisms (SNPs) of GIP and four tag SNPs of glucose-dependent insulinotropic polypeptide receptor (GIPR) among 2884 community-based individuals from Han Chinese populations. Linear analysis was applied to test the associations of these variants with visceral fat area (VFA) and subcutaneous fat area (SFA) quantified by magnetic resonance imaging as well as glucose-related traits. We found that the C allele of rs4794008 of GIP tended to increase the VFA and the VFA/SFA ratio in all subjects (P=0.050 and P=0.054, respectively), and rs4794008 was associated with the VFA/SFA ratio in males (P=0.041) after adjusting for the BMI. The VFA-increasing allele of rs4794008 was not related to any glucose metabolism traits. However, rs9904288 of GIP was associated with the SFA in males as well as glucose-related traits in all subjects (P range, 0.004-0.049), and the GIPR variants displayed associations with both fat- and glucose-related traits. The results could provide the evidence that GIP might modulate visceral fat accumulation via incretin function or independent of incretin.


Arabidopsis PYL8 Plays an Important Role for ABA Signaling and Drought Stress Responses.
Plants are frequently exposed to numerous environmental stresses such as dehydration and high salinity, and have developed elaborate mechanisms to counteract the deleterious effects of stress. The phytohormone abscisic acid (ABA) plays a critical role as an integrator of plant responses to water-limited condition to activate ABA signal transduction pathway. Although perception of ABA has been suggested to be important, the function of each ABA receptor remains elusive in dehydration condition. Here, we show that ABA receptor, pyrabactin resistance-like protein 8 (PYL8), functions in dehydration conditions. Transgenic plants overexpressing PYL8 exhibited hypersensitive phenotype to ABA in seed germination, seedling growth and establishment. We found that hypersensitivity to ABA of transgenic plants results in high degrees of stomatal closure in response to ABA leading to low transpiration rates and ultimately more vulnerable to drought than the wild-type plants. In addition, high expression of ABA maker genes also contributes to altered drought tolerance phenotype. Overall, this work emphasizes the importance of ABA signaling by ABA receptor in stomata during defense response to drought stress.


Treatment of natto, a fermented soybean preparation, to prevent excessive plasma vitamin K concentrations in patients taking warfarin.
The purpose of this study is to find a method of cooking natto that prevents the appearance of high-plasma vitamin K concentrations after the consumption of natto, so that patients taking warfarin can benefit from eating natto. Five cooking methods were examined to determine which could most effectively decrease the count of the living Bacillus subtilis in natto. Volunteers ate natto or treated natto, and their plasma vitamin K level was measured at 5, 8, 24 and 48 h thereafter. One gram of natto contained 9.7+/-0.1 Log cfu/mL of Bacillus subtilis. Boiling significantly reduced the Bacillus subtilis count to 5.1+/-0.3 Log cfu/mL, and concomitantly reduced the content of menaquinone-7 (MK-7), which is a form of vitamin K synthesized by Bacillus subtilis, from 660.40+/-65.32 ng/mL to 78.50+/- 11.12 ng/mL. Untreated natto increased the MK-7 concentration in blood from 1.86+/-1.51 ng/mL to 14.54+/-4.12 ng/mL at 5 h after intake, and the MK-7 concentration remained elevated at 8, 24 and 48 h (7.29+/-2.20, 6.97+/-2.60, and 5.37+/-1.94 ng/mL, respectively). In contrast, boiled natto increased plasma MK-7 only mildly (from 1.61+/-1.11 to 4.02+/-0.82 ng/ mL at 5 h) and the concentration remained relatively stable up to 48 h (3.46+/-0.83, 4.22+/-1.51 and 2.77+/-0.75 ng/mL at 8, 24 and 48 h, respectively). In conclusion, boiled natto did not cause a marked increase in the plasma concentration of vitamin K in subjects who consumed it. Thus, patients on warfarin may be able to eat boiled natto without ill effects.


Protective effect of Lycium barbarum polysaccharides against high-fat diet-induced renal injury and lipid deposition in rat kidneys.
This study aimed to explore the protective effect of Lycium barbarum polysaccharides (LBPs) against hyperlipidemia and lipid-induced renal injury in a rat model. Male Sprague-Dawley rats (n=30) were randomly divided into three equal groups: a control group (fed a regular diet) and two experimental groups (fed a high-fat diet). By feeding rats a high-fat diet for 12 weeks, an animal model of hyperlipidemia was established, after which one experimental group received oral LBPs at a dose of 300 mg/kg per day. Blood lipids, renal function, and urinary proteins were measured after 12 weeks. Changes in renal pathology and expression levels of sterol regulatory element binding transcription factor 1 (SREBP-1), interleukin-6 (IL- 6), tumor necrosis factor-alpha (TNF-α), AMP-activated protein kinase (AMPK) were determined. Rats with hyperlipidemia induced by a high-fat diet showed increases in blood lipids and blood urea nitrogen, serum creatinine, and urinary protein, as well as increases in renal levels of SREBP-1, TNF-α, and IL-6 and decreases in renal levels of adiponectin and AMPK. Administration of LBPs restored blood lipid, blood urea nitrogen, serum creatinine, and urinary protein levels, downregulated renal levels of SREBP-1, TNF-α, and IL-6, and upregulated renal levels of adiponectin and AMPK. These results indicate that LBPs may mediate lipid metabolism, enhance anti-inflammatory responses, and ameliorate renal injury caused by lipid metabolism isorders in a rat model of hyperlipidemia.


Bed rest with and without hospitalisation in multiple pregnancy for improving perinatal outcomes.
Strict or partial bed rest in hospital or at home is commonly recommended for women with multiple pregnancy to improve pregnancy outcomes. In order to advise women to rest in bed for any length of time, a policy for clinical practice needs to be supported by reliable evidence and weighed against possible adverse effects resulting from prolonged activity restriction. The objective of this review is to assess the effectiveness of bed rest in hospital or at home to improve perinatal outcomes in women with a multiple pregnancy. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 May 2016), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (30 May 2016) and reference lists of retrieved studies. We selected all individual and cluster-randomised controlled trials evaluating the effect of strict or partial bed rest at home or in hospital compared with no activity restriction during multiple pregnancy. Two review authors independently assessed trials for inclusion, extracted data and methodological quality. We evaluated the quality of the evidence using the GRADE approach and summarised it in 'Summary of findings' tables. We included six trials, involving a total of 636 women with a twin or triplet pregnancy (total of 1298 babies). We assessed all of the included trials as having a low risk of bias for random sequence generation. Apart from one trial with an unclear risk of bias, we judged all remaining trials to be of low risk of bias for allocation concealment.Five trials (495 women and 1016 babies) compared strict bed rest in hospital with no activity restriction at home. There was no difference in the risk of very preterm birth (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.66 to 1.58, five trials, 495 women, assuming complete correlation between twins/triplets, low-quality evidence), perinatal mortality (RR 0.65, 95% CI 0.35 to 1.21, five trials, 1016 neonates, assuming independence between twins/triplets, low-quality evidence) and low birthweight (RR 0.95, 95% CI 0.75 to 1.21, three trials, 502 neonates, assuming independence between twins/triplets, low-quality evidence). We observed no differences for the risk of small-for-gestational age (SGA) (RR 0.75, 95% CI 0.56 to 1.01, two trials, 293 women, assuming independence between twins/triplets, low-quality evidence) and prelabour preterm rupture of the membrane (PPROM) (RR 1.30, 95% CI 0.71 to 2.38, three trials, 276 women, low-quality evidence). However, strict bed rest in hospital was associated with increased spontaneous onset of labour (RR 1.05, 95% CI 1.02 to 1.09, P = 0.004, four trials, 488 women) and a higher mean birthweight (mean difference (MD) 136.99 g, 95% CI 39.92 to 234.06, P = 0.006, three trials, 314 women) compared with no activity restriction at home.Only one trial (141 women and 282 babies) compared partial bed rest in hospital with no activity restriction at home. There was no evidence of a difference in the incidence of very preterm birth (RR 2.30, 95% CI 0.84 to 6.27, 141 women, assuming complete correlation between twins, low-quality evidence) and perinatal mortality (RR 4.17, 95% CI 0.90 to 19.31, 282 neonates, assuming complete independence twins, low-quality evidence) between the intervention and control group. Low birthweight was not reported in this trial. We found no differences in the risk of PPROM and SGA between women receiving partial bed rest and the control group (low-quality evidence). Women on partial bed rest in hospital were less likely to develop gestational hypertension compared with women without activity restriction at home (RR 0.30, 95% CI 0.16 to 0.59, P = 0.0004, 141 women).Strict or partial bed rest in hospital was found to have no impact on other secondary outcomes. None of the trials reported on costs of the intervention or adverse effects such as the development of venous thromboembolism or psychosocial effects. The evidence to date is insufficient to inform a policy of routine bed rest in hospital or at home for women with a multiple pregnancy. There is a need for large-scale, multicenter randomised controlled trials to evaluate the benefits, adverse effects and costs of bed rest before definitive conclusions can be drawn.


