The era of molecular and other non-culture-based methods in diagnosis of sepsis.
Sepsis, a leading cause of morbidity and mortality throughout the world, is a clinical syndrome with signs and symptoms relating to an infectious event and the consequent important inflammatory response. From a clinical point of view, sepsis is a continuous process ranging from systemic inflammatory response syndrome (SIRS) to multiple-organ-dysfunction syndrome (MODS). Blood cultures are the current "gold standard" for diagnosis, and they are based on the detection of viable microorganisms present in blood. However, on some occasions, blood cultures have intrinsic limitations in terms of sensitivity and rapidity, and it is not expected that these drawbacks will be overcome by significant improvements in the near future. For these principal reasons, other approaches are therefore needed in association with blood culture to improve the overall diagnostic yield for septic patients. These considerations have represented the rationale for the development of highly sensitive and fast laboratory methods. This review addresses non-culture-based techniques for the diagnosis of sepsis, including molecular and other non-culture-based methods. In particular, the potential clinical role for the sensitive and rapid detection of bacterial and fungal DNA in the development of new diagnostic algorithms is discussed.


Microbial nitrogen limitation in the mammalian large intestine.
Resource limitation is a fundamental factor governing the composition and function of ecological communities. However, the role of resource supply in structuring the intestinal microbiome has not been established and represents a challenge for mammals that rely on microbial symbionts for digestion: too little supply might starve the microbiome while too much might starve the host. We present evidence that microbiota occupy a habitat that is limited in total nitrogen supply within the large intestines of 30 mammal species. Lowering dietary protein levels in mice reduced their faecal concentrations of bacteria. A gradient of stoichiometry along the length of the gut was consistent with the hypothesis that intestinal nitrogen limitation results from host absorption of dietary nutrients. Nitrogen availability is also likely to be shaped by host-microbe interactions: levels of host-secreted nitrogen were altered in germ-free mice and when bacterial loads were reduced via experimental antibiotic treatment. Single-cell spectrometry revealed that members of the phylum Bacteroidetes consumed nitrogen in the large intestine more readily than other commensal taxa did. Our findings support a model where nitrogen limitation arises from preferential host use of dietary nutrients. We speculate that this resource limitation could enable hosts to regulate microbial communities in the large intestine. Commensal microbiota may have adapted to nitrogen-limited settings, suggesting one reason why excess dietary protein has been associated with degraded gut-microbial ecosystems.


Pre-existing mental disorder, clinical profile, inpatient services and costs in people hospitalised following traumatic spinal injury: a whole population record linkage study.
Risk of traumatic injury is increased in individuals with mental illness, substance use disorder and dual diagnosis (mental disorders); these conditions will pre-exist among individuals hospitalised with acute traumatic spinal injury (TSI). Although early intervention can improve outcomes for people who experience mental disorders or TSI, the incidence, management and cost of this often complex comorbid health profile is not sufficiently understood. In a whole population cohort of patients hospitalised with acute TSI, we aimed to describe the prevalence of pre-existing mental disorders and compare differences in injury epidemiology, costs and inpatient allied health service access. Record linkage study of all hospitalised cases of TSI between June 2013 and June 2016 in New South Wales, Australia. TSI was defined by specific International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification (ICD-10-AM) codes. Mental disorder status was considered as pre-existing where specific ICD-10-AM codes were recorded in incident admissions. 13 489 individuals sustained acute TSI during this study. 13.11%, 6.06% and 1.82% had pre-existing mental illness, substance use disorder and dual diagnosis, respectively. Individuals with mental disorder were older (p<0.001), more likely to have had a fall or self-harmed (p<0.001), experienced almost twice the length of stay and inpatient complications, and increased injury severity compared with individuals without mental disorder (p<0.001). Individuals hospitalised for TSI with pre-existing mental disorder have greater likelihood of increased injury severity and more complex, costly acute care admissions compared with individuals without mental disorder. Care pathway optimisation including prevention of hospital-acquired complications for people with pre-existing mental disorders hospitalised for TSI is warranted.


Persistent high frequency of human immunodeficiency virus-specific cytotoxic T cells in peripheral blood of infected donors.
Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTLs) are thought to play a major role in the immune response to HIV infection. The HIV-specific CTL response is much stronger than previously documented in an infectious disease, yet estimates of CTL frequency derived from limiting-dilution analysis (LDA) are relatively low and comparable to other viral infections. Here we show that individual CTL clones specific for peptides from HIV gag and pol gene products are present at high levels in the peripheral blood of three infected patients and that individual CTL clones may represent between 0.2% and 1% of T cells. Previous LDA in one donor had shown a frequency of CTL precursors of 1/8000, suggesting that LDA may underestimate CTL effector frequency. In some donors individual CTL clones persisted in vivo for at least 5 years. In contrast, in one patient there was a switch in CTL usage suggesting that different populations of CTLs can be recruited during infection. These data imply strong stimulation of CTLs, potentially leading some clones to exhaustion.


Impact of EGFR mutation detection methods on the efficacy of erlotinib in patients with advanced EGFR-wild type lung adenocarcinoma.
Methods used for epidermal growth factor receptor (EGFR) mutation testing vary widely. The impact of detection methods on the rates of response to EGFR-tyrosine kinase inhibitors (TKIs) in EGFR-wild type (wt) lung adenocarcinoma patients is unknown. We recruited the Group-I patients to evaluate the efficacy of erlotinib in patients with EGFR-wt lung adenocarcinoma by either direct sequencing (DS) or mutant type-specific sensitive (MtS) methods in six medical centers in Taiwan. Cross recheck of EGFR mutations was performed in patients who achieved objective response to erlotinib and had adequate specimens. The independent Group-II lung adenocarcinoma patients whose EGFR mutation status determined by DS were recruited to evaluate the potential limitations of three MtS methods. In Group-I analysis, 38 of 261 EGFR-wt patients (14.6%) achieved partial response to erlotinib treatment. Nineteen patients (50.0%) had adequate specimens for cross recheck of EGFR mutations and 10 of them (52.6%) had changes in EGFR mutation status, 5 in 10 by DS and 5 in 9 by MtS methods originally. In Group-II analysis, 598 of 996 lung adenocarcinoma patients (60.0%) had detectable EGFR mutations. The accuracy rates of the three MtS methods, MALDI-TOF MS, Scorpions ARMS and Cobas, were 87.8%, 86.8% and 85.8%, respectively. A significant portion of the erlotinib responses in EGFR-wt lung adenocarcinoma patients were related to the limitations of detection methods, not only DS but also MtS methods with similar percentages. Prospective studies are needed to define the proper strategy for EGFR mutation testing.


Association of socioeconomic status with overall overweight and central obesity in men and women: the French Nutrition and Health Survey 2006.
Identification of subpopulations at high risk of overweight and obesity is crucial for prevention and management of obesity in different socioeconomic status (SES) categories. The objective of the study was to describe disparities in the prevalence of overweight and obesity across socioeconomic status (SES) groups in 18-74 year-old French adults. Analyses were based on a multistage stratified random sample of non-institutionalized adults aged 18-74-years-old from the French Nutrition and Health Survey (ENNS), a cross-sectional national survey carried out in 2006/2007. Collected data included measured anthropometry (weight, height and waist circumference (WC)), demographic and SES data (occupation, education and frequency of holiday trips as a marker of family income). SES factors associated with overweight (BMI > or = 25) and central obesity (WC above gender-specific references) were identified using multiple logistic regression. Almost half (49.3%) of French adults were overweight or obese and 16.9% were obese. In men, the risk of overall overweight or obesity was associated with occupation (p < 0.05), whereas the risk of central obesity was independently associated with occupation (p < 0.05) and frequency of holiday trips (p < 0.01). In women, both overall and central overweight and obesity were independently associated with educational level (respectively p < 10(-3) and p < 10(-3)) and frequency of holiday trips (respectively p < 0.05 and p < 10-3). The prevalence of overweight and obesity was found to be similar to that of several neighbouring western European countries, and lower than the UK and eastern Europe. Risk of being overweight or obese varied across SES groups both in men and women, but associations were different between men and women, indicating differing determinants.


Do surgical interventions for limb lymphoedema reduce cellulitis attack frequency?
Recurrent cellulitis is a frequent and challenging complication of lymphoedema. British Lymphology Society cellulitis guidelines state that decongestive lymphatic therapy reduces the frequency of cellulitis attacks, but do not mention the effect of surgical interventions. This systematic review aims to assess whether surgical interventions for lymphoedema reduce the frequency of attacks of cellulitis. Embase, Medline, and the Cochrane database were searched for relevant articles from database inception to January 2016. Four hundred and thirty-six abstracts were retrieved. Studies were included which contained quantitative data on cellulitis incidence before and after a surgical intervention. Two independent reviewers applied selection criteria, selecting 27 papers for full text review. Two were unavailable in the UK from any source. A variety of surgical techniques were utilized in the 25 papers included: lymphaticovenous anastomosis, superficial-to-deep lymphaticolymphatic anastomosis, lymph node transfer, Charles procedure, muscle flap transfer, Homan's procedure, and subcutaneous tissue excision below skin flaps. Five studies combined techniques. One study compared the intervention to a control group (physical therapy). Cellulitis incidence was decreased following surgical intervention in 24/25 studies included. Eight had quantifiable reductions in cellulitis over a set follow-up period; in the other 16 preoperative incidence was not precisely defined. Surgery appears effective at reducing cellulitis incidence in lymphoedema. However, high quality evidence from randomized controlled trials is lacking. Future research should concentrate on comparison with control groups, for example compression alone versus compression with surgical intervention, in patients with lymphoedema and greater than two attacks of cellulitis per year.


Dosage patterns in methadone treatment: results from a national survey, 1988-2005.
To examine the extent to which U.S. methadone maintenance facilities meet established standards for minimum dosages, 1988-2005. Data were collected from a nationally representative sample of outpatient treatment facilities in 1988 (n=172), 1990 (n=140), 1995 (n=116), 2000 (n=150), and 2005 (n=146). Random-effects multiple regression analysis was used to examine unit characteristics associated with below recommended doses. Data regarding the proportion of patients who received maintenance dosages of <40, 60, and 80 mg/day were collected from unit directors and clinical supervisors. Forty-four percent of patients receive doses of at least 80 mg/day--the threshold identified as recommended practice in recent work. Thirty-four percent of patients receive doses below 60 mg/day, while 17 percent receive doses below 40 mg/day. Units that serve a high proportion of African American or Latino clients were more likely to report low-dose care. Units managed by individuals who strongly favor abstinence models (e.g., Narcotics Anonymous) were more likely to provide low-dose care. One-third of methadone facilities provide doses below recommended levels. Managerial attitudes about abstinence and their relationship to low doses underscore the contested role of methadone in treatment of opiate disorders.


