Prevention and treatment of traumatic brain injury-related delirium: a systematic review.
Our systematic review examines the effectiveness and safety of non-pharmacologic and pharmacologic interventions in preventing or treating traumatic brain injury (TBI)-related delirium in acute care. We searched four electronic databases (MEDLINE, EMBASE, CENTRAL/CDSR, and PsycINFO) to identify randomized controlled trials (RCTs), quasi-experimental, and observational studies. Eligible studies included adults with TBI, at least one comparator group, delirium as an outcome and took place in acute care. Two reviewers independently completed all study screening, data abstraction, and risk of bias assessment using the Cochrane risk of bias 2 tool for RCTs or risk of bias in non-randomized studies-of interventions tool for observational studies. We implemented the PROGRESS-Plus framework to describe social determinants of health (SDoH) reporting. We identified 20,022 citations, reviewed 301 in full text, and included eight studies in the descriptive synthesis. The mean age of study participants ranged from 32 to 62 years. 12.5% of included studies reported SDoH. Included studies had moderate-to-high risk of bias. Studies compared reorientation programs and an intervention bundle to usual care, but these interventions were not better than usual care in treating TBI-related delirium. Individual studies found that rosuvastatin and aripiprazole were more efficacious than placebo, and dexmedetomidine was more efficacious than propofol and haloperidol for preventing TBI-related delirium. No studies reported safety as the primary outcome. We identified efficacious pharmacologic interventions for preventing TBI-related delirium, but these studies were at moderate-to-high risk of bias, which limits our confidence in these findings. Future studies should incorporate safety outcomes, and a diverse study population, including older adults.


The acute and chronic effects of (+) and (-) oxaprotiline upon melatonin secretion in normal subjects.
Ten healthy male subjects were treated for three weeks with (+)oxaprotiline, a selective inhibitor of noradrenaline (NA) uptake and with (-)oxaprotiline which does not inhibit NA uptake. Plasma melatonin concentrations were measured throughout the night at 0, 1, 7 and 21 days and were higher during treatment with (+)oxaprotiline than with (-)oxaprotiline for the entire three weeks of treatment. Since NA stimulates the production and secretion of melatonin, these results are consistent with a sustained increase in noradrenergic activity within the pineal, during 21 days of treatment with an effective NA uptake inhibitor.


Heterogeneous distribution of left ventricular contractile injury in chronic aortic insufficiency.
Global systolic strain has been described previously in patients with chronic aortic insufficiency (AI). This study explored regional differences in contractile injury. Tagged magnetic resonance images of the left ventricle (LV) were acquired and analyzed to calculate systolic strain in 42 patients with chronic AI. Multiparametric systolic strain analysis was applied to relate cardiac function in AI patients to a normal strain database (N = 60). AI patients were classified as having normal or poor function based on their results. A two-way repeated-measures analysis of variance was applied to analyze regional differences in injury. The mean and standard deviation of raw strain values (circumferential strain, longitudinal strain, and minimum principal strain angle) are presented over the entire LV in our normal strain database. Of the 42 patients with AI, 15 could be defined as having poor function by multiparametric systolic strain analysis. In AI patients with poor function, statistical analysis showed significant differences in injury between standard LV regions (F(3.69,44.33) = 3.47, p = 0.017) and levels (F(1.49,17.88) = 4.41, p = 0.037) of the LV, whereas no significant differences were seen in the group with normal cardiac function. Patients with poor function, as defined by multiparametric systolic strain z scores, exhibit a consistent, heterogeneous pattern of contractile injury in which the septum and posterior regions at the base are most injured.


Single-step purification of epoxide hydrolase from rat liver microsomes using monoclonal-antibody chromatography.
Monoclonal antibody to rat liver microsomal epoxide hydrolase has been obtained after immunization of mice with the enzyme prepared by conventional methods. Antibody from ascitic fluid was purified and coupled to CNBr-activated Sepharose 4B, to give a specific affinity column. Monoclonal-antibody affinity chromatography provided a rapid single-step method of purifying to homogeneity active epoxide hydrolase from crude solubilized microsomes. The techniques used offer an effective method for characterization of a non-inhibitory monoclonal antibody.


Gallbladder carcinosarcoma masquerading as a hepatic abscess.
Carcinosarcomas of the gallbladder are extremely rare tumors and infrequently reported in the literature. We demonstrate a case of a 64-year-old female who presented with a 2-month history of a right upper quadrant mass, intermittent fevers, and abdominal distension following recent travel to Ghana. A computed tomography (CT) scan of the abdomen and pelvis demonstrated a large hepatic lesion with co-existing gallbladder distension, suggestive of a hepatic abscess. The patient was initially managed with intravenous antibiotics but failed to respond to treatment. A subsequent magnetic resonance imaging (MRI) scan of the liver showed a locally invasive lobulated soft tissue lesion arising from the gallbladder fundus and extending into the liver parenchyma. The lesion was surgically excised with a central hepatectomy. Histopathologic analysis showed a carcinosarcoma of the gallbladder.


Ophthalmic artery Doppler as a measure of severe pre-eclampsia.
To identify differences in orbital flow behavior in mild and severe pre-eclamptic women compared with healthy pregnant women, demonstrated by ophthalmic artery Doppler indexes. Ophthalmic artery Doppler indexes of 20 mild and 20 severe pre-eclamptic women were compared with 51 healthy pregnant women. Right and left eye Doppler index means were evaluated and the resistance index (RI), pulsatility index (PI), peak systolic velocity (PSV), end diastolic velocity (EDV), and peak ratio (PR) were calculated. Statistically significant differences were observed between PR, PSV, and EDV (P=0.0009, P=0.0020, P=0.0001) ophthalmic artery Doppler in a comparison of women with mild and severe pre-eclampsia. Statistically significant differences were seen between all Doppler indexes of the study group and healthy pregnant women. Ophthalmic PR, PSV, and EDV were significantly higher in severe pre-eclamptic cases but other index parameters did not show any difference. An elevation of diastolic and systolic flow occurred when pre-eclampsia became severe. Orbital vascular impedance reduction with orbital hyperperfusion was present in severe pre-eclamptic women compared with mild pre-eclamptic and healthy pregnant women. Ophthalmic Doppler is a novel parameter that may be useful in the diagnosis of severe pre-eclampsia.


Complementary and Integrative Treatments for Attention-Deficit/Hyperactivity Disorder in Youth.
First-line psychopharmacologic and psychosocial treatments for attention-deficit/hyperactivity disorder in children are effective but limited by tolerability and accessibility problems. Many complementary and integrative strategies have been investigated as alternative or adjunctive treatments for the disorder, and the literature has progressed to meta-analyses for several. Although heterogeneity of study methods and risk of bias pervades the literature, we conclude that Omega-3 supplementation, dietary restriction of artificial food colorings, and physical activity can be considered evidence-based. Additionally, meditation, yoga, and sleep hygiene are safe, partially effective, cost effective and sensible adjunctive treatment strategies.


Syntaxin 6: A novel predictive and prognostic biomarker in papillary renal cell carcinoma.
Syntaxin 6 is a SNARE family protein known to play an important role in intracellular trafficking. Here, we examined the tumorogenic role of syntaxin 6 in renal cell carcinoma (RCC). The Cancer Genome Atlas (TCGA) was queried for clinicopathologic data and syntaxin 6 expression. We found a significant difference in overall survival (OS) between groups, with high syntaxin 6 expression correlating with decreased survival. When stratifying the data based on histological subtype, the papillary RCC subtype exhibited a significant correlation between syntaxin 6 expression and survival. Using ROC curve, we calculated the area under the curve (AUC) to determine the ability of syntaxin 6 to predict 3-year overall survival. The AUC for syntaxin 6 was 0.73, significantly higher compared to 0.52 for T stage. Next, syntaxin 6 expression was evaluated in clear cell (786-O and Caki-1) and papillary (Caki-2 and ACHN) RCC cells. Syntaxin 6 expression was higher in Caki-1 and ACHN RCC cells. Silencing of syntaxin 6 in ACHN cells significantly decreased the cell viability (p < 0.001). Overall, syntaxin 6 could be a prognostic biomarker for patients with papillary RCC and syntaxin 6 inhibitors hold promise as a novel therapy against RCC.


Epstein-Barr virus as a marker of survival after Hodgkin's lymphoma: a population-based study.
Epstein-Barr virus (EBV) in Hodgkin's lymphoma (HL) cells has been considered as a prognostic marker for this heterogeneous disease, but studies have yielded mixed findings, likely because of selected patient series and failure to acknowledge an effect of age on outcome. This study assessed survival after HL in a population-based cohort large enough to examine the joint effects of EBV with other factors including age, sex, and histologic subtype. Included were 922 patients with classical HL diagnosed between mid-1988 and 1997 in the Greater San Francisco Bay Area, with archived biopsy specimens assayed for EBV with immunohistochemistry and in situ hybridization. Vital status was followed through December 30, 2003 (median follow-up time, 97 months). Overall and disease-specific survival were analyzed with the Kaplan-Meier method and Cox proportional hazards regression models. In children less than 15 years old, EBV presence was suggestively associated (P = .07) with favorable survival. In adults aged 15 to 44 years, EBV did not affect HL outcome, although a protective effect was suggested. In older adults (45 to 96 years), EBV presence nearly doubled the risk of overall and HL-specific mortality but only for patients with nodular sclerosis (NS) histologic subtype (hazard ratio for death = 2.5; 95% CI, 1.5 to 4.3). In HL, EBV tumor cell presence is associated with better survival in young patients and poorer survival in older patients with NS, independent of other factors. Variation in outcome by age and histology could indicate biologically distinct disease entities. Evidence that EBV is a meaningful prognostic marker may have therapeutic relevance.


Influence of age on amikacin pharmacokinetics in patients without renal disease. Comparison with gentamicin and tobramycin.
The influence of age on amikacin pharmacokinetics was examined in 87 patients with normal renal function. All patients had a gram negative infection, were febrile, weighed within 20% of their ideal body weight, did not receive penicillin antibiotics concurrently, had normal hematocrits and had a measured 24 h creatinine clearance greater than 80 ml/min/1.73 m2. 31 patients were 20-39 years old, 27 patients were between the ages of 40-59 years, and 29 patients were 60-79 years old. These patients were compared to patients in similar previous studies who received gentamicin or tobramycin. No significant differences in clearance, volume of distribution or half-life were found due to age within a single drug group (amikacin, gentamicin, or tobramycin) or among the 3 drug groups. However, a substantial amount of intersubject variability existed in the calculated pharmacokinetic parameters. Patients over 40 years old tended to be underdosed with amikacin and the other 2 aminoglycosides. The average amikacin dose needed to achieve the desired steady-state concentrations was 18.9 mg/kg/day. 52% of the amikacin patients required doses greater than the recommended maximum (15 mg/kg/day). Since aminoglycoside pharmacokinetics do not change as age increases, doses do not need to be arbitrarily changed in older patients with normal renal function.