[Development of a novel transdermal delivery system of peptide and protein drugs using microneedle arrays].
Transdermal delivery of peptide and protein drugs may be limited by the stratum corneum, which is a protective barrier against the entry of microorganisms and water. Many approaches have been utilized to promote peptide and protein drugs delivery across the stratum corneum, including chemical enhancer modification and physical disruption of barrier function. However, it has been difficult to achieve therapeutic levels of peptide and protein drugs via this route without any skin irritation. Recently, attention has been paid to the possibility of using microneedle arrays in delivering peptide and protein drugs into the skin. As a novel and minimally invasive approach, microneedle arrays are capable of creating superficial pathways across the skin for peptide and protein drugs to achieve enhanced transdermal drug delivery. This method combines the efficacy of conventional injection needles with the convenience of transdermal patches, while minimizing the disadvantages of these administration methods. Therefore, microneedle arrays are a very useful alternative method for delivering peptide and protein drugs from the skin into the systemic circulation without any serious damage to skin. In this review, recent challenges in the developments of microneedle arrays for the delivery of peptide and protein drugs are summarized. Then, future developments of microneedle arrays for the delivery of peptide and protein drugs are also discussed in order to improve their therapeutic efficacy and safety.


Gene expression profiling in TWIST-depleted gastric cancer cells.
TWIST is an important transcription factor during embryonic development and has recently been found to promote the epithelial-mesenchymal transition (EMT) phenomenon seen during the initial steps of tumor metastasis. To further investigate the potential targets and interacting genes of TWIST in human gastric cancer, we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion. Moreover, TWIST-depleted HGC-27 cells showed a reversal of the morphologic and molecular changes associated with EMT. These results provide evidence that TWIST regulates the expression of several genes involved in the differentiation, adhesion, and proliferation of gastric cancer cells. The role of TWIST in the development of certain types of gastric cancer is discussed.


Corylin Suppresses Hepatocellular Carcinoma Progression via the Inhibition of Epithelial-Mesenchymal Transition, Mediated by Long Noncoding RNA GAS5.
Corylin is a flavonoid extracted from the nuts of Psoralea corylifolia L. (Fabaceae), which is a widely used anti-inflammatory and anticancer herb in China. Recent studies revealed antioxidant, anti-inflammatory, and bone differentiation-promoting effects of corylin. However, there are no studies examining the anticancer activity of corylin. In this study, we used cells and animal models to examine the antitumor effects of corylin on hepatocellular carcinoma (HCC) and then studied its downstream regulatory mechanisms. The results showed that corylin significantly inhibited the proliferation, migration, and invasiveness of HCC cells and suppressed epithelial-mesenchymal transition. We found that the anti-HCC mechanism of corylin's action lies in the upregulation of tumor suppressor long noncoding RNA growth arrest-specific transcript 5 (GAS5) and the activation of its downstream anticancer pathways. In animal experiments, we also found that corylin can significantly inhibit tumor growth without significant physiological toxicity. The above results suggest that corylin has anti-HCC effects and good potential as a clinical treatment.


Copper(II) complexes of salen analogues with two differently substituted (push-pull) salicylaldehyde moieties. A study on the modulation of electronic asymmetry and nonlinear optical properties.
This paper presents some copper(II) complexes of salen analogues in which the two salicylaldehyde moieties carry different (electron donor, D, and acceptor, A) substituents in position 5, producing a push-pull charge asymmetry. The X-ray structures of some compounds show the presence of pairs of stacked molecules with head-to-tail intermolecular associations. The geometries of all complexes have been optimized through density functional theory (DFT) studies, which have shown that a major influence on the coordination bond lengths is given by the presence of the electron acceptor NO2 group. Such an influence operates mainly on the Cu-phenolato bonds: elongation of the Cu-O distance of the 5-nitrosalicylaldehyde moiety, with a concomitant decrease of the other Cu-O distance; the Cu-N bonds are less affected. The D groups have only a minor influence. The nonlinear optical responses, microgBetavec, of some molecules have been determined by EFISH measurements, and the Beta-vec values have been obtained using the DFT-calculated microg values because solubility problems hampered the experimental measurements of microg of some derivatives; the former, however, have been found to be in agreement with the experimental values that could be obtained. Deconvolution of the absorption bands in the near-UV region has allowed recognition of the charge-transfer (CT) transition, assigned to a ligand-to-metal CT (LMCT) by time-dependent DFT computations; we have then used the solvatochromism of this transition to obtain Beta0 and BetaCT values using the two-state model. These values were compared with those obtained by computational studies, which have also allowed evaluation of the influence of the substituents on the directions of microg and Betatot.


Relationships between Sleep Patterns, Health Risk Behaviors, and Health Outcomes among School-Based Population of Adolescents: A Panel Analysis of the Korean Children and Youth Panel Survey.
Sleep patterns among adolescents are related to health outcomes and health risk behaviors. This study aimed to describe sleep patterns of Korean adolescents and to find the association between sleep patterns and health risk behaviors and health outcomes. Using the junior high school students' panel data (n = 2351, 12-15 years old) from the Korean Children and Youth Panel Survey, this study described the sleep patterns operationalized as rising time, bedtime, and sleep duration both on weekdays and weekends. The relationships of sleep patterns with health outcomes and/or health risk behaviors were tested using mixed effect linear regression for continuous health variables and using mixed effect logit regression for binary health variables. Obesity status, the number of chronic symptoms, self-rated health status, smoking, and alcohol consumption were associated with rising time on weekdays after controlling for gender, living area, and housing type. The same set of variables except for the number of chronic symptoms were associated with bedtime during the weekdays. Sleep duration during the weekdays was associated with obesity status, smoking, and alcohol consumption. Similar patterns of association between sleep pattern variables during the weekends and health-related outcome variables were found, but were less obvious than those for weekdays. Significant relationships between sleep patterns and various health-related variables were found among adolescents in Korea. The results from this study indicate that helping adolescents change their sleeping times as necessary to ensure adequate sleep should be considered important in diminishing health risk behaviors and promoting positive health outcomes.


Bone stiffness in children: part I. In vivo assessment of the stiffness of femur and tibia in children.
Although there are many publications concerning the mechanical behavior of adult bone, there are few data about mechanical properties of children's bone. In vivo bone stiffness measurement with Orthometer device has been validated and extensively used in adults to assess bone healing after fracture or lengthening. We hypothesized that in vivo stiffness measurement with Orthometer was applicable in children and was correlated with age, height, body weight, and corpulence index. The purpose was to establish baseline stiffness values for femur and tibia in growing children.Sixteen bone measurements (7 femurs and 9 tibias) were obtained during application of an external fixator for leg lengthening in 11 children aged between 5.5 and 16.7 years. A 3-point bending test with an Orthometer was carried out on the intact bone (before osteotomy) under general anesthesia. The anteroposterior stiffness measurement was successful in all children of the series, aged from 5.5 to 16.7 years. A wide variation of femoral and tibial bone stiffness values were observed. The use of a unique value as in adults as the end point of bending stiffness during bone healing process is not possible for children. The anteroposterior bone stiffness was found to have linear correlation with children's height and body weight, but not with age and corpulence indexes. The original data obtained by this study will give a stiffness reference for height and weight and could be useful as reference values for monitoring of healing process after fracture or limb lengthening.


