A brief review on correlates of physical activity and sedentariness in youth.
Better understanding of the correlates of physical activity and sedentary behaviors in youth will support the development of effective interventions that promote a physically active lifestyle and prevent a sedentary lifestyle. The main goal of this systematic review is to summarize and update the existing literature on correlates of young people's physical activity, insufficient physical activity, and sedentary behavior. A systematic review was conducted and included studies published between January 1999 and January 2005. The 60 reviewed studies showed that for children (age range 4-12), gender (male), self-efficacy, parental physical activity (for boys), and parent support were positively associated with physical activity. For adolescents (age range 13-18), positive associations with physical activity were found for gender (male), parental education, attitude, self-efficacy, goal orientation/motivation, physical education/school sports, family influences, and friend support. For adolescents, a positive association was found between gender (male) and sedentary behavior, whereas an inverse association was found between gender and insufficient physical activity. Ethnicity (Caucasian), socioeconomic status, and parent education were found to be inversely associated with adolescents' sedentary behaviors. For children, the evidence was insufficient to draw conclusions about correlates of insufficient physical activity and sedentary behavior. To gain more insight in the correlates of change in physical activity levels, more prospective studies are needed. Moreover, further research is needed examining the correlates of insufficient physical activity and sedentary behaviors, to develop effective interventions that may help children and adolescents diminish the time they spend on inactive behaviors.


Inhibition of glutathione synthesis eliminates the adaptive response of ascitic hepatoma 22 cells to nedaplatin that targets thioredoxin reductase.
Thioredoxin reductase (TrxR) is a target for cancer therapy and the anticancer mechanism of cisplatin involves TrxR inhibition. We hypothesize that the anticancer drug nedaplatin (NDP), an analogue of cisplatin and a second-generation platinum complex, also targets TrxR. Furthermore, we investigate whether the therapeutic efficacy of NDP can be enhanced by simultaneous modulation of 1) TrxR, via NDP, and 2) glutathione (GSH), via the GSH synthesis inhibitor buthionine sulfoximine (BSO). Mice bearing ascitic hepatoma 22 (H22) cells were treated with NDP alone or NDP plus BSO. TrxR activity of H22 cells was inhibited by NDP in a dose-dependent manner. A high correlation between the inhibition of TrxR activity at 6h and the inhibition of ascitic fluid volume at 72h was established (r=0.978, p<0.01). As an adaptive response, the viable ascitic cancer cells after NDP treatment displayed an enlarged cell phenotype, assembled with several-fold more antioxidant enzymes and GSH-predominant non-protein free thiols. This adaptive response was largely eliminated when BSO was co-administered with NDP, leading to the decimation of the H22 cell population without enhancing renal toxicity, since at this dose, NDP did not inhibit renal TrxR activity. In conclusion, the pharmacological effect of NDP involves TrxR inhibition, and the adaptive response of NDP-treated ascitic H22 cells can be efficiently counteracted by BSO. Simultaneous modulation of TrxR and GSH on ascitic H22 cells using NDP plus BSO greatly enhances therapeutic efficacy as compared with the single modulation of TrxR using NDP alone.


Clinical and molecular epidemiology of Staphylococcus aureus catheter-related bacteremia in children.
Staphylococcus aureus (SA) is an important cause of catheter-related bacteremia (CRB). The USA300 clone increasingly causes healthcare associated infections. We compared children with SA-CRB due to USA300 versus non-USA300 isolates and identified risk factors for complications. Children at Texas Children's Hospital (TCH) with SA-CRB were identified from a prospective S. aureus surveillance study. S. aureus isolates were characterized by methicillin susceptibility and pulsed field gel electrophoresis. From August 2001 to October 2007, 112 children with a first episode of SA-CRB and corresponding isolates were identified. USA300 accounted for 21 isolates. Metastatic infection complicated 10.7% of cases and was associated with methicillin resistance. Other complications were recurrence (n = 16), death (n = 13), thrombosis (n = 9), and intravascular "cast" (n = 6). Four patients with non-USA300 SA-CRB had endocarditis. Prolonged bacteremia was more common in methicillin-resistant SA (12/29) than in methicillin-susceptible SA SA-CRB (14/83) (P = 0.007). Complications were more common in patients with bacteremia > or =4 days (16/26 [61.5%]) versus patients with bacteremia <4 days (25/86 [29%]) (P = 0.003). The complication rate was lower in patients who had the catheter removed <4 days (22.5%) versus patients whose catheter was removed > or =4 days after infection or not removed (44.4%) (P = 0.02). Children with USA300 versus non-USA300 isolates did not differ with respect to frequency or type of complications. At Texas Children's Hospital, the USA300 clone caused 19% of initial SA-CRB episodes and was associated with methicillin resistance. Complications occurred in 36.6% of the patients and were associated with prolonged bacteremia and catheter removal > or =4 days after infection or failure to remove the catheter.