Characterization of a 6Li-loaded liquid organic scintillator for fast neutron spectrometry and thermal neutron detection.
The characterization of a liquid scintillator incorporating an aqueous solution of enriched lithium chloride to produce a scintillator with 0.40% (6)Li is presented, including the performance of the scintillator in terms of its optical properties and neutron response. The scintillator was incorporated into a fast neutron spectrometer, and the light output spectra from 2.5 MeV, 14.1 MeV, and (252)Cf neutrons were measured using capture-gated coincidence techniques. The spectrometer was operated without coincidence to perform thermal neutron measurements. Possible improvements in spectrometer performance are discussed.


Up-regulation of Bcl-2 through hyperbaric pressure transfection of TGF-beta1 ameliorates ischemia-reperfusion injury in rat cardiac allografts.
Oxidative stress after ischemia-reperfusion of cardiac allografts leads to activation of cardiomyocytes and production of cytokines. Bcl-2, an inhibitor of the apoptotic pathway, also has strong antioxidant properties. Ischemia-reperfusion injury after transplantation leads to decreased bcl-2 and increased tumor necrosis factor (TNF)-alpha levels. Transforming growth factor (TGF)-beta1 is known to attenuate ischemia-reperfusion injury and inhibits apoptosis of myofibroblasts. We hypothesize that TGF-beta1, prevents bcl-2 cleavage and increased TNF-alpha production. Rat PVG donor hearts were heterotopically transplanted into ACI recipients. Donor hearts were procured and assigned to groups: (1) intracoronary TGF-beta1 (200 ng/ml) perfusion and pressure at 78 psi for 45 minutes (n = 4); (2) intracoronary TGF-beta1 perfusion and incubation for 45 minutes without pressure (n = 4), (3) saline perfusion and incubation for 45 minutes without pressure (n = 4). Hearts were procured 4 hours after transplantation and analyzed by reverse transcriptase-polymerase chain reaction for bcl-2 mRNA expression, ELISA for TNF-alpha, and for myeloperoxidase activity (MPO). Bcl-2 decreased in untreated animals (bcl-2:G3PDH ratio = 0.85 +/- 0.73 vs 1.16 +/- 0.11, not significant [NS]), whereas TNF-alpha increased to 669.99 +/- 127.09 vs 276.84 +/- 73.65 pg/mg total protein in controls (p < 0.003). In TGF-beta(1) pressure-treated hearts, bcl-2 was up-regulated (2.49 +/- 0.6 vs 1.16 +/- 0.11, controls, p < 0.005), whereas TNF-alpha was unchanged (396.1 +/- 100.38 vs 276.84 +/- 73.65 pg/mg, NS). Hearts treated with TGF-beta1 and pressure showed significant up-regulation of bcl-2 compared with hearts treated with TGF-beta1 without pressure (2.49 +/- 0.6 vs 1.17 +/- 0.6, p < 0.02). MPO showed no differences. Bcl-2 is down-regulated and TNF-alpha up-regulated in this model of ischemia-reperfusion injury. Furthermore, TGF-beta1 is linked to this process and ameliorates reperfusion injury by up-regulating bcl-2 and inhibiting TNF-alpha. Therapeutic overexpression of myocardial TGF-beta1 may be clinically useful to control ischemia-reperfusion injury associated with cardiac transplantation.


[Comparison of oxidative stress markers in exhaled breath condensate and in serum of patients with tuberculosis and sarcoidosis].
Tuberculosis and sarcoidosis represent the granulomatous diseases. The aim of the study was to compare the markers of oxidative stress: in exhaled breath condensate (EBC) and in serum of patients with tuberculosis and sarcoidosis. 19 patients with active lung tuberculosis and 15 patients with sarcoidosis were enrolled into the study. As a control served 15 healthy subjects. Hydrogen peroxide (H2O2) was measured in EBC and the ends products of lipid peroxidation (TBARs) were assessed in serum. The concentrations of H202 and TBARs (1022.96+/-186.02 nM and 4.22+/-0. 80 microM, respectively) were significantly higher in patients with tuberculosis as compared with the controls (398.15+/-37.10 nM and 0.48+/-0.17 microM, respectively). The patients with sarcoidosis revealed only the significantly elevated levels of hydrogen peroxide (963.30+/-105.77 nM) in breath condensate. It was found that local and systemic oxidative stress were present in patients with tuberculosis, while in those with sarcoidosis existed only the local reaction.


Blood pressure trends associated with changes in height and weight from early adolescence to young adulthood.
In children, blood pressure is more closely related to height and indices of maturation than to age. This study extends observations on the relationship between height, weight, maturation and blood pressure during early adolescence into young adulthood. Standardized measurements of blood pressure, height, and weight were initially obtained in all 14-15 year old adolescents (N = 304) in a rural Kentucky school system. Measurements were repeated 5 and 8 years later. Adolescents with relatively high blood pressures continued to have higher blood pressures as young adults. Increases in systolic and diastolic blood pressure over time were related to increases of relative weight in both sexes (p less than 0.0001 and p less than 0.005, respectively), and in males increases of systolic blood pressure were related to increases of height (p less than 0.005). However, males who attained their full height at younger ages had higher blood pressures both during adolescence and subsequently, as young adults. Thus blood pressure of young adults is related to blood pressure in adolescence, relative weight and change in relative weight since adolescence, and in males to age of maturation as determined by the age at which adult height is attained.


Kin preference and partner choice: patrilineal descent and biological kinship in Lamaleran cooperative relationships.
This paper presents a comparison of social kinship (patrilineage) and biological kinship (genetic relatedness) in predicting cooperative relationships in two different economic contexts in the fishing and whaling village of Lamalera, Indonesia. A previous analysis (Alvard, Human Nature 14:129-163, 2003) of boat crew affiliation data collected in the village in 1999 found that social kinship (patrilineage) was a better predictor of crew affiliation than was genetic kinship. A replication of this analysis using similar data collected in 2006 finds the same pattern: lineage is a better predictor than genetic kinship of crew affiliation, and the two together explain little additional variance over that explained by lineage alone. However, an analogous test on food-sharing relationships finds the opposite pattern: biological kinship is a better predictor of food-sharing relationships than is social kinship. The difference between these two cooperative contexts is interpreted in terms of kin preferences that shape partner choice, and the relative autonomy with which individuals can seek to satisfy those preferences. Drawing on stable matching theory, it is suggested that unilineal descent may serve as a stable compromise among multiple individuals' incongruent partner preferences, with patriliny favored over matriliny in the crew-formation context because it leads to higher mean degrees of relatedness among male cooperators. In the context of food-sharing, kin preferences can be pursued relatively autonomously, without the necessity of coordinating preferences with those of other households through the institution of lineage.


Fun cube based brain gym cognitive function assessment system.
The aim of this study is to design and develop a fun cube (FC) based brain gym (BG) cognitive function assessment system using the wireless sensor network and multimedia technologies. The system comprised (1) interaction devices, FCs and a workstation used as interactive tools for collecting and transferring data to the server, (2) a BG information management system responsible for managing the cognitive games and storing test results, and (3) a feedback system used for conducting the analysis of cognitive functions to assist caregivers in screening high risk groups with mild cognitive impairment. Three kinds of experiments were performed to evaluate the developed FC-based BG cognitive function assessment system. The experimental results showed that the Pearson correlation coefficient between the system's evaluation outcomes and the traditional Montreal Cognitive Assessment scores was 0.83. The average Technology Acceptance Model 2 score was close to six for 31 elderly subjects. Most subjects considered that the brain games are interesting and the FC human-machine interface is easy to learn and operate. The control group and the cognitive impairment group had statistically significant difference with respect to the accuracy of and the time taken for the brain cognitive function assessment games, including Animal Naming, Color Search, Trail Making Test, Change Blindness, and Forward / Backward Digit Span.


Ginsenoside Rd Improves Learning and Memory Ability in APP Transgenic Mice.
Alzheimer's disease (AD) is a complicated neurodegenerative disease which causes memory loss and dementia. Many researchers have revealed the vital roles of β-amyloid proteins (Aβ) in the proceeds of AD. Aβ deposition in AD patients' brains might function as immune stimulus, and inflammation is believed to play an important role in AD pathologically. We experimentally used amyloid β-protein precursor (APP) transgenic (Tg) mice in this study to further clarify the neuroprotective effects of ginsenoside Rd on AD and its possible mechanisms. It was found that Rd could improve learning and memory ability in APP Tg mice, probably through inhibiting the transcription activity of NFκB. With the activation of the NFκB pathway being suppressed, the reduction of pro-inflammatory cytokines and the generation of protective factors had been increased ultimately. In conclusion, Rd had a neuroprotective effect on APP Tg mice, and it can be used as an alternative drug therapy in AD patients for their memory dysfunction.


Study on prevalence and bacterial etiology of mastitis, and effects of subclinical mastitis and stage of lactation on SCC in dairy goats in Egypt.
In Egypt, inadequate information on prevalence and epidemiology of caprine mastitis is available. This study was designed to investigate prevalence and etiological agents of caprine mastitis and assess the efficacy of somatic cell count (SCC) as marker of subclinical mastitis (SCM) in dairy goats. This study was carried out on 249 randomly selected lactating goats in different lactation stages and examined clinically. Of these animals, 477 milk samples were aseptically collected and screened for bacterial carriage. SCC was assessed in 234 apparently normal milk samples, and SCC ≥ 106 cells/ml was indicator for SCM. Prevalence of clinical mastitis (CM) was 33.73% and 16.87% at animal and udder-half levels, respectively. SCM was 52.56% in the apparently healthy halves. Culture results proved single infection in 49.69% of samples, mixed infection in 23.9% of samples, and 26.41% of samples were negative. Coagulase negative staphylococci (CNS) were the most predominant bacteria (58.75%), then Staphylococcus aureus (S. aureus) (24.375%), and Streptococci (1.875%) were the least. No significant difference was recorded between mean of SCC in bacteriologically positive and negative samples, neither in those with SCC ≤ 106 nor with SCC ≥ 106 cells/ml both in middle and late lactation stages. Besides, the percentage of animals harboring SCC ≥ 106 cells/ml and negative for bacteriology in late lactation stage was 3 times (28.57%) more than in midlactation (9.3%). We can assume that SCC is not proper indicator for intra-mammary inflammation (IMI) in goats, and bacteriological examination remains more efficient, despites being time consuming and expensive.