Persistent lymphopenia is a risk factor for ICU-acquired infections and for death in ICU patients with sustained hypotension at admission.
Severely ill patients might develop an alteration of their immune system called post-aggressive immunosuppression. We sought to assess the risk of ICU-acquired infection and of mortality according to the absolute lymphocyte count at ICU admission and its changes over 3 days. Adults in ICU for at least 3 days with a shock or persistent low blood pressure were extracted from a French ICU database and included. We evaluated the impact of the absolute lymphocyte count at baseline and its change at day 3 on the incidence of ICU-acquired infection and on the 28-day mortality rate. We categorized lymphocytes in 4 groups: above 1.5 × 103 cells/µL; between 1 and 1.5 × 103 cells/µL; between 0.5 and 1 × 103 cells/µL; and below 0.5 × 103 cells/µL. A total of 753 patients were included. The median lymphocyte count was 0.8 × 103 cells/µL [0.51-1.29]. A total of 174 (23%) patients developed infections; the 28-day mortality rate was 21% (161/753). Lymphopenia at admission was associated with ICU-acquired infection (p < 0.001) but not with 28-day mortality. Independently of baseline lymphocyte count, the absence of lymphocyte count increase at day 3 was associated with ICU-acquired infection (sub-distribution hazard ratio sHR: 1.37 [1.12-1.67], p = 0.002) and with 28-day mortality (sHR: 1.67 [1.37-2.03], p < 0.0001). Lymphopenia at ICU admission and its persistence at day 3 were associated with an increased risk of ICU-acquired infection, while only persisting lymphopenia predicted increased 28-day mortality. The lymphocyte count at ICU admission and at day 3 could be used as a simple and reproductive marker of post-aggressive immunosuppression.


Convective Leakage Makes Heparin Locking of Central Venous Catheters Ineffective Within Seconds: Experimental Measurements in a Model Superior Vena Cava.
Central venous catheters (CVCs), placed in the superior vena cava (SVC) for hemodialysis or chemotherapy, are routinely filled while not in use with heparin, an anticoagulant, to maintain patency and prevent thrombus formation at the catheter tip. The heparin-locking procedure, however, places the patient at risk for systemic bleeding, as heparin is known to leak from the catheter into the blood stream. We provide evidence from detailed in vitro experiments that shows the driving mechanism behind heparin leakage to be convective-diffusive transport due to the pulsatile flow surrounding the catheter. This novel mechanism is supported by experimental planar laser-induced fluorescence (PLIF) and particle image velocimetry (PIV) measurements of flow velocity and heparin transport from a CVC placed inside a model SVC inside a pulsatile flow loop. The results predict an initial, fast (<10 s), convection-dominated phase that rapidly depletes the concentration of heparin in the near-tip region, the region of the catheter with side holes. This is followed by a slow, diffusion-limited phase inside the catheter lumen, where the concentration is still high, that is insufficient at replenishing the lost heparin concentration in the near-tip region. The results presented here, which are consistent with previous in vivo estimates of 24 hour leakage rates, predict that the concentration of heparin in the near-tip region is essentially zero for the majority of the interdialytic phase, rendering the heparin locking procedure ineffective.


Hygiene trained nursing staff at wards – What can this additional educated nurses achieve?
Background: Hygiene deficits can cause hospital-acquired infections. To meet this public health problem the Robert Koch-Institute advocates the employment of infection control link nurses (ICLN). Aim: This study aimed to evaluate the experiences of ICLNs working in the University Hospital of Cologne. Method: A cross-sectional survey of all ICLNs (n = 64) working at the University Hospital of Cologne was carried out by a self developed questionaire. The data were assessed descriptively. Results: The return rate was 45.3 % (n = 29). The ICLNs were very satisfied with the ICLN training and felt well prepared for their task. The collaboration with other nursing staff, their head nurse and the Department of Hygiene was also positively evaluated. However, only one third of the respondents was satisfied with their working conditions and only half of them indicated feeling that the efforts they made so far were successful. This study also found that, many of the legal intended services were rarely performed. The study identified two barriers to implementation of ICLNs. On the one hand, the release from other routine nursing duties and on the other hand a lack of acceptance of the role by physicians. Conclusions: The task ahead is to find ways to exempt ICLNs from other duties and to involve the physicians more intensely in the implementation of ICLNs.


CT and MR imaging features in phosphaturic mesenchymal tumor-mixed connective tissue: A case report.
Phosphaturic mesenchymal tumor-mixed connective tissue (PMT-MCT) is rare and usually benign and slow-growing. The majority of these tumors is associated with sporadic tumor-induced osteomalacia (TIO) or rickets, affect middle-aged individuals and are located in the extremities. Previous imaging studies often focused on seeking the causative tumors of TIO, not on the radiological features of these tumors, especially magnetic resonance imaging (MRI) features. PMT-MCT remains a largely misdiagnosed, ignored or unknown entity by most radiologists and clinicians. In the present case report, a review of the known literature of PMT-MCT was conducted and the CT and MRI findings from three patient cases were described for diagnosing the small subcutaneous tumor. Typical MRI appearances of PMT-MCT were isointense relative to the muscles on T1-weighted imaging, and markedly hyperintense on T2-weighted imaging containing variably flow voids, with markedly heterogeneous/homogenous enhancement on post contrast T1-weighted fat-suppression imaging. Short time inversion recovery was demonstrated to be the optimal sequence in localizing the tumor.


Acute central neuropeptide Y administration increases food intake but does not affect hepatic very low-density lipoprotein (VLDL) production in mice.
Central neuropeptide Y (NPY) administration stimulates food intake in rodents. In addition, acute modulation of central NPY signaling increases hepatic production of very low-density lipoprotein (VLDL)-triglyceride (TG) in rats. As hypertriglyceridemia is an important risk factor for atherosclerosis, for which well-established mouse models are available, we set out to validate the effect of NPY on hepatic VLDL-TG production in mice, to ultimately investigate whether NPY, by increasing VLDL production, contributes to the development of atherosclerosis. Male C57Bl/6J mice received an intracerebroventricular (i.c.v.) cannula into the lateral (LV) or third (3V) ventricle of the brain. One week later, after a 4 h fast, the animals received an intravenous (i.v.) injection of Tran(35)S (100 µCi) followed by tyloxapol (500 mg/kg body weight; BW), enabling the study of hepatic VLDL-apoB and VLDL-TG production, respectively. Immediately after the i.v. injection of tyloxapol, the animals received either an i.c.v. injection of NPY (0.2 mg/kg BW in artificial cerebrospinal fluid; aCSF), synthetic Y1 receptor antagonist GR231118 (0.5 mg/kg BW in aCSF) or vehicle (aCSF), or an i.v. injection of PYY3-36 (0.5 mg/kg BW in PBS) or vehicle (PBS). Administration of NPY into both the LV and 3V increased food intake within one hour after injection (+164%, p<0.001 and +367%, p<0.001, respectively). NPY administration neither in the LV nor in the 3V affected hepatic VLDL-TG or VLDL-apoB production. Likewise, antagonizing central NPY signaling by either PYY3-36 or GR231118 administration did not affect hepatic VLDL production. In mice, as opposed to rats, acute central administration of NPY increases food intake without affecting hepatic VLDL production. These results are of great significance when extrapolating findings on the central regulation of hepatic VLDL production between species.


Eye care services for the populations of remote districts in eastern Taiwan: a practical framework using a Mobile Vision Van Unit.
To put a blindness prevention program into practice in remote districts of Eastern Taiwan, a Mobile Vision Van Unit (MVVU) was established to work as a community eyecare station. The aim of this study was to describe the operation and challenges encountered with this unit and its efficacy in expanding eyecare services. A population-based primary eyecare model was applied to a population in remote regions of eastern Taiwan. An MVVU, equipped with an autorefractometer, a non-contact tonometer, a slit-lamp biomicroscope, a retinoscope, an ophthalmoscope and a mini optician workshop was taken into remote areas of eastern Taiwan to provide comprehensive eyecare services. An integrated vertical referral system for further diagnosis and treatment was also employed. Data including the services provided, spectacles dispensed, health promotion activities conducted and the effectiveness of the model were collected and analysed. The main outcome measures were practicability of a primary eyecare model, prevalence of visual impairment and the major causes in middle-aged and elderly patients. Between 2002 and 2008, a total of 600 primary eyecare services were delivered to 28 indigenous villages and remote townships in eastern Taiwan. The MVVU screened a total of 35 275 inhabitants. The ages of those screened ranged from preschool children to the elderly, and 2073 patients were referred to secondary or tertiary centres in the middle-aged and elderly blindness prevention program. On-site dispensing of low-cost spectacles and the rapid delivery of more complex prescriptions were provided without charge to 1816 participants who could not afford glasses. In addition, 118 eye health educational programs and training courses for paramedical personnel and volunteers were conducted. An MVVU model for blindness prevention is highly feasible in its efficiency and cost-effectiveness in communities with deficient medical resources.