Racial differences in the frequency of depressive symptoms among community dwelling elders: the role of socioeconomic factors.
In a biracial sample of community dwelling elders (n=4162, the Duke EPESE), African-Americans endorsed more items than Whites on a standardized depression scale, the CES-D, in unadjusted, cross-sectional analyses. However, indices of socioeconomic status (e.g., education and problems meeting needs) were found to mediate the relationship between race and depression. When these socioeconomic variables were included in cross-sectional analyses, the association between depressive symptoms and race reversed such that Whites were significantly more likely to endorse depressive symptoms than African-Americans. Further, whereas in unadjusted, longitudinal analyses, race was unrelated to changes in depressive symptoms over time, with the inclusion of the socioeconomic variables Whites were found to endorse more depressive symptoms than African-Americans. We conclude that socioeconomic variables influence the size and direction of racial differences in the endorsement of depressive symptoms in community dwelling elders.


Changes in Serum Fatty Acid Levels During the First Year After Bariatric Surgery.
We have assessed the effects of laparoscopic sleeve gastrectomy (LSG) and biliopancratic diversion with a duodenal switch (BPDDS) on fatty acid (FA) levels in serum. In particular, we examine the impact of surgery on the ratio of the FAs eicosapentaenoic acid (EPA) to arachidonic acid (AA) which impacts, e.g., cardiovascular health. Our hypothesis is that LSG and BPDDS influence the FA levels but that BPDDS may have a more persistent impact since BPDSS superimposes intestinal malabsorption on gastric restriction. Serum samples after overnight fasting were collected 3 months and 1 day before surgery and 3 days, 3 months, and 12 months after surgery from 10 BPDDS patients and 23 LSG patients. The levels of 16 FAs were quantified by gas chromatography. Preoperative and postoperative concentrations of EPA and AA and the ratio of EPA to AA were compared by Wilcoxon signed-rank test corrected for multiple testing using false discovery rate. The ratio of EPA/AA at each of the three postoperative sampling points was lower than at the two preoperative sampling points for BPDDS with p < 0.05 after correcting significance levels for multiple testing. For LSG, the ratio was lower with p < 0.05 at 3 days and at 3 months after surgery, but not after 12 months. Both LSG and BPDDS lower the ratio of EPA/AA significantly and below recommended values, but LSG patients resurge toward normal values after approximately 12 months, while BPDDS patients do not.


Antibacterial activity and cytotoxicity of PEGylated poly(amidoamine) dendrimers.
We have investigated the antibacterial activity and cytotoxicity of a series of amino-terminated poly(amidoamine) (PAMAM) dendrimers modified with poly(ethylene glycol) (PEG) groups. The antibacterial activity of the PAMAM dendrimers and their derivatives against the common ocular pathogens, Pseudomonas aeruginosa and Staphylococcus aureus, was evaluated by their minimum inhibitory concentrations (MICs). For the unmodified third and fifth generation (G3 and G5) amino-terminated dendrimers, the MICs against both P. aeruginosa and S. aureus were in the range of 6.3-12.5 microg mL(-1), comparable to that of the antimicrobial peptide LL-37 (1.3-12.5 microg mL(-1)) and within the wide range of 0.047-128 microg mL(-1) for the fluoroquinolone antibiotics. PEGylation of the dendrimers decreased their antibacterial activities, especially for the Gram-positive bacteria (S. aureus). The reduction in potency