Towards the simulation of bone-implant systems with a stratified material model.
The clinical performance of medical devices is becoming increasingly important for the requirements of modern development processes and the associated regulations. However, the evidence for this performance can often only be obtained very late in the development process via clinical trials or studies. The purpose of the presented work is to show that the simulation of bone-implant systems has advanced in various aspects, including cloud-based execution, Virtual Clinical Trials, and material modeling towards a point where and widespread utilization in healthcare for procedure planning and enhancing practices seems feasible. But this will only hold true if the virtual cohort data build from clinical Computer Tomography data are collected and analysed with care. An overview of the principal steps necessary to perform Finite Element Method based structural mechanical simulations of bone-implant systems based on clinical imaging data is presented. Since these data form the baseline for virtual cohort construction, we present an enhancement method to make them more accurate and reliable. The findings of our work comprise the initial step towards a virtual cohort for the evaluation of proximal femur implants. In addition, results of our proposed enhancement methodology for clinical Computer Tomography data that demonstrate the necessity for the usage of multiple image reconstructions are presented. Simulation methodologies and pipelines nowadays are mature and have turnaround times that allow for a day-to-day use. However, small changes in the imaging and the preprocessing of data can have a significant impact on the obtaind results. Consequently, first steps towards virtual clinical trials, like collecting bone samples, are done, but the reliability of the input data remains subject to further research and development.


TRAIL inhibition by soluble death receptor 5 protects against acute myocardial infarction in rats.
Acute myocardial infarction (AMI) is associated with high morbidity and mortality. An effective therapeutic strategy is to rescue cardiomyocytes from death. Apoptosis is a key reason of cardiomyocyte death that can be prevented. In this study, we investigated the role of TNF-related apoptosis-inducing ligand (TRAIL) in initiating apoptosis by binding to death receptor 5 (DR5), and this procession is inhibited by soluble DR5 (sDR5) in rats after AMI. First, we found that the level of TRAIL in serum was down-regulated in AMI patients. Then, TRAIL and DR5 expression was analysed in the myocardium of rats after AMI, and their expression was up-regulated. sDR5 treatment reduced the myocardial infarct size and the levels of CK-MB and cTn-I in serum. The expression of caspase 3 and PARP is decreased, but the anti-apoptotic factor Bcl-2 was increased in sDR5 treatment rats after AMI. DR5 expression was also analysed after sDR5 treatment and it was down-regulated, and a low level of DR5 expression seemed to be beneficial for the myocardium. Overall, our findings indicated that sDR5 decreases myocardial damage by inhibiting apoptosis in rat after AMI. We expect to observe the potential therapeutic effects of sDR5 on AMI in the future.


Lessons Learned from Routine Intraoperative Ureteral Margin Frozen Sections during Radical Cystectomy.
We examined the practice patterns of intraoperative ureteral frozen section during radical cystectomy and the impact of ureteral margin positivity on operative characteristics and oncologic outcomes. The records of patients who underwent radical cystectomy at our institution from 2004 to 2011 were identified. Intraoperative ureteral frozen section characteristics were examined, including number, laterality, positivity, conversion to negative and final permanent section status. Logistic regression analysis was performed for predictors of operative time, change in urinary diversion, and biopsy confirmed upper tract recurrence and metastasis. A total of 590 intraoperative ureteral frozen sections were sent for analysis from 241 patients (mean age 69 years). The sections were positive in 12.9% of cases and conversion to negative was accomplished in 82%. Multiple sections were associated with longer operating time (561 vs 511 minutes, p=0.011). Sensitivity for the sections was 100% and specificity was 93.6%. Taking multiple ureteral resections did not alter the planned urinary diversion in any patient or increase perioperative complication rates. At a mean followup of 22±19.8 months, 7 patients (3%) experienced upper tract recurrence. Intraoperative ureteral frozen section conversion to negative was associated with improved overall survival but not with upper tract recurrence. Our practice of taking intraoperative ureteral frozen sections provided excellent sensitivity and specificity, and the prolonged operative time did not translate into increased perioperative complications. Conversion of positive to negative was associated with improved overall survival, independent of patient comorbidities and post-operative complications. No association was seen with upper tract recurrence but this was likely due to our high conversion rate to negative margins (82%), negative permanent section ureteral margin status in 97% of cases and the long followup time needed to demonstrate an association.


Histological examination of the gallbladder following routine cholecystectomy? A selective analysis is justified.
It was hitherto common practice to analyse each removed gallbladder for the presence of gall bladder cancer (GBC) although this approach may be questioned. The aim of this study was to determine whether a policy of selective histopathological analysis (Sel-HPA) is oncologically safe and cost effective. This retrospective study was conducted in a single Dutch teaching hospital. Immediately following cholecystectomy, the surgeon decided on the basis of inspection and palpation whether histological examination was indicated. The Dutch Comprehensive Cancer Organisation (IKNL) registry was used to identify the number of GBC during this time period. Of 2271 patients who underwent a cholecystectomy in our institution between January 2012 and December 2017, 1083 (47.7%) were deemed indicated for histopathological analysis. Sixteen pathological gallbladders (1.5%) were identified in that period (intestinal metaplasia, n = 3; low grade dysplasia n = 7; carcinoma n = 6). During follow-up, no patient was found to have GBC recurrence in the population whose gallbladder was not sent for pathology (52.3%, n = 1188, median 49 months of follow up). The percentage of gallbladders that were analysed decreased over the six years of observation from 83% to 38%. Our policy of Sel-HP saved over €65 000. A policy of selective histopathology after cholecystectomy is oncologically safe and reduces costs.


Increased need for medical interventions in infants with velocardiofacial (deletion 22q11) syndrome.
Ten of 12 patients diagnosed with deletion 22q11.2 in infancy required a total of 26 hospitalizations during their first year of life. After heart disease, feeding and respiratory problems were the most frequent reasons for intervention.


NMDA receptor, PKC and ERK prevent fos expression induced by the activation of group I metabotropic glutamate receptors in the spinal trigeminal subnucleus oralis.
Fos, a protein product of immediate early gene c-fos, has been used as a marker for activation of nociceptive neurons in central nervous system including spinal trigeminal nucleus (Vsp). By noxious stimulation applied to orofacial area, the expression of Fos occurred in the Vsp pars oralis (Vo), the subnucleus receiving inputs from trigeminal primary afferents that predominantly innervate intraoral receptive fields. The present study demonstrates that the in vitro activation of group I metabotropic glutamate receptors (mGluRs; mGluR1 and 5) by bath-application of their well-known agonist (S)-3,5-dihydroxyphenylglycine (DHPG) increased the number of Fos-expressing neurons in the Vo area. In addition, bath application of DHPG caused inward currents, a parameter of neuronal excitation, in the Vo neurons held at -70 mV in voltage-clamp mode of whole-cell recordings. In further experiments characterizing two phenomena, the increased Fos expression in the Vo was mediated by an additive activation of both mGluR1 and mGluR5, which required the activation of N-methyl-D-aspartate (NMDA) receptors, protein kinase C (PKC) and extracellular signal-regulated kinase (ERK). In contrast, the inward currents were mediated only by mGluR1, but not by others. The data resulting from this in vitro study indicate that the DHPG-induced membrane depolarisation or neuronal excitation may be upstream to, or skip, the NMDA receptor, PKC and ERK pathways for the DHPG-induced Fos expression.


Immunogenicity and safety of simplified vaccination schedules for the CYD-TDV dengue vaccine in healthy individuals aged 9-50 years (CYD65): a randomised, controlled, phase 2, non-inferiority study.
Three doses of the licensed tetravalent dengue vaccine CYD-TDV (Dengvaxia, Sanofi Pasteur, Lyon France) are immunogenic and effective against symptomatic dengue in individuals aged 9 years and older who are dengue seropositive. Previous trials have provided some evidence that antibody responses elicited after just one dose or two doses of CYD-TDV might be similar to those elicited after three doses. We compared antibody responses following one-dose, two-dose, and three-dose vaccination regimens in individuals who were dengue seropositive at baseline up to 1 year after the last injection. In this randomised, controlled, phase 2, non-inferiority study (CYD65), healthy individuals aged 9-50 years were recruited from the community in three sites in Colombia and three sites in the Philippines. Participants were randomly assigned (1:1:1), using a permuted block method with stratification by site and age group, to receive, at 6-month intervals (on day 0, month 6, and month 12), three doses of CYD-TDV (three-dose group), one dose of placebo (on day 0) and two doses of CYD-TDV (at months 6 and 12; two-dose group), or two doses of placebo (on day 0 and month 6) and one dose of CYD-TDV (at month 12; one-dose group). Each dose of CYD-TDV was 0·5 mL, administered subcutaneously into the deltoid of the upper arm. Participants, study staff, investigators, and the funder were masked to group assignment. The co-primary endpoints were geometric mean titres (GMTs) of neutralising antibodies against each dengue virus serotype at 28 days and 1 year after the last vaccine injection. After a protocol amendment during the conduct of the study, the original co-primary objectives of non-inferiority of the one-dose and two-dose groups to the three-dose group were altered to include non-inferiority of the two-dose group to the three-dose group only, to be assessed in individuals who were dengue seropositive at baseline. Non-inferiority was shown if the lower limit of the 95% CI for the ratio of GMTs (GMR) at 28 days and 1 year between groups was more than 0·5 for each serotype. The analysis of the coprimary objectives was done in the per-protocol analysis dataset, which included all participants who had been vaccinated, had no protocol deviations, and had a valid serology test result for at least one dengue serotype at 28 days after the third injection. Safety was assessed throughout in all participants who received at least one injection of study drug, regardless of serostatus. This trial is registered with ClinicalTrials.gov, NCT02628444, and is closed to accrual. Between May 2, 2016, and Sept 16, 2016, we recruited and enrolled 1050 individuals, of whom 1048 received at least one injection and 993 had at least one blood sample taken (full-analysis dataset; 333 in three-dose group, 328 in two-dose group, and 332 in one-dose group). 860 (86·6%) of 993 participants in the full-analysis dataset were dengue seropositive at baseline. Non-inferiority (two dose vs three dose) was shown for each serotype at both 28 days and 1 year among dengue-seropositive participants (number of participants assessed: 272 [two-dose group], 265 [three-dose group] at 28 days; and 190 [two-dose group], 185 [three-dose group] at 1 year). At 28 days after the last injection, neutralising antibody GMTs were 899 (95% CI 752-1075) in the two-dose group versus 822 (700-964) in the three dose group against dengue serotype 1 (GMR 1·09 [95% CI 0·86-1·39]); 869 (754-1002) versus 875 (770-995) against serotype 2 (GMR 0·99 [0·82-1·20]); 599 (524-685) versus 610 (535-694) against serotype 3 (GMR 0·98 [0·82-1·18]); and 510 (453-575) versus 531 (470-601) against serotype 4 (GMR 0·96 [0·81-1·14]). At year 1, GMTs had decreased but remained above baseline for all serotypes: 504 (95% CI 403-630) in the two-dose group versus 490 (398-604) in the three-dose group against serotype 1 (GMR 1·03 [0·76-1·40]); 737 (611-888) versus 821 (704-957) against serotype 2 (GMR 0·90 [0·71-1·14]); 437 (368-519) versus 477 (405-561) against serotype 3 (GMR 0·92 [0·72-1·16]); and 238 (205-277) versus 270 (235-310) against serotype 4 (GMR 0·88 [0·72-1·09]). Reactogenicity profiles were similar across treatment groups. Most unsolicited adverse events after any injection were non-serious and systemic in nature. During the study, 60 serious adverse events were reported in 58 participants (14 in three-dose group, 26 in two-dose group, 18 in one-dose group), mostly infection and infestations or injury, poisoning, and procedural complications. No serious adverse events of special interest or admissions to hospital for dengue occurred. Two deaths occurred, unrelated to study treatment. A two-dose CYD-TDV regimen might be an alternative to the licensed three-dose regimen in individuals who are dengue seropositive at baseline and aged 9 years and older. Vaccination with a reduced number of doses could lead to improved vaccine compliance and coverage, especially in low-resource settings. Sanofi Pasteur.