Incorporating patient preferences into clinical trial design: results of the opinions of patients on treatment implications of new studies (OPTIONS) project.
Traditionally, clinical outcomes comprising composite end points in cardiovascular trials are assigned equal weights in statistical analyses. However, the importance of weighting outcomes according to their relative severity is now recognized. This study aimed to elicit patients' perceptions of the importance of cardiovascular outcomes and treatment complications and compare them with those of clinicians. Interviewer-administered surveys, including rating, ranking, point-allocation and trade-off exercises, were conducted in 52 adults with confirmed coronary disease or previous myocardial infarction. Patients viewed "death" as the most severe cardiovascular outcome, followed by cardiogenic shock, congestive heart failure (CHF), and repeat myocardial infarction (re-MI), the same pattern observed in clinician responses in a previous study. Most patients were willing to accept a 3-fold increase in risk of systemic bleed (SB) or nonfatal intracranial hemorrhage (ICH) for a 20% reduction in risk of cardiogenic shock or 60% reduction in risk of CHF, but only a 2-fold increase in the risk of SB or ICH for a 20% reduction in risk of CHF or 60% reduction in risk of re-MI and no increase in risk of SB or ICH for a 20% reduction in risk of re-MI. Similar patterns were seen in a previous study of trade-offs in clinicians. Although patients' preferences appear to be comparable with those of clinicians, patients may be less willing than clinicians to tolerate potential treatment complications. The methods used in this study offer a feasible approach to incorporating patient preferences into cardiovascular trials and warrant further investigation in broader patient populations.


Concentration-dependent interaction of theophylline with d-tubocurarine.
The interaction of theophylline with d-tubocurarine chloride (dTC) was examined in rabbits. After steady-state subtherapeutic (less than 10 mg/l), therapeutic (10-20 mg/l), and toxic (greater than 20 mg/l) concentrations of theophylline, dose-response curves for dTC were determined and compared with controls that received no theophylline. At therapeutic concentrations of theophylline the effective dose for 50% inhibition of twitch (ED50) for dTC (mean +/- SE, 0.115 +/- 0.016 mg/kg) was significantly shifted to the left in comparison with the control (0.165 +/-0.008 mg/kg). The ED50 of dTC for the subtherapeutic group was 0.143 +/- 0.011 mg/kg, which was less than the control but not of statistical significance (P = 0.1). The ED50 for the toxic theophylline group was 0.168 +/- 0.003 mg/kg, which was not significantly different from controls but significantly different from the theophylline therapeutic and subtherapeutic groups. Thus, toxic concentrations of theophylline reversed the potentiating effects of therapeutic and subtherapeutic concentrations of dTC dose-response curves. Therefore, depending on concentration, theophylline exhibits a biphasic interaction with dTC. Surgical patients on theophylline may require less dTC intraoperatively. More importantly, the use of theophylline in the postoperative period to reverse anesthetic effects may result in recurarization.


Service guidelines based on Resource Utilization Groups Version III for Home Care provide decision-making support for case managers.
Increasing costs and budget reductions combined with increasing demand from our growing, aging population support the need to ensure that the scarce resources allocated to home care clients match client needs. This article details how Integrated Home Care for the Calgary Zone of Alberta Health Services considered ethical and economic principles and used data from the Resident Assessment Instrument for Home Care (RAI-HC) and case mix indices from the Resource Utilization Groups Version III for Home Care (RUG-III/HC) to formulate service guidelines. These explicit service guidelines formalize and support individual resource allocation decisions made by case managers and provide a consistent and transparent method of allocating limited resources.


[Autophagy Markers Induced by Influenza Virus and MUC1 Expressions in Cancer-Derived Cell Lines].
Influenza virus-induced autophagy is often accompanied by apoptosis and results in cell death in virus-infected cells. It is well known that autophagy is modulated by the mTOR/PI3K/Akt pathway, which plays an important role in the response to the presence of energy sources and external stimuli. This pathway is modulated by mucin 1 (MUC1), which has extracellular and intracellular components and plays an important role in metastasis and chemotherapeutic resistance. In this study, it was aimed to investigate the expression of MUC1 after the inoculation of influenza viruses into the cancer-derived cell cultures and, accordingly, the changes in autophagy markers such as mTOR and LC3B. In this study, MCF-7, HeLa and A-549 cell lines were used which have adenocarcinoma origin. To control the growth of influenza virus in these cells, the MDCK cell line was also inoculated. Centrifuge-enhanced shell-vial cell culture method was used in all experiments. Influenza A (H1N1) pdm09 strain was inoculated into these cell lines then the expressions of viral nucleic acid and cycle threshold (Ct) of MUC1, mTOR, LC3B associated genes were investigated by quantitative real-time reverse transcriptase polymerase chain reaction (qRTPCR) method in the samples taken from the supernatants of all cells at the end of the 48-hour incubation period. To investigate whether these markers were present in cells, after all cells were permeabilized with paraformaldehyde, cell-coated infected coverslips were stained with fluorescent labeled monoclonal antibodies developed against MUC1, mTOR, LC3B and influenza virus antigens. In the examination of fluorescence microscopy, all of the cell cultures (MCF-7, He-La and A-549) infected with influenza virus yielded positive results in terms of LC3B, mTOR and MUC1 monoclonal antibody staining, whereas all of the non-infected cells were found negative. Cycle threshold values of MUC1, LC3B and mTOR associated genes were found to be lower in A-549 cell line inoculated with influenza virus. Although protein expression was demonstrated in MCF-7 and He-La cell lines, similar changes were not detected in the 1/Ct values of genes in the autophagy pathway. The Ct value of the MUC1 gene was found to be higher only in the MCF-7 cell line after inoculation. In conclusion, it was observed that the specific expression pattern for influenza virus-induced autophagy was formed only in the A-549 cell line among the adenocarcinoma cells. It was thought that this relationship could constitute a dataset in further research on lung adenocarcinoma. However, in future studies, the determination of the expression of these genes at the protein level by using further tests will provide better comparison of the results.


Associations Between Sign Language Skills and Resting-State Functional Connectivity in Deaf Early Signers.
The processing of a language involves a neural language network including temporal, parietal, and frontal cortical regions. This applies to spoken as well as signed languages. Previous research suggests that spoken language proficiency is associated with resting-state functional connectivity (rsFC) between language regions and other regions of the brain. Given the similarities in neural activation for spoken and signed languages, rsFC-behavior associations should also exist for sign language tasks. In this study, we explored the associations between rsFC and two types of linguistic skills in sign language: phonological processing skill and accuracy in elicited sentence production. Fifteen adult, deaf early signers were enrolled in a resting-state functional magnetic resonance imaging (fMRI) study. In addition to fMRI data, behavioral tests of sign language phonological processing and sentence reproduction were administered. Using seed-to-voxel connectivity analysis, we investigated associations between behavioral proficiency and rsFC from language-relevant nodes: bilateral inferior frontal gyrus (IFG) and posterior superior temporal gyrus (STG). Results showed that worse sentence processing skill was associated with stronger positive rsFC between the left IFG and left sensorimotor regions. Further, sign language phonological processing skill was associated with positive rsFC from right IFG to middle frontal gyrus/frontal pole although this association could possibly be explained by domain-general cognitive functions. Our findings suggest a possible connection between rsFC and developmental language outcomes in deaf individuals.


A non-invasive acoustical method to measure the mean roughness height of the free surface of a turbulent shallow water flow.
In this paper, the directivity of the airborne sound field scattered by a dynamically rough free flow surface in a flume is used to determine the mean roughness height for six hydraulic conditions in which the uniform depth of the turbulent flow. The nonlinear curve fitting method is used to minimize the error between the predicted directivity and directivity data. The data fitting algorithm is based on the averaged solution for the scattered sound pressure as a function of angle which is derived through the Kirchhoff integral and its approximations. This solution takes into account the directivity of the acoustic source. For the adopted source and receiver geometry and acoustic frequency it is shown that the contribution from the stationary phase point (single specular point on the rough surface) yields similar results to those which can be obtained through the full Kirchhoff's integral. The accuracy in the inverted mean roughness height is comparable to that achieved with an array of conductive wave probes. This method enables non-invasive estimation of the flow Reynolds number and uniform flow depth.