Sex-specific characteristics of cardiac function, geometry, and mass in young adult elite athletes.
To study young adult elite athletes with age- and sex-matched sedentary controls to assess sex-specific differences for left ventricular (LV) and right ventricular (RV) volumes and mass as well as for LV contraction and relaxation. A total of 23 male athletes (mean age 25 +/- 4 years, training 22 +/- 7 hours/week in rowing, swimming, or triathlon) and 20 female athletes (mean age 24 +/- 4 years, training 19 +/- 5 hours/week in rowing, swimming, or triathlon) and age- and sex-matched sedentary controls (21 male/17 female) underwent cardiovascular magnetic resonance (CMR) imaging (1.5 Tesla). Cardiac phase contrast imaging using a black-blood k-space segmented gradient echo sequence was used for analysis of cardiac contraction and relaxation and steady-state free-precession cine images were acquired for determination of cardiac volumes and mass. Male and female athletes showed similar increases in LV and RV volume and mass indices when compared to controls (ranging between 15% and 42%). No sex-specific differences in training effect on LV and RV volumes, mass indices, and ejection fractions, as well as LV to RV ratios of these volume and mass indices (parameters of balanced LV and RV dilatation and hypertrophy) were observed (all P for interaction >0.05). Similarly, no sex-specific differences in training effect on cardiac contraction and relaxation were found (all P for interaction >0.05). Young adult elite athletes do not show sex-specific adaptive structural and functional changes to exercise training in accordance with the benign nature of the hypertrophy associated with athlete's heart.


Denaturation of the simian virus 40 origin of replication mediated by human replication protein A.
The initiation of simian virus 40 (SV40) replication requires recognition of the viral origin of replication (ori) by SV40 T antigen, followed by denaturation of ori in a reaction dependent upon human replication protein A (hRPA). To understand how origin denaturation is achieved, we constructed a 48-bp SV40 "pseudo-origin" with a central 8-nucleotide (nt) bubble flanked by viral sequences, mimicking a DNA structure found within the SV40 T antigen-ori complex. hRPA bound the pseudo-origin with similar stoichiometry and an approximately fivefold reduced affinity compared to the binding of a 48-nt single-stranded DNA molecule. The presence of hRPA not only distorted the duplex DNA flanking the bubble but also resulted in denaturation of the pseudo-origin substrate in an ATP-independent reaction. Pseudo-origin denaturation occurred in 7 mM MgCl2, distinguishing this reaction from Mg2+-independent DNA-unwinding activities previously reported for hRPA. Tests of other single-stranded DNA-binding proteins (SSBs) revealed that pseudo-origin binding correlates with the known ability of these SSBs to support the T-antigen-dependent origin unwinding activity. Our results suggest that hRPA binding to the T antigen-ori complex induces the denaturation of ori including T-antigen recognition sequences, thus releasing T antigen from ori to unwind the viral DNA. The denaturation activity of hRPA has the potential to play a significant role in other aspects of DNA metabolism, including DNA repair.


Melatonin and celecoxib improve the outcomes in hamsters with experimental pancreatic cancer.
Pancreatic cancer is a major health problem because of the aggressiveness of the disease and the lack of effective systemic therapies. Melatonin (MEL) has antioxidant activity and prevents experimental genotoxicity. The specific inhibitor of cyclooxygenase-2 (COX-2), celecoxib (CEL), increases the efficacy of chemoradiotherapy in advanced pancreatic cancer. The objective of the study was the comparison and synergic effect of MEL and CEL during either the induction or progression phases of the tumor process, measuring parameters of oxidative stress, number of tumor nodules and survival of animals with pancreatic cancer. Pancreatic cancer was induced by N-nitrosobis (2-oxopropyl)amine) (BOP) in Syrian hamsters. Melatonin and/or CEL were administered during the induction, postinduction as well as during both phases. The presence of tumor nodules were observed macroscopically in pancreatic and splenic areas, and the levels of lipoperoxides (LPO), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) in pancreatic tissue were measured. The increases in tumor nodules and LPO as well as the reductions in GSH and enzymatic antioxidants in the pancreas induced by BOP were related to a lower survival rate of animals. The administration of MEL exerted a more potent beneficial effect than CEL treatment on the reduction in tumor nodules, oxidative stress and death of experimental BOP-treated animals. The combined treatment only exerted a synergistic beneficial effect when administered during the induction phase. Melatonin by itself had significant beneficial actions in improving the survival of hamsters.


Long-term outcome of major psychoses. I. Schizophrenia and affective disorders compared with psychiatrically symptom-free surgical conditions.
We conducted a 30- to 40-year field follow-up of 685 patients with schizophrenia, affective disorders, and nonpsychiatric conditions. Long-term outcome was analyzed in terms of the patients' marital, residential, occupational, and psychiatric status. On the whole, psychiatric patients showed a significantly poorer outcome than the surgical controls. On the basis of long-term outcome, schizophrenia, and affective disorders, selected according to the specified research criteria, were significantly different: schizophrenia definitely showed poorer outcome than affective disorders. However, no significant differences in all four outcome variables were found between mania and depression. We hope that the present data on long-term outcome of the typical cases can be used to compare outcome of other psychiatric disorders, such as undiagnosed psychoses, having mixtures of schizophrenic and affective features. In doing this, we hope to charify our understanding of undiagnosed psychoses and their relationship to schizophrenia and affective disorders.


Developmentally invariant dissociations in children's true and false memories: not all relatedness is created equal.
The role of categorical versus associative relations in 5-, 7-, and 11-year-old children's true and false memories was examined using the Deese-Roediger-McDermott (DRM) paradigm and categorized lists of pictures or words with or without category labels as primes. For true items, recall increased with age and categorized lists were better recalled than DRM lists. For false items, recall increased with age except for picture lists, there were no differences between categorized and DRM lists and no effect of priming, and there were fewer false memories for pictures than words. Like adults, children's false memories are based on associative not thematic relations, whereas their veridical memories depend on both. This new, developmentally invariant dissociation is consistent with knowledge- and resource-based models of memory development.


Discovery of novel papillomaviruses in the critically endangered Malayan and Chinese pangolins.
Pangolins are scaly and toothless mammals which are distributed across Africa and Asia. Currently, the Malayan, Chinese and Philippine pangolins are designated as critically endangered species. Although few pangolin viruses have been described, their viromes have received more attention following the discovery that they harbour sarbecoviruses related to SARS-CoV-2. Using large-scale genome mining, we discovered novel lineages of papillomaviruses infecting the Malayan and Chinese pangolins. We were able to assemble three complete circular papillomavirus genomes with an intact coding capacity and five additional L1 genes encoding the major capsid protein. Phylogenetic analysis revealed that seven out of eight L1 sequences formed a monophyletic group which is the sister lineage to the Tupaia belangeri papillomavirus 1, isolated from Yunnan province in China. Additionally, a single L1 sequence assembled from a Chinese pangolin was placed in a clade closer to Alphapapillomavirus and Omegapapillomavirus. Examination of the SRA data from 95 re-sequenced genomes revealed that 49.3% of Malayan pangolins and 50% of Chinese pangolins were positive for papillomavirus reads. Our results indicate that pangolins in South-East Asia are the hosts of diverse and highly prevalent papillomaviruses, and highlight the value of in silico mining of host sequencing data for the discovery of novel viruses.


10-valent pneumococcal non-typeable Haemophilus influenzae protein-D conjugate vaccine (PHiD-CV) induces memory B cell responses in healthy Kenyan toddlers.
Memory B cells are long-lived and could contribute to persistence of humoral immunity by maintaining the plasma-cell pool or making recall responses upon re-exposure to an antigen. We determined the ability of a pneumococcal conjugate vaccine to induce anti-pneumococcal memory B cells. Frequencies of memory B cells against pneumococcal capsular polysaccharides from serotypes 1, 6B, 14, 19F and 23F were determined by cultured B cell enzyme-linked immunospot (ELISPOT) in 35 children aged 12-23 months who received pneumococcal non-typeable Haemophilus influenzae protein-D conjugate vaccine (PHiD-CV). The relationships between plasma antibodies and memory B cell frequencies were also assessed. After two doses of PHiD-CV, the proportion of subjects with detectable memory B cells against pneumococcal capsular polysaccharides increased significantly for serotypes 1 (3-45%; P < 0·01), 19F (21-66%; P < 0·01) and 23F (13-36%; P = 0·02), but not serotypes 6B (24-42%; P = 0·24) and 14 (21-40%; P = 0·06). Correlations between antibodies and memory B cells were weak. Carriage of serotype 19F at enrolment was associated with poor memory B cell responses against this serotype at subsequent time-points (day 30: non-carriers, 82% versus carriers, 0%, P < 0·01; day 210: non-carriers, 72% versus carriers, 33%, P = 0·07). PHiD-CV is capable of inducing memory B cells against some of the component pneumococcal capsular polysaccharides.


A randomized comparative trial on the therapeutic efficacy of topical aloe vera and Calendula officinalis on diaper dermatitis in children.
Diaper dermatitis (DD) is a common inflammatory disorder among children and infants. The objective of the present randomized and double-blind trial was to compare the therapeutic efficacies of aloe vera cream and Calendula officinalis ointment on the frequency and severity of DD in children. Sixty-six infants with DD (aged < 3 years) were randomized to receive either aloe cream (n = 32) or Calendula ointment (n = 34). Infants were treated with these drugs 3 times a day for 10 days. The severity of dermatitis was graded at baseline as well as at the end of trial using a 5-point scale. The adverse effects of study medications were assessed during the trial. Although improvement in the severity of DD was observed in both treatment groups (P < 0.001), patients receiving Calendula ointment had significantly fewer rash sites compared to aloe group (P = 0.001). No adverse effect was reported from either of the medications. The evidence from this study suggests that topical aloe and in particular Calendula could serve as safe and effective treatment for the treatment of diaper dermatitis in infants.