The role of RNase H2 in processing ribonucleotides incorporated during DNA replication.
Saccharomyces cerevisiae RNase H2 resolves RNA-DNA hybrids formed during transcription and it incises DNA at single ribonucleotides incorporated during nuclear DNA replication. To distinguish between the roles of these two activities in maintenance of genome stability, here we investigate the phenotypes of a mutant of yeast RNase H2 (rnh201-RED; ribonucleotide excision defective) that retains activity on RNA-DNA hybrids but is unable to cleave single ribonucleotides that are stably incorporated into the genome. The rnh201-RED mutant was expressed in wild type yeast or in a strain that also encodes a mutant allele of DNA polymerase ε (pol2-M644G) that enhances ribonucleotide incorporation during DNA replication. Similar to a strain that completely lacks RNase H2 (rnh201Δ), the pol2-M644G rnh201-RED strain exhibits replication stress and checkpoint activation. Moreover, like its null mutant counterpart, the double mutant pol2-M644G rnh201-RED strain and the single mutant rnh201-RED strain delete 2-5 base pairs in repetitive sequences at a high rate that is topoisomerase 1-dependent. The results highlight an important role for RNase H2 in maintaining genome integrity by removing single ribonucleotides incorporated during DNA replication.


The scientific roots of José A. Campos-Ortega, a German neurobiologist born in Spain.
In this review article, we shall focus our attention on the initial steps in the research career of José A. Campos-Ortega and the studies he undertook. Particular emphasis will be placed on how these early experiences shaped his personality and his future scientific contributions.


Where does it hurt? Small area estimates and inequality in the prevalence of chronic pain.
Chronic pain affects up to half of UK adults, impacting quality of life and demand on local health services. Whilst local health planning is currently based on subnational prevalence estimates, associations between pain and sociodemographic characteristics suggest that inequalities in the prevalence of chronic and high-impact chronic pain between neighbourhoods within local authorities are likely. We aimed to derive lower super output area (LSOA) estimates of the prevalence of chronic and high-impact chronic pain. Presence of self-reported chronic and high-impact chronic pain were measured in adults aged 35+ in North Staffordshire and modelled using multilevel regression as a function of demographic and geographic predictors. Multilevel model predictions were post-stratified using the North Staffordshire age-sex population structure and LSOA demographic characteristics to estimate the prevalence of chronic and high-impact chronic pain in 298 LSOAs, corrected for ethnic diversity underrepresented in the data. Confidence intervals were generated for high-impact chronic pain using bootstrapping. Data were analysed from 4162 survey respondents (2358 women, 1804 men). The estimated prevalence of chronic and high-impact chronic pain in North Staffordshire LSOAs ranged from 18.6% to 50.1% and 6.18 [1.71, 16.0]% to 33.09 [13.3, 44.7]%, respectively. Prevalence of chronic and high-impact chronic pain in adults aged 35+ varies substantially between neighbourhoods within local authorities. Further insight into small-area level variation will help target resources to improve the management and prevention of chronic and high-impact chronic pain to reduce the impact on individuals, communities, workplaces, services and the economy. Post-stratified multilevel model predictions can produce small-area estimates of pain prevalence and impact. The evidence of substantial variation indicates a need to collect local-level data on pain and its impact to understand health needs and to guide interventions.


Implant verification cast--a predictable restorative system in implant prosthodontics.
An implant verification cast is designed to provide an accurate representation of dental implant positions extraorally. It can be used by the laboratory as a trusted cast to create a passively fitting framework and by the clinician to verify framework fit prior to intraoral trial. This article discusses the treatment philosophy behind this specific cast and reviews applications, fabrication techniques and benefits of the verification cast compared to the conventional technique.


[Safety and short-term efficacy of renal sympathetic denervation in the treatment of resistant hypertension].
Transcatheter renal sympathetic denervation (RDN) is a novel technology/therapy in treating resistant hypertension. The present study aims to evaluate the safety and short-term efficacy of RDN for the treatment of resistant hypertension in a Chinese population. This prospective single-center pilot study was the first one conducted in China with Medtronic Ardian Symplicity Catheter System. Eight patients (6 males and 2 females) with resistant hypertension underwent RDN at our hospital from February to April 2012. All patients were followed up at one month and three months post-RDN. Blood pressure, use of antihypertensive medications, renal function and complications were recorded and analyzed. At one month and three months post-RDN, 24-hour ambulatory blood pressure monitoring showed mean systolic blood pressure and diastolic blood pressure decreased 10 (0 - 18) 13 (3 - 19) and 8 (-2 - 15), 9 (2 - 16) mm Hg throughout 24 hours respectively (P < 0.05, vs baseline). The number of drugs decreased from 4.3 ± 0.5 to 2.8 ± 0.9 and 2.5 ± 0.7 post-RSD respectively (P < 0.01). There was no significant change of renal function (P > 0.05). No complications were observed. The preliminary results revealed that RDN was safe and effective for the treatment of resistant hypertension in the Chinese population during a 3-month follow-up. Further large and long-term studies are warranted.


Personalized digital extension services and agricultural performance: Evidence from smallholder farmers in India.
Productivity growth in smallholder agriculture is an important driver of rural economic development and poverty reduction. However, smallholder farmers often have limited access to information, which can be a serious constraint for increasing productivity. One potential mechanism to reduce information constraints is the public agricultural extension service, but its effectiveness has often been low in the past. Digital technologies could enhance the effectiveness of extension by reducing outreach costs and helping to better tailor the information to farmers' individual needs and conditions. Using primary data from India, this study analyses the association between digital extension services and smallholder agricultural performance. The digital extension services that some of the farmers use provide personalized information on the types of crops to grow, the types and quantities of inputs to use, and other methods of cultivation. Problems of selection bias in the impact evaluation are reduced through propensity score matching (PSM) combined with estimates of farmers' willingness to pay for digital extension. Results show that use of personalized digital extension services is positively and significantly associated with input intensity, production diversity, crop productivity, and crop income.


Candletoxins A and B, 2 new aromatic esters of 12-deoxy-16-hydroxy-phorbol, from the irritant latex of Euphoria poisonii Pax.
2 new aromatic esters of 12-deoxy-16-hydroxy-phorbol, known as candletoxins A and B, were isolated from the irritant latex of Euphorbia poisonii Pax. Compound A was identified as 12-deoxy-phorbol-13-O-phenylacetate-16-O-alpha-methyl-butyrate-20-acetate, and compound B was the C-20 desacetyl analogue.


One novel SNP of growth hormone gene and its associations with growth and carcass traits in ducks.
In this study, the growth hormone (GH) gene was studied as a candidate gene for growth and carcass traits of three duck populations (Cherry Valley duck, Muscovy duck and Jingjiang duck). Three pairs of primers were designed to detect single nucleotide polymorphisms of introns 2, 3 and 4 of the GH gene by polymerase chain reaction-restriction fragment length polymorphism and sequencing methods. Only the products amplified from intron 2 displayed polymorphism. The results showed one novel polymorphism: a variation in intron 2 of GH gene (C172T, JN408701 and JN408702). It was associated with some growth and carcass traits in three duck populations including birth weight, 8-week weight, carcass weight, breast muscle weight, leg muscle weight, eviscerated weight, lean meat rate, dressing percentage, etc. And the TT and CT genotypes were associated with superior growth and carcass traits in carcass weight, dressing percentage and percentage of eviscerated weight. Therefore, the variation in intron 2 of GH may be a molecular marker for superior growth and carcass traits in above duck populations.


Up-regulation and redistribution of protein kinase C-δ in chronically hypoxic heart.
The adaptation to chronic hypoxia confers long-lasting cardiac protection against acute ischemia-reperfusion injury. Protein kinase C (PKC) appears to play a role in the cardioprotective mechanism but the involvement of individual PKC isoforms remains unclear. The aim of this study was to examine the effects of chronic intermittent hypoxia (CIH; 7,000 m, 8 h/day) and acute administration of PKC-δ inhibitor (rottlerin, 0.3 mg/kg) on the expression and subcellular distribution of PKC-δ and PKC-ε in the left ventricular myocardium of adult male Wistar rats by Western blot and quantitative immunofluorescence microscopy. CIH decreased the total level of PKC-ε in homogenate without affecting the level of phosphorylated PKC-ε (Ser729). In contrast, CIH up-regulated the total level of PKC-δ as well as the level of phosphorylated PKC-δ (Ser643) in homogenate. Rottlerin partially reversed the hypoxia-induced increase in PKC-δ in the mitochondrial fraction. Immunofluorescent staining of ventricular cryo-sections revealed increased co-localization of PKC-δ with mitochondrial and sarcolemmal membranes in CIH hearts that was suppressed by rottlerin. The formation of nitrotyrosine as a marker of oxidative stress was enhanced in CIH myocardium, particularly in mitochondria. The expression of total oxidative phosphorylation complexes was slightly decreased by CIH mainly due to complex II decline. In conclusion, up-regulated PKC-δ in CIH hearts is mainly localized to mitochondrial and sarcolemmal membranes. The inhibitory effects of rottlerin on PKC-δ subcellular redistribution and cardioprotection (as shown previously) support the view that this isoform plays a role in the mechanism of CIH-induced ischemic tolerance.