[Informed consent--on the right of self-determination].
The idea of informed consent asks for the right of self-determination which is very difficult to achieve. Human life does not depend on one's will, and neither does suffering. That is human being does not control one's own life, even though one must be responsible for it. The right of self-determination has long and struggling history. As a result we have acquired the concept of informed consent. And then the physician-patient relationship is no longer considered to be based on paternalism and now the new model is seeked for. All human beings are mortal and cannot inevitably escape suffering. Therefore we must consider the physician-patient relationship as the one based on equality. The problem of self-determination should arise from this understanding.


Effect of Zinc Supplementation on Renal Anemia in 5/6-Nephrectomized Rats and a Comparison with Treatment with Recombinant Human Erythropoietin.
Anemia is a severe complication in patients with chronic kidney disease (CKD). Treatment with exogenous erythropoietin (EPO) can correct anemia in many with CKD. We produced 5/6-nephrectomized rats that became uremic and anemic at 25 days post surgery. Injection of the anemic 5/6-nephrectomized rats with 2.8 mg zinc/kg body weight raised their red blood cell (RBC) levels from approximately 85% of the control to 95% in one day and continued for 4 days. We compared the effect of ZnSO4 and recombinant human erythropoietin (rHuEPO) injections on relieving anemia in 5/6-nephrectomized rats. After three consecutive injections, both the ZnSO4 and rHuEPO groups had significantly higher RBC levels (98 ± 6% and 102 ± 6% of the control) than the saline group (90 ± 3% of the control). In vivo, zinc relieved anemia in 5/6-nephrectomized rats similar to rHuEPO. In vitro, we cultured rat bone marrow cells supplemented with ZnCl2, rHuEPO, or saline. In a 4-day suspension culture, we found that zinc induced erythropoiesis similar to rHuEPO. When rat bone marrow cells were supplement-cultured with zinc, we found that zinc stimulated the production of EPO in the culture medium and that the level of EPO produced was dependent on the concentration of zinc supplemented. The production of EPO via zinc supplementation was involved in the process of erythropoiesis.


Evaluating the medical evidence for quality improvement.
Neonatal-Perinatal Medicine has had both its triumphs and its disasters regarding the dissemination of new interventions. Evidence-based medicine (EBM), the integration of clinical expertise, patient values, and best evidence for decision making in patient care, provides a blueprint for how to safely and effectively continue make headway in our rapidly changing field. The principles of EBM have been discussed in multiple articles and primers. EBM involves formulating the appropriate question, finding the evidence, appraising the evidence, and evaluating the clinician's performance in implementing these practices. At an institutional level, this type of thorough evidence review is critical to successful quality improvement projects, particularly if these projects hope to improve clinical outcome. On evaluation of best practice, one sees great variation in the implementation of practices that are strongly evidence based (increased use of antenatal steroids, decreased use of postnatal steroids), practices rich in evidence lacking certainty regarding the best approach (prophylactic indomethacin to prevent intraventricular hemorrhage), and widespread dissemination of practices that have little evidence to support their use (stabilization on high-frequency ventilation).


Effect of burst and recombination models for Monte Carlo transport of interacting carriers in a-Se x-ray detectors on Swank noise.
The authors describe the modification to a previously developed Monte Carlo model of semiconductor direct x-ray detector required for studying the effect of burst and recombination algorithms on detector performance. This work provides insight into the effect of different charge generation models for a-Se detectors on Swank noise and recombination fraction. The proposed burst and recombination models are implemented in the Monte Carlo simulation package, ARTEMIS, developed by Fang et al. ["Spatiotemporal Monte Carlo transport methods in x-ray semiconductor detectors: Application to pulse-height spectroscopy in a-Se," Med. Phys. 39(1), 308-319 (2012)]. The burst model generates a cloud of electron-hole pairs based on electron velocity, energy deposition, and material parameters distributed within a spherical uniform volume (SUV) or on a spherical surface area (SSA). A simple first-hit (FH) and a more detailed but computationally expensive nearest-neighbor (NN) recombination algorithms are also described and compared. Simulated recombination fractions for a single electron-hole pair show good agreement with Onsager model for a wide range of electric field, thermalization distance, and temperature. The recombination fraction and Swank noise exhibit a dependence on the burst model for generation of many electron-hole pairs from a single x ray. The Swank noise decreased for the SSA compared to the SUV model at 4 V/μm, while the recombination fraction decreased for SSA compared to the SUV model at 30 V/μm. The NN and FH recombination results were comparable. Results obtained with the ARTEMIS Monte Carlo transport model incorporating drift and diffusion are validated with the Onsager model for a single electron-hole pair as a function of electric field, thermalization distance, and temperature. For x-ray interactions, the authors demonstrate that the choice of burst model can affect the simulation results for the generation of many electron-hole pairs. The SSA model is more sensitive to the effect of electric field compared to the SUV model and that the NN and FH recombination algorithms did not significantly affect simulation results.


Neurotoxicity of fragrance compounds: A review.
Fragrance compounds are chemicals belonging to one of several families, which are used frequently and globally in cosmetics, household products, foods and beverages. A complete list of such compounds is rarely found on the ingredients-list of such products, as "fragrance mixtures" are defined as "trade secrets" and thus protected by law. While some information regarding the general toxicity of some of these compounds is available, their neurotoxicity is known to a lesser extent. Here, we discuss the prevalence and neurotoxicity of fragrance compounds belonging to the three most common groups: phthalates, synthetic musks and chemical sensitizers.


Unit root properties of OECD health care expenditure and GDP data.
This note reconsiders the unit root properties of health care expenditure (HCE) and gross domestic product (GDP) for OECD countries. The time-series properties of this data set has been much discussed in the literature with contrasting results from the application of a range of test procedures. We use a recently developed test to examine the relationship between the two variables. The results in this paper confirm earlier findings that when the data are considered as a panel, there is strong evidence of unit roots in both GDP and HCE data.


Hybrid reduced graph for SAR studies.
The purpose of this work is the definition and evaluation of both atomic and local new hybrid indices. Inspired by the Refractotopological State Index for Atoms, the new atomic indices are theoretically supported by graph theory principles. The local indices, named Descriptor Centres (DCs), are obtained from the sum of the atomic values of the atoms in the selected group. Different classifiers were used for structure-activity relationship (SAR) studies, including multilayer perceptron (MLP), support vector machines (SVM) and meta-classifiers. Prediction with SVM and MLP was around 60%, but the best result was obtained with the meta-classifiers, bagging, decorate and others, with more than 92% accurate prediction. These new hybrid descriptors derived from the Refractotopological State Index for Atoms show a low mutual correlation coefficient. The same behaviour is found in the analogously defined Descriptors Centres. The best results are obtained with the inclusion of the distance between DCs with the use of meta-classifiers.


JWA deficiency induces malignant transformation of murine embryonic fibroblast cells.
The present study aimed to investigate the effects of JWA knockout (JWA-/-) on malignant transformation of murine embryonic fibroblast (MEF) cells using a conditional JWA-/- mouse model. Once MEF cells were prepared, the potential role of JWA-/- on proliferation, migration, invasion and colony formation of MEF cells was investigated by cytological examination. The effects of JWA-/- on the regulation and protein expression levels of epithelial-mesenchymal transition (EMT)-related proteins in MEF cells, including poly(ADP-ribose) polymerase-1 (PARP-1), vimentin, β-catenin and E-cadherin, were investigated using western blot analysis. The tumorigenicity of JWA deficiency was explored using nude mouse xenografts and subcutaneous inoculation of MEF cells exhibiting JWA-/-. JWA-/- was able to increase cell proliferation, migration, invasion and colony formation in the malignant transformation of MEF cells. The protein expression levels of PARP-1, vimentin and β-catenin were upregulated, whereas E-cadherin was downregulated in JWA-/- MEF cells. The tumor formation was observed in mice following subcutaneous inoculation of MEF with JWA-/-, whereas no tumor was formed in the mice treated with functional JWA MEF cells. In conclusion, the present findings suggest that JWA-/- has important roles in cell proliferation, migration, invasion and colony formation and is able to induce the malignant transformation of MEF cells. The expression levels of EMT-related proteins changed and tumorigenicity increased in JWA-/- MEF cells compared with cells with functional JWA. The present findings indicate that JWA may function as an anti-oncogene in tumorigenesis.


Iron-enriched oligodendrocytes: a reexamination of their spatial distribution.
Previous histochemical studies of iron in the brain demonstrated iron enrichment in oligodendrocytes, but the iron-enriched oligodendrocytes had a spatially restricted distribution that excluded major white matter tracts. In this study we used techniques designed to permeabilize tissue, combined with iron histochemistry, and we observed iron-enriched oligodendrocytes in regions previously thought to lack such cells. Our data suggest that most, if not all, oligodendrocytes are enriched in iron. We suggest that iron functions in the formation and/or maintenance of the myelin sheet and may play a role in the pathology of myelin diseases.