Role of local immunosuppression in murine fetoplacental listeriosis.
Recent evidence suggests that local immunoregulation may prevent rejection of the placenta by the mother. This local immunoregulation may also compromise the response to placental infection. Listeria monocytogenes infection in 121 pregnant mice and 1,050 fetoplacental units was examined and the kinetics of bacterial growth in various maternal and fetal tissues were determined. A subset of pregnant mice developed overwhelming placental listeria infections. Pregnancy did not impair the maternal immune response in the liver and spleen. Pregnant mice without placental infection had numbers of listeria equivalent to nonpregnant controls and mice immunized during pregnancy had significantly less listeria than nonimmunized controls. The secondary response in immunized pregnant mice had no effect on the development of placental infection and the histologic features of placental infection were distinct from those in other organs. Our data suggest that an ineffective local immune response may contribute to the pathogenicity of listeria for the placenta.


The A2A adenosine receptor rescues the urea cycle deficiency of Huntington's disease by enhancing the activity of the ubiquitin-proteasome system.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The resultant mutant Htt protein (mHtt) forms aggregates in the brain and several peripheral tissues (e.g. the liver) and causes devastating neuronal degeneration. Metabolic defects resulting from Htt aggregates in peripheral tissues also contribute to HD pathogenesis. Simultaneous improvement of defects in both the CNS and peripheral tissues is thus the most effective therapeutic strategy and is highly desirable. We earlier showed that an agonist of the A(2A) adenosine receptor (A(2A) receptor), CGS21680 (CGS), attenuates neuronal symptoms of HD. We found herein that the A(2A) receptor also exists in the liver, and that CGS ameliorated the urea cycle deficiency by reducing mHtt aggregates in the liver. By suppressing aggregate formation, CGS slowed the hijacking of a crucial transcription factor (HSF1) and two protein chaperons (Hsp27 and Hsp70) into hepatic Htt aggregates. Moreover, the abnormally high levels of high-molecular-mass ubiquitin conjugates in the liver of an HD mouse model (R6/2) were also ameliorated by CGS. The protective effect of CGS against mHtt-induced aggregate formation was reproduced in two cells lines and was prevented by an antagonist of the A(2A) receptor and a protein kinase A (PKA) inhibitor. Most importantly, the mHtt-induced suppression of proteasome activity was also normalized by CGS through PKA. Our findings reveal a novel therapeutic pathway of A(2A) receptors in HD and further strengthen the concept that the A(2A) receptor can be a drug target in treating HD.


China's achievements and challenges in improving health insurance coverage.
China has undertaken waves of healthcare reforms to keep pace with its rapid economic growth. By 2011, universal health insurance coverage was successfully achieved through the creation of a basic social medical insurance system. Growing economic power, extensive government subsidies, and strategies for program implementation are critical to that achievement. However, the breadth and depth of coverage varies considerably across insurance schemes and localities. The disjointed insurance scheme led to inequality in coverage, accessibility, and affordability of medical services, lopsided allocation of health resources, and increasing medical expenditures, and these remain crucial challenges for healthcare insurance coverage. This paper describes societal conditions, polices, achievements and challenges in improving health insurance coverage in China. Thailand's experience in universal health insurance coverage and its implications for China's new medical reform are also discussed. Solutions including sustainable increases in government investment, transformation of payment methods, reinforcement of primary health care delivery and the referral system, and standardization of benefits packages are strongly recommended to address challenges in China's long-running medical reform.


Distinct expression profiles of TGF-beta1 signaling mediators in pathogenic SIVmac and non-pathogenic SIVagm infections.
The generalized T-cell activation characterizing HIV-1 and SIVmac infections in humans and macaques (MACs) is not found in the non-pathogenic SIVagm infection in African green monkeys (AGMs). We have previously shown that TGF-beta1, Foxp3 and IL-10 are induced very early after SIVagm infection. In SIVmac-infected MACs, plasma TGF-beta1 induction persists during primary infection 1. We raised the hypothesis that MACs are unable to respond to TGF-beta1 and thus cannot resorb virus-driven inflammation. We therefore compared the very early expression dynamics of pro- and anti-inflammatory markers as well as of factors involved in the TGF-beta1 signaling pathway in SIV-infected AGMs and MACs. Levels of transcripts encoding for pro- and anti-inflammatory markers (tnf-alpha, ifn-gamma, il-10, t-bet, gata-3) as well as for TGF-beta1 signaling mediators (smad3, smad4, smad7) were followed by real time PCR in a prospective study enrolling 6 AGMs and 6 MACs. During primary SIVmac infection, up-regulations of tnf-alpha, ifn-gamma and t-bet responses (days 1-16 p.i.) were stronger whereas il-10 response was delayed (4th week p.i.) compared to SIVagm infection. Up-regulation of smad7 (days 3-8 p.i.), a cellular mediator inhibiting the TGF-beta1 signaling cascade, characterized SIV-infected MACs. In AGMs, we found increases of gata-3 but not t-bet, a longer lasting up-regulation of smad4 (days 1-21 p.i), a mediator enhancing TGF-beta1 signaling, and no smad7 up-regulations. Our data suggest that the inability to resorb virus-driven inflammation and activation during the pathogenic HIV-1/SIVmac infections is associated with an unresponsiveness to TGF-beta1.


Electro-optical characteristics of holographic polymer dispersed liquid crystal gratings doped with nanosilver.
We report on the synthesis and characteristics of a holographic polymer dispersed liquid crystal (H-PDLC) switchable grating based on nano-Ag particles. The influence of doping different concentrations of nano-Ag on the diffraction efficiency, driving voltage, and response time of the H-PDLC grating is investigated. The best grating characteristics were achieved with 0.05% nano-Ag doping. Calculated and experimental results reveal that the improvement of the characteristics is likely due to the surface plasmon effect of nano-Ag.


Targeting JAK1/STAT3 signaling suppresses tumor progression and metastasis in a peritoneal model of human ovarian cancer.
JAK/STAT3 is one of the major signaling pathways that is aberrantly activated in ovarian cancer and associated with tumor progression and poor prognosis in patients with ovarian cancer. In this study, we evaluated the therapeutic potential of targeting JAK/STAT3 signaling in ovarian cancer using a peritoneal dissemination mouse model. We developed this mouse model by injecting a metastatic human ovarian cancer cell line, SKOV3-M-Luc, into the peritoneal cavity of immunodeficient mice. This model displayed a phenotype similar to late-stage ovarian cancer, including extensive peritoneal metastasis and ascites production. The constitutive activation of STAT3 in human ovarian cancer cells appeared to be mediated by an autocrine cytokine loop involving the IL6 family of cytokines and JAK1 kinase. shRNA-mediated knockdown of JAK1 or STAT3 in ovarian cancer cells led to reduced tumor growth, decreased peritoneal dissemination, and diminished ascites production, suggesting a critical role of STAT3 in ovarian cancer progression. Similar results were obtained when a small-molecule inhibitor (JAKi) of the JAK1 kinase was used to treat ovarian cancer in this model. In addition, we found that the expression level of IL6 was correlated with activation of STAT3 in ovarian cancer cells both in vitro and in vivo, suggesting a potential application of IL6 as a biomarker. Altogether, our results demonstrate that targeting JAK1/STAT3, using shRNA knockdown or a small-molecule inhibitor, effectively suppressed ovarian tumor progression and, therefore, could be a potential novel therapeutic approach for treating advanced ovarian cancer.


Randomised trial of educational visits to enhance use of systematic reviews in 25 obstetric units.
To evaluate the effectiveness of an educational visit to help obstetricians and midwives select and use evidence from a Cochrane database containing 600 systematic reviews. Randomised single blind controlled trial with obstetric units allocated to an educational visit or control group. 25 of the 26 district general obstetric units in two former NHS regions. The senior obstetrician and midwife from each intervention unit participated in educational visits. Clinical practices of all staff were assessed in 4508 pregnancies. Single informal educational visit by a respected obstetrician including discussion of evidence based obstetrics, guidance on implementation, and donation of Cochrane database and other materials. Rates of perineal suturing with polyglycolic acid, ventouse delivery, prophylactic antibiotics in caesarean section, and steroids in preterm delivery, before and 9 months after visits, and concordance of guidelines with review evidence for same marker practices before and after visits. Rates varied greatly, but the overall baseline mean of 43% (986/2312) increased to 54% (1189/2196) 9 months later. Rates of ventouse delivery increased significantly in intervention units but not in control units; there was no difference between the two types of units in uptake of other practices. Pooling rates from all 25 units, use of antibiotics in caesarean section and use of polyglycolic acid sutures increased significantly over the period, but use of steroids in preterm delivery was unchanged. Labour ward guidelines seldom agreed with evidence at baseline; this hardly improved after visits. Educational visits cost pound860 each (at 1995 prices). There was considerable uptake of evidence into practice in both control and intervention units between 1994 and 1995. Our educational visits added little to this, despite the informal setting, targeting of senior staff from two disciplines, and donation of educational materials. Further work is needed to define cost effective methods to enhance the uptake of evidence from systematic reviews and to clarify leadership and roles of senior obstetric staff in implementing the evidence.


Pallidotomy in Parkinson's disease increases supplementary motor area and prefrontal activation during performance of volitional movements an H2(15)O PET study.
Supplementary motor area and right dorsal prefrontal cortex activation in Parkinson's disease is selectively impaired during volitional limb movements. Since posteroventral pallidotomy improves motor performance in Parkinson's disease patients 'off' medication (i.e. off medication for 9-12 h), we hypothesized that it would also concomitantly increase supplementary motor area and dorsal prefrontal cortex activation. Six Parkinson's disease patients with a median total motor Unified Parkinson's Disease Rating Scale (UPDRS) of 52.5 (range 34-66) 'off' medication underwent unilateral right posteroventral pallidotomy. The patients had H2(15)O PET when 'off' medication before and 3-4 months after surgery. Each PET study comprised four to six measurements of regional cerebral blood flow either at rest or while performing regularly paced joystick movements in freely selected directions (forward, backward, left or right) using the left hand. Pre- and postoperative scans were performed in an identical manner and the associated levels of activation were compared using statistical parametric mapping. After pallidotomy, the median total motor UPDRS score 'off' medication decreased by 34.7% (P = 0.03) and mean response times of joystick movements following the pacing tones improved by 13.8% (P = 0.08). Relative increases in activation of the supplementary motor area and right dorsal prefrontal cortex were observed during joystick movements (P < 0.001). Decreased activation was seen in the region of the right pallidum (P = 0.001). We conclude that pallidotomy reduces pallidal inhibition of thalamocortical circuits and reverses, at least partially, the impairment of supplementary motor area and dorsal prefrontal cortex activation associated with Parkinson's disease.


Evaluation of denoising algorithms for biological electron tomography.
Tomograms of biological specimens derived using transmission electron microscopy can be intrinsically noisy due to the use of low electron doses, the presence of a "missing wedge" in most data collection schemes, and inaccuracies arising during 3D volume reconstruction. Before tomograms can be interpreted reliably, for example, by 3D segmentation, it is essential that the data be suitably denoised using procedures that can be individually optimized for specific data sets. Here, we implement a systematic procedure to compare various nonlinear denoising techniques on tomograms recorded at room temperature and at cryogenic temperatures, and establish quantitative criteria to select a denoising approach that is most relevant for a given tomogram. We demonstrate that using an appropriate denoising algorithm facilitates robust segmentation of tomograms of HIV-infected macrophages and Bdellovibrio bacteria obtained from specimens at room and cryogenic temperatures, respectively. We validate this strategy of automated segmentation of optimally denoised tomograms by comparing its performance with manual extraction of key features from the same tomograms.


Assessment of the ecotoxicity of the pharmaceuticals bisoprolol, sotalol, and ranitidine using standard and behavioral endpoints.
The pharmaceuticals bisoprolol (BIS), sotalol (SOT), and ranitidine (RAN) are among the most consumed pharmaceuticals worldwide and are frequently detected in different aquatic ecosystems. However, very few ecotoxicity data are available in the literature for them. To help fill these data gaps, toxicity tests with the algae Raphidocelis subcapitata, the macrophyte Lemna minor, the cnidarian Hydra attenuata, the crustacean Daphnia similis, and the fish Danio rerio were performed for assessing the ecotoxicity of these pharmaceuticals. Standard, as well as non-standard endpoint, was evaluated, including the locomotor behavior of D. rerio larvae. Results obtained for SOT and RAN showed that acute adverse effects are not expected to occur on aquatic organisms at the concentrations at which these pharmaceuticals are usually found in fresh surface waters. On the other hand, BIS was classified as hazardous to the environment in the acute III category. Locomotor behavior of D. rerio larvae was not affected by BIS and RAN. A disturbance on the total swimming distance at the dark cycle was observed only for larvae exposed to the highest test concentration of 500 mg L-1 of SOT. D. similis reproduction was affected by BIS with an EC10 of 3.6 (0.1-34.0) mg L-1. A risk quotient (RQ) of 0.04 was calculated for BIS in fresh surface water, considering a worst-case scenario. To the best of our knowledge, this study presents the first chronic toxicity data with BIS on non-target organisms.


Improved OTU-picking using long-read 16S rRNA gene amplicon sequencing and generic hierarchical clustering.
High-throughput bacterial 16S rRNA gene sequencing followed by clustering of short sequences into operational taxonomic units (OTUs) is widely used for microbiome profiling. However, clustering of short 16S rRNA gene reads into biologically meaningful OTUs is challenging, in part because nucleotide variation along the 16S rRNA gene is only partially captured by short reads. The recent emergence of long-read platforms, such as single-molecule real-time (SMRT) sequencing from Pacific Biosciences, offers the potential for improved taxonomic and phylogenetic profiling. Here, we evaluate the performance of long- and short-read 16S rRNA gene sequencing using simulated and experimental data, followed by OTU inference using computational pipelines based on heuristic and complete-linkage hierarchical clustering. In simulated data, long-read sequencing was shown to improve OTU quality and decrease variance. We then profiled 40 human gut microbiome samples using a combination of Illumina MiSeq and Blautia-specific SMRT sequencing, further supporting the notion that long reads can identify additional OTUs. We implemented a complete-linkage hierarchical clustering strategy using a flexible computational pipeline, tailored specifically for PacBio circular consensus sequencing (CCS) data that outperforms heuristic methods in most settings: https://github.com/oscar-franzen/oclust/ . Our data demonstrate that long reads can improve OTU inference; however, the choice of clustering algorithm and associated clustering thresholds has significant impact on performance.


In vivo tumor suppression activity by T cell-specific T-bet restoration.
T-box-containing protein expressed in T cells (T-bet) is a master transcription factor for the development of interferon (IFN) gamma-producing T helper 1 (Th1) cells and also functions in other immune cells including natural killer (NK), cytotoxic T lymphocytes and dendritic cells. T-bet-deficient mice increased susceptibility to viral infection and tumor development due to the defective functions of immune cells. T-bet is known to play a key role in NK-mediated antimetastatic response; however, it remains to be characterized whether T-bet is essential for in vivo tumor suppression mediated by T cells. Here, we have investigated in vivo tumor suppression effect of T-bet-restored T cells using T cell-specific and inducible T-bet transgenic mice generated in a T-bet-deficient background. T-bet-null mice increased susceptibility to tumor development, whereas induction of T cell-specific T-bet expression upon melanoma cell injection substantially suppressed tumor development by inducing IFNgamma production in T cells and tumor cell apoptosis. Late induction of T-bet expression in tumor-bearing mice produced comparable amounts of IFNgamma with control and significantly decreased tumor volume. In addition, increased melanoma lung metastasis in T-bet-deficient mice was strikingly inhibited by T-bet restoration in T cells. Intravenous injection of activated Th1 cells, not T-bet-null Th1 cells, attenuated metastatic melanoma progression, in addition, restoration of T-bet in T-bet-null Th1 cells certainly retrieved antimetastatic activity. These results suggest that T-bet expression in T cells is crucial for the control of tumor development and antimetastatic activity.


Accurate phenotypic classification and exome sequencing allow identification of novel genes and variants associated with adult-onset hearing loss.
Adult-onset progressive hearing loss is a common, complex disease with a strong genetic component. Although to date over 150 genes have been identified as contributing to human hearing loss, many more remain to be discovered, as does most of the underlying genetic diversity. Many different variants have been found to underlie adult-onset hearing loss, but they tend to be rare variants with a high impact upon the gene product. It is likely that combinations of more common, lower impact variants also play a role in the prevalence of the disease. Here we present our exome study of hearing loss in a cohort of 532 older adult volunteers with extensive phenotypic data, including 99 older adults with normal hearing, an important control set. Firstly, we carried out an outlier analysis to identify genes with a high variant load in older adults with hearing loss compared to those with normal hearing. Secondly, we used audiometric threshold data to identify individual variants which appear to contribute to different threshold values. We followed up these analyses in a second cohort. Using these approaches, we identified genes and variants linked to better hearing as well as those linked to worse hearing. These analyses identified some known deafness genes, demonstrating proof of principle of our approach. However, most of the candidate genes are novel associations with hearing loss. While the results support the suggestion that genes responsible for severe deafness may also be involved in milder hearing loss, they also suggest that there are many more genes involved in hearing which remain to be identified. Our candidate gene lists may provide useful starting points for improved diagnosis and drug development.


Introduction of potentially allergenic foods in the infant's diet during the first year of life in five European countries.
Little information is available on infants' age at first introduction of potentially allergenic foods as part of complementary feeding. We aimed to analyze age at the introduction of potentially allergenic foods in healthy term infants relative to recommendations in 5 European countries. Recruitment was conducted from October 2002 to June 2004. A total of 1,678 infants [588 breastfed (BF) and 1,090 formula-fed (FF) infants] were studied. In 1,368 infants, at least one 3-day weighed food diary at the age of 1-9 and 12 completed months was available. Six percent of BF infants and 13% of FF infants consumed some potentially allergenic food already prior to the recommended minimum age of 4 months, and 4% of BF infants and 11% of FF infants had already received gluten. There were significant differences in the timing of the introduction of potentially allergenic foods between the countries at the age of 4-6 months (p < 0.001). The time of first introduction of potentially allergenic foods in infants differed significantly between countries, and they were introduced much earlier than recommended in some countries. FF infants received potentially allergenic foods earlier than BF infants. Better information and counseling of parents is desirable.


First Report of Embellisia allii Causing Skin Blotch and Bulb Canker on Garlic in California.
In April 2011, commercial garlic (Allium sativum) in Monterey County, CA showed symptoms of an undocumented disease. Bulb and stem sheaths were dark, decayed, and sloughing off the plants. Dissection of diseased sheaths revealed black hyphae between layers. Lower leaves wilted, turned tan, and dried up. Disease occurred in small patches scattered in two fields. In the patches, disease incidence was as much as 50%; however, overall field incidence was less than 1%. Isolations from 80% (16 of 20 plants) of collected plants resulted in the recovery of a dark olivaceous black fungus. Conidiophores were geniculate and brown and conidia were borne singly, brown, and ellipsoidal to cylindrical. Conidia had two to five but mostly three transverse septa. Longitudinal septa were infrequent and apical cells were rounded. Conidia measured (19.0-) 26.3 to 36.6 (-42.8) × (6.7-) 9.2 to 9.9 (-12.9) μm. Dark, intercalary chlamydospores were observed as colonies aged. DNA sequencing of the internal transcribed spacer (ITS) regions of four, single-spored isolates was completed with primers ITS1 and ITS4 (3). Sequences of all isolates (GenBank Nos. JN588614 to JN588617) were identical and 100% similar to Embellisia allii (AY278840). On the basis of morphological and molecular data, the fungus was identified as E. allii (Campanile) Simmons (1). Pathogenicity of four of the sequenced E. allii isolates and one additional E. allii isolate was tested using inoculum grown on acidified potato dextrose agar and garlic (cv. California Late) planted into 15-cm pots. A transverse incision was made at a point 2 cm above the garlic bulb so that a colonized agar plug could be inserted between the second and third sheath layer. The stem was then wrapped with Parafilm. Ten plants per isolate were inoculated and kept in a greenhouse (24 to 26°C). Seven to eight days after inoculation, the tissue around the incision turned tan and dark fungal growth was observed. Fourteen days after inoculation, the inoculated area was necrotic and dark fungal growth developed between stem layers. E. allii was reisolated from all inoculated plants and matched the morphological characteristics of the original isolates. Control plants, inoculated with uncolonized agar plugs, developed no symptoms. This experiment was repeated with similar results. In addition, one isolate was used to inoculate leek (A. porrum cv. Lancelot) and onion (A. cepa cv. Evergreen). Similar symptoms developed on these two species and E. allii was reisolated from all plants. To our knowledge, this is the first documentation of skin blotch and bulb canker caused by E. allii on garlic in California. Affected plants were of poor quality and could not be harvested. Our findings that garlic isolates of E. allii can infect leek and onion provide preliminary evidence that this pathogen is not restricted to garlic; this information may be useful to growers when considering crop rotations. E. allii has been reported on garlic in a number of places in Africa, Asia, Europe, the Middle East, and North and South America (2). The sequenced E. allii isolates are deposited in the fungal collection at the CDFA Plant Pest Diagnostics Lab (CDFA798-801). References: (1) J. C. David. Mycopathologia 116:59, 1991. (2) D. F. Farr and A. Y. Rossman. Fungal Databases. Systematic Mycology and Microbiology Laboratory, ARS, USDA. Retrieved from http://nt.ars-grin.gov/fungaldatabases/ , August 8, 2011, (3) B. M. Pryor and D. M. Bigelow. Mycologia 95:1141, 2003.