Leukocyte subpopulations and arteriogenesis: specific role of monocytes, lymphocytes and granulocytes.
Circulating leukocytes play a crucial role during arteriogenesis. However, known pro-arteriogenic compounds (MCP-1, GM-CSF) acting via monocytic pathways also exert positive effects on granulocytes and lymphocytes. The role of these two cell types in arteriogenesis remains yet to be clarified, which was the aim of the current study. Ninety New Zealand White Rabbits received either phosphate buffered saline (PBS), monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), neutrophil activating protein-2 (NAP-2) or lymphotactin (Ltn) via osmotic minipumps after unilateral femoral artery ligation. In vitro stimulation and in vivo assessment of chemoattraction confirmed cell-specific action of the compounds in rabbits. Arteriogenesis was evaluated by angiography and collateral conductance measurements using fluorescent microspheres. Quantitative immunohistology was used to quantify transmigrated leukocyte subtypes after infusion of the factors. MCP-1 infusion attracts monocytes and granulocytes, whereas IL-8 attracts all three cell types albeit monocytes to a significantly lower degree than MCP-1. NAP-2 and lymphotactin selectively attract granulocytes, respectively, lymphocytes. Of the tested cytokines, only MCP-1 stimulates arteriogenesis, as assessed by collateral conductance measurements ((ml/(min 100 mmHg)): PBS, 50.70+/-5.15; MCP-1, 216.30+/-12.30; IL-8, 58.91+/-5.56; NAP-2, 66.83+/-8.72; Ltn, 52.80+/-5.37) and angiographic findings. This study for the first time provides evidence that not granulocytes or T-lymphocytes but monocytes are the key mediators of arteriogenesis.


Induction of proteolytic activity in serum by treatment with anionic detergents and organic solvents.
Using casein plates as a sensitive assay for proteolytic activity, it was observed that sodium-dodecyl sulfate (SDS) and other anionic detergents induce caseinolysis when mixed with sera and plasma. Caseinolysis was dependent on the presence of plasminogen in the fluids and could be blocked by inhibitors of serine proteases and antibody to plasminogen. Similarly, organic solvents such as isopropanol induced caseinolysis after mixing with plasma, but not normal serum. Isopropanol dissociated complexes of alpha 1-antitrypsin or alpha 2-macroglobulin with trypsin preformed in vitro. As both SDS and organic solvents are widely used in biochemical investigations of biological fluids, attention should be paid to the possible induction of proteolysis.


Electrophoretic analysis of the ribonucleoproteins of hepatitis delta virus.
Replication of hepatitis delta virus (HDV) is dependent on delta antigen (deltaAg), an HDV-encoded protein, which binds to HDV RNA and is capable of multimerization. To characterize HDV-specific ribonucleoprotein complexes (RNP) we used electrophoresis into non-denaturing agarose gels followed by northern analysis, to detect HDV RNA, and immunoblot, to detect deltaAg. We studied RNP from three sources: (i) vRNP, disrupted virions obtained from infected woodchuck serum; (ii) sRNP, disrupted particles secreted from transfected cultured cells; and (iii) cRNP, isolated from cells in which HDV genome replication was occurring. sRNP were approximately 28% smaller than vRNP. Treatment of vRNP with aurin tricarboxylic acid disrupted both deltaAg-deltaAg and deltaAg-RNA interactions while vanadyl ribonucleosides released the RNA without causing detectable disruption of the multimeric deltaAg complex. cRNP were smaller and more heterogeneous than vRNP and sRNP, and probably contained host components. The application of these electrophoretic procedures, and especially the use of prior treatments with vanadyl ribonucleoside complexes have provided valuable information on the RNP of HDV, and we expect they should find applicability in RNP studies of other RNA viruses.


Embryonal tumor with multilayered rosettes: illustrative case and review of the literature.
Embryonal tumor with multilayered rosettes (ETMR) is a very rare entity and has seldom been reported. It has been newly defined tumor entity included in the latest update (revised fourth edition) of WHO 2016 Classification of Tumors of the Central Nervous System which portends a uniform dismal prognosis and survival even with the best of multimodality approaches. This report documents the presentation of a 2-year-old girl with voluminous intracranial ETMR in the right parieto-occipital region. We describe clinical diagnosis, histological aspects, radiological features, and current management of this very aggressive tumor. Pediatric intracranial ETMR is a highly aggressive neoplasm, and it should be considered in the differential diagnosis of pediatric brain tumors.


Insulin-like growth factor-1 receptor signaling in 3T3-L1 adipocyte differentiation requires lipid rafts but not caveolae.
Previously, we have found that lipid rafts/caveolae were essential for insulin-like growth factor-1 (IGF-1) receptor signaling during 3T3-L1 preadipocytes differentiation induction. However, it was not identified as to which of the membrane lipid-ordered microdomains mediates the receptor signal. Using small double-stranded RNA-mediated interference (RNAi), we successfully suppressed the caveolin-1 protein expression. In cells stably transfected with vector expressing small interfering RNA (siRNA) fragment, no caveolin-1 protein or caveola was detected. On the other hand, removal of caveolin-1 did not affect the caveolinless lipid rafts or the localization of IGF-1 receptor in lipid rafts on plasma membrane. IGF-1 receptor signal transduction and induced cellular differentiation were normal in RNAi cells with only lipid rafts. Furthermore, these IGF-1 receptor signaling events were still sensitive to the cholesterol-binding reagents. Thus, our results suggest that lipid rafts are sufficient for IGF-1 receptor signaling and the recruitment of signal molecules by caveolin-1 is not essential for IGF-1 receptor signaling.


Lessons from a Customer Discovery Study: a Technology-Based Cancer Support Program for Asian American Breast Cancer Survivors.
A culturally tailored technology-based cancer support program was recently developed and tested among Asian American breast cancer survivors. To explore future opportunities to sustain the program, the research team participated in the SPeeding Research-tested INTervention (SPRINT) program sponsored by the National Cancer Institute. The purpose of this discussion paper is to share the lessons that the research team gained from a customer discovery study through the SPRINT program. During the SPRINT program, a total of 73 stakeholders were recruited through a snowball sampling across the globe. Semi-structured interviews were conducted for customer discovery through WebEX, phone calls, and in-person visits (50 in-person interviews, 4 phone interviews, and 19 WebEx interviews). All the interviews were recorded using audio-taping or writing memos. Also, the research team wrote memos on the issues/concerns related to the project during the interview process. Then, the transcripts and memos were analyzed using a content analysis to provide evidence for the lessons. The themes reflecting the lessons from the customer discovery study included (a) "who are the stakeholders"; (b) "depending on stakeholders"; (c) "what works or not"; (d) "personal versus family responsibilities"; and (e) "depending on countries' situations." These lessons could provide directions for future development and implementation of technology-based cancer support programs for Asian American breast cancer survivors.


Peroxidase activity in salivary glands and saliva of beige (Chediak-Higashi) mice.
Peroxidase activity was lower in the submandibular and parotid glands of beige mice than in controls. A lower level of activity was also observed in the isoproterenol-elicited saliva of beige mice.


Critical care in obstetrics: a strategy for addressing maternal mortality.
The acute rise in maternal morbidity and mortality in the United States is in part because of an increasingly medically complex obstetrical population. An estimated 1% to 3% of all obstetrical patients require intensive care, making timely delivery and availability of critical care imperative. The shifting landscape in obstetrical acuity places a burden on obstetrical providers, many of whom have limited experience in identifying and responding to critical illness. The levels of maternal care definitions by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine designate hospitals based on the availability of obstetrical resources and highlight the need for critical care resources and expertise. The growing need for critical care skills in the evolving contemporary obstetrical landscape serves as an opportunity to redefine the concept of delivery of care for high-risk obstetrical patients. We summarized the key tenets in the prevention of maternal morbidity and mortality, including the use of evidence-based tools for risk stratification and timely referral of patients to facilities with appropriate resources; innovative pathways for hospitals to provide critical care consultations on labor and delivery; and training of obstetrical providers in high-yield critical care skills, such as point-of-care ultrasonography. These critical care-focused interventions are key in addressing an increasingly complex obstetrical patient population while providing an educational foundation for the training of future obstetrical providers.


Uncovering hidden trends: identifying time trajectories in risk factors documented in clinical notes and predicting hospitalizations and emergency department visits during home health care.
This study aimed to identify temporal risk factor patterns documented in home health care (HHC) clinical notes and examine their association with hospitalizations or emergency department (ED) visits. Data for 73 350 episodes of care from one large HHC organization were analyzed using dynamic time warping and hierarchical clustering analysis to identify the temporal patterns of risk factors documented in clinical notes. The Omaha System nursing terminology represented risk factors. First, clinical characteristics were compared between clusters. Next, multivariate logistic regression was used to examine the association between clusters and risk for hospitalizations or ED visits. Omaha System domains corresponding to risk factors were analyzed and described in each cluster. Six temporal clusters emerged, showing different patterns in how risk factors were documented over time. Patients with a steep increase in documented risk factors over time had a 3 times higher likelihood of hospitalization or ED visit than patients with no documented risk factors. Most risk factors belonged to the physiological domain, and only a few were in the environmental domain. An analysis of risk factor trajectories reflects a patient's evolving health status during a HHC episode. Using standardized nursing terminology, this study provided new insights into the complex temporal dynamics of HHC, which may lead to improved patient outcomes through better treatment and management plans. Incorporating temporal patterns in documented risk factors and their clusters into early warning systems may activate interventions to prevent hospitalizations or ED visits in HHC.


Analysis of antibody response in goats to caprine herpesvirus 1.
Serum samples of goats experiencing natural and experimental infections and/or reactivation of caprine herpesvirus 1 (CpHV.1) were analysed with neutralization and Western blotting (WB) tests. WB immunological patterns resulted differently and related to neutralizing titers. In serum samples having neutralizing titer 1:2-1:4, antibodies to two proteins of Mw of 150 and 34 kDa were present. Antibodies against several proteins, two of those being characterized by monoclonal antibodies as gB and gC, were visualized by WB in sera having titer > or = 1:8. The neutralizing antibody titers and the pattern of antibody reactivity were hypothesized to modulate the reactivation and re-excretion process of CpHV.1.


Hazard report. Physio-Control Lifepak 20 defibrillator/monitor may misrepresent critical failures as incomplete self-test.
ECRI Institute is concerned that the Physio-Control Lifepak 20's display of "Self-test did not complete" does not adequately alert users that the device may be inoperative. Users need to be aware that the message may indicate a more serious problem and must be trained on how to respond to the message when encountered during routine inspection and during emergency use. In addition, users should configure their Lifepak 20 units to print self-test results to provide a permanent indicator if a problem occurs.