Monitoring methaemoglobinaemia in birds using 5 μL of whole blood.
Methaemoglobin (MetHb) forming compounds such as para-aminopropiophenone (PAPP) and sodium nitrite (NaNO2) have recently been adopted for the lethal control of a range of invasive carnivores and mustelids. Determining the relative hazard of these compounds to non-target bird species is an important component of ecological risks evaluation. Problematically, some potential non-target bird species may be as small as 10 g in body mass, thus placing limitations on blood volumes that can be routinely sampled. Accordingly, we developed methods to quantify markers of increasing methaemoglobinaemia at their point of collection that required only 5 μL of whole blood. A 3 μL blood aliquot is pipetted into a plastic micro-cuvette and placed in a custom made holder optically coupled to the Ocean Optics spectrometer, enabling absorbance for oxyhaemoglobin (HbO: 575 nm) and MetHb (630 nm) to be determined. Haemoglobin (HbFe2+), packed cell volume (PCV) and lactate (LAC) data were generated from the remaining 2 μL aliquot apportioned to biosensor strips for the Cera-Check® and Lactate Scout® point-of-care devices. After oral doses of PAPP, a methaemoglobinaemia absorbance index (MAI = absorbance 575 nm-absorbance 630 nm) was strongly and significantly associated with dose-dependent declines in HbFe2+ in 9 bird species. Quantifying dose-dependent responses to MetHb-forming agents at the point of sample collection avoids analytical and storage artifacts arising from sample degradation that appears to be a much greater problem in avian blood compared to mammalian blood.


The hypolipidemic effect of a new ACAT inhibitor, VULM 1457, in diabetic-hypercholesterolaemic rats.
The use of inhibitors of enzyme acyl-CoA: cholesterol acyltransferase (ACAT) seems to be a novel potential approach for a therapeutic treatment of dyslipidaemias and atherosclerosis. VULM 1457 is an ACAT inhibitor, which has expressed potent hypolipidemic and antiatherosclerotic effects in previous studies. In this study, we used streptozocin-induced diabetic rats, which were fed a fat-cholesterol diet to evaluate the affect of VULM 1457 on the atherogenic lipids levels in both plasma and liver. VULM 1457, with a slight influence on triglyceride levels, significantly reduced plasma and hepatic cholesterol concentrations (p < 0.05, p < 0.001; respectively) in the diabetic-hypercholesterolaemic rats.


In vitro cell composition identification of wood decay fungi by Fourier transform infrared spectroscopy.
Decay pathogens follow dissimilar metabolic mechanisms to cause irreversible damage to woody tissues. The objective of this study is to perform inter- and intra-species microbial cell structural comparison using attenuated total reflectance Fourier transform infrared spectroscopy. Representative fungi species, causing brown rot and white rot, namely, Postia placenta and Trametes versicolor, respectively, were cultured in laboratory conditions. In vitro spectral measurements were performed at periodic two week intervals of fungal growth. The study shows structural differences for both species of fungi. The prominent presence of protein amide, carbohydrate and carboxyl bands was of interest. Spectral deconvolution of the infrared broadband around approximately 3300 cm-1 produced peaks at four different wavenumbers. The hydrogen bond energy obtained at the four wavenumbers, from deconvolution, varied from approximately 41 kJ mol-1 to approximately 7 kJ mol-1, indicating the presence of strong and weak forces in microbial cell structure. The hydrogen bond distance, obtained at the deconvoluted wavenumbers, varied between 2.7 Å-2.8 Å, indicating the presence of short and long-distance forces within microbial cells. Microscopic observation showed mycelium colonization, hyphal tip and lateral branching.


From the Gut to the Heart: Campylobacter jejuni Enteritis Leading to Myopericarditis.
Campylobacter jejuni enteritis is the most common enteric infection in the developed world. Although rare, pericarditis and myopericarditis have been increasingly documented as complications following campylobacteriosis. The present paper implicates that myopericarditis and non-ischemic cardiomyopathy following Campylobacter jejuni infection might be more prevalent than initially thought and perhaps underreported so far. Therefore, it is imperative to perform the appropriate initial diagnostic testing, including stool cultures, in order to make an accurate diagnosis early in the course of the disease. Identifying the etiology of myopericarditis as bacterial will ensure appropriate treatment with antibiotics in addition to the cardiac medications needed for supportive care.


Evaluating the association of workplace psychosocial stressors with occupational injury, illness, and assault.
This research project characterizes occupational injuries, illnesses, and assaults (OIIAs) as a negative outcome associated with worker exposure to generalized workplace abuse/harassment, sexual harassment, and job threat and pressure. Data were collected in a nationwide random-digit-dial telephone survey conducted during 2003-2004. There were 2151 study interviews conducted in English and Spanish. Analyses included cross tabulation with Pearson's Chi-Square and logistic regression analyses. Three hundred and fifty-one study participants reported having an OIIA during the 12 months preceding the study. Occurrences of generalized workplace harassment (OR = 1.53; CI = 1.33-1.75, p ≤ 0.05); sexual harassment (OR = 1. 18; CI = 1.04-.34, p ≤ 0.05); and job pressure and threat (OR = 1.26; CI = 1.10-1.45, p ≤ 0.05) were significantly associated with reporting an OIIA. The psychosocial environment is significantly associated with an increased risk of OIIA. Further research is needed to understand causal pathways and to explore potential interventions.


Anomalous Origin of a Right Coronary Artery from Pulmonary Artery.
Congenital defects of the coronary arteries are noted in 0.2-1.4% of the general population. The first case of an anomalous origin of right coronary artery from pulmonary artery (ARCAPA) was described by Brooks in 1885. ARCAPA has an overall incidence of 0.002% in the general population. Most of the cases are asymptomatic; however, it can lead to serious complications such as heart failure, ischemia, and sudden death. A 57-year-old man presented to the cardiologist's office with complaints of shortness of breath and fatigue. The patient also had a previous history of coronary stents and heart failure. Initially, he was evaluated with a stress test which was reported as abnormal. The patient then underwent an invasive coronary angiography that revealed anomalous origin of the right coronary artery (RCA) and multivessel disease. Cardiothoracic surgery evaluated the patient and coronary artery bypass graft was performed. During the surgery, the anomalous origin of RCA from the pulmonary artery was identified and was successfully corrected by reimplanting the RCA into the ascending aorta. The anomalous origin of RCA is a rare yet life-threatening condition. The RCA due to its location of origin from the pulmonary artery tends to be a low-pressure vessel with a very thin and fragile wall. It also serves as a retrograde venous conduit from the left coronary circulation into the pulmonary artery. This connection results in a left-to-right shunt that explains the increase in oxygen saturation in the pulmonary artery and the high cardiac output which is normally seen in these cases. The clinical presentation can vary from coronary ischemia to heart failure or sudden death. Therefore, surgical correction is recommended even in asymptomatic patients. We present a case of an anomalous origin of RCA from the pulmonary artery which, unlike the origin of left coronary from pulmonary artery, is very rare. Patients with this condition should have early correction even if they are asymptomatic in order to prevent long-term complications.


Adenine Components in Biomimetic Metal-Organic Frameworks for Efficient CO2 Photoconversion.
Visible-light driven photoconversion of CO2 into energy carriers is highly important to the natural carbon balance and sustainable development. Demonstrated here is the adenine-dependent CO2 photoreduction performance in green biomimetic metal-organic frameworks. Photocatalytic results indicate that AD-MOF-2 exhibited a very high HCOOH production rate of 443.2 μmol g-1 h-1 in pure aqueous solution, and is more than two times higher than that of AD-MOF-1 (179.0 μmol g-1 h-1 ) in acetonitrile solution. Significantly, experimental and theoretical evidence reveal that the CO2 photoreduction reaction mainly takes place at the aromatic nitrogen atom of adenine molecules through a unique o-amino-assisted activation rather than at the metal center. This work not only serves as an important case study for the development of green biomimetic photocatalysts used for artificial photosynthesis, but also proposes a new catalytic strategy for efficient CO2 photoconversion.