Uptake of the human papillomavirus vaccine in Kenya: testing the health belief model through pathway modeling on cohort data.
Many studies investigate HPV vaccine acceptability, applying health behavior theories to identify determinants; few include real uptake, the final variable of interest. This study investigated the utility of the Health Belief Model (HBM) in predicting HPV vaccine uptake in Kenya, focusing on the importance of promotion, probing willingness to vaccinate as precursor of uptake and exploring the added value of personal characteristics. Longitudinal data were collected before and after a pilot HPV vaccination program in Eldoret among mothers of eligible girls (N = 255). Through pathway modeling, associations between vaccine uptake and the HBM constructs, willingness to vaccinate and adequate promotion were examined. Adequate promotion was defined as a personal evaluation of promotional information received. Finally, baseline cervical cancer awareness and socio-demographic variables were added to the model verifying their direct, mediating or moderating effects on the predictive value of the HBM. Perceiving yourself as adequately informed at follow-up was the strongest determinant of vaccine uptake. HBM constructs (susceptibility, self-efficacy and foreseeing father's refusal as barrier) only influenced willingness to vaccinate, which was not correlated with vaccination. Baseline awareness of cervical cancer predicted uptake. The association between adequate promotion and vaccination reveals the importance of triggers beyond personal control. Adoption of new health behaviors might be more determined by organizational variables, such as promotion, than by prior personal beliefs. Assessing users' and non-users' perspectives during and after implementing a vaccination program can help identifying stronger determinants of vaccination behavior.


Proton pump inhibitors use and risk of developing spontaneous bacterial peritonitis in cirrhotic patients: A systematic review and meta-analysis.
Spontaneous bacterial peritonitis (SBP) is one of the most common infectious diseases in patients with cirrhosis and is associated with serious prognosis. A prevailing dogma posits that SBP is exacerbated by the frequent use of proton pump inhibitors (PPIs). To re-assess the association between PPIs use and SBP incidence with larger and better-quality data. The studies were identified by searching Proquest, Medline, and Embase for English language articles published between January 2008 and March 2020 using the following keywords alone or in combination: anti-ulcer agent, antacid, proton pump inhibitor, proton pumps, PPI, omeprazole, rabeprazole, lansoprazole, pantoprazole, esomeprazole, peritonitis, spontaneous bacterial peritonitis, SBP, ascites, cirrhosis, ascitic and cirrhotic. Three authors critically reviewed all of the studies retrieved and selected those judged to be the most relevant. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was followed. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Sub-group analyses were done to decrease the heterogeneity. A total of twenty-three studies: seven case-control, and sixteen cohorts, involving 10,386 patients were analyzed. The overall results showed a statistically significant association between SBP and PPIs use (pooled odds ratio (OR): 1.80, 95% CI of 1.41 to 2.31). Substantial heterogeneity was observed. On subgroup analysis involving cohort studies, the association was weaker (OR: 1.55 with 95% CI of 1.16 to 2.06 p < 0.00001) but still statistically significant and with high heterogeneity (Chi2p = 57.68; I2 = 74%). For case-control studies, the OR was 2.62 with a 95% CI of 1.94 to 3.54. The funnel plot was asymmetric and Egger's test confirmed asymmetry suggesting publication bias (intercept = - 0.05, SE = 0.27, P = 0.850 two-tailed). This meta-analysis sheds light on the conflicting results raised by previous studies regarding the association of SBP with PPIs use. Our meta-analysis showed that there is a weak association, although statistically significant, between SBP and PPIs use. However, the magnitude of the possible association diminished when analysis focused on higher quality data that were more robust. Thus, this updated meta-analysis suggests judicious use of PPIs among cirrhotic patients with ascites.


Drug Interactions With Oral Inhaled Medications.
Objective: To evaluate the potential for drug interactions with oral inhaled medications (OIMs). OIMs include bronchodilators (β-agonists and antimuscarinics), corticosteroids, combination products (2 or more agents combined within a single inhalation device), antibiotics, prostacyclins, anesthetics, acetylcysteine, mucolytics, insulin, antivirals, nitric oxide, and nicotine replacement. Data Sources: A systemic literature search (1980 to May 2018) was performed using PubMed and EBSCO to locate relevant articles. The MESH terms used included each specific medication available as an OIM as well as "drug interactions." DAILYMED was used for product-specific drug interactions. Study Selection and Data Extraction: The search was conducted to identify drug interactions with OIMs. The search was limited to those articles studying human applications with OIMs and publications using the English language. Case reports, clinical trials, review articles, treatment guidelines, and package labeling were selected for inclusion. Data Synthesis: Primary literature and package labeling indicate that OIMs are subject to pharmacokinetic and pharmacodynamics interactions. The most frequently identified clinically significant drug interaction is an inhaled corticosteroid when combined with a potent CYP 450 inhibitor such as a protease inhibitor or antifungal. Conclusions: The available literature indicates that OIMs are associated with clinically significant drug interactions and subsequent adverse reactions. Clinicians in all practice settings should be mindful of this potential to minimize adverse effects and optimize therapy.


Polymerase/DNA interactions and enzymatic activity: multi-parameter analysis with electro-switchable biosurfaces.
The engineering of high-performance enzymes for future sequencing and PCR technologies as well as the development of many anticancer drugs requires a detailed analysis of DNA/RNA synthesis processes. However, due to the complex molecular interplay involved, real-time methodologies have not been available to obtain comprehensive information on both binding parameters and enzymatic activities. Here we introduce a chip-based method to investigate polymerases and their interactions with nucleic acids, which employs an electrical actuation of DNA templates on microelectrodes. Two measurement modes track both the dynamics of the induced switching process and the DNA extension simultaneously to quantitate binding kinetics, dissociation constants and thermodynamic energies. The high sensitivity of the method reveals previously unidentified tight binding states for Taq and Pol I (KF) DNA polymerases. Furthermore, the incorporation of label-free nucleotides can be followed in real-time and changes in the DNA polymerase conformation (finger closing) during enzymatic activity are observable.


Results of a program for the prevention of blindness caused by retinopathy of prematurity in southern Brazil.
To describe the results of a program for the prevention of blindness caused by retinopathy of prematurity implemented in 2002 at a tertiary-care hospital, according to screening criteria adopted in Brazil, and to compare some aspects with the criteria adopted by other countries. Descriptive observational study including all preterm infants born at this hospital weighing <or= 1,500 g at birth and/or gestational age <or= 32 weeks who survived up to the sixth week after birth, between October 2002 and June 2006. Ophthalmic examinations were performed from the sixth week of life and repeated as necessary until remission of the disease. A total of 300 newborns were included and there were 18 cases of treatable threshold disease (18/300, 6%) according to the Brazilian criteria. One patient was not treated because s/he developed the disease after hospital discharge and did not turn up for examination in order to initiate treatment. According to the criteria suggested by industrialized countries, the total number of exams would be reduced under the same circumstances, but 11.76% of the cases of threshold disease would not be detected. The Brazilian criteria for neonatal screening were efficient in detecting treatable cases. Blindness was averted in 17 preterm infants in the study period. The universal use of such program at teaching hospitals or in the public and private health networks could help prevent one of the main causes of preventable and treatable blindness among infants in developing countries. Currently, a change in these criteria in Brazil may compromise the diagnosis of some treatable patients.


Inhibitory Effects of Lipopeptides and Glycolipids on C. albicans-Staphylococcus spp. Dual-Species Biofilms.
Microbial biofilms strongly resist host immune responses and antimicrobial treatments and are frequently responsible for chronic infections in peri-implant tissues. Biosurfactants (BSs) have recently gained prominence as a new generation of anti-adhesive and antimicrobial agents with great biocompatibility and were recently suggested for coating implantable materials in order to improve their anti-biofilm properties. In this study, the anti-biofilm activity of lipopeptide AC7BS, rhamnolipid R89BS, and sophorolipid SL18 was evaluated against clinically relevant fungal/bacterial dual-species biofilms (Candida albicans, Staphylococcus aureus, Staphylococcus epidermidis) through quantitative and qualitative in vitro tests. C. albicans-S. aureus and C. albicans-S. epidermidis cultures were able to produce a dense biofilm on the surface of the polystyrene plates and on medical-grade silicone discs. All tested BSs demonstrated an effective inhibitory activity against dual-species biofilms formation in terms of total biomass, cell metabolic activity, microstructural architecture, and cell viability, up to 72 h on both these surfaces. In co-incubation conditions, in which BSs were tested in soluble form, rhamnolipid R89BS (0.05 mg/ml) was the most effective among the tested BSs against the formation of both dual-species biofilms, reducing on average 94 and 95% of biofilm biomass and metabolic activity at 72 h of incubation, respectively. Similarly, rhamnolipid R89BS silicone surface coating proved to be the most effective in inhibiting the formation of both dual-species biofilms, with average reductions of 93 and 90%, respectively. Scanning electron microscopy observations showed areas of treated surfaces that were free of microbial cells or in which thinner and less structured biofilms were present, compared to controls. The obtained results endorse the idea that coating of implant surfaces with BSs may be a promising strategy for the prevention of C. albicans-Staphylococcus spp. colonization on medical devices, and can potentially contribute to the reduction of the high economic efforts undertaken by healthcare systems for the treatment of these complex fungal-bacterial infections.


Characteristics of carotid atherosclerotic plaques of chronic lipid apheresis patients as assessed by in vivo high-resolution CMR--a comparative analysis.
Components of carotid atherosclerotic plaques can reliably be identified and quantified using high resolution in vivo 3-Tesla CMR. It is suspected that lipid apheresis therapy in addition to lowering serum lipid levels also has an influence on development and progression of atherosclerotic plaques. The purpose of this study was to evaluate the influence of chronic lipid apheresis (LA) on the composition of atherosclerotic carotid plaques. 32 arteries of 16 patients during chronic LA-therapy with carotid plaques and stenosis of 1-80% were matched according to degree of stenosis with 32 patients, who had recently suffered an ischemic stroke. Of these patients only the asymptomatic carotid artery was analyzed. All patients underwent black-blood 3 T CMR of the carotids using parallel imaging and dedicated surface coils. Cardiovascular risk factors were recorded. Morphology and composition of carotid plaques were evaluated. For statistical evaluation Fisher's Exact and unpaired t-test were used. A p-value <0.05 was considered statistically significant. Patients in the LA-group were younger (63.5 vs. 73.9. years, p<0.05), had a higher prevalence of hypercholesterolemia and of established coronary heart disease in patients and in first-degree relatives (p<0.05, respectively). LA-patients had smaller maximum wall areas (49.7 vs. 59.6mm2, p<0.05), showed lower prevalence of lipid cores (28.1% vs. 56.3%, p<0.05) and the lipid content was smaller than in the control group (5.0 vs. 11.6%, p<0.05). Minimum lumen areas and maximum total vessel areas did not differ significantly between both groups. Results of this study suggest that, despite a severer risk profile for cardiovascular complications in LA-patients, chronic LA is associated with significantly lower lipid content in carotid plaques compared to plaques of patients without LA with similar degrees of stenosis, which is characteristic of clinically stable plaques.


Investigating the racioethnic differences in the link between workplace racioethnic dissimilarity and life satisfaction.
Though researchers have examined racioethnic dissimilarity in the workplace, few have looked at how it relates to life satisfaction, and none have examined prospective racioethnic differences in this linkage. This study used data from a nationally representative interview survey of more than 500 people employed in the United States to test relationships between workplace dissimilarity, prejudice, racioethnicity, and life satisfaction. We found that the dissimilarity-satisfaction linkage is positive for Black and Hispanic Americans and negative for White Americans. Further exploring the latter finding, our results showed that the negative association between dissimilarity and life satisfaction was present only among White Americans higher in prejudice. This study extends the literature on interracioethnic interactions and further illustrates the importance of reducing prejudice in organizational settings.


Mapping the Electronic Health Record: A Method to Study Display Fragmentation.
Electronic health records have often been criticized for poor interaction design. One major problem is the 'display fragmentation problem' i.e. the fact that conventional EHRs require the user to view many screens and retain information in memory or external tools rather than being able to view all relevant information together, increasing cognitive load and the possibility of errors and inefficiency. We describe a method for evaluating and depicting the extent of display fragmentation and discuss its potential uses in comparing systems, identifying navigation pathways and information juxtaposition, and improving EHR interaction design.


In-Hospital Neurologic Complications in Adult Patients Undergoing Venoarterial Extracorporeal Membrane Oxygenation: Results From the Extracorporeal Life Support Organization Registry.
To elucidate the epidemiology, complication profiles, hospital outcome, and predisposing factors of CNS complications occurring during venoarterial extracorporeal membrane oxygenation in adults. Retrospective analysis of the Extracorporeal Life Support Organization registry. Data reported to Extracorporeal Life Support Organization by 230 extracorporeal membrane oxygenation centers from 1992 to 2013. Patients more than 16 years old supported with a single-run of venoarterial extracorporeal membrane oxygenation. None. We examined 4,522 adult patients supported with venoarterial extracorporeal membrane oxygenation and included in the Extracorporeal Life Support Organization registry. Venoarterial extracorporeal membrane oxygenation was used for cardiac dysfunction in 3,005 patients (66.5%), cardiopulmonary resuscitation in 877 patients (19.4%), and respiratory failure in 640 patients (14.1%), respectively. Multivariate logistic regression was performed to identify factors independently associated with CNS injury. Neurologic complications occurred in 682 patients (15.1%), and included brain death in 358 patients (7.9%), cerebral infarction in 161 patients (3.6%), seizures in 83 patients (1.8%), and cerebral hemorrhage in 80 patients (1.8%). Multiple CNS complications in the same patient occurred in 70 cases. Hospital mortality in patients with CNS complications was 89%, compared with 57% in patients without (p < 0.001). In a multivariable model, age, pre-extracorporeal membrane oxygenation cardiac arrest, the use of inotropes on extracorporeal membrane oxygenation, and post-extracorporeal membrane oxygenation hypoglycemia were shown to be associated with CNS complications. Neurologic complications in adult patients on venoarterial extracorporeal membrane oxygenation support are common and associated with poor survival. Further research should focus on better understanding and management of brain/extracorporeal membrane oxygenation interaction to avoid such catastrophic complications.


Children of homosexuals more apt to be homosexuals? A reply to Morrison and to Cameron based on an examination of multiple sources of data.
Ten narrative studies involving family histories of 262 children of gay fathers and lesbian mothers were evaluated statistically in response to Morrison's (2007) concerns about Cameron's (2006) research that had involved three narrative studies. Despite numerous attempts to bias the results in favour of the null hypothesis and allowing for up to 20 (of 63, 32%) coding errors, Cameron's (2006) hypothesis that gay and lesbian parents would be more likely to have gay, lesbian, bisexual or unsure (of sexual orientation) sons and daughters was confirmed. Percentages of children of gay and lesbian parents who adopted non-heterosexual identities ranged between 16% and 57%, with odds ratios of 1.7 to 12.1, depending on the mix of child and parent genders. Daughters of lesbian mothers were most likely (33% to 57%; odds ratios from 4.5 to 12.1) to report non-heterosexual identities. Data from ethnographic sources and from previous studies on gay and lesbian parenting were re-examined and found to support the hypothesis that social and parental influences may influence the expression of non-heterosexual identities and/or behaviour. Thus, evidence is presented from three different sources, contrary to most previous scientific opinion, even most previous scientific consensus, that suggests intergenerational transfer of sexual orientation can occur at statistically significant and substantial rates, especially for female parents or female children. In some analyses for sons, intergenerational transfer was not significant. Further research is needed with respect to pathways by which intergenerational transfer of sexual orientation may occur. The results confirm an evolving tendency among scholars to cite the possibility of some degree of intergenerational crossover of sexual orientation.


Ethical justifications for access to unapproved medical interventions: an argument for (limited) patient obligations.
Many health care systems include programs that allow patients in exceptional circumstances to access medical interventions of as yet unproven benefit. In this article we consider the ethical justifications for-and demands on-these special access programs (SAPs). SAPs have a compassionate basis: They give patients with limited options the opportunity to try interventions that are not yet approved by standard regulatory processes. But while they signal that health care systems can and will respond to individual suffering, SAPs have several disadvantages, including the potential to undermine regulatory and knowledge-generation structures that constitute significant public goods. The "balance" between these considerations depends in part on how broadly SAPs are used, but also on whether SAPs can be made to contribute to the generation of knowledge about the effects of health interventions. We argue that patients should usually be required to contribute outcome data while using SAPs.


The small effects of political advertising are small regardless of context, message, sender, or receiver: Evidence from 59 real-time randomized experiments.
Evidence across social science indicates that average effects of persuasive messages are small. One commonly offered explanation for these small effects is heterogeneity: Persuasion may only work well in specific circumstances. To evaluate heterogeneity, we repeated an experiment weekly in real time using 2016 U.S. presidential election campaign advertisements. We tested 49 political advertisements in 59 unique experiments on 34,000 people. We investigate heterogeneous effects by sender (candidates or groups), receiver (subject partisanship), content (attack or promotional), and context (battleground versus non-battleground, primary versus general election, and early versus late). We find small average effects on candidate favorability and vote. These small effects, however, do not mask substantial heterogeneity even where theory from political science suggests that we should find it. During the primary and general election, in battleground states, for Democrats, Republicans, and Independents, effects are similarly small. Heterogeneity with large offsetting effects is not the source of small average effects.


Spectrum of acute kidney injury in critically ill patients: A single center study from South India.
Acute kidney injury (AKI) is common in intensive care unit (ICU) and carries a high mortality rate. Reliable and comparable data about the clinical spectrum of AKI is necessary for optimizing management. The study was conducted to describe epidemiology, etiology, clinical characteristics and outcome of AKI in critically ill patients without pre-existing renal disease, diagnosed using RIFLE criteria. We retrospectively analyzed data of 500 adult patients admitted to ICU with AKI or who developed AKI in ICU. Patients with pre-existing renal disease, renal transplant recipients were excluded. AKI was predominantly encountered in older males. Diabetes, hypertension, coronary artery disease were the most commonly prevalent comorbidities. Sepsis was the most common cause of AKI, accounting for 38.6% of patients. 24.4% belonged to risk class, 37.0% to injury class, 35.0% to failure class, 3% to loss and 0.6% to ESRD class of the RIFLE criteria. Renal replacement therapy (RRT) was required in 37.2% (n = 186) of patients. About 60% recovered complete renal function. Chronic kidney disease (CKD) was a sequel in 2.4% (n = 12) of patients. Average duration of ICU stay was 5.6 days. Crude mortality rate was 37.6% (n = 188). In critically ill patients without pre-existing renal disease, elderly age, male sex, type 2 diabetes along with a primary diagnosis of sepsis were most commonly associated with AKI. Majority of the patients' recovered complete renal function.


Dielectric back scattering patterns for light trapping in thin-film Si solar cells.
We experimentally compare the light trapping efficiency of dielectric and metallic backscattering patterns in thin-film a-Si:H solar cells. We compare devices with randomly patterned Ag back contacts that are covered with either flat or patterned aluminum-doped ZnO (AZO) buffer layers and find the nanostructure at the AZO/a-Si:H interface is key to achieve efficient light trapping. Simulations show that purely dielectric scattering patterns with flat Ag and a patterned AZO/a-Si:H interface can outperform geometries in which the Ag is also patterned. The scattering from the dielectric patterns is due to geometrical Mie resonances in the AZO nanostructures. The optimized dielectric geometries avoid parasitic Ohmic losses due to plasmon resonances in the Ag, and open the way to a large number of new light trapping designs based on purely dielectric resonant light scattering.


Effectiveness and safety of liposomal amphotericin B for visceral leishmaniasis under routine program conditions in Bihar, India.
We evaluated, through the prospective monitoring of 251 patients at Sadar Hospital in Bihar, India, the effectiveness and safety of 20 mg/kg body weight of liposomal amphotericin B for the treatment of visceral leishmaniasis. The treatment success rates for the intention-to-treat, per protocol, and intention-to-treat worse-case scenario analyses were 98.8%, 99.6%, and 81.3%, respectively. Nearly one-half of patients experienced mild adverse events, but only 1% developed serious but non-life-threatening lips swelling. The lost to follow-up rate was 17.5%. Our findings indicate that the 20 mg/kg body weight treatment dosage is effective and safe under routine program conditions. Given that the exorbitant cost of liposomal amphotericin B is a barrier to its widespread use, we recommend further study to monitor and evaluate a lowered dosage and a shorter treatment course.


Proton pump inhibitor usage and the associated risk of pneumonia in patients with chronic kidney disease.
Chronic kidney disease (CKD) is a serious medical problem and public health issue in Taiwan. Gastrointestinal symptoms frequently occur in patients with CKD, and proton pump inhibitors (PPIs) have therapeutic indications for gastrointestinal disorders involving excessive acid production. However, PPIs may also increase the risk of developing pneumonia through acute and irreversible gastric acid suppression. This study aimed to characterize differences in the risk of pneumonia in patients with CKD who use PPIs. This population-based case-control cohort study in Taiwan collected data from the Taiwan Health Insurance Research Database. Cases studied consisted of all patients in the database with an initial diagnosis of CKD during the 5-year period from 1997 to 2002. Each patient with CKD who used PPIs during this 5-year period was tracked to identify the occurrence of any type of pneumonia. We estimated the adjusted hazard ratios (HRs) and 95% confidence interval (95% CI) by using multiple logistic regression analysis. The adjusted HR of the risk of pneumonia for patients with CKD using PPIs was 2.21 (95% CI = 1.59-3.07, p < 0.001). The risk of pneumonia was found to be positively associated with administration of PPIs. We observed a greater risk of pneumonia in patients with CKD using PPIs than in patients not using PPIs. Results of this study suggest that use of PPIs in CKD patients may be associated with increasing the risk of pneumonia. Physicians should exercise caution while prescribing PPIs for patients with CKD.


Expression of the miR-190 family is increased under DDT exposure in vivo and in vitro.
A non-genotoxic insecticide dichlorodiphenyltrichloroethane (DDT), can affect mRNA and microRNA levels, however, its precise mechanism of action remains poorly understood. Using in silico methods we found that the rat miR-190 family is potentially regulated by CAR and ER receptors activated by DDT. We showed that exposure to DDT results in a dose- and organ-dependent increase in the expression of miR-190a, -190b in the liver, uterus, ovaries and mammary gland of female Wistar rats. Additionally, we demonstrate a decrease in protein product level of Tp53inp1, the target gene of these microRNAs, in the rat uterus. It is known that miR-190 is probably regulated by ER in humans, thus we measured the level of miR-190a, -190b in primary cultures of malignant and normal human endometrial cells treated with different doses of DDT. We detected an increase in miR-190b level in normal endometrial cells under DDT exposure. Thus, our results indicate that DDT exposure lead to change in the expression of oncogenic miR-190 family and its target gene Tp53inp1 which may be due to activation of CAR and ER.


Pathology of Neurodegenerative Diseases.
Neurodegenerative disorders are characterized by progressive loss of selectively vulnerable populations of neurons, which contrasts with select static neuronal loss because of metabolic or toxic disorders. Neurodegenerative diseases can be classified according to primary clinical features (e.g., dementia, parkinsonism, or motor neuron disease), anatomic distribution of neurodegeneration (e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations), or principal molecular abnormality. The most common neurodegenerative disorders are amyloidoses, tauopathies, α-synucleinopathies, and TDP-43 proteinopathies. The protein abnormalities in these disorders have abnormal conformational properties. Growing experimental evidence suggests that abnormal protein conformers may spread from cell to cell along anatomically connected pathways, which may in part explain the specific anatomical patterns observed at autopsy. In this review, we detail the human pathology of select neurodegenerative disorders, focusing on their main protein aggregates.


Utility of normal tissue-to-tumor α/β ratio when evaluating isodoses of isoeffective radiation therapy treatment plans.
To achieve a better understanding of the effect of the number of fractions on normal tissue sparing for equivalent tumor control in radiation therapy plans by using equivalent biologically effective dose (BED) isoeffect calculations. The simple linear quadratic (LQ) model was assumed to be valid up to 10 Gy per fraction. Using the model, we formulated a well-known mathematical equality for the tumor prescription dose and probed and solved a second mathematical problem for normal tissue isoeffect. That is, for a given arbitrary relative isodose distribution (treatment plan in percentages), 2 isoeffective tumor treatment regimens (N fractions of the dose D and n fractions of the dose d) were denoted, which resulted in the same BED (corresponding to 100% prescription isodose). Given these situations, the LQ model was further exploited to mathematically establish a unique relative isodose level, z (%), for the same arbitrary treatment plan, where the BED to normal tissues was also isoeffective for both fractionation regimens. For the previously stated problem, the relative isodose level z (%), where the BEDs to the normal tissue were also equal, was defined by the normal tissue α/β ratio divided by the tumor α/β times 100%. Fewer fractions offers a therapeutic advantage for those portions of the normal tissue located outside the isodose surface, z, whereas more fractions offer a therapeutic advantage for those portions of the normal tissue within the isodose surface, z. Relative isodose-based treatment plan evaluations may be useful for comparing isoeffective tumor regimens in terms of normal tissue effects. Regions of tissues that would benefit from hypofractionation or standard fractionation can be identified.


"Endomicrobia": cytoplasmic symbionts of termite gut protozoa form a separate phylum of prokaryotes.
Lignocellulose digestion by wood-feeding termites depends on the mutualistic interaction of unusual, flagellate protists located in their hindgut. Most of the flagellates harbor numerous prokaryotic endosymbionts of so-far-unknown identity and function. Using a full-cycle molecular approach, we show here that the endosymbionts of the larger gut flagellates of Reticulitermes santonensis belong to the so-called termite group 1 (TG-1) bacteria, a group of clones previously obtained exclusively from gut homogenates of Reticulitermes speratus that are only distantly related to other bacteria and are considered a novel bacterial phylum based on their 16S rRNA gene sequences. Fluorescence in situ hybridization with specifically designed oligonucleotide probes confirmed that TG-1 bacteria are indeed located within the flagellate cells and demonstrated that Trichonympha agilis (Hypermastigida) and Pyrsonympha vertens (Oxymonadida) harbor phylogenetically distinct populations of symbionts (<95% sequence similarity). Transmission electron microscopy revealed that the symbionts are small, spindle-shaped cells (0.6 microm in length and 0.3 microm in diameter) surrounded by two membranes and located within the cytoplasm of their hosts. The symbionts of the two flagellates are described as candidate species in the candidate genus "Endomicrobium." Moreover, we provide evidence that the members of the TG-1 phylum, for which we propose the candidate name "Endomicrobia," are phylogenetically extremely diverse and are present in and also restricted to the guts of all lower termites and wood-feeding cockroaches of the genus Cryptocercus, the only insects that are in an exclusive, obligately mutualistic association with such unique cellulose-fermenting protists.


Activation of multidrug efflux transporter activity at fertilization in sea urchin embryos (Strongylocentrotus purpuratus).
This study presents functional and molecular evidence for acquisition of multidrug transporter-mediated efflux activity as a consequence of fertilization in the sea urchin. Sea urchin eggs and embryos express low levels of efflux transporter genes with homology to the multidrug resistance associated protein (mrp) and permeability glycoprotein (p-gp) families of ABC transporters. The corresponding efflux activity is low in unfertilized eggs but is dramatically upregulated within 25 min of fertilization; the expression of this activity does not involve de novo gene expression and is insensitive to inhibitors of transcription and translation indicating activation of pre-existing transporter protein. Our study, using specific inhibitors of efflux transporters, indicates that the major activity is from one or more mrp-like transporters. The expression of activity at fertilization requires microfilaments, suggesting that the transporters are in vesicles and moved to the surface after fertilization. Pharmacological inhibition of mrp-mediated efflux activity with MK571 sensitizes embryos to the toxic compound vinblastine, confirming that one role for the efflux transport activity is embryo protection from xenobiotics. In addition, inhibition of mrp activity with MK571 alone retards mitosis indicating that mrp-like activity may also be required for early cell divisions.


Imaging of Nonmalignant Adrenal Lesions in Children.
The adrenal glands in children can be affected by a variety of benign lesions. The diagnosis of adrenal lesions can be challenging, but assessment of morphologic changes in correlation with the clinical presentation can lead to an accurate diagnosis. These lesions can be classified by their cause: congenital (eg, discoid adrenal gland, horseshoe adrenal gland, and epithelial cysts), vascular and/or traumatic (eg, adrenal hemorrhage), infectious (eg, granulomatous diseases), enzyme deficiency disorders (eg, congenital adrenal hyperplasia [CAH] and Wolman disease), benign neoplasms (eg, pheochromocytomas, ganglioneuromas, adrenal adenomas, and myelolipomas), and adrenal mass mimics (eg, extralobar sequestration and extramedullary hematopoiesis). Multimodality cross-sectional imaging helps to define the origin, extent, and relationship of these lesions to adjacent structures, as well as to guide treatment management. The anatomic and functional imaging modalities used to evaluate pediatric adrenal lesions include ultrasonography, computed tomography (CT), magnetic resonance imaging, and iodine 123 metaiodobenzylguanidine scintigraphy. Identifying the imaging features of nonmalignant adrenal lesions is helpful to distinguish these lesions from malignant adrenal neoplasms. Identifying characteristic imaging findings (eg, enlarged adrenal glands, with cerebriform surface, and stippled echogenicity in CAH; a T2-hyperintense mass with avid contrast enhancement in pheochromocytoma; low CT attenuation [<10 HU] and signal intensity drop on opposed-phase chemical shift images in adenoma; and enhancing suprarenal mass supplied by a systemic feeding artery in extralobar sequestration) can aid in making the correct diagnosis. In addition, clinical features (eg, ambiguous genitalia in CAH and hypertension in pheochromocytoma) can also guide the radiologist toward the correct diagnosis. ©RSNA, 2017.


Advances in the pathogenesis and treatment of polycystic kidney disease.
Polycystic kidney disease (PKD) is the most common genetic cause of chronic renal failure. Mouse models of PKD, especially those with mutations in genes that are orthologous to human disease genes, have provided insights into the pathogenesis of cyst formation and advanced the preclinical testing of new drugs. PKD is a ciliopathy that arises from abnormalities in the primary cilium, a sensory organelle present on the surface of most cells. The primary cilium is required for the maintenance of planar cell polarity, which regulates tubular diameter. Acute kidney injury stimulates cell proliferation and promotes cyst formation in a mouse model of PKD. Studies of signaling pathways that are perturbed in PKD have identified new potential therapeutic targets. Drugs that have shown beneficial effects in orthologous animal models of PKD include tolvaptan, octreotide, src inhibitors, CFTR inhibitors, pioglitazone, etanercept, and triptolide. Abnormalities in the primary cilium perturb signaling pathways that regulate renal epithelial cell growth and differentiation and lead to the formation of kidney cysts. Acute kidney injury promotes cyst formation and may underlie the variability in disease progression that is observed in affected individuals. Several promising new therapeutic agents that have been validated in orthologous animal models have entered clinical trials in humans.


Differential regulation of NSC phenotype and genotype by chronically activated microglia within cocultures.
Under disease or injury conditions in the central nervous system (CNS), activated microglia release cytokines and chemokines to modulate the microenvironment and influence tissue remodeling. To exploit the full potential of neural stem cell (NSC) transplantation approaches, a permissive microenvironment needs to be created for their survival, homing and differentiation. To investigate the role of chronically activated microglia in the fate of NSCs, spontaneously immortalized murine microglial cells (SIM-A9) were cocultured with embryonic murine cortical NSCs on 2D substrates or within 3D gels. Standalone NSC cultures served as controls. Cytokines and chemokines released by NSCs and SIM-A9 cells in standalone and cocultures were quantified. Coculturing with SIM-A9 cells suppressed NSC viability, neurite outgrowth, neural differentiation and TUJ1 gene expression, and promoted glia formation in both 2D and 3D cultures, over a 10-day period. The seven most-abundantly released analytes by microglia (MCP-1, MIP2, G-CSF, MIP-1α, MIP-1β, TNF-α, IL-6) were tested for their individual effects on NSCs, to investigate if the outcomes in cocultures were due to the synergistic effects of analytes or the influence of any individual analyte. All the seven analytes significantly suppressed cell survival compared to controls, but exposure to MIP-1β, IL-6, or MCP-1 enhanced neurite outgrowth and neural lineage commitment. Results attest to (i) the strong role of activated microglia in regulating NSC fate, (ii) the utility of selective analytes released by activated microglia in promoting neurogenesis and neuritogenesis, and (iii) the need to protect transplanted NSCs from the host inflammatory microenvironment to ensure their survival and functionality in treating neurological disorders.


Induction dose of propofol in patients using cannabis.
An estimated 150 million people worldwide use cannabis. The effect of cannabis on anaesthetic requirements in humans does not appear to have been studied. In this prospective, randomized, single-blinded study, 30 male patients using cannabis more than once per week (group C) and 30 nonusers (group NC), aged 18-50 years, were induced with propofol 1.5, 2, 2.5, 3 or 3.5 mg kg. Additional doses were given when required. The primary outcome was the 50% effective dose of propofol and successful induction was determined by loss of consciousness with a bispectral index value of less than 60 and satisfactory insertion of a laryngeal mask. Propofol requirements to achieve these outcomes were recorded. The dose required to achieve the target bispectral index value was not significantly higher in group C, but group C required a significantly higher propofol dose to achieve laryngeal mask insertion (314.0 +/- 109.3 vs. 263.2 +/- 69.5 mg, P < 0.04). The estimated effective propofol induction dose in 50-95% of patients did not significantly differ between groups. We conclude that cannabis use increases the propofol dose required for satisfactory clinical induction when inserting a laryngeal mask.


Screen-based entertainment time, all-cause mortality, and cardiovascular events: population-based study with ongoing mortality and hospital events follow-up.
The aim of this study was to examine the independent relationships of television viewing or other screen-based entertainment ("screen time") with all-cause mortality and clinically confirmed cardiovascular disease (CVD) events. A secondary objective was to examine the extent to which metabolic (body mass index, high-density lipoprotein and total cholesterol) and inflammatory (C-reactive protein) markers mediate the relationship between screen time and CVD events. Although some evidence suggests that prolonged sitting is linked to CVD risk factor development regardless of physical activity participation, studies with hard outcomes are scarce. A population sample of 4,512 (1,945 men) Scottish Health Survey 2003 respondents (≥35 years) were followed up to 2007 for all-cause mortality and CVD events (fatal and nonfatal combined). Main exposures were interviewer-assessed screen time (<2 h/day; 2 to <4 h/day; and ≥4 h/day) and moderate to vigorous intensity physical activity. Two hundred fifteen CVD events and 325 any-cause deaths occurred during 19,364 follow-up person-years. The covariable (age, sex, ethnicity, obesity, smoking, social class, long-standing illness, marital status, diabetes, hypertension)-adjusted hazard ratio (HR) for all-cause mortality was 1.52 (95% confidence interval [CI]: 1.06 to 2.16) and for CVD events was 2.30 (95% CI: 1.33 to 3.96) for participants engaging in ≥4 h/day of screen time relative to <2 h/day. Adjusting for physical activity attenuated these associations only slightly (all-cause mortality: HR: 1.48, 95% CI: 1.04 to 2.13; CVD events: HR: 2.25, 95% CI: 1.30 to 3.89). Exclusion of participants with CVD events in the first 2 years of follow-up and previous cancer registrations did not change these results appreciably. Approximately 25% of the association between screen time and CVD events was explained collectively by C-reactive protein, body mass index, and high-density lipoprotein cholesterol. Recreational sitting, as reflected by television/screen viewing time, is related to raised mortality and CVD risk regardless of physical activity participation. Inflammatory and metabolic risk factors partly explain this relationship.


Histological comparison of healing following tooth extraction with ridge preservation using enamel matrix derivatives versus Bio-Oss Collagen: a pilot study.
The goal of the present clinical study was to evaluate new bone formation in human extraction sockets augmented with enamel matrix derivatives (EMD) and Bio-Oss Collagen. Patients with symmetrical single-rooted teeth in the bilateral quadrants of the upper jaw condemned for extraction participated in this study. Following extraction, the sockets (20 sockets) were randomly augmented using either EMD or Bio-Oss Collagen. After 3 months of healing, bone biopsies were obtained and prepared for histological analyses. Dental implants were then placed. Implant stability quotient (ISQ) readings were obtained for each implant at the time of surgery and at 1 and 3 months postoperatively. The mean new bone formation was 34.57 ± 25.67% in the EMD sites and 28.80 ± 16.14% in the Bio-Oss Collagen sites. There was no significant difference between the groups. The ISQ values were significantly higher for the implants placed in the EMD sites at the first and third months, but no significant differences were observed in the ISQ values for the implants placed in the Bio-Oss Collagen sites. The augmentation of the extraction sockets with EMD or Bio-Oss Collagen leads to similar behaviour in bone regeneration.


Characterization of a rat liver glucuronosyltransferase that glucuronidates the selective D1 antagonist, SCH 23390, and other benzazepines.
SCH 23390 is a novel benzazepine that selectively blocks dopamine receptors of the D1 subtype. Glucuronidation of this selective D1 antagonist was studied in vitro using rat liver microsomes. Methods to separate SCH 23390 glucuronide from SCH 23390 were developed which utilized either HPLC techniques or solvent extraction of SCH 23390 with 3-heptanone. Formation of a SCH 23390 glucuronide was confirmed upon incubation of SCH 23390 and UDPGA with naive rat liver microsomes. Liver enzyme activity for SCH 23390 glucuronidation was also enhanced after addition of the detergents, Lubrol or Triton X-100, to the naive liver microsomes. Kinetic analyses indicated an apparent Vmax and Km for UDPGA as 120.9 pmol/mg protein/min and 0.63 mM, and an apparent Vmax and Km for SCH 23390 as 282.4 pmol/mg protein/min and 0.41 microM. Further characterization of the liver enzyme responsible for the glucuronidation of SCH 23390 revealed a stereoselective substrate preference similar to that seen with the D1 dopamine receptor. Substrate inhibition studies indicated that SCH 23390, haloperidol, apomorphine, and alpha-naphthol demonstrated the highest affinity for the glucuronosyltransferase enzyme. However, (-)-sulpiride, raclopride, and endogenous substrates such as dopamine, serotonin, epinephrine, and norepinephrine demonstrated low affinity for the liver enzyme. These studies describe a rat liver glucuronosyltransferase with a unique substrate specificity toward selected dopaminergic agents. Finally, induction profiles revealed that neither phenobarbital (100 mg/kg, ip, for 3 days), beta-naphthoflavone (100 mg/kg, ip, for 4 days), nor 3-methylcholanthrene (80 mg/kg, ip, for 4 days) enhanced liver glucuronosyltransferase activity for SCH 23390 glucuronidation.