Nutrient over-enrichment and light limitation of seagrass communities in the Indian River Lagoon, an urbanized subtropical estuary.
Historically, extensive seagrass meadows were common throughout the Indian River Lagoon (IRL) in east-central Florida, USA. Between 2011 and 2017, widespread catastrophic seagrass losses (~95%) occurred in the IRL following unprecedented harmful algal blooms (HABs), including persistent brown tides (Aureoumbra lagunensis). Little is known about how dissolved nutrients and chlorophyll a are related to light limitation or how biochemical factors, such as the elemental composition (C:N:P) and stable isotope signatures (δ13C, δ15N), of seagrasses within the IRL relate to coverage. Accordingly, we conducted a survey from 2013 to 2015 at 20 sites to better understand these relationships. Results showed a negative correlation between DIN and salinity, indicating freshwater inputs as a DIN source. Seawater N:P ratios and chlorophyll a concentrations were higher in the urbanized, poorly-flushed northern IRL segments. Kd values were higher in the wet season and often exceeded seagrass light requirements (0.8 m-1) for restoration, demonstrating light limitation. Species distribution varied by location. Halodule wrightii was ubiquitous, whereas Syringodium filiforme was not found in the northernmost segments. Thalassia testudinum was only present in the two southernmost segments that had the lowest TDN and highest light availability (Kd). Blade %N and %P also frequently exceeded critical values of 1.8% and 0.2%, respectively, especially in the northern segments. Further, δ15N was positively correlated with ammonium, suggesting wastewater as a major N source. The δ13C values indicated a trend of increasing light limitation from south to north, which helps explain the recent catastrophic loss of seagrasses in the northern IRL. Overall, elemental composition reflected high N-availability and seagrass species distributions were relatable to spatial trends in N and light limitation. For effective restoration, resource managers must reduce N-loading to the IRL to diminish HABs and increase light availability. Regular biochemical monitoring of seagrass tissue should also be implemented during restoration efforts.


Synergistic antimalarial activity of dapsone/dihydrofolate reductase inhibitors and the interaction of antifol, antipyrimidine and antipurine combinations against Plasmodium falciparum in vitro.
Using low folate, low p-aminobenzoic acid medium, 2 isolates of Plasmodium falciparum were tested in vitro against a wide range of antimetabolite compounds with known or potential antimalarial activity. ID50 values (the concentration of compound causing 50% inhibition of [3H]hypoxanthine incorporation) were determined for each compound against both isolates. The compounds tested may affect folate, pyrimidine or purine metabolism in malaria parasites and various combinations of compounds were examined for further synergistic antimalarial effects. The combination of any of the dihydrofolate reductase inhibitors cycloguanil, pyrimethamine or WR 99210 with the sulphone drug dapsone demonstrated strongly synergistic antimalarial activity. Combinations of dihydrofolate reductase inhibitors with the antipyrimidine compounds pyrazofurin or menoctone, or with the antipurine compounds tubercidin, bredinin or hadacidin, or with primaquine, failed to demonstrate synergistic activity. Most combinations of an antipurine with an antipyrimidine compound also failed to show any synergistic effect. However, weak synergism was consistently seen in the tubercidin/pyrazofurin and tubercidin/menoctone combinations. Over the 48 h intraerythrocytic cycle using tightly synchronized parasites, tubercidin demonstrated both a cytotoxic and a cytostatic effect.


Reliability of the respiratory rate and oxygenation index for successful high-flow nasal cannula support in coronavirus disease pneumonia: a retrospective cohort study.
High-flow nasal cannula (HFNC) therapy is an important non-invasive respiratory support in acute respiratory failure, including coronavirus disease (COVID-19) pneumonia. Although the respiratory rate and oxygenation (ROX) index is a simple and useful predictor for HFNC failure and mortality, there is limited evidence for its use in patients with COVID-19 pneumonia. We aimed to evaluate the ROX index as a predictor for HFNC failure in patients with COVID-19 pneumonia. We also evaluated the ROX index as a predictor for 28-day mortality. In this single-center, retrospective, cohort study, 248 patients older than 18 years of age with COVID-19 pneumonia received HFNC therapy for acute respiratory failure. The ROX index was evaluated within 4 h from the start of HFNC therapy. Past medical history, laboratory data, and the ROX index were evaluated as predictors for HFNC failure and 28-day mortality. The ROX index < 4.88 showed a significantly high risk ratio for HFNC failure (2.13 [95% confidence interval [CI]: 1.47 - 3.08], p < 0.001). The ROX index < 4.88 was significantly associated with 28-day mortality (p = 0.049) in patients with COVID-19 pneumonia receiving HFNC therapy. Age, chronic hypertension, high lactate dehydrogenase level, and low ROX index showed significantly high risk ratio for HFNC failure. C-reactive protein level and low ROX index were predictors of 28-day morality. The ROX index is a useful predictor for HFNC success and 28-day mortality in patients with COVID-19 pneumonia receiving HFNC therapy. An independent ethics committee approved the study (Research Ethics Review Committee of Kobe City Medical Center General Hospital [number: zn220303; date: February 21, 2022]), which was performed in accordance with the Declaration of Helsinki, Guidelines for Good Clinical Practice.


[Cloning, expression and purification of silent information regulator 2 from Giardia lamblia].
To clone and express silent information regulator 2 (Sir2) gene from Giardia lamblia. The GlSir2 gene was amplified by PCR from genomic DNA of Giardia lamblia (Chinese strain C2 clone). PCR product was cloned into pMD-19T vector and transformed into E coli JM109. The recombinant plasmid was sequenced and then cloned into the pET28b vector. The pET28b-Gl1Sir2 recombinant plasmid was transformed into E. coli BL21(DE3), followed by expression of the protein induced by IPTG. The recombinant protein was analyzed by SDS-PAGE. Inclusion bodies were dissolved with 8 mol/L urea, and the supernatant was collected and applied to Ni2+ affinity chromatography. The purified recombinant protein was renatured by dialysis and verified by Western blotting using anti-His tag antibody. GlSir2 gene sequence was cloned. The GISir2 open reading frame (1 680 bp) encoded a 559-amino acid protein with Mr 62 800. The recombinant plasmid pET28b-GlSir2 expressed an inclusion body protein of GISir2 after being induced with IPTG. The protein purity reached above 80% after purification. The purified protein was renatured by dialysis. The recombinant GISir2 was recognized by anti-His tag antibody. The coding sequence of GLSir2 gene was cloned and expressed in vitro. The recombinant protein was identified by anti-His tag antibody.


High-harmonic generation in solids driven by counter-propagating pulses.
We used two 800 nm laser pulses propagating in the opposite directions, to drive the emission of high-order vacuum ultra-violet harmonics off of the surface of an MgO (100) single crystal. We demonstrated the advantages that our approach provides compared to a single beam geometry, in both forward and backward emission.


A model for the study of lymph node metastasis from oral carcinoma by serial transplantation of metastatic tumor in hamsters.
A new model of lymph node metastasis was successfully established by serial transplantation of a metastatic tumor to the submandibular lymph node from a chemically induced squamous cell carcinoma of the tongue into the buccal pouch in hamsters. Tongue carcinomas were induced by application of a 0.5% solution of 9,10-dimethyl-1,2-benzanthracene (DMBA) in acetone. The tongue tumors and metastatic tumors to the submandibular lymph nodes were transplanted to the buccal pouch of recipient hamsters. In the first generation, lymph node metastases were found only in hamsters that received a metastatic tumor. The metastatic tumors to the lymph nodes were maintained by serial transplantation into the buccal pouch from metastatic sites until the eleventh generation. The incidence of lymph node metastasis exceeded 90% in animals after the ninth generation.


Ultrastructural study of pleural lymphatic drainage unit and effect of nitric oxide on the drainage capacity of pleural lymphatic stomata in the rat.
The objective of this study was twofold: first to investigate the ultrastructure of the lymphatic drainage unit on the costal pleura of rats by electron microscopy, and secondly to examine the effect of nitric oxide on the pleural lymphatic stomata and fluid absorption from the pleural cavity. The lymphatic drainage unit of the rat costal pleura is composed of three special components: the lymphatic stomata between the mesothelial cells, the initial part of the lymphatic vessels and the underlying connective tissue containing many foramina. The unit is the main passage to drainage fluid, particles and cells in the pleural space. To investigate the regulator of the lymph drainage, nitric oxide synthase inhibitor and nitric oxide donor were injected into the peritoneal cavity of the rats, respectively. Trypan blue was used as tracer. The ultrastructural changes of pleural lymphatic stomata were observed under scanning electron microscope and analyzed by a computer image processing system. It turned out that the area and density of the pleural lymphatic stomata were positively correlated with the nitric oxide quantity (p < 0.05). After the tracer was injected into the pleural cavity, the nitric oxide donor group exhibited a higher trypan blue concentration than the control group (p < 0.05). The ability of the pleura to absorb trypan blue was enhanced because of the larger opening of the lymphatic stomata (p < 0.05). It is suggested that nitric oxide can increase lymphatic absorption of the pleura by opening pleural lymphatic stomata.


Incidental versus clinically evident thyroid cancer: a 5-year follow-up study.
The incidence of differentiated thyroid cancer in patients undergoing surgery for presumed benign thyroid disease (incidental thyroid cancer) is not negligible. The purpose of this study was to verify if incidental thyroid cancers have a different clinical course than the clinically evident thyroid cancer. A group of patients with incidental thyroid cancer (n = 95) has been compared to a control group with clinically evident thyroid cancer (n = 93). Both the histology and the outcome after a 5-year follow-up have been compared. At the univariate analysis, the groups demonstrated significant differences in many pathologic features, remnant ablation (p < .001), and persistent disease (p = .006). Nevertheless, the multivariate analysis revealed that the outcome was not influenced by the preoperative or the incidental diagnosis. Incidental thyroid cancers show a different pathological pattern when compared to clinically evident thyroid cancers. Nonetheless, the final outcome is not influenced by preoperative or postoperative diagnosis. Hence, patients with incidental thyroid cancer should follow the same postoperative protocols of patients with clinically evident thyroid cancer.


Antitumor activity of novel N-sulfonylpyrimidine derivatives on the growth of anaplastic mammary carcinoma in vivo.
The purpose of this study was to investigate in vivo antitumor activity of newly synthesized N-sulfonylpyrimidine derivatives 1-(p-toluenesulfonyl)cytosine (4H), 1-(p-toluenesulfonyl)cytosine hydrochloride (4HxHCl) and zinc(II) complex of 1-(p-toluenesulfonyl)cytosine (4K). In order to do that we have used mouse anaplastic mammary carcinoma (AMCa). Tumor cells (10(6)) in a volume of 0.02 ml were transplanted into the thigh of the right hind leg of CBA mice. All compounds were dissolved in distilled water immediately before injecting to animals. Antitumor effect of these compounds depends on drug doses and time interval between tumor transplantation and drug application. Further the efficacy of these compounds depends on number of drug injections, i. e. whether drug was given in single or in multiple doses. Multiple doses of 400 mg/kg of 1-(p-toluenesulfonyl)cytosine (4H) showed good antitumor effect when applied on day 1, 3, 5, 7 and 9 after tumor transplantation. Still good but slightly lower antitumor effect was also achieved when that compound was given in a single dose (1,200 mg/kg) on day 1 after tumor transplantation. The longest period of tumor growth time was obtained after application of 1-(p-toluenesulfonyl)cytosine hydrochloride (4HxHCl) given as a single dose (300 mg/kg) on day 1 or on day 6 after tumor implantation. However, antitumor effect of zinc(II) complex of 1-(p-toluenesulfonyl)cytosine (4K) was very strong when 300 mg/kg was given on day 1 or day 6, while this effect was slightly lower when drug (200 mg/kg/inj) was given on day 1, 3, 5, 7 and 9 or on day 6, 8, 10, 12 and 14. In this work it has been found that N-1-sulfonylcytosine derivatives have strong antitumor activity against mouse mammary carcinoma which is a good reason for further research of these compounds both in experimental and preclinical studies.


"Twitchin-actin linkage hypothesis" for the catch mechanism in molluscan muscles: evidence that twitchin interacts with myosin, myorod, and paramyosin core and affects properties of actomyosin.
"Twitchin-actin linkage hypothesis" for the catch mechanism in molluscan smooth muscles postulates in vivo existence of twitchin links between thin and thick filaments that arise in a phosphorylation-dependent manner [N.S. Shelud'ko, G.G. Matusovskaya, T.V. Permyakova, O.S. Matusovsky, Arch. Biochem. Biophys. 432 (2004) 269-277]. In this paper, we proposed a scheme for a possible catch mechanism involving twitchin links and regulated thin filaments. The experimental evidence in support of the scheme is provided. It was found that twitchin can interact not only with mussel myosin and rabbit F-actin but also with the paramyosin core of thick filaments, myorod, mussel thin filaments, "natural" F-actin from mussel, and skeletal myosin from rabbit. No difference was revealed in binding of twitchin with mussel and rabbit myosin. The capability of twitchin to interact with all thick filament proteins suggests that putative twitchin links can be attached to any site of thick filaments. Addition of twitchin to a mixture of actin and paramyosin filaments, or to a mixture of Ca(2+)-regulated actin and myosin filaments under relaxing conditions caused in both cases similar changes in the optical properties of suspensions, indicating an interaction and aggregation of the filaments. The interaction of actin and myosin filaments in the presence of twitchin under relaxing conditions was not accompanied by an appreciable increase in the MgATPase activity. We suggest that in both cases aggregation of filaments was caused by formation of twitchin links between the filaments. We also demonstrate that native thin filaments from the catch muscle of the mussel Crenomytilus grayanus are Ca(2+)-regulated. Twitchin inhibits the ability of thin filaments to activate myosin MgATPase in the presence of Ca(2+). We suggest that twitchin inhibition of the actin-myosin interaction is due to twitchin-induced switching of the thin filaments to the inactive state.


Structural studies of parkin and sacsin: Mitochondrial dynamics in neurodegenerative diseases.
Neurodegenerative diseases are prevalent, chronic diseases emanating from the dysfunction or death of neurons. The disrupted mitochondrial dynamics observed in a large number of neurodegenerative diseases suggests a common etiology with the possibility of therapies targeting multiple diseases. This review highlights the contributions of structural studies of disease-related proteins to the understanding of neurodegenerative disease pathogenesis and especially the cellular events leading to disruptions in mitochondrial dynamics and function. The examples used are parkin and sacsin, two proteins linked respectively to autosomal-recessive early-onset PD and autosomal-recessive spastic ataxia of Charlevoix-Saguenay. Structural studies of parkin and sacsin explain the pathogenicity of a large number of disease-associated mutations and reveal insights into their cellular functions related to mitochondrial dynamics.


Vaginal gel versus intramuscular progesterone for luteal phase supplementation: a prospective randomized trial.
The aim of this randomized study was to compare the efficacy of intramuscular progesterone (IMP) and progesterone in vaginal gel (VGP) at two different doses for luteal support in IVF. A total of 412 patients, aged between 28 and 37 years, were randomized into three groups. The day after oocyte retrieval each patient began supplementation with one of the following: IMP 50 mg daily (150 patients), VGP 90 mg once daily (143 patients), or VPG 90 mg twice daily (148 patients). No significant difference was found between the three groups in any of the endpoints. The rate of positive beta-human chorionic gonadotrophin per transfer was 38.4% with IMP, 35.0% with VPG once daily and 43.1% with VPG twice daily. Clinical pregnancy rate per transfer and implantation rate were 32.6% and 19.6% with IMP, 26.3% and 16.4% with one dose of VGP, and 37.2% and 21.1% with two doses of VGP. Live birth rate per transfer was 26.1%, 23.4% and 29.9%, respectively. Progesterone vaginal gel can be successfully used as an alternative to intramuscular progesterone for luteal support in IVF. One daily dose appears sufficient to induce clinical pregnancies and live births at a rate comparable to intramuscular supplementation.


CHOROIDAL THICKNESS AFTER FULL-FLUENCE AND HALF-FLUENCE PHOTODYNAMIC THERAPY IN CHRONIC CENTRAL SEROUS CHORIORETINOPATHY.
To compare clinical outcomes after full-fluence and half-fluence photodynamic therapy (PDT) in chronic central serous chorioretinopathy, focusing on changes in subfoveal choroidal thickness (SFCT) using enhanced depth imaging optical coherence tomography. Retrospective, comparative interventional case series. In the full-fluence (n = 25) and half-fluence groups (n = 43), SFCT decreased from 351 ± 70 μm and 362 ± 63 μm at baseline to 276 ± 65 μm and 322 ± 70 μm at 3 months and remained at 267 ± 66 μm and 318 ± 76 μm at 12 months, respectively (all P < 0.001, for each comparison with baseline). The change in SFCT was greater in the full-fluence group than in the half-fluence group (P = 0.001). In the half-fluence group, SFCT was thicker in the treated eye than in the fellow eye (P = 0.045), whereas in the full-fluence group, the difference in SFCT was not significant (P = 0.209). Best-corrected visual acuity and central retinal thickness improved after PDT in both groups (all P < 0.001). However, the differences between the groups were not significant (P = 0.873 and P = 0.124, respectively). The results at 1 year show that full-fluence PDT reduces SFCT more than half-fluence PDT, and that SFCT after half-fluence PDT was still thicker than that in the fellow eye. The clinical implications of this finding for long-term outcomes including recurrence rate remain to be elucidated.


Serial measurements of serum calcium, magnesium, parathyroid hormone, calcitonin, and 25-hydroxy-vitamin D in premature and term infants during the first week of life.
The mean +/- SEM of the cord, 48-hr, and 7-day values for serum calcium, magnesium, human calcitonin (HCT), parathyroid hormone (PTH), and 25-hydroxy-vitamin D (25-OHD) for premature and term infants can be seen in Table 1. Mean cord calcium concentrations were similar for term and premature infants. Serum calcium concentrations fell in both term and premature infants at 48 hr, but decreased more in the premature infants (from 10.23 +/- 0.30 to 8.74 +/- 0.19 mg/dl) than in the term infants (from 10.5 +/- 0.26 to 9.6 +/- 0.23 mg/dl). Serum calcium values increased from 48 hr to 7 days in both groups, and there was no significant difference between term and premature infants' serum calcium concentrations (10.6 +/- 0.28 and 10.12 +/- 0.3 mg/dl, respectively) at that time. There was no significant difference between term and premature cord serum magnesium concentrations. Serum magnesium concentrations increased similarly by 48 hr in both groups and remained at these concentrations at 7 days of life. Serum HCT concentrations were elevated above normal adult levels (71.9 +/- 6.6 pg/ml, 81% less than 100 pg/ml, n = 63) in both premature and term cord sera, but premature cord concentrations (146 +/- 24 pg/ml) were significantly higher than term cord concentration (91 +/- 21 pg/ml). Both term and premature infants displayed a 2-3-fold increase in serum HCT by 48 hr and a partial fall by 7 days to concentrations still above those seen in cord sera (Fig. 1). Nine of 10 premature and 9 of 10 term infants had undetectable PTH concentrations in cord sera. In two premature infants, PTH serum concenttration remained undetectable at 48 hr. However, the majority of both premature and term infants had elevated levels of PTH at 48 hr. The mean PTH concentrations were lower but still elevated at 7 days with the suggestion of higher concentrations in premature infants (Fig 2). There were no significant differences in serum 25-OHD concentrations between term and premature sera at birth or at 7 days. There was a weakly positive correlation between 25-OHD and cord calcium (r = 0.45, P less than 0.05), and a negative correlation between cord calcium and 48-hr PTH (r = -0.53, P less than 0.01). Calcium and magnesium were significantly positively correlated in 48-hr (r = 0.83) and 7-day (r = 0.84) sera in premature infants but not in term infants. Cord 25-OHD and cord HCT levels were significantly positively correlated (r = 0.80, P less than 0.01) in the term infants but not the premature infants.


Morphometric analysis of hippocampus and intracranial formations based on their stages in patients diagnosed with major cognitive disorder.
Alzheimer's disease (AD) is a major cognitive disorder classified as a common type of dementia. Magnetic resonance imaging (MRI) is the most practical method for diagnostic purposes in AD. The aim of the study was to determine the volume of the hippocampus and intracranial structures in AD using MRI. A total of 102 patients with AD were classified based on the mini mental test scores as early, moderate, and advanced stage. The control group included 35 healthy subjects. MRI were compared between the patients and control groups based on the calculations made utilizing volBrain software. Intracranial volumetric parameters were also compared between the three stages of AD. The white matter volumes, total hippocampus, total cerebrum, right cerebrum, left cerebrum, truncus encephalic, total nucleus caudatus and total corpus amygdaloideum were significantly increased in the AD. The white matter volumes, right hippocampus, left hippocampus, total cerebrum, left cerebrum, and right cerebellum were significantly increased in the patients in the early stage compared to the patients in the advanced stage AD. The most efficient volumetric study in AD could be performed by obtaining long-term periodic morphometric data of an early diagnosed and regularly followed-up patient population.


Effects of endotoxic shock in several functions of murine peritoneal macrophages.
Gram negative sepsis and septic shock continue to be a major medical problem, with a complex physiopathology and it is associated with high mortality. Although secretion of cytokines such as tumor necrosis factor-alpha by macrophages is the principal host mediator of septic shock, other characteristic functions of macrophages implicated in their phagocytic capacity have not been studied in the process of endotoxic shock. In the present study we have used an intraperitoneal injection of E. coli lipopolysaccharide (LPS) (100 mg/kg) in order to obtain an endotoxic shock model in adult female BALB/c mice. Peritoneal cell suspensions were obtained at several times (2, 4, 12 or 24 h) after injection and the following functions were studied on the peritoneal macrophages: adherence to substrate, mobility (spontaneous and directed or chemotaxis), ingestion of particles and superoxide anion production. The results showed a stimulation of adherence, ingestion and superoxide production as well as a decrease of chemotaxis in the animals injected with LPS. These effects changed with time after LPS injection. Thus, the increase of adherence and the decrease of mobility were higher during the first hours, whereas the increase in ingestion and superoxide production turned larger with time.


Correlation between cataract and glutathione metabolism.
Riboflavin status was studied in 156 older healthy people living at home in The Netherlands by assaying erythrocyte glutathione reductase (with and without FAD). The average activation coefficient of glutathione reductase was found to be 1.42 +/- 0.19. 7% of the population studied showed cataract (based on the eye examination). It seems that no correlation exists between cataract and riboflavin deficiency.


Highly transparent light emitting diodes on graphene encapsulated Cu nanowires network.
The internal quantum efficiency of blue LEDs is almost close to the limit, therefore, advanced transparent electrode has been long explored for gaining high external quantum efficiency. However, work function mismatch at electrode-semiconductor interface remains the fundamental difficulty in obtaining low resistance ohmic contact. Here, we demonstrate the gas phase encapsulation of graphene layer on superfine Cu nanowires network by chemical vapor deposition for highly transparent LEDs. The fast encapsulation of graphene shell layer on Cu nanowires achieves high optoelectronic performance (33 Ω/sq @ 95% T), broad transparency range (200~3000 nm) and strong antioxidant stability. A novel phenomenon of scattered-point contact is revealed at the Cu nanowires/GaN interface. Point discharge effect is found to produce locally high injection current through contact points, which can effectively overcome Schottky barrier and form ohmic contact. The transparent LED on Cu@graphene nanowire network is successfully lighted with bright blue emission.


Alternative Splicing of Key Genes in LOX Pathway Involves Biosynthesis of Volatile Fatty Acid Derivatives in Tea Plant (Camellia sinensis).
Volatile fatty acid derivatives (VFADs) produced in tea plants (Camellia sinensis) not only have been shown to function as defense compounds but also impart a "fresh green" odor to green tea products; however, little is known about alternative splicing (AS) of genes in regulating the production of VFADs in plants. In this study, the contents of VFADs and corresponding transcriptome profiles were obtained in five different months (April, June, August, September, and October). Correlation analysis identified seven unique transcripts of enzyme-coding genes (CsLOX2, CsLOX4, CsADH4, CsADH8, and CsADH10), which are responsible for regulating VFAD biosynthesis; four AS transcripts of these genes (CsLOX2, CsLOX4, CsADH4, and CsADH8) were validated by RT-PCR. By employing the gene-specific antisense oligodeoxynucleotide-mediated reduction method, we found the expression levels of alternatively spliced transcripts of CsLOX4-iso1, CsLOX4-iso2, and CsADH4-iso3 were lower, and the contents of cis-3-hexenol were correspondingly reduced in the leaves of tea plant; this result suggested that the AS play important roles in regulating biosynthesis of VFADs in C. sinensis. Our results provide new insights into the important contribution of AS events in regulating the VFAD biosynthesis in tea plant.


Intracellular Cholesterol Pools Regulate Oncogenic Signaling and Epigenetic Circuitries in Early T-cell Precursor Acute Lymphoblastic Leukemia.
Early T-cell acute lymphoblastic leukemia (ETP-ALL) is an aggressive hematologic malignancy associated with early relapse and poor prognosis that is genetically, immunophenotypically, and transcriptionally distinct from more mature T-cell acute lymphoblastic leukemia (T-ALL) tumors. Here, we leveraged global metabolomic and transcriptomic profiling of primary ETP- and T-ALL leukemia samples to identify specific metabolic circuitries differentially active in this high-risk leukemia group. ETP-ALLs showed increased biosynthesis of phospholipids and sphingolipids and were specifically sensitive to inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme in the mevalonate pathway. Mechanistically, inhibition of cholesterol synthesis inhibited oncogenic AKT1 signaling and suppressed MYC expression via loss of chromatin accessibility at a leukemia stem cell-specific long-range MYC enhancer. In all, these results identify the mevalonate pathway as a druggable novel vulnerability in high-risk ETP-ALL cells and uncover an unanticipated critical role for cholesterol biosynthesis in signal transduction and epigenetic circuitries driving leukemia cell growth and survival. Overtly distinct cell metabolic pathways operate in ETP- and T-ALL pointing to specific metabolic vulnerabilities. Inhibition of mevalonate biosynthesis selectively blocks oncogenic AKT-MYC signaling in ETP-ALL and suppresses leukemia cell growth. Ultimately, these results will inform the development of novel tailored and more effective treatments for patients with high-risk ETP-ALL. This article is highlighted in the In This Issue feature, p. 587.


Catalytic hydroaminations of alkynes: a facile protocol to vinyl-carbazole derivatives via a frustrated Lewis pair mechanism.
N-Vinylcarbazoles are important skeletons for photoluminescent materials. Herein, a transition metal-free, B(C6F5)3 mediated carbazolation reaction of alkynes is reported, providing 24 variants of N-vinylcarbazole derivatives. These N-vinylcarbazole products were obtained in good to excellent yields (up to 99%) under mild reaction conditions and could be performed on a gram scale.


Achieving Higher Diagnostic Results in Stereotactic Brain Biopsy by Simple and Novel Technique.
Neurosurgeons have preferred to perform the stereotactic biopsy for pathologic diagnosis when the intracranial pathology located eloquent areas and deep sites of the brain. To get a higher ratio of definite pathologic diagnosis during stereotactic biopsy and develop practical method. We determined at least two different target points and two different trajectories to take brain biopsy during stereotactic biopsy. It is a different way from the conventional stereotactic biopsy method in which one point has been selected to take a biopsy. We separated our patients into two groups, group 1 (N=10), and group 2 (N= 19). We chose one target to take a biopsy in group 1, and two different targets and two different trajectories in group 2. In group 2, one patient underwent craniotomy due to hemorrhage at the site of the biopsy during tissue biting. However, none of the patients in both groups suffered any neurological complication related biopsy procedure. In group 1, two of 10 cases, and, in group 2, fourteen of 19 cases had positive biopsy harvesting. These results showed statistically significant difference between group 1 and group 2 (P<0.05). Regarding these results, choosing more than one trajectories and taking at least six specimens from each target provides higher diagnostic rate in stereotaxic biopsy taking method.


Ultrastructural immunogold localization of subcellular sites of TNF-alpha in colonic Crohn's disease.
Tumor necrosis factor-alpha, a proinflammatory cytokine, might have an important role(s) in initiating, modifying, and/or sustaining chronic inflammatory processes such as those that characterize Crohn's disease, an inflammatory bowel disease of unknown etiology. We used an immunogold ultrastructural morphometric approach to localize tumor necrosis factor-alpha in colonic Crohn's disease biopsies. Tumor necrosis factor-alpha was present in seven cell types (fibroblasts, eosinophils, mast cells, macrophages, colonic epithelial absorptive cells, Paneth cells, neutrophils). Tumor necrosis factor-alpha-containing subcellular organelles included lipid bodies (fibroblasts, eosinophils, macrophages, mast cells, colonic epithelial cells, neutrophils), secretory granules (eosinophils, Paneth cells), phagolysosomes (macrophages, colonic epithelial cells), and Golgi structures and vesicle membranes (neutrophils). A gradient of extracellular tumor necrosis factor-alpha immunoreactivity surrounded eosinophils, mast cells, and macrophages. P values of gold counts/microns2 were significant for all cells, organelles, and extracellular spaces measured, and all positive structures significantly exceeded the background labeling density/microns2. Specificity controls (normal rabbit serum, tumor necrosis factor-alpha-absorbed primary antibody) either failed to label these sites or gave markedly reduced specific tumor necrosis factor-alpha labeling, respectively. These findings represent the first ultrastructural localization of the subcellular sites of TNF-alpha in vivo in seven cell lineages in human colonic tissues.


A panel of four decreased serum microRNAs as a novel biomarker for early Parkinson's disease.
Sensitive, non-invasive biomarkers that facilitate Parkinson's disease (PD) detection and stage assignment are currently unavailable. The objective of this study is to investigate the potential of circulating microRNAs (miRNAs) as novel biomarkers for PD. Solexa sequencing technology and quantitative real-time PCR were applied to screen and verify altered serum miRNAs in PD patients. Serum miR-141, miR-214, miR-146b-5p, and miR-193a-3p were decreased significantly in PD patients compared with controls. Furthermore, the 4-miRNA panel enabled the differentiation of HY stage 1 and 2 PD patients from controls. The four serum miRNAs may represent novel biomarkers for the early detection of PD.


Biosensor based on ds-DNA decorated chitosan modified multiwall carbon nanotubes for voltammetric biodetection of herbicide amitrole.
The interaction of amitrole and salmon sperm ds-DNA was studied using UV-vis and differential pulse voltammetry (DPV) at both bare and DNA-modified electrodes. Amitrole showed an oxidation peak at 0.445 V at a bare pencil graphite electrode (PGE). When ds-DNA was added into the amitrole solution, the peak current of amitrole decreased and the peak potential underwent a shift. UV-vis spectra showed that the absorption intensity of the ds-DNA at 260 nm decreased with increasing amitrole concentration, proving the interaction between amitrole and the ds-DNA. The results also showed that amitrole could interact with the ds-DNA molecules via the intercalative binding mode. Finally, a pretreated pencil graphite electrode (PGE) modified with multiwall carbon nanotubes (MWCNTs) and chitosan (CHIT) decorated with the ds-DNA were tested in order to determine amitrole content in solution. Electrochemical oxidation of amitrole bonded on DNA/MWCNTs-CHIT/PGE was used to obtain an analytical signal. A linear dependence was observed to exist between the peak current and 0.025-2.4 ng mL(-1) amitrole with a detection limit of 0.017 ng mL(-1). The sensor showed a good selectivity and precision for the determination of amitrole. Finally, applicability of the biosensor was evaluated by measuring the analyte in soil and water samples with good selectivity.


PM10 source apportionment in a Swiss Alpine valley impacted by highway traffic.
Although trans-Alpine highway traffic exhaust is one of the major sources of air pollution along the highway valleys of the Alpine regions, little is known about its contribution to residential exposure and impact on respiratory health. In this paper, source-specific contributions to particulate matter with an aerodynamic diameter < 10 μm (PM10) and their spatio-temporal distribution were determined for later use in a pediatric asthma panel study in an Alpine village. PM10 sources were identified by positive matrix factorization using chemical trace elements, elemental, and organic carbon from daily PM10 filters collected between November 2007 and June 2009 at seven locations within the village. Of the nine sources identified, four were directly road traffic-related: traffic exhaust, road dust, tire and brake wear, and road salt contributing 16 %, 8 %, 1 %, and 2 % to annual PM10 concentrations, respectively. They showed a clear dependence with distance to highway. Additional contributions were identified from secondary particles (27 %), biomass burning (18 %), railway (11 %), and mineral dust including a local construction site (13 %). Comparing these source contributions with known source-specific biomarkers (e.g., levoglucosan, nitro-polycyclic aromatic hydrocarbons) showed high agreement with biomass burning, moderate with secondary particles (in winter), and lowest agreement with traffic exhaust.