Coupled cell-free synthesis, segregation, and core glycosylation of a secretory protein.
mRNA from rat mammary glands 13-15 days post partum was translated in a wheat germ cell-free system either in the absence or in the presence of ribosome-denuded membranes prepared from isolated rough microsomes of dog pancreas. Newly synthesized alpha-lactalbumin was identified by immunoprecipitation with a monospecific rabbit antiserum against rat alpha-lactalbumin and was characterized by partial amino-terminal sequence determination and by lectin affinity chromatography. In the absence of membranes a presumably unglycosylated form of alpha-lactalbumin was synthesized that bound neither to concanavalin A-Sepharose nor to Ricinus communis lectin-agarose and that contained an amino-terminal signal peptide region comprising 19 amino acid residues. In the presence of membranes a processed form was synthesized that lacked the signal peptide portion and that had an amino-terminal sequence identical to that of mature alpha-lactalbumin. Furthermore, this processed form was found to be segregated, presumably within the microsomal vesicles, because it was resistant to post-translational proteolysis. It was also found to be glycosylated, and because it bound to concanavalin A-Sepharose, from which it could be eluted specifically by alpha-methyl mannoside, but not to R. communis lectin-agarose, it was presumably core-glycosylated. Processing, segregation, and core glycosylation were observed to proceed only when membranes were present during translation and not when they were added after translation.


Speckle experiments in random lasers.
We present measurements of speckle in a random laser. We analyze its first-order statistics and show that, contrary to what might be expected for passive systems, analyses of the intensity distribution P(I) and the speckle spot size do provide information about light transport inside the system. P(I) is used to determine the degree to which an incident probe is amplified by the random laser. The shrinking speckle spot size reflects the change in path length distribution P(Lambda); we deduce that the average path length <Lambda> in the studied random laser is two times longer above threshold than in a passive diffusive system.


[Stability of Shigella flexneri attenuated strain 2A 77 ADE- RIF-r after cultivation in a fermenter and lyophilization].
The method for the cultivation of S. flexneri attenuated strain 2a 77 ade- rifr in a fermenter with the use of casein fermentative broth containing 200-250 mg% of amino nitrogen has been developed. No changes in the properties of the initial strain have been found after its cultivation in a fermenter or after the lyophilization of the cultures grown in a fermenter. After cultivation in casein fermentative broth with 100 mg% of amino nitrogen the presence of S-R dissociation has been established, the S colonies having the properties of the initial strain. The reversion of the R colonies to prototrophism in adenine and differences in the level of their resistance to rifampicin are observed. The study of the plasmid profile of the initial strain and its ade+ revertants has revealed the disappearance of plasmids with a molecular weight of 140 MD in these revertants. All clones under study (ade+ and ade-) show negative results in the keratoconjunctival test. The conditions of cultivation and the causes of reversion are discussed.


Exploring the journey of emodin as a potential neuroprotective agent: Novel therapeutic insights with molecular mechanism of action.
Emodin is an anthraquinone derivative found in the roots and bark of a variety of plants, molds, and lichens. Emodin has been used as a traditional medication for more than 2000 years and is still common in numerous herbal drugs. Emodin is plentiful in the three plant families, including Polygonaceae (Rheum, Rumex, and Polygonum spp.), Fabaceae (Cassia spp.), and Rhamnaceae (Rhamnus, Frangula, and Ventilago spp.). Emerging experimental evidences indicate that emodin confers a wide range of pharmacological activities; special focus was implemented toward neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, cerebral ischemia, anxiety and depression, schizophrenia, chronic hyperglycemic peripheral neuropathy, etc. Numerous preclinical evidences were established in support of the neuroprotection of emodin. However, this review highlighted the role of emodin as a potent neurotherapeutic agent; therefore, its evidence-based functionality on neurological disorders (NDs).


Effects of sharing information on drug administration errors in pediatric wards: a pre-post intervention study.
Drug administration errors are more likely to reach the patient than other medication errors. The main aim of this study was to determine whether the sharing of information on drug administration errors among health care providers would reduce such problems. This study involved direct, undisguised observations of drug administrations in two pediatric wards of a major teaching hospital in Kuala Lumpur, Malaysia. This study consisted of two phases: Phase 1 (pre-intervention) and Phase 2 (post-intervention). Data were collected by two observers over a 40-day period in both Phase 1 and Phase 2 of the study. Both observers were pharmacy graduates: Observer 1 just completed her undergraduate pharmacy degree, whereas Observer 2 was doing her one-year internship as a provisionally registered pharmacist in the hospital under study. A drug administration error was defined as a discrepancy between the drug regimen received by the patient and that intended by the prescriber and also drug administration procedures that did not follow standard hospital policies and procedures. Results from Phase 1 of the study were analyzed, presented and discussed with the ward staff before commencement of data collection in Phase 2. A total of 1,284 and 1,401 doses of drugs were administered in Phase 1 and Phase 2, respectively. The rate of drug administration errors reduced significantly from Phase 1 to Phase 2 (44.3% versus 28.6%, respectively; P<0.001). Logistic regression analysis showed that the adjusted odds of drug administration errors in Phase 1 of the study were almost three times that in Phase 2 (P<0.001). The most common types of errors were incorrect administration technique and incorrect drug preparation. Nasogastric and intravenous routes of drug administration contributed significantly to the rate of drug administration errors. This study showed that sharing of the types of errors that had occurred was significantly associated with a reduction in drug administration errors.


The identification of AMZ2 as a candidate causative gene in a severe teratozoospermia patient characterized by vacuolated spermatozoa.
Teratozoospermia with cephalic defects is one of the most severe types of sperm defects known to date. While several monogenic factors are linked to cephalic abnormalities, such as globozoospermia and macrozoospermia, the genetic cause of vacuolated spermatozoa remains inadequately described. Here, we analyzed whole-exome sequencing (WES) data for an individual from a consanguineous family with severely vacuolated spermatozoa. The analysis revealed a novel homozygous c.520A>G (p.Thr174Ala) variant in the archaelysin family metallopeptidase 2 (AMZ2), a gene that encodes a zinc metalloprotease previously shown to be highly expressed in the testes and sperm. Multiple algorithms predicted this variant to be a damaging mutation. Consistent with an autosomal recessive mode of inheritance, this variant was inherited from heterozygous parental carriers. To investigate the potential pathogenicity of the identified variant, we compared the AMZ2 expression in sperm cells from the patient with the AMZ2 variant and from a healthy control. Immunoblot analysis revealed that the homozygous missense variant in AMZ2 abolished AMZ2 expression in the spermatozoa. Our findings reveal a candidate causative gene for vacuolated spermatozoa.


RF-MEMS Monolithic K and Ka Band Multi-State Phase Shifters as Building Blocks for 5G and Internet of Things (IoT) Applications.
RF-MEMS, i.e., Micro-Electro-Mechanical Systems (MEMS) for Radio Frequency (RF) passive components, exhibit interesting characteristics for the upcoming 5G and Internet of Things (IoT) scenarios, in which reconfigurable broadband and frequency-agile devices, like high-order switching units, tunable filters, multi-state attenuators, and phase shifters will be necessary to enable mm-Wave services, small cells, and advanced beamforming. In particular, satellite communication systems providing high-speed Internet connectivity utilize the K and Ka bands, which offer larger bandwidth compared to lower frequencies. This paper focuses on two design concepts of multi-state phase shifter designed and manufactured in RF-MEMS technology. The networks feature 4 switchable stages (16 states) and are developed for the K and Ka bands. The proposed phase shifters are realized in a surface micromachining RF-MEMS technology and the experimentally measured parameters are compared with Finite Element Method (FEM) multi-physical electromechanical and RF simulations. The simulated phase shifts at both the operating bands fit well the measured value, despite the measured losses (S21) are larger than 5-7 dB if compared to simulations. However, such a non-ideality has a technological motivation that is explained in the paper and that will be fixed in the manufacturing of future devices.


Urban form and scale shaped the agroecology of early 'cities' in northern Mesopotamia, the Aegean and Central Europe.
Agricultural extensification refers to an expansive, low-input production strategy that is land rather than labour limited. Here, we present a robust method, using the archaeological proxies of cereal grain nitrogen isotope values and settlement size, to investigate the relationship between agricultural intensity and population size at Neolithic to Bronze/Iron Age settlement sites in northern Mesopotamia, the Aegean and south-west Germany. We conclude that urban form-in particular, density of occupation-as well as scale shaped the agroecological trajectories of early cities. Whereas high-density urbanism in northern Mesopotamia and the Aegean entailed radical agricultural extensification, lower density urbanism in south-west Germany afforded more intensive management of arable land. We relate these differing agricultural trajectories to long-term urban growth/collapse cycles in northern Mesopotamia and the Aegean, on the one hand, and to the volatility of early Iron Age elite power structures and urban centralization in south-west Germany, on the other.


Factor V inhibitor: case report.
Acquired inhibitors to coagulation factors are rare, certainly those directed against factor V. A total of around 150 cases have so far been reported, of which the greater part was due to bovine thrombin exposure. We report the case of a patient who developed a factor V inhibitor during a postoperative period. This report describes possible aetiologies, varying clinical conditions and treatment possibilities as described in the literature. Furthermore, this case report is an example of the often unpredictable disease progression in a patient with existence of a factor V inhibitor.


Risperidone-associated, benign transient visual disturbances in schizophrenic patients with a past history of LSD abuse.
Two schizophrenic patients, who had a prior history of LSD abuse and who had previously developed EPS with classic antipsychotics, were successfully treated with risperidone. They both reported short episodes of transient visual disturbances, which appeared immediately after starting treatment with risperidone. This imagery resembled visual disturbances previously experienced as "flashbacks" related to prior LSD consumption. Risperidone administration was continued and the visual disturbances gradually wore off. During a six-month follow-up period, there was no recurrence of visual disturbances. This phenomenon may be interpreted as a benign, short-term and self-limiting side effect which does not contraindicate the use of risperidone or interfere with treatment. Conclusions based on two case reports should be taken with appropriate caution.


Association with right atrial strain with right atrial pressure: an invasive validation study.
Echocardiographic assessment of right atrial pressure (RAP) from inferior vena cava (RAPIVC) dimension may underestimate catheter-derived (RAPC). As right atrial (RA) deformation, measured by speckle tracking, is preload-dependent, we hypothesized that RA strain may improve estimation of RAPC. Right atrial strain components [RA reservoir function (ƐR), peak RA contraction (ƐCT) and RA conduit function (ƐCD)] were measured in 125 of 175 patients who had echocardiography and invasive measures of RAP (median difference 1 day). To determine whether RA strain measures differentiated patients with correct vs incorrect RAPIVC assessment, categories with RAPIVC values < 3, 8 and > 15 mmHg were compared with RAPC groups < 3, 4-7, 8-10, 11-14 and > 15 mmHg. Non-invasively determined RAP was significantly lower (p = 0.001) than invasively determined RAPC, with a weak correlation (r = 0.35, p < 0.001). RA strain components were associated with RA size, RV function and IVC size. In those with RAPIVC > 15 mmHg, half of patients were categorized into RAP < 10 mmHg. There were no significant differences in RA characteristics that differentiated patients in whom echocardiographic estimation of RAP was inaccurate. Right atrial strain measures were feasible, and had associations with RA size, RV systolic function and IVC size. Right atrial strain was significantly different between those with normal vs raised pressure, but it did not identify those with incorrect echocardiographic assessment of RAP.


To what extent does severity of loneliness vary among different mental health diagnostic groups: A cross-sectional study.
Loneliness is a common and debilitating problem in individuals with mental health disorders. However, our knowledge on severity of loneliness in different mental health diagnostic groups and factors associated with loneliness is poor, thus limiting the ability to target and improve loneliness interventions. The current study investigated the association between diagnoses and loneliness and explored whether psychological and social factors were related to loneliness. This study employed a cross-sectional design using data from a completed study which developed a measure of social inclusion. It included 192 participants from secondary, specialist mental health services with a primary diagnosis of psychotic disorders (n = 106), common mental disorders (n = 49), or personality disorders (n = 37). The study explored differences in loneliness between these broad diagnostic groups, and the relationship to loneliness of: affective symptoms, social isolation, perceived discrimination, and internalized stigma. The study adhered to the STROBE checklist for observational research. People with common mental disorders (MD = 3.94, CI = 2.15 to 5.72, P < 0.001) and people with personality disorders (MD = 4.96, CI = 2.88 to 7.05, P < 0.001) reported higher levels of loneliness compared to people with psychosis. These differences remained significant after adjustment for all psychological and social variables. Perceived discrimination and internalized stigma were also independently associated with loneliness and substantially contributed to a final explanatory model. The severity of loneliness varies between different mental health diagnostic groups. Both people with common mental disorders and personality disorders reported higher levels of loneliness than people with psychosis. Addressing perceived mental health discrimination and stigma may help to reduce loneliness.


The dynamic distribution of CARD11 at the immunological synapse is regulated by the inhibitory kinesin GAKIN.
T cell receptor (TCR) signaling to NF-κB is required for antigen-induced T cell activation. We conducted an expression-cloning screen for modifiers of CARD11, a critical adaptor in antigen receptor signaling, and identified the kinesin-3 family member GAKIN as a CARD11 inhibitor. GAKIN negatively regulates TCR signaling to NF-κB, associates with CARD11 in a signal-dependent manner and can compete with the required signaling protein, Bcl10, for association. In addition, GAKIN dynamically localizes to the immunological synapse and regulates the redistribution of CARD11 from the central region of the synapse to a distal region. We propose that CARD11 scaffold function and occupancy at the center of the synapse are negatively regulated by GAKIN to tune the output of antigen-receptor signaling.


Clinical testing of an innovative tool for the assessment of biomechanical strategies: the Timed "Up and Go" Assessment of Biomechanical Strategies (TUG-ABS) for individuals with stroke.
To investigate the reliability and construct and criterion- related validities of the Timed "Up and Go" Assessment of Biomechanical Strategies (TUG-ABS), when used with subjects with hemiparesis due to stroke within clinical settings. Construct validity was investigated by the following methods: the known groups, convergence, discriminant analyses, and the opinions of clinical professionals, who used the TUG-ABS with subjects with stroke. The criterion-related validity was investigated by comparing the realtime and video observation scores. Inter-rater reliability was investigated by two independent examiners using both realtime and video observations. The TUG-ABS differentiated people with stroke from healthy controls (p < 0.001), was correlated with the time spent to perform the TUG (rs = –0.85; p < 0.001), and correctly classified 98% of the subjects with stroke (p < 0.001). In addition, all of the clinicians who used the TUG-ABS in their clinical settings, provided positive evaluations. Agreement was also observed between real-time and video observations (0.27 ≤ kappa ≤ 0.85; p < 0.01). Furthermore, the TUG-ABS was reliable for both real-time (0.24 ≤ kappa ≤ 1.00; p < 0.05) and video observations (0.15 ≤ kappa ≤ 0.94; p < 0.05). The TUG-ABS demonstrated good construct and criterion-related validities, as well as reliability, when applied in subjects with stroke within clinical settings, which supported the theoretical assumptions employed for its development.


Impacts of pesticide use on semen characteristics among rice farmers in Kienxuong District, Thaibinh Province, Vietnam.
This case-control study assessed the effects of pesticide use on semen characteristics among rice farmers of Kienxuong District, Thaibinh Province, Vietnam. Semen samples of 1,036 rice farmers were obtained by manual masturbation and screened at Commune Health Stations. Of these, 156 abnormal semen samples were identified; 314 rice farmers with normal semen were recruited as controls. The semen characteristics (volume, sperm concentration, total sperm count, motility, vitality and morphology) of the cases were considerably poorer than the controls. Factors associated with abnormal semen after adjusting for age, smoking and alcohol drinking by logistic regression were: distance of less than 300 meters from household to rice fields and duration of work over 10 years as a farmer (adjusted OR = 3.16, 95% Cl: 1.97-5.05 and adjusted OR = 3.98, 95% Cl: 2.20-7.21, respectively). Rice farmers without personal protective equipment (PPE) when spraying pesticides and without pesticide training (adjusted OR = 3.05, Cl: 1.92-4.85 and adjusted OR = 1.90, Cl: 1.14-3.16, respectively) were also at risk for abnormal semen compared to controls. These findings showed the strength of association between pesticide use and abnormal semen characteristics among rice farmers in Kienxuong District, Thaibinh Province, Vietnam.


Agenesis of corpus callosum and anophthalmia in the asplenia syndrome. A recognisable association?
We present a newborn infant with the asplenia syndrome and unique associated features of corpus callosum agenesis, anophthalmia and coloboma. Previous reports of eye abnormalities or corpus callosum agenesis in patients with asplenia suggest that this may represent a distinct clinically recognisable entity of abnormal lateralisation.