Systematic Review and Meta-Analysis: Dose-Response Relationship of Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder.
Previous studies suggested that the treatment response to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder follows a flat response curve within the therapeutic dose range. The present study was designed to clarify the relationship between dosage and treatment response in major depressive disorder. The authors searched PubMed for randomized placebo-controlled trials examining the efficacy of SSRIs for treating adults with major depressive disorder. Trials were also required to assess improvement in depression severity at multiple time points. Additional data were collected on treatment response and all-cause and side effect-related discontinuation. All medication doses were transformed into imipramine-equivalent doses. The longitudinal data were analyzed with a mixed-regression model. Endpoint and tolerability analyses were analyzed using meta-regression and stratified subgroup analysis by predefined SSRI dose categories in order to assess the effect of SSRI dosing on the efficacy and tolerability of SSRIs for major depressive disorder. Forty studies involving 10,039 participants were included. Longitudinal modeling (dose-by-time interaction=0.0007, 95% CI=0.0001-0.0013) and endpoint analysis (meta-regression: β=0.00053, 95% CI=0.00018-0.00088, z=2.98) demonstrated a small but statistically significant positive association between SSRI dose and efficacy. Higher doses of SSRIs were associated with an increased likelihood of dropouts due to side effects (meta-regression: β=0.00207, 95% CI=0.00071-0.00342, z=2.98) and decreased likelihood of all-cause dropout (meta-regression: β=-0.00093, 95% CI=-0.00165 to -0.00021, z=-2.54). Higher doses of SSRIs appear slightly more effective in major depressive disorder. This benefit appears to plateau at around 250 mg of imipramine equivalents (50 mg of fluoxetine). The slightly increased benefits of SSRIs at higher doses are somewhat offset by decreased tolerability at high doses.


Development of a trauma-specific quality-of-life measurement.
Complex, disease-specific factors help to determine posttraumatic quality of life (QoL), but current practice uses outcome measures generated from the general population. Trauma survivorship has grown rapidly, while defining the factors that influence posttraumatic QoL has lagged. This study sought to develop a valid and reliable trauma-specific QoL measure to help guide future posttraumatic research and clinical care. Qualitative data were collected from adult trauma patients and their caregivers (Phase 1). Subsequent analysis of these data resulted in the development of a 59-item QoL questionnaire. The 59-item trauma-specific QoL (T-QoL) questionnaire was then administered to adult trauma patients (n = 394), and a factor analysis was conducted. The validity of the final T-QoL measurement tool was assessed (n = 111) using the Medical Outcomes Study 36-Item Short Form Health Survey version 2 (SF-36v2) and the PTSD Checklist-Civilian Version (PCL-C) (Phase 2). A five-component structure using 43 items seemed to best represent the data. The five components included emotional well-being, functional engagement, recovery/resilience, peritraumatic experience, and physical well-being. Four of the five components were found to have strong Cronbach's α scores (>0.7), demonstrating consistent interitem reliability. All subscales of the T-QoL correlated negatively with the PCL-C (p < 0.01), demonstrating that as the T-QoL increases, the likelihood of PTSD decreases. The physical well-being subscale of the T-QoL correlated significantly with the SF-36v2 physical component score, as did the emotional well-being subscale with the SF-36v2 mental component score (p < 0.05). This study used the experiences of trauma victims and their informal caregivers to develop a five-component, 43-item questionnaire with domains that are unique to trauma populations. Its accuracy and validity were confirmed using the PCL-C and the SF-36v2. We believe that the T-QoL represents a novel tool that can be used by trauma professionals to positively impact research efforts and clinical care. Prognostic study, level II.


Monoubiquitination and endocytosis direct gamma-secretase cleavage of activated Notch receptor.
Activation of mammalian Notch receptor by its ligands induces TNFalpha-converting enzyme-dependent ectodomain shedding, followed by intramembrane proteolysis due to presenilin (PS)-dependent gamma-secretase activity. Here, we demonstrate that a new modification, a monoubiquitination, as well as clathrin-dependent endocytosis, is required for gamma-secretase processing of a constitutively active Notch derivative, DeltaE, which mimics the TNFalpha-converting enzyme-processing product. PS interacts with this modified form of DeltaE, DeltaEu. We identified the lysine residue targeted by the monoubiquitination event and confirmed its importance for activation of Notch receptor by its ligand, Delta-like 1. We propose a new model where monoubiquitination and endocytosis of Notch are a prerequisite for its PS-dependent cleavage, and discuss its relevance for other gamma-secretase substrates.


Medical Help-Seeking for Sexual Concerns in Prostate Cancer Survivors.
Although sexual dysfunction is common after prostate cancer, men's decisions to seek help for sexual concerns are not well understood. Describe predictors of actual prior help-seeking and intended future medical help-seeking for sexual dysfunction in prostate cancer survivors. A cross-sectional survey of 510 prostate cancer survivors assessed masculine beliefs, attitudes, support/approval from partner/peer networks (subjective norm), and perceived control as predictors of medical help-seeking for sexual concerns. A theory of planned behavior (TPB) perspective was used to examine actual prior and planned future behavior and contributing factors. Statistical analyses included multiple and logistic regressions. Intention to see a doctor for sexual advice or help in the next 6 months was measured using the intention subscale adapted from the Attitudes to Seeking Help after Cancer Scale. Prior help-seeking was measured with a dichotomous yes/no scale created for the study. Men were Mage 71.69 years (SD = 7.71); 7.54 years (SD = 4.68) post-diagnosis; received treatment(s) (58.1% radical prostatectomy; 47.1% radiation therapy; 29.4% hormonal ablation); 81.4% reported severe ED (IIED 0-6) and 18.6% moderate-mild ED (IIED 7-24). Overall, 30% had sought sexual help in the past 6 months, and 24% intended to seek help in the following 6 months. Prior help-seeking was less frequent among men with severe ED. Sexual help-seeking intentions were associated with lower education, prior sexual help-seeking, sexual importance/ priority, emotional self-reliance, positive attitude, and subjective norm (R(2) = 0.56). The TPB has utility as a theoretical framework to understand prostate cancer survivors' sexual help-seeking decisions and may inform development of more effective interventions. Masculine beliefs were highly salient. Men who were more emotionally self-reliant and attributed greater importance to sex formed stronger help-seeking intentions. Subjective norm contributed most strongly to help-seeking intentions suggesting that health professionals/partners/peers have a key role as support mechanisms and components of psycho-sexual interventions.


Reproduction after myomectomy: comparison of patients with and without second-look laparoscopy.
Myomectomy is associated with a high risk of de-novo adhesion formation that may decrease fertility. The purpose of this study was to compare the reproductive outcome of patients after laparoscopic or open myomectomy who underwent second-look (SL) hysteroscopy and laparoscopy including adhesiolysis with patients with no SL intervention. A total of 170 patients underwent open or laparoscopic myomectomy at one centre. All patients were recommended SL. Reproductive results were analyzed in 12 and 24 months intervals following myomectomy. Out of 170 post-myomectomy patients 96 signed informed consent with SL (group A) and 74 withheld (group B). The cumulative pregnancy rate in the 24-months follow-up was: 61.4% and 66.7% (p = 0.535) in group A and group B respectively. Adhesions of adnexa were observed and lysed in the overall of 34.0% of patients at the time of SL. Intrauterine synechiae were present in 1.56% of patients at the SL hysteroscopy. No case of uterine rupture during pregnancy or delivery was recorded. Our results show that the pregnancy rate of patients after myomectomy who underwent SL hysteroscopy and laparoscopy is similar to that of patients with no SL procedure. Adhesiolysis performed during SL does not seem to improve the reproductive outcome of post-myomectomy patients.


Effectiveness of physical activity promoting technology-based distance interventions compared to usual care. Systematic review, meta-analysis and meta-regression.
Technology has been thought to have strong potential for promoting physical activity, but the evidence has remained unclear. The aim of this study was to examine whether a technology-based distance intervention promoting physical activity is more effective than a physical activity intervention without the use of technology. This systematic review is registered in Prospero (CRD42016035831). A systematic literature search of studies published between January 2000 to December 2015 was conducted in CENTRAL, EMBASE, Ovid MEDLINE, CINAHL, PsycINFO, OT-Seeker, WOS and PEDro. Studies were selected by two independent authors applying the following PICOS criteria P) adults, I) technology-based distance intervention promoting physical activity, C) distance intervention promoting physical activity without technology, O) physical activity, S) RCT. Quality was assessed following the guidelines of Cochrane Back Review Group. Meta-analysis and meta-regression were performed using R. From 3 031 studies, 23 randomized controlled trials with a total of 4 645 participants were included in the meta-analysis. The quality of the studies was moderate (mean 6 out of the maximum 12, with range of 4-9). Technology-based interventions were 12% more effective than similar or minimal control interventions in increasing physical activity (RR: 1.12; 95% CI: 1.01 to 1.25, P=0.03). Compared to minimal control interventions, technology-based interventions were 19% more effective (RR: 1.19; 95% CI 1.05 to 1.35, P=0.0096). In the interventions targeting patients, use of technology was 25% more effective than non-use (P=0.027). No differences were observed in physical activity between the effectiveness of interactive, non-interactive and self-monitoring technologies. Study quality, intervention duration and whether the measures used were subjective or objective were not significantly related to the amount of physical activity engaged in. Technology-based delivery of interventions seems to be more effective than usual care in promoting physical activity, particularly in the interventions targeting patients. Future research should investigate the cost-effectiveness of the use of distance technology for this purpose. Technology benefits rehabilitation, and can be considered for use in clinical practice, may adequately replace face-to-face meetings and stimulate more intensive rehabilitation in daily life.


A randomized controlled trial of cognitive-behavioral treatment for depression versus relaxation training for alcohol-dependent individuals with elevated depressive symptoms.
A previous pilot study found positive outcomes among alcohol-dependent individuals with elevated depressive symptoms who received cognitive-behavioral treatment for depression (CBT-D; n = 19) compared with a relaxation training control (RTC; n = 16). The current study represents a replication of this pilot study using a larger sample size and a longer follow-up assessment period. Patients entering a partial hospital drug and alcohol treatment program who met criteria for alcohol dependence and elevated depressive symptoms (Beck Depression Inventory score ≥ 15) were recruited and randomly assigned to receive eight individual sessions of CBT-D (n = 81) or RTC (n = 84). There were significant improvements in depressive and alcohol use outcomes over time for all participants.Compared with RTC, the CBT-D condition had significantly lower levels of depressive symptoms, as measured by the Beck Depression Inventory, at the 6-week follow-up. However, this effect was inconsistent because there were no differences in the Modified Hamilton Rating Scale for Depression between conditions at that time point and there were no significant differences at any other follow-up. No significant between-group differences on alcohol use outcomes were found. The current findings did not replicate the positive outcomes observed in the CBT-D condition in our previous pilot study. Possible explanations for why these findings were not replicated are discussed, as are theoretical and clinical implications of using CBT-D in alcohol treatment.


IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn's disease.
A novel T helper (Th) cell lineage, Th17, that exclusively produces the proinflammatory cytokine interleukin 17 (IL17) has been reported to play important roles in various inflammatory diseases. IL23 is also focused upon for its potential to promote Th17. Here, the roles of the IL23/IL17 axis in inflammatory bowel diseases such as ulcerative colitis (UC) and Crohn's disease (CD) were investigated. Mucosal samples were obtained from surgically resected specimens (controls, n = 12; UC, n = 17; CD, n = 22). IL17 production by isolated peripheral blood (PB) and lamina propria (LP) CD4(+) cells was examined. Quantitative PCR amplification was performed to determine the mRNA expression levels of IL17, interferon gamma (IFNgamma), IL23 receptor (IL23R) and retinoic acid-related orphan receptor gamma (RORC) in LP CD4(+) cells, and IL12 family members, such as IL12p40, IL12p35 and IL23p19, in whole mucosal specimens. The effects of exogenous IL23 on IL17 production by LP CD4(+) cells were also examined. IL17 production was higher in LP CD4(+) cells than in PB. Significant IL17 mRNA upregulation in LP CD4(+) cells was found in UC, while IFNgamma was increased in CD. IL23R and RORC were upregulated in LP CD4(+) cells isolated from both UC and CD. IL17 production was significantly increased by IL23 in LP CD4(+) cells from UC but not CD. Upregulated IL23p19 mRNA expression was correlated with IL17 in UC and IFNgamma in CD. IL23 may play important roles in controlling the differential Th1/Th17 balance in both UC and CD, although Th17 cells may exist in both diseases.


Regulation of leukotriene and 5oxoETE synthesis and the effect of 5-lipoxygenase inhibitors: a mathematical modeling approach.
5-lipoxygenase (5-LO) is a key enzyme in the synthesis of leukotrienes and 5-Oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (oxoETE). These inflammatory signaling molecules play a role in the pathology of asthma and so 5-LO inhibition is a promising target for asthma therapy. The 5-LO redox inhibitor zileuton (Zyflo IR/CR(®)) is currently marketed for the treatment of asthma in adults and children, but widespread use of zileuton is limited by its efficacy/safety profile, potentially related to its redox characteristics. Thus, a quantitative, mechanistic description of its functioning may be useful for development of improved anti-inflammatory targeting this mechanism. A mathematical model describing the operation of 5-LO, phospholipase A2, glutathione peroxidase and 5-hydroxyeicosanoid dehydrogenase was developed. The catalytic cycles of the enzymes were reconstructed and kinetic parameters estimated on the basis of available experimental data. The final model describes each stage of cys-leukotriene biosynthesis and the reactions involved in oxoETE production. Regulation of these processes by substrates (phospholipid concentration) and intracellular redox state (concentrations of reduced glutathione, glutathione (GSH), and lipid peroxide) were taken into account. The model enabled us to reveal differences between redox and non-redox 5-LO inhibitors under conditions of oxidative stress. Despite both redox and non-redox inhibitors suppressing leukotriene A4 (LTA4) synthesis, redox inhibitors are predicted to increase oxoETE production, thus compromising efficacy. This phenomena can be explained in terms of the pseudo-peroxidase activity of 5-LO and the ability of lipid peroxides to transform 5-LO into its active form even in the presence of redox inhibitors. The mathematical model developed described quantitatively different mechanisms of 5-LO inhibition and simulations revealed differences between the potential therapeutic outcomes for these mechanisms.


Mesogenic gold complexes showing aggregation-induced enhancement of phosphorescence in both crystalline and liquid-crystalline phases.
Mesogenic Au complexes with a biphenyl core were synthesized as new AIEgens, and their thermodynamic and photophysical properties were discussed. Similar to Au complexes with a phenyl core which have been reported previously, the complexes with a short alkoxy chain formed dimers in the crystal form. However, the complexes with a long alkoxy chain formed two-dimensional layer structures through multiple intermolecular interactions in both the crystalline and liquid-crystalline (LC) phases. The present Au complexes showed a high thermochemical stability against thermal decomposition and a high thermodynamic stability of the LC phase. Moreover, these materials exhibited intensive phosphorescence with a large quantum yield (∼66%) in the crystals. In the crystal and LC phase with a layer structure, the phosphorescence intensity was enhanced only on aggregation. Thus, these mesogenic Au complexes can be expected to be useful as phosphorescent AIEgens.


Cone contributions to cat retinal ganglion cell receptive fields.
Extracellular microelectrode recordings were made from ganglion cells of the intact, in situ eyes of adult common domestic cats. Three different photopic systems, with peak spectral sensitivities at 450, 500, and 556 nm, were observed. All ganglion cells received input from a cone system with a peak spectral sensitivity of 556 nm. The blue-sensitive cone system was observed in about one-half of the ganglion cells studied. In each case the 450-nm cone system contributed to only one functional type of response, either ON or OFF, in the same cell. The other two photopic systems most often contributed to both the ON and OFF responses of an individual ganglion cell. In four cases the 450-nm cone system mediated responses that were opponent to those of the other two photopic systems. The third photopic mechanism has a peak spectral sensitivity at 500 nm and contributed to most receptive field surrounds and many receptive field centers. It is distinguished from the rod system by the occurrence of a break in both dark-adaptation curves and increment-sensitivity curves. No apparent differences in receptive field cone contributions between brisk-sustained and brisk-transient cells were seen.


Screening assay for inhibitors of a recombinant Streptococcus pneumoniae UDP-glucose pyrophosphorylase.
The UDP-glucose pyrophosphorylase of Streptococcus pneumoniae (GalUSpn) is absolutely required for the biosynthesis of capsular polysaccharide, the sine qua non virulence factor of pneumococcus. Since the eukaryotic enzymes are completely unrelated to their prokaryotic counterparts, we propose that the GalU enzyme is a critical target to fight the pneumococcal disease. A recombinant GalUSpn was overexpressed and purified. An enzymatic assay that is rapid, sensitive and easy to perform was developed. This assay was appropriate for screening chemical libraries for searching GalU inhibitors. This work represents a fundamental step in the exploration of novel antipneumococcal drugs.


Positron emission tomography evaluation of oxime countermeasures in live rats using the tracer O-(2-[18 F]fluoroethyl)-O-(p-nitrophenyl)methylphosphonate [18 F]-VXS.
Oxime antidotes regenerate organophosphate-inhibited acetylcholinesterase (AChE). Although they share a common mechanism of AChE reactivation, the rate and amount of oxime that enters the brain are critical to the efficacy, a process linked to the oxime structure and charge. Using a platform based on the organophosphate [18 F]-VXS as a positron emission tomography tracer for active AChE, the in vivo distribution of [18 F]-VXS was evaluated after an LD50 dose (250 μg/kg) of the organophosphate paraoxon (POX) and following oximes as antidotes. Rats given [18 F]-VXS tracer alone had significantly higher radioactivity (two- to threefold) in the heart and lung than rats given LD50 POX at 20 or 60 min prior to [18 F]-VXS. When rats were given LD50 POX followed by 2-PAM (cationic), RS194b (ionizable), or monoisonitrosoacetone (MINA) (neutral), central nervous system (CNS) radioactivity returned to levels at or above untreated naive rats (no POX), whereas CNS radioactivity did not increase in rats given the dication oximes HI-6 or MMB-4. MINA showed a significant, pairwise increase in CNS brain radioactivity compared with POX-treated rats. This new in vivo dynamic platform using [18 F]-VXS tracer measures and quantifies peripheral and CNS relative changes in AChE availability after POX exposure and is suitable for comparing oxime delivery and AChE reactivation in rats.


An international review of the frequency of single-bicycle crashes (SBCs) and their relation to bicycle modal share.
To study cyclists' share of transport modes (modal share) and single-bicycle crashes (SBCs) in different countries in order to investigate if the proportion of cyclist injuries resulting from SBCs is affected by variation in modal share. A literature search identified figures (largely from western countries) on SBC casualties who are fatally injured, hospitalised or treated at an emergency department. Correlation and regression analyses were used to investigate how bicycle modal share is related to SBCs. On average, 17% of fatal injuries to cyclists are caused by SBCs. Different countries show a range of values between 5% and 30%. Between 60% and 95% of cyclists admitted to hospitals or treated at emergency departments are victims of SBCs. The proportion of all injured cyclists who are injured in SBCs is unrelated to the share of cycling in the modal split. The share of SBC casualties among the total number of road crash casualties increases proportionally less than the increase in bicycle modal share. While most fatal injuries among cyclists are due to motor vehicle-bicycle crashes, most hospital admissions and emergency department attendances result from SBCs. As found in previous studies of cyclists injured in collisions, this study found that the increase in the number of SBC casualties is proportionally less than the increase in bicycle modal share.


Brain activation during anticipation of sound sequences.
Music consists of sound sequences that require integration over time. As we become familiar with music, associations between notes, melodies, and entire symphonic movements become stronger and more complex. These associations can become so tight that, for example, hearing the end of one album track can elicit a robust image of the upcoming track while anticipating it in total silence. Here, we study this predictive "anticipatory imagery" at various stages throughout learning and investigate activity changes in corresponding neural structures using functional magnetic resonance imaging. Anticipatory imagery (in silence) for highly familiar naturalistic music was accompanied by pronounced activity in rostral prefrontal cortex (PFC) and premotor areas. Examining changes in the neural bases of anticipatory imagery during two stages of learning conditional associations between simple melodies, however, demonstrates the importance of fronto-striatal connections, consistent with a role of the basal ganglia in "training" frontal cortex (Pasupathy and Miller, 2005). Another striking change in neural resources during learning was a shift between caudal PFC earlier to rostral PFC later in learning. Our findings regarding musical anticipation and sound sequence learning are highly compatible with studies of motor sequence learning, suggesting common predictive mechanisms in both domains.


von Willebrand factor, Jedi knight of the bloodstream.
When blood vessels are cut, the forces in the bloodstream increase and change character. The dark side of these forces causes hemorrhage and death. However, von Willebrand factor (VWF), with help from our circulatory system and platelets, harnesses the same forces to form a hemostatic plug. Force and VWF function are so closely intertwined that, like members of the Jedi Order in the movie Star Wars who learn to use "the Force" to do good, VWF may be considered the Jedi knight of the bloodstream. The long length of VWF enables responsiveness to flow. The shape of VWF is predicted to alter from irregularly coiled to extended thread-like in the transition from shear to elongational flow at sites of hemostasis and thrombosis. Elongational force propagated through the length of VWF in its thread-like shape exposes its monomers for multimeric binding to platelets and subendothelium and likely also increases affinity of the A1 domain for platelets. Specialized domains concatenate and compact VWF during biosynthesis. A2 domain unfolding by hydrodynamic force enables postsecretion regulation of VWF length. Mutations in VWF in von Willebrand disease contribute to and are illuminated by VWF biology. I attempt to integrate classic studies on the physiology of hemostatic plug formation into modern molecular understanding, and point out what remains to be learned.


Collagen Membranes Adsorb the Transforming Growth Factor-β Receptor I Kinase-Dependent Activity of Enamel Matrix Derivative.
Enamel matrix derivative (EMD) and collagen membranes (CMs) are simultaneously applied in regenerative periodontal surgery. The aim of this study is to evaluate the ability of two CMs and a collagen matrix to adsorb the activity intrinsic to EMD that provokes transforming growth factor (TGF)-β signaling in oral fibroblasts. Three commercially available collagen products were exposed to EMD or recombinant TGF-β1, followed by vigorous washing. Oral fibroblasts were either seeded directly onto collagen products or were incubated with the respective supernatant. Expression of TGF-β target genes interleukin (IL)-11 and proteoglycan 4 (PRG4) was evaluated by real time polymerase chain reaction. Proteomic analysis was used to study the fraction of EMD proteins binding to collagen. EMD or TGF-β1 provoked a significant increase of IL-11 and PRG4 expression of oral fibroblasts when seeded onto collagen products and when incubated with the respective supernatant. Gene expression was blocked by the TGF-β receptor I kinase inhibitor SB431542. Amelogenin bound most abundantly to gelatin-coated culture dishes. However, incubation of palatal fibroblasts with recombinant amelogenin did not alter expression of IL-11 and PRG4. These in vitro findings suggest that collagen products adsorb a TGF-β receptor I kinase-dependent activity of EMD and make it available for potential target cells.


Hate Crimes Against Trans People: Assessing Emotions, Behaviors, and Attitudes Toward Criminal Justice Agencies.
Based on a survey of 593 lesbian, gay, bisexual, and transgender (LGBT) people in the United Kingdom, this study shows that direct anti-LGBT hate crimes (measured by direct experiences of victimization) and indirect anti-LGBT hate crimes (measured by personally knowing other victims of hate crime) are highly prolific and frequent experiences for LGBT people. Our findings show that trans people are particularly susceptible to hate crimes, both in terms of prevalence and frequency. This article additionally highlights the negative emotional and (intended) behavioral reactions that were correlated with an imagined hate crime scenario, showing that trans people are more likely to experience heightened levels of threat, vulnerability, and anxiety compared with non-trans LGB people. The study found that trans people are also more likely to feel unsupported by family, friends, and society for being LGBT, which was correlated with the frequency of direct (verbal) abuse they had previously endured. The final part of this study explores trans people's confidence levels in the Government, the police, and the Crown Prosecution Service (CPS) in relation to addressing hate crime. In general, trans people felt that the police are not effective at policing anti-LGBT hate crime, and they are not respectful toward them as victims; this was especially true where individuals had previous contact with the police. Respondents were also less confident in the CPS to prosecute anti-LGBT hate crimes, though the level of confidence was slightly higher when respondents had direct experience with the CPS. The empirical evidence presented here supports the assertion that all LGBT people, but particularly trans individuals, continue to be denied equal participation in society due to individual, social, and structural experiences of prejudice. The article concludes by arguing for a renewed policy focus that must address this issue as a public health problem.


Evolution of silver nanoparticles in the rat lung investigated by X-ray absorption spectroscopy.
Following a 6-h inhalation exposure to aerosolized 20 and 110 nm diameter silver nanoparticles, lung tissues from rats were investigated with X-ray absorption spectroscopy, which can identify the chemical state of silver species. Lung tissues were processed immediately after sacrifice of the animals at 0, 1, 3, and 7 days post exposure and the samples were stored in an inert and low-temperature environment until measured. We found that it is critical to follow a proper processing, storage and measurement protocol; otherwise only silver oxides are detected after inhalation even for the larger nanoparticles. The results of X-ray absorption spectroscopy measurements taken in air at 85 K suggest that the dominating silver species in all the postexposure lung tissues were metallic silver, not silver oxide, or solvated silver cations. The results further indicate that the silver nanoparticles in the tissues were transformed from the original nanoparticles to other forms of metallic silver nanomaterials and the rate of this transformation depended on the size of the original nanoparticles. We found that 20 nm diameter silver nanoparticles were significantly modified after aerosolization and 6-h inhalation/deposition, whereas larger, 110 nm diameter nanoparticles were largely unchanged. Over the seven-day postexposure period the smaller 20 nm silver nanoparticles underwent less change in the lung tissue than the larger 110 nm silver nanoparticles. In contrast, silica-coated gold nanoparticles did not undergo any modification processes and remained as the initial nanoparticles throughout the 7-day study period.


Hierarchical requirement of SWI/SNF in retinoblastoma tumor suppressor-mediated repression of Plk1.
Plk1 (Polo-like kinase 1) is a critical regulator of cell cycle progression that harbors oncogenic activity and exhibits aberrant expression in multiple tumors. However, the mechanism through which Plk1 expression is regulated has not been extensively studied. Here we demonstrate that Plk1 is a target of the retinoblastoma tumor suppressor (RB) pathway. Activation of RB and related pocket proteins p107/p130 mediate attenuation of Plk1. Conversely, RB loss deregulates the control of Plk1 expression. RB pathway activation resulted in the repression of Plk1 promoter activity, and this action was dependent on the SWI/SNF chromatin remodeling complex. Although SWI/SNF subunits are lost during tumorigenesis and cooperate with RB for transcriptional repression, the mechanism through which SWI/SNF impinges on RB action is unresolved. Therefore, we delineated the requirement of SWI/SNF for three critical facets of Plk1 promoter regulation: transcription factor binding, corepressor binding, and histone modification. We find that E2F4 and pocket protein association with the Plk1 promoter is independent of SWI/SNF. However, these analyses revealed that SWI/SNF is required for histone deacetylation of the Plk1 promoter. The importance of SWI/SNF-dependent histone deacetylation of the Plk1 promoter was evident, because blockade of this event restored Plk1 expression in the presence of active RB. In summary, these data demonstrate that Plk1 is a target of the RB pathway. Moreover, these findings demonstrate a hierarchical role for SWI/SNF in the control of promoter activity through histone modification.


Anti-human immunodeficiency virus activity of oligosaccharides from rooibos tea (Aspalathus linearis) extracts in vitro.
The active substances, acid polysaccharides, were extracted with 1% sodium hydroxide from the leaves of rooibos tea (Aspalathus linearis), Du Zhong Cha (Eucommia ulmoides Oliv.) and Japanese tea leaves (Camellia sinensis var. sinensis). The alkaline extracts of Rooibos tea and Du-Zhong tea leaves, but not Japanese tea leaves suppressed the HIV-induced cytopathicity using HIV (HTLV-III) infected MT-4 cells, having extremely low cytotoxicity: Its 50% effective concentration (EC50) was 12-67 micrograms/mL, white 50% cytotoxic concentration (CC50) was higher than 1.0 mg/mL. The active substances were purified with ethanol precipitation. The substances were composed of 27% of reducing sugar, 46% of neutral sugars and 22% of uronic acid. A LD50 of the alkaline extracts from rooibos tea was higher than 1.2 g/kg body weight. Acid degradated substances composed of disaccharides and trisaccharides, were also suppressed the HIV-induced cytopathicity. From these results, it is probable that acid polysaccharides from rooibos tea were extremely safe, and that HIV infection may be suppressed by daily intake of the alkaline extracts of rooibos tea and Du-Zhong tea.


The BRCA1-binding protein BRAP2 can act as a cytoplasmic retention factor for nuclear and nuclear envelope-localizing testicular proteins.
Regulation of nuclear protein import is central to many cellular processes such as development, with a key mechanism being factors that retain cargoes in the cytoplasm that normally localize in the nucleus. The breast cancer antigen BRCA1-binding protein BRAP2 has been reported as a novel negative regulator of nuclear import of various nuclear localization signal (NLS)-containing viral and cellular proteins, but although implicated in differentiation pathways and highly expressed in tissues including testis, the gamut of targets for BRAP2 action in a developmental context is unknown. As a first step towards defining the BRAP2 interactome, we performed a yeast-2-hybrid screen to identify binding partners of BRAP2 in human testis. Here we report characterization for the first time of three of these: the high mobility group (HMG)-box-domain-containing chromatin component HMG20A, nuclear mitotic apparatus protein NuMA1 and synaptic nuclear envelope protein SYNE2. Co-immunoprecipitation experiments indicate association of BRAP2 with HMG20A, NuMA1, and SYNE2 in testis, underlining the physiological relevance of the interactions, with immunohistochemistry showing that where BRAP2 is co-expressed with HMG20A and NuMA1, both are present in the cytoplasm, in contrast to their nuclear localization in other testicular cell types. Importantly, quantitative confocal microscopic analysis of cultured cells indicates that ectopic expression of BRAP2 inhibits nuclear localization of HMG20A and NuMA1, and prevents nuclear envelope accumulation of SYNE2, the first report of BRAP2 altering localization of a non-nuclear protein. These results imply for the first time that BRAP2 may have an important role in modulating subcellular localization during testicular development.


A neuroanatomical framework for the central modulation of respiratory sensory processing and cough by the periaqueductal grey.
Sensory information arising from the airways is processed in a distributed brain network that encodes for the discriminative and affective components of the resultant sensations. These higher brain networks in turn regulate descending motor control circuits that can both promote or suppress behavioural responses. Here we explore the existence of possible descending neural control pathways that regulate airway afferent processing in the brainstem, analogous to the endogenous descending analgesia system described for noxious somatosensation processing and placebo analgesia. A key component of this circuitry is the midbrain periaqueductal grey, a region of the brainstem recently highlighted for its altered activity in patients with chronic cough. Understanding the nature and plasticity of descending neural control may help identify novel central therapeutic targets to alleviate the neuronal hypersensitivity underpinning many symptoms of respiratory disease.


Intracranial tuberculoma: comparison of MR with pathologic findings.
To compare the MR signal intensity patterns and enhancement pattern of intracranial tuberculomas with their histopathologic features. MR images of six patients with surgically proved intracranial tuberculoma were reviewed retrospectively and were compared with histologic findings of the resected specimen. Detailed histologic examination was performed to look for the extent and characteristics of caseation necrosis, fibrosis, and inflammatory cellular infiltrates at each area of different signal intensities and at the enhancing areas on MR. Signal intensities for T1- and T2-weighted images were compared with normal gray matter. On T1-weighted images, the granulomas showed a slightly hyperintense rim surrounded by a complete or partial rim of slight hypointensity and central isointensity or mixed isointensity and hyperintensity in five patients and homogeneous isointensity in one patient. Histologically, the zone of central isointensity or mixed intensity corresponded to caseation necrosis plus adjacent cellular infiltrates. The hyperintense and hypointense rims corresponded to the layers of collagenous fiber and the layers of the inflammatory cellular infiltrates, respectively. On T2-weighted images, the entire portion of the granuloma showed slightly heterogeneous isointensity or hypointensity with small markedly hypointense foci in five patients, and a hyperintense center surrounded by a hypointense rim in one patient. Histologic layers were not discriminated on T2-weighted images. On postcontrast T1-weighted images, there were single or multiple conglomerate ring enhancements within a tuberculoma in all six patients, corresponding to the layers of both collagenous and inflammatory cells. Combination of the described signal intensity patterns and conglomerate ringlike enhancing appearance of the lesion is characteristic of tuberculoma, and may play an important role in differentiating intracranial tuberculomas from other ring-enhancing brain lesions.


Capillary assembly as a tool for the heterogeneous integration of micro- and nanoscale objects.
During the past decade, capillary assembly in topographical templates has evolved into an efficient method for the heterogeneous integration of micro- and nano-scale objects on a variety of surfaces. This assembly route has been applied to a large spectrum of materials of micrometer to nanometer dimensions, supplied in the form of aqueous colloidal suspensions. Using systems produced via bulk synthesis affords a huge flexibility in the choice of materials, holding promise for the realization of novel superior devices in the fields of optics, electronics and health, if they can be integrated into surface structures in a fast, simple, and reliable way. In this review, the working principles of capillary assembly and its fundamental process parameters are first presented and discussed. We then examine the latest developments in template design and tool optimization to perform capillary assembly in more robust and efficient ways. This is followed by a focus on the broad range of functional materials that have been realized using capillary assembly, from single components to large-scale heterogeneous multi-component assemblies. We then review current applications of capillary assembly, especially in optics, electronics, and in biomaterials. We conclude with a short summary and an outlook for future developments.


Examination of the structural, convergent, and incremental validity of the Reynolds Intellectual Assessment Scales (RIAS) with a clinical sample.
Empirical examination of the Reynolds Intellectual Assessment Scales (RIAS; C. R. Reynolds & R. W. Kamphaus, 2003a) has produced mixed results regarding its internal structure and convergent validity. Various aspects of validity of RIAS scores with a sample (N = 521) of adolescents and adults seeking psychological evaluations at a university-based clinic were examined. Results from exploratory factor analysis indicated only 1 factor, and confirmatory factor analysis (CFA) indicated that the 1-factor model was a good fit and a better fit than the 2-factor model. Hierarchical factor analysis indicated the higher order, general intelligence factor accounted for the largest amount of variance. Correlations with other measures of verbal/crystallized and nonverbal/fluid intelligence were supportive of the convergent validity of the Verbal Intelligence Index but not the Nonverbal Intelligence Index. Joint CFA with these additional measures resulted in a superior fit of the 2-factor model compared with the 1-factor model, although the Odd-Item-Out subtest was found to be a poor measure of nonverbal/fluid intelligence. Incremental validity analyses indicated that the Composite Intelligence Index explained a medium to large portion of academic achievement variance; the NIX and VIX explained a small amount of remaining variance. Implications regarding interpretation of the RIAS when assessing similar individuals are discussed.


Experimental T-2 toxicosis in swine following inhalation exposure: clinical signs and effects on hematology, serum biochemistry, and immune response.
Nine- to ten-week-old, male castrated, specific pathogen-free derived pigs, weighing 34 to 42 kg, were exposed to a T-2 toxin aerosol (390 micrograms/liter, 1.5 microM mass median aerodynamic diameter) for a time period which allowed an amount equivalent to 8 mg/kg to be nebulized (six pigs). Control animals (five pigs) were exposed to an equivalent amount of the nebulized vehicle. Pigs were immunized subcutaneously with sheep red blood cells on Days 0 and 21. Whole blood and serum samples were taken periodically for clinical pathologic and immunologic studies. Pigs were closely observed, and daily rectal temperatures and weekly weights were measured. The T-2-treated pigs vomited and exhibited cyanosis, anorexia, lethargy, lateral recumbency, slightly elevated rectal temperature, and depressed body weight gain. The lymphocyte count decreased while the neutrophil count increased. The concentrations of total serum protein and hemoglobin declined. There was a marked increase in serum alkaline phosphatase activity on Day 1, followed by a marked and persistent decrease. Mitogen-induced (Con A, PHA, and PWM) blastogenic responses of peripheral blood mononuclear cells and hemagglutination titers to SRBC were also transiently decreased. Thus, inhalation exposure of pigs to a sublethal dose of T-2 toxin caused clinical signs of toxicity and adverse effects on clinical pathologic parameters and immune responses; however, most of these effects were short-lived. The changes described in our study resemble those reported in pigs given T-2 toxin by intravascular injection.


Factorial validity of the Maslach Burnout Inventory (MBI-HSS) among Spanish professionals.
To assess the factorial validity and internal consistency of the Maslach Burnout Inventory (MBI-HSS). In a sample consisting of 705 Spanish professionals from diverse occupational sectors (health, education, police and so one), seven plausible factorial models hypothesized were compared using LISREL 8. The four-factor oblique solution and the three-factor oblique solution showed the best and similar fit. Deletion of Item 12 and Item 16, taking into consideration the suggestions in the manual, improved the goodness of fit for both models. The four-factor oblique model suggests that, in addition to Emotional Exhaustion (EE) and Depersonalization (DP), Personal Accomplishment (PA) consists of two components labeled here Self-Competence (Items 4, 7, 17, and 21) and the Existential Component (Items 9, 12, 18, and 19). However, the alpha coefficient was relatively low for the Self-Competence component, suggesting that it is more suitable to estimate the syndrome as a three-dimensional construct. The Cronbach's alpha was satisfactory for PA (alpha =.71) and EE (alpha =.85), and moderate for DP (alpha =.58). The results show that the MBI-HSS offers factorial validity and its scales present internal consistency to evaluate the quality of working life for Spanish professionals.


Experience with a once-daily aminoglycoside program administered to 2,184 adult patients.
Once-daily aminoglycoside (ODA) regimens have been instituted to maximize bacterial killing by optimizing the peak concentration/MIC ratio and to reduce the potential for toxicity. We initiated an ODA program at our institution that utilizes a fixed 7-mg/kg intravenous dose with a drug administration interval based on estimated creatinine clearance: > or = 60 ml/min every 24 h (q24h), 59 to 40 ml/min q36h, and 39 to 20 ml/min q48h. Subsequent interval adjustments are made by using a single concentration in serum and a nomogram designed for monitoring of ODA therapy. Since initiation of the program, 2,184 patients have received this ODA regimen. The median dose was 450 (range, 200 to 925) mg, while the median length of therapy was 3 (range, 1 to 26) days. The median age of the population was 46 (range, 13 to 97) years. Gentamicin accounted for 94% of the aminoglycoside use, and the majority (77%) of patients received the drug q24h. The 36-, 48-, and > 48-h intervals were used for 15, 6, and 2% of this population, respectively. Three patients exhibited clinically apparent ototoxicity. Twenty-seven patients (1.2%) developed nephrotoxicity (the Hartford Hospital historical rate is approximately 3 to 5%) after a median of 7 (range, 3 to 19) days of therapy. On the basis of a prospective evaluation of 58 patients and follow-up of additional patients via clinician reports, we have noted no apparent alterations in clinical response with our ODA program. This ODA program appears to be clinically effective, reduces the incidence of nephrotoxicity, and provides a cost-effective method for administration of aminoglycosides by reducing ancillary service time and serum aminoglycoside determinations.


Data do count! Collection and use of maternal mortality data in Peru, 1990-2005, and improvements since 2005.
This paper reports on a qualitative, exploratory study in 2005, based on interviews with 15 key decision-makers from the Peruvian Ministry of Health responsible for maternal mortality prevention and officials responsible for national data and information on maternal deaths. The main aims were to find out the sources of data and information used by Ministry of Health officials for programme planning and decision-making, whether policies and programmes were informed by the data available, and data flows among central decision-makers within the Ministry and between Ministry and regional and local health centres. Information systems require staff and systems capable of collecting, processing, analysing and sharing data. In Peru, none of these conditions was fulfilled in a homogeneous way. Vertical programmes in the poorest regions had funds for information systems and infrastructure, but limited technical and human resources. Public health workers were overwhelmed with provision of services and not always trained in data collection or informatics. Thus, quality of data collection and analysis varied greatly across regions. Data collection and usage since the study have been improved, reflected in a fall in maternal mortality ratios and women's increased use of maternity services, but efforts to maintain and improve data quality must continue to ensure that initiatives to prevent maternal mortality can be monitored and services improved.


A genome-wide association study for coronary artery disease identifies a novel susceptibility locus in the major histocompatibility complex.
Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with coronary artery disease (CAD) and/or myocardial infarction risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered. We performed a discovery meta-analysis of 5 GWAS involving 13 949 subjects (7123 cases, 6826 control subjects) imputed at approximately 5 million single nucleotide polymorphisms, using pilot 1000 Genomes-based haplotypes. Promising loci were followed up in an additional 5 studies with 11 032 subjects (5211 cases, 5821 control subjects). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome-wide significance in the combined analysis (rs3869109; p(discovery)=3.3×10(-7), p(replication)=5.3×10(-4)p(combined)=1.12×10(-9)). A subanalysis combining discovery GWAS showed an attenuation of significance when stringent corrections for European population structure were used (P=4.1×10(-10) versus 3.2×10(-7)), suggesting that the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity, and self-cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common HLA alleles into the discovery subjects; however, no single common HLA type contributed significantly or fully explained the observed association. We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T-cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s).


The perfectionism model of binge eating: tests of an integrative model.
This study proposes, tests, and supports the perfectionism model of binge eating (PMOBE), a model aimed at explaining why perfectionism is related to binge eating. According to this model, socially prescribed perfectionism (SPP) confers risk for binge eating by generating exposure to 4 triggers of binge episodes: interpersonal discrepancies, low interpersonal esteem, depressive affect, and dietary restraint. In testing the PMOBE, a daily diary was completed by 566 women for 7 days. Predictions derived from the PMOBE were supported, with tests of mediation suggesting that the indirect effect of SPP on binge eating through triggers of binge episodes was significant. Reciprocal relations were also observed, with certain triggers of binge episodes predicting binge eating (and vice versa). Results supported the incremental validity of the PMOBE over and above self-oriented perfectionism and neuroticism and the generalizability of this model across Asian and European Canadian participants. The PMOBE offers a novel view of individuals with high levels of SPP as active agents who raise their risk of binge eating by generating conditions in their daily lives that are conducive to binge episodes.


Olfactory projectome in the zebrafish forebrain revealed by genetic single-neuron labelling.
Chemotopic odour representations in the olfactory bulb are transferred to multiple forebrain areas and translated into appropriate output responses. However, a comprehensive projection map of bulbar output neurons at single-axon resolution is lacking in vertebrates. Here we unravel a projectome of the zebrafish olfactory bulb through genetic single-neuron tracing and image registration. We show that five major target regions receive distinct modes of projections from olfactory bulb glomeruli. The central portion of posterior telencephalon receives non-selective, interspersed inputs from all glomeruli, whereas the ventral telencephalon is diffusely innervated by axons from particular glomerular clusters. The right habenula and posterior tuberculum (diencephalic nuclei) receive convergent inputs from restricted and all glomerular clusters, respectively. The bulbar recurrent projections are coarsely topographic. Thus, the primary chemotopic organization is transformed into distinct sensory representations in higher olfactory centres. These findings provide a framework to understand general principles as well as species-specific features in decoding of odour information.


The basal Lutetian Transgression on the Tethyan shelf of the European craton (Adelholzen beds, Eastern Alps, Germany).
The middle Eocene Adelholzen beds were deposited on the northern part of the Tethyan shelf of the European Plate. In the Eastern Alps, the Wimmern section near Teisendorf (Germany) is the only known outcrop exposing the basal unconformity of this sequence. The outcrop comprises an 8 m thick condensed transgressive shallow marine succession characterized by glauconite-rich weakly consolidated greensand and mudstone containing abundant larger benthic foraminifera. It spans the lower part of calcareous nannoplankton Zone NP15 (Sub-Zones NP15a and lower part of NP15b), planktonic foraminifera Sub-Zone E7b and Zone E8 partim and the upper part of shallow benthic Zone SBZ13. The landward migration of the paleo-shoreline was not an effect of flexural downbending of the European Plate but can be correlated to the major unconformity at the base of eustatic supercycle TA3. The onset of this sea-level rise was in the latest part of Biochron NP14b and almost coincided with the NP14b/NP15a-boundary.


Application of a new chiral phosphepine to the catalytic asymmetric synthesis of highly functionalized cyclopentenes that bear an array of heteroatom-substituted quaternary stereocenters.
Through the design and synthesis of a new chiral phosphepine, the first catalytic asymmetric method for the [3 + 2] cycloaddition of allenes with olefins has been developed that generates cyclopentenes that bear nitrogen-, phosphorus-, oxygen-, and sulfur-substituted quaternary stereocenters. A wide array of racemic γ-substituted allenes can be employed in this stereoconvergent process, which occurs with good enantioselectivity, diastereoselectivity, regioselectivity, and yield. Mechanistic studies, including a unique observation of a (modest) kinetic resolution of a racemic allene, are consistent with addition of the phosphepine to the allene being the turnover-limiting step of the catalytic cycle.


Cognitive profile difference between Allen Cognitive Levels 4 and 5 in schizophrenia.
We compared the pattern of cognitive deficits exhibited by people with schizophrenia at Allen Cognitive Level (ACL) 4 with that of people at Level 5. Participants were classified into two groups on the basis of their ACL Screen scores: ACL 4 (n = 35) and ACL 5 (n = 41). We assessed cognitive functions and psychotic symptoms in all participants. Multivariate analysis of covariance controlling for gender and negative symptoms revealed that people at ACL 4 performed significantly worse than those at ACL 5 on processing speed, verbal memory, and working memory. The discriminant analysis with all cognitive variables produced a classification accuracy of 78% in differentiation of cognitive levels. We verified the validity of the hierarchy of cognitive disability for ACLs 4 and 5 in people with schizophrenia.


Collective motion and density fluctuations in bacterial colonies.
Flocking birds, fish schools, and insect swarms are familiar examples of collective motion that plays a role in a range of problems, such as spreading of diseases. Models have provided a qualitative understanding of the collective motion, but progress has been hindered by the lack of detailed experimental data. Here we report simultaneous measurements of the positions, velocities, and orientations as a function of time for up to a thousand wild-type Bacillus subtilis bacteria in a colony. The bacteria spontaneously form closely packed dynamic clusters within which they move cooperatively. The number of bacteria in a cluster exhibits a power-law distribution truncated by an exponential tail. The probability of finding clusters with large numbers of bacteria grows markedly as the bacterial density increases. The number of bacteria per unit area exhibits fluctuations far larger than those for populations in thermal equilibrium. Such "giant number fluctuations" have been found in models and in experiments on inert systems but not observed previously in a biological system. Our results demonstrate that bacteria are an excellent system to study the general phenomenon of collective motion.


Micro- and nano-technologies to probe the mechano-biology of the brain.
Biomechanical forces have been demonstrated to influence a plethora of neuronal functions across scales including gene expression, mechano-sensitive ion channels, neurite outgrowth and folding of the cortices in the brain. However, the detailed roles biomechanical forces may play in brain development and disorders has seen limited study, partly due to a lack of effective methods to probe the mechano-biology of the brain. Current techniques to apply biomechanical forces on neurons often suffer from low throughput and poor spatiotemporal resolution. On the other hand, newly developed micro- and nano-technologies can overcome these aforementioned limitations and offer advantages such as lower cost and possibility of non-invasive control of neuronal circuits. This review compares the range of conventional, micro- and nano-technological techniques that have been developed and how they have been or can be used to understand the effect of biomechanical forces on neuronal development and homeostasis.


The role of genetic variation near interferon-kappa in systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome-wide scan implicated the IFNK locus in SLE susceptibility. We studied IFNK single nucleotide polymorphisms (SNPs) in 3982 SLE cases and 4275 controls, composed of European (EA), African-American (AA), and Asian ancestry. rs12553951C was associated with SLE in EA males (odds ratio = 1.93, P = 2.5 x 10(-4)), but not females. Suggestive associations with skin phenotypes in EA and AA females were found, and these were also sex-specific. IFNK SNPs were associated with increased serum type I IFN in EA and AA SLE patients. Our data suggest a sex-dependent association between IFNK SNPs and SLE and skin phenotypes. The serum IFN association suggests that IFNK variants could influence type I IFN producing plasmacytoid dendritic cells in affected skin.


Zebrafish cyp11c1 Knockout Reveals the Roles of 11-ketotestosterone and Cortisol in Sexual Development and Reproduction.
Androgen is essential for male development and cortisol is involved in reproduction in fishes. However, the in vivo roles of cortisol and specific androgens such as 11-ketotestosterone (11-KT) in reproductive development need to be described with genetic models. Zebrafish cyp11c1 encodes 11β-hydroxylase, which is essential for the biosynthesis of 11-KT and cortisol. In this study, we generated a zebrafish mutant of cyp11c1 (cyp11c1-/-) and utilized it to clarify the roles of 11-KT and cortisol in sexual development and reproduction. The cyp11c1-/- fish had smaller genital papilla and exhibited defective natural mating but possessed mature gametes and were found at a sex ratio comparable to the wildtype control. The cyp11c1-/- males showed delayed and prolonged juvenile ovary-to-testis transition and displayed defective spermatogenesis at adult stage, which could be rescued by treatment with 11-ketoandrostenedione (11-KA) at certain stages. Specifically, during testis development of cyp11c1-/- males, the expression of insl3, cyp17a1, and amh was significantly decreased, suggesting that 11-KT is essential for the development and function of Leydig cells and Sertoli cells. Further, spermatogenesis-related dmrt1 was subsequently downregulated, leading to insufficient spermatogenesis. The cyp11c1-/- females showed a reduction in egg spawning and a failure of in vitro germinal vesicle breakdown, which could be partially rescued by cortisol treatment. Taken together, our study reveals that zebrafish Cyp11c1 is not required for definite sex differentiation but is essential for juvenile ovary-to-testis transition, Leydig cell development, and spermatogenesis in males through 11-KT, and it is also involved in oocyte maturation and ovulation in females through cortisol.


A review of adjuvants for Leishmania vaccine candidates.
Over the last decade, there has been a flurry of research on adjuvants for vaccines, and several novel adjuvants are now licensed products or in late stage clinical development. The success of adjuvants in enhancing the immune response to antigens has led many researchers to re-focus their vaccine development programs. Although several vaccine candidates have been tested against leishmaniasis, there is yet no effective vaccine against this parasitic disease. Recent research has documented that efforts to develop effective Leishmania vaccine have been limited due to lack of an appropriate adjuvant. In view of this, this review paper outlines some of the adjuvants that have been used in Leishmania vaccine candidates and cites a few of the responses obtained from these studies. The aim of the present review is to consolidate these findings to facilitate the application of these adjuvants in general and experimental vaccinology.


Functional evaluation of cerebral microembolization in the rat.
This study investigates the effects of cerebral microembolism on motor performance and risk assessment behavior in the rat. Cerebral infarcts were produced in rats by injecting small plastic beads into the left heart ventricle under short-acting anesthesia. The functional outcome was tested 24 h later by subjecting the animals to a series of consecutive behavioral tests. Thereafter, the rats were anesthetized and underwent magnetic resonance imaging. On average about seven infarcts per brain were found. The volume of the individual infarcts was largest in the hippocampus (mean=4.26 mm(3)) and smallest in the white matter (mean=0.83 mm(3)). Embolized animals performed spontaneous and evident locomotion. The activity was, however, significantly decreased compared to rats treated with vehicle. More specific tests for motor ability revealed reduced gait capacity and muscular strength. A significant relationship was found between behaviors reflecting motor ability and the total volume of infarcted tissue in the brain stem, cortex and cerebellum. Also the behavioral profile of risk and benefit assessment was found to be altered by the microembolization. It is concluded that the combination of the microembolization method and behavioral tests provides a valuable tool for further studies of the pathophysiology of, and potential treatment for, cerebral infarction.


Differential requirement for satellite cells during overload-induced muscle hypertrophy in growing versus mature mice.
Pax7+ satellite cells are required for skeletal muscle fiber growth during post-natal development in mice. Satellite cell-mediated myonuclear accretion also appears to persist into early adulthood. Given the important role of satellite cells during muscle development, we hypothesized that the necessity of satellite cells for adaptation to an imposed hypertrophic stimulus depends on maturational age. Pax7CreER-R26RDTA mice were treated for 5 days with vehicle (satellite cell-replete, SC+) or tamoxifen (satellite cell-depleted, SC-) at 2 months (young) and 4 months (mature) of age. Following a 2-week washout, mice were subjected to sham surgery or 10 day synergist ablation overload of the plantaris (n = 6-9 per group). The surgical approach minimized regeneration, de novo fiber formation, and fiber splitting while promoting muscle fiber growth. Satellite cell density (Pax7+ cells/fiber), embryonic myosin heavy chain expression (eMyHC), and muscle fiber cross sectional area (CSA) were evaluated via immunohistochemistry. Myonuclei (myonuclei/100 mm) were counted on isolated single muscle fibers. Tamoxifen treatment depleted satellite cells by ≥90% and prevented myonuclear accretion with overload in young and mature mice (p < 0.05). Satellite cells did not recover in SC- mice after overload. Average muscle fiber CSA increased ~20% in young SC+ (p = 0.07), mature SC+ (p < 0.05), and mature SC- mice (p < 0.05). In contrast, muscle fiber hypertrophy was prevented in young SC- mice. Muscle fiber number increased only in mature mice after overload (p < 0.05), and eMyHC expression was variable, specifically in mature SC+ mice. Reliance on satellite cells for overload-induced hypertrophy is dependent on maturational age, and global responses to overload differ in young versus mature mice.


The Janus face of schizotypy: enhanced spiritual connection or existential despair?
It has been asserted that schizotypy has a negative relationship with subjective well-being. By employing a multidimensional measure of spiritual well being with 400 British College students we report a more complex relationship. The Multidimensional Inventory for Religious/Spiritual Well-Being and Schizotypal Personality Questionnaire-Brief Version were used and analysis made use of Canonical Correlational Analysis. Results suggested that two distinct relationships emerged between schizotypy and spirituality. First, a positive association between cognitive/perceptual features of schizotypy and spiritual connectedness emerged. Second a more global negative relationship between feelings of spiritual isolation and despair was found for all aspects of schizotypy. These findings challenge the previous literature based on one-dimensional subjective well being measures which have found only a negative relationship. However, the positive association between connectedness and cognitive-perceptual aspects of schizotypy raises import questions about the possible benefit of certain types of schizotypal experience.


MyAirCoach: the use of home-monitoring and mHealth systems to predict deterioration in asthma control and the occurrence of asthma exacerbations; study protocol of an observational study.
Asthma is a variable lung condition whereby patients experience periods of controlled and uncontrolled asthma symptoms. Patients who experience prolonged periods of uncontrolled asthma have a higher incidence of exacerbations and increased morbidity and mortality rates. The ability to determine and to predict levels of asthma control and the occurrence of exacerbations is crucial in asthma management. Therefore, we aimed to determine to what extent physiological, behavioural and environmental data, obtained by mobile healthcare (mHealth) and home-monitoring sensors, as well as patient characteristics, can be used to predict episodes of uncontrolled asthma and the onset of asthma exacerbations. In an 1-year observational study, patients will be provided with mHealth and home-monitoring systems to record daily measurements for the first-month (phase I) and weekly measurements during a follow-up period of 11 months (phase II). Our study population consists of 150 patients, aged ≥18 years, with a clinician's diagnosis of asthma, currently on controller medication, with uncontrolled asthma and/or minimally one exacerbation in the past 12 months. They will be enrolled over three participating centres, including Leiden, London and Manchester. Our main outcomes are the association between physiological, behavioural and environmental data and (1) the loss of asthma control and (2) the occurrence of asthma exacerbations. This study was approved by the Medical Ethics Committee of the Leiden University Medical Center in the Netherlands and by the NHS ethics service in the UK. NCT02774772.


Expression of MYCN in Multipotent Sympathoadrenal Progenitors Induces Proliferation and Neural Differentiation, but Is Not Sufficient for Tumorigenesis.
Neuroblastoma is a pediatric malignancy of the sympathetic ganglia and adrenal glands, hypothesized to originate from progenitors of the developing sympathetic nervous system. Amplification of the MYCN oncogene is a genetic marker of risk in this disease. Understanding the impact of oncogene expression on sympathoadrenal progenitor development may improve our knowledge of neuroblastoma initiation and progression. We isolated sympathoadrenal progenitor cells from the postnatal murine adrenal gland by sphere culture and found them to be multipotent, generating differentiated colonies of neurons, Schwann cells, and myofibroblasts. MYCN overexpression in spheres promoted commitment to the neural lineage, evidenced by an increased frequency of neuron-containing colonies. MYCN promoted proliferation of both sympathoadrenal progenitor spheres and differentiated neurons derived from these spheres, but there was also an increase in apoptosis. The proliferation, apoptosis, and neural lineage commitment induced by MYCN are tumor-like characteristics and thereby support the hypothesis that multipotent adrenal medullary progenitor cells are cells of origin for neuroblastoma. We find, however, that MYCN overexpression is not sufficient for these cells to form tumors in nude mice, suggesting that additional transforming mutations are necessary for tumorigenesis.


Natal and neonatal teeth: a review.
The presence of teeth in newborn is uncommon. Sometimes it occurs, appearing in about one in every 2,000 to 3,000 live births. Natal teeth are teeth already present at time of birth, neonatal teeth erupt during the first 30 days after birth. The normal eruption of the first teeth is quite exciting but their occurrence at birth or few days after birth is quite disturbing because of societal unpleasant reaction towards it in some communities and calls for concern. The majority of natal and neonatal teeth represent the early eruption of normal primary teeth. Less than 10% of natal teeth are supernumerary. Although the majority of natal teeth are isolated incidents, their presence may be associated with some syndromes. Complications include discomfort during suckling causing irritation and trauma to infants tongue, sublingual ulceration, laceration of the mother's breasts and aspiration of the teeth. The objective of the present study was to present a review of the literature on the current information on this topic and give treatment options if necessary.


Acceptance and commitment therapy-based behavioral intervention for insomnia: a pilot randomized controlled trial.
To evaluate a protocol for acceptance and commitment therapy-based behavioral intervention for insomnia (ACT-BBI-I) in adults compared to cognitive behavioral therapy for insomnia (CBT-I). Forty-five adults with chronic insomnia were randomized to ACT-BBI-I or CBT-I. Both interventions were performed in six weekly group sessions. The common treatment elements in both protocols included stimulus control and sleep restriction. CBT-I is focused on the cognitive restructuring of maladaptive beliefs about sleep and the daytime effects of insomnia. ACT-BBI-I focuses on therapeutic processes of acceptance, availability, values, defusion, and commitment. The results were evaluated through the following instruments: a sleep diary, the Insomnia Severity Index, the Epworth Sleepiness Scale, the Hospital Anxiety and Depression Scale, the Acceptance and Action Questionnaire-II, and the Dysfunctional Beliefs and Attitudes about Sleep scale. Both interventions had a significant positive impact on sleep patterns, insomnia, anxiety, beliefs about sleep, and psychological flexibility. All improvement was maintained at the 6-month follow-up. The results suggest that integrating principles of ACT with behavioral techniques may be useful for treating insomnia. Further research should identify whether the principles of ACT result in added effectiveness compared to behavioral components alone. RBR-7nc5wq.


Liposomal formulation and antitumor activity of 14-O-palmitoyl-hydroxyrubicin.
The 14-O-palmitoyl ester of 3'-deamino-3'-hydroxydoxorubicin was synthesized to study the liposomal formulation and biological activity properties conferred by the attachment of a lipophilic group to position 14 of the anthracycline molecule. The entrapment efficiency of 14-O-palmitoyl-hydroxyrubicin in multilamellar vesicles composed of dimyristoylphosphatidyl choline and dimyristoylphosphatidyl glycerol was greater than 99%. In addition, the stability of liposomes containing 14-O-palmitoyl-hydroxyrubicin was greater than 99% at 14 days as assessed by the amount of drug leaking out of the liposomes and the absence of crystals of free drug in the liposome pellet. Esterification at position 14 did not significantly decrease the potency of the parent compound 3'-hydroxydoxorubicin. Liposome-entrapped 14-O-palmitoyl-hydroxyrubicin was significantly more active than doxorubicin against two murine tumor models. Against ip L-1210 leukemia, liposome-entrapped 14-O-palmitoyl-hydroxyrubicin injected i.p. into mice at doses of 60 and 80 mg/kg resulted in a %T/C value (median survival of treated/control animals x 100) of greater than 600, with 3-4 of 6 animals being cured, whereas in the same experiments, doxorubicin injected at the optimal dose (10 mg/kg) resulted in a %T/C value of 340, with 1 of 6 animals being cured. In animals bearing liver metastases of M-5076 reticulosarcoma, liposome-entrapped 14-O-palmitoyl-hydroxyrubicin showed significant antitumor activity when given on a three-i.v.-injection schedule of 20 mg/kg on days 4, 8, and 12 (%T/C, 175), whereas doxorubicin injected at optimal doses of 6-8 mg/kg on the same days was devoid of antitumor activity (%T/C, 129-133). These results indicate that esterification at position 14 enhances the affinity of this type of compounds for lipid bilayers without negatively affecting their biological activity.


Age-related impairment of quality of joint motion in vibroarthrographic signal analysis.
Aging is associated with degenerative changes in articular surfaces leading to quantitative and qualitative impairment of joint motion. Therefore, the aim of this study is to evaluate an age-related quality of the patellofemoral joint (PFJ) motion in the vibroarthrographic (VAG) signal analysis. Two hundred and twenty individuals were enrolled in this study and divided into five groups according to age. The VAG signals were collected during flexion/extension knee motion using an acceleration sensor and described using four parameters (VMS, P1, P2, and H). We observed that values of parameters VMS, P1, and P2 increase in accordance with the age, but H level decreases. The most significant differences were achieved between the youngest and the oldest participants' groups. Moreover, we show that parameters VMS, P1, and P2 positively correlate with age, contrary to negatively associated H parameter. Our results suggest that the impairment of joint motion is a result of age-related osteoarticular degenerative changes.


Hodgkin Lymphoma, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.
The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. Current management of classic HL involves initial treatment with chemotherapy alone or combined modality therapy followed by restaging with PET/CT to assess treatment response. Overall, the introduction of less toxic and more effective regimens has significantly advanced HL cure rates. This portion of the NCCN Guidelines focuses on the management of classic HL.


Life cycle of Renylaima capensis, a brachylaimid trematode of shrews and slugs in South Africa: two-host and three-host transmission modalities suggested by epizootiology and DNA sequencing.
The life cycle of the brachylaimid trematode species Renylaima capensis, infecting the urinary system of the shrew Myosorex varius (Mammalia: Soricidae: Crocidosoricinae) in the Hottentots Holland Nature Reserve, South Africa, has been elucidated by a study of its larval stages, epizootiological data in local snails and mammals during a 34-year period, and its verification with mtDNA sequencing. Parasites obtained from dissected animals were mounted in microscope slides for the parasitological study and measured according to standardized methods. The mitochondrial DNA cox1 gene was sequenced by the dideoxy chain-termination method. The slugs Ariostralis nebulosa and Ariopelta capensis (Gastropoda: Arionidae) act as specific first and second intermediate hosts, respectively. Branched sporocysts massively develop in A. nebulosa. Intrasporocystic mature cercariae show differentiated gonads, male terminal duct, ventral genital pore, and usually no tail, opposite to Brachylaimidae in which mature cercariae show a germinal primordium and small tail. Unencysted metacercariae, usually brevicaudate, infect the kidney of A. capensis and differ from mature cercariae by only a slightly greater size. The final microhabitats are the kidneys and ureters of the shrews, kidney pelvis and calyces in light infections and also kidney medulla and cortex in heavy infections. Sporocysts, cercariae, metacercariae and adults proved to belong to R. capensis by analysis of a 437-bp-long cox1 fragment, which was identical except for three mutations in metacercariae, of which only one silent. Epizootiological studies showed usual sporocyst infection in A. nebulosa and very rare metacercarial infection in A. capensis, which does not agree with high prevalences and intensities in the shrews. The presence of monotesticular adult forms and larval prevalences and intensities observed suggest that R. capensis may use two transmission strategies, a two-host life cycle by predation of A. nebulosa harbouring intrasporocystic cercariae may be the normal pattern, whereas a second mollusc host is just starting to be introduced. In shrews, a tissue-traversing, intraorganic migration followed by an interorganic migration to reach and penetrate the outer surface of either of both kidneys should occur. For first slug infection, the fluke takes advantage of the phenomenon that M. varius always urinate during defaecation. Consequently, in Brachylaimidae, the second intermediate mollusc host should evolutionarily be seen as a last addition to the cycle and their present adult stage microhabitat restricted to digestive tract and related organs as a loss of the tissue-traversing capacity of the metacercaria.


Epidemiologic factors associated with seropositivity to human papillomavirus type 16 and 18 virus-like particles and risk of subsequent infection in men.
Our understanding of humoral response to human papillomavirus (HPV) infection has been mainly derived from studies in women. The role of serum antibodies in the natural history of HPV in men has yet to be investigated. Data from 285 male participants of a natural history study were used to determine the epidemiologic factors associated with HPV 16/18 seropositivity and explore the role of HPV 16 and 18 serum antibodies in subsequent HPV infections. Serum antibodies were detected by use of HPV 16- and 18 virus-like particles enzyme-linked immunoassay. Logistic regression and Generalized Estimating Equation was used for the evaluation of risk factors. The risk of subsequent HPV infection by baseline antibody status was assessed by incidence rate ratio and its confidence intervals. Men ages 36 to 44 years compared with men ages 18 to 25 years were four times more likely to be seropositive to HPV 16/18. In addition, being divorced, separated, or widowed; being a former smoker; and having sex with men was positively and independently associated with HPV 16/18 seropositivity. Our findings on the potential role of HPV 16 or 18 serum antibodies in subsequent infection were inconclusive. Large prospective studies are warranted to adequately address questions on the role of natural immunity in the natural history of HPV infections in men.


Metabolomics reveals a link between homocysteine and lipid metabolism and leukocyte telomere length: the ENGAGE consortium.
Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 individuals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological samples from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10-6), methionine (p-value = 9.2 × 10-5), tyrosine (p-value = 2.1 × 10-4), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10-4), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10-4), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10-4). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.


Synthesis of full length and truncated microcin B17 analogues as DNA gyrase poisons.
Microcin B17 (MccB17) is a post-translationally modified peptide containing thiazole and oxazole heterocycles that interrupt the peptide backbone. MccB17 is capable of poisoning DNA gyrase through stabilization of the gyrase-DNA cleavage complex and has therefore attracted significant attention. Using a combination of Fmoc-strategy solid-phase peptide synthesis and solution-phase fragment assembly we have prepared a library of full-length and truncated MccB17 analogues to investigate key structural requirements for gyrase-poisoning activity. Synthetic peptides lacking the glycine-rich N-terminal portion of the full-length sequence showed strong stabilization of the gyrase-DNA cleavage complex with increased potency relative to the full-length sequences. This truncation, however, led to a decrease in antibacterial activity of these analogues relative to their full-length counterparts indicating a potential role of the N-terminal region of the natural product for cellular uptake.


Eco-Evolutionary Theory and Insect Outbreaks.
Eco-evolutionary theory argues that population cycles in consumer-resource interactions are partly driven by natural selection, such that changes in densities and changes in trait values are mutually reinforcing. Evidence that the theory explains cycles in nature, however, is almost nonexistent. Experimental tests of model assumptions are logistically impractical for most organisms, while for others, evidence that population cycles occur in nature is lacking. For insect baculoviruses in contrast, tests of model assumptions are straightforward, and there is strong evidence that baculoviruses help drive population cycles in many insects, including the gypsy moth that we study here. We therefore used field experiments with the gypsy moth baculovirus to test two key assumptions of eco-evolutionary models of host-pathogen population cycles: that reduced host infection risk is heritable and that it is costly. Our experiments confirm both assumptions, and inserting parameters estimated from our data into eco-evolutionary insect-outbreak models gives cycles closely resembling gypsy moth outbreak cycles in North America, whereas standard models predict unrealistic stable equilibria. Our work shows that eco-evolutionary models are useful for explaining outbreaks of forest insect defoliators, while widespread observations of intense selection on defoliators in nature and of heritable and costly resistance in defoliators in the lab together suggest that eco-evolutionary dynamics may play a general role in defoliator outbreaks.


Fluctuations as stochastic deformation.
A notion of stochastic deformation is introduced and the corresponding algebraic deformation procedure is developed. This procedure is analogous to the deformation of an algebra of observables like deformation quantization, but for an imaginary deformation parameter (the Planck constant). This method is demonstrated on diverse relativistic and nonrelativistic models with finite and infinite degrees of freedom. It is shown that under stochastic deformation the model of a nonrelativistic particle interacting with the electromagnetic field on a curved background passes into the stochastic model described by the Fokker-Planck equation with the diffusion tensor being the inverse metric tensor. The first stochastic correction to the Newton equations for this system is found. The Klein-Kramers equation is also derived as the stochastic deformation of a certain classical model. Relativistic generalizations of the Fokker-Planck and Klein-Kramers equations are obtained by applying the procedure of stochastic deformation to appropriate relativistic classical models. The analog of the Fokker-Planck equation associated with the stochastic Lorentz-Dirac equation is derived too. The stochastic deformation of the models of a free scalar field and an electromagnetic field is investigated. It turns out that in the latter case the obtained stochastic model describes a fluctuating electromagnetic field in a transparent medium.


Correlation of histologic and clinical images to determine the diagnostic value of fluorescein angiography for studying retinal capillary detail.
To delineate morphometric and quantitative features of the capillary image derived from high-resolution fundus fluorescein angiography (FFA) and consequently determine the diagnostic value of FFA for studying the retinal capillary circulation. Retinal capillary images obtained from healthy young subjects using high-resolution FFA were compared with confocal scanning laser microscopic capillary images derived from the retinas of age-matched human donors. Confocal microscopic images were acquired from retinal flatmount tissue after central retinal artery cannulation, perfusion fixation, and antibody labeling. Capillary images from equivalent retinal regions were morphologically and quantitatively analyzed in both groups. Ten human subjects (mean age, 27.4 years) were used for FFA studies, and five cadaveric eyes (mean donor age, 26.5 years) were used for histologic studies. In histologic specimens the density of the superficial capillary network was significantly greater than that of the deep capillary network. Despite use of a healthy young population, only 30% of high-resolution FFA studies provided clear capillary images. The configuration of the capillary network in FFA images was comparable to the superficial capillary network in confocal microscope images; however, the density of the capillary network in FFA images was consistently lower than that of histologic images. FFA provides incomplete morphologic information about the superficial capillary network and even less information about the deep capillary network. Caution should, therefore, be exercised when using FFA data to extrapolate information about microvascular histopathologic processes. The usefulness of newer technology for studying retinal capillary detail should be investigated.


Carbon nanotube nucleation driven by catalyst morphology dynamics.
In situ observation of the carbon nanotube nucleation process accompanied by dynamic reconstruction of the catalyst particle morphology is considered within a thermodynamic approach. It reveals the driving force for the detachment of the sp(2)-carbon cap, so-called lift-off-a crucial event in nanotube growth. A continuum model and detailed atomistic calculations identify the critical factors in the lift-off process: (i) catalyst surface energy, affected by the chemisorbed carbon atoms at the exterior surface of the catalyst, exposed to the carbon feedstock; and (ii) the emergence of a pristine, high-energy facet under the sp(2)-carbon dome. This further allows one to evaluate the range of carbon feedstock chemical potential, where the lift-off process occurs, to be followed by emergence of single-walled nanotube, and provides insights into observed catalyst morphology oscillations leading to formation of multiwalled carbon nanotubes.


Airway management and morbid obesity.
Morbidly obese patients present with excess fatty tissue externally on the breast, neck, thoracic wall and abdomen and internally in the mouth, pharynx and abdomen. This excess tissue tends to make access (intubation, tracheostomy) to and patency (during sedation or mask ventilation) of the upper airway and the function of the lungs (decreased residual capacity and aggravated ventilation perfusion mismatch) worse than in lean patients. Proper planning and preparation of airway management is essential, including elevation of the patient's upper body, head and neck. Preoxygenation is mandatory in morbidly obese patients and should be followed by actions to counteract atelectasis formation. The decision as to weather to use a rapid sequence induction, an awake intubation or a standard induction with hypnotics should depend on the thorough airway examination and comorbidity and should not be based solely on whether morbid obesity is present or not. It is important to ensure sufficient depth of anaesthesia before initiating manipulation of the airway because inadequate anaesthesia depth predisposes to aspiration if airway management becomes difficult. The intubating laryngeal mask airway is more efficient in the morbidly obese patients than in lean patients and serves as a rescue device for both failed ventilation and failed intubation. In the 24 h following anaesthesia, morbidly obese patients experience frequent oxygen desaturation periods that can be counteracted by continuous positive airway pressure, noninvasive ventilation and physiotherapy.


The neuropsychiatry of neuroacanthocytosis syndromes.
The neuroacanthocytoses are a group of disorders characterised by peripheral blood acanthocytes, central nervous system as well as neuromuscular symptoms. These disorders uniformly result in pathology in the basal ganglia, which account for the characteristic motor symptoms such as chorea or dystonia, but may also account for the apparent elevated rates of major mental disorders in these syndromes. Elevated rates of dysexecutive syndromes, obsessive-compulsive disorder, depression and schizophrenia-like psychosis appear to occur in chorea-acanthocytosis, McLeod's syndrome, pantothenate kinase-associated neurodegeneration, and Huntington's disease-like 2. Disruptions to key frontostriatal loops secondary to pathology in the striatum and pallidum appear to predispose individuals to major neuropsychiatric syndromes; however, treatment can be instituted for a number of these manifestations, which lessens the overall burden of disease in neuroacanthocytosis patients and their families.


Dose Escalation of Tamoxifen in Patients with Low Endoxifen Level: Evidence for Therapeutic Drug Monitoring-The TADE Study.
Endoxifen is the major mediator of tamoxifen effect and endoxifen levels <15 nmol/L may be associated with increased risk of breast cancer recurrence. We increased tamoxifen dose in breast cancer patients with low endoxifen levels and assessed the influence of various parameters on reaching 15 nmol/L and 30 nmol/L endoxifen levels. Tamoxifen dose was increased in those with endoxifen levels below 30 nmol/L. Toxicity, including hot flash score, was measured. CYP2D6 metabolizer status was classified as ultra-rapid (UM), extensive (EM), intermediate (IM), or poor (PM) based genotype of somatic DNA. Dosage was escalated in 68 of 122 participants. On 20 mg tamoxifen, 24% had endoxifen levels below 15 nmol/L and this reduced to 6% following dose escalation. In over 50% of cases, there was no identified cause for low endoxifen. Low baseline endoxifen level, and not CYP2D6 metabolizer status, independently predicted reaching threshold targets for both the 15 nmol/L and 30 nmol/L targets (P = 0.04 and 0.003 respectively). The 15 nmol/L target was reached in all UM/EM and IM patients, 63% of PM patients, and 58% of those with baseline endoxifen of <10 nmol/L. There was no correlation between hot flash score and genotype or any tamoxifen metabolite level including endoxifen (R = 0.07). Low endoxifen on standard dose tamoxifen was the only independent predictor of failure to achieve potentially therapeutic levels. Trials examining tamoxifen dose escalation and breast cancer outcome should be guided by endoxifen levels alone, without reference to CYP2D6 genotype or presence of hot flashes. Clin Cancer Res; 22(13); 3164-71. ©2016 AACRSee related commentary by Hertz and Rae, p. 3121.


Development and application of an aggregate adherence metric derived from population pharmacokinetics to inform clinical trial enrichment.
Nonadherence to prescribed medication is a common barrier to effective treatment, and current options to determine adherence are limited. This study describes development of an aggregate adherence measure based on population pharmacokinetics (PK), and its comparison to a subjective questionnaire, the Morisky 8-item medication adherence scale (MMAS8), in a trial of psychiatric patients on stable doses of oral aripiprazole. A comprehensive model was first built using plasma drug concentration data from 24 clinical studies comprising 448 patients with over 13,500 observations. Application of this model to independent patient profiles for a given drug-dosing regimen were used to generate the primary aggregate adherence metric, a ratio of observed versus expected plasma exposures at steady-state. Although the metric is capable of comparing relative adherence across groups, simulations showed that the metric is not sufficiently sensitive as an individual diagnostic in all cases. There were no trends observed between results from calculated aggregate adherence metrics and total scores from MMAS8 in a single-visit clinical trial of 47 patients with bipolar 1 disorder or schizophrenia who were on stable doses of aripiprazole, although a strong association was observed for one MMAS8 question. The range of the metric calculated for patients was between 0.16 and 3.15. The described approach of a novel "reverse" application of population PK to quantify relative adherence with an aggregate measure may be influential for both clinical and pharmacometric communities.


Viral diversity in swine intestinal mucus used for the manufacture of heparin as analyzed by high-throughput sequencing.
Heparin is one of the main pharmaceutical products manufactured from raw animal material. In order to describe the viral burden associated with this raw material, we performed high-throughput sequencing (HTS) on mucus samples destined for heparin manufacturing, which were collected from European pigs. We identified Circoviridae and Parvoviridae members as the most prevalent contaminating viruses, together with viruses from the Picornaviridae, Astroviridae, Reoviridae, Caliciviridae, Adenoviridae, Birnaviridae, and Anelloviridae families. Putative new viral species were also identified. The load of several known or novel small non-enveloped viruses, which are particularly difficult to inactivate or eliminate during heparin processing, was quantified by qPCR. Analysis of the combined HTS and specific qPCR results will influence the refining and validation of inactivation procedures, as well as aiding in risk analysis of viral heparin contamination.


Age differences in personality across the adult life span: parallels in five cultures.
Both cross-sectional and longitudinal studies in the United States have shown consistent changes between college age and middle adulthood. There appear to be declines in 3 of the 5 major factors of personality--Neuroticism, Extraversion, and Openness--and increases in Agreeableness and Conscientiousness. To examine cross-cultural generalizability of these findings, translations of the Revised NEO Personality Inventory were administered to samples in Germany, Italy, Portugal, Croatia, and South Korea (N = 7,363). Similar patterns of age differences were seen in each country, for both men and women. Common trends were also seen for the more specific traits that define the major factors. Because these nations differ substantially in culture and recent history, results suggest the hypothesis that these are universal maturational changes in adult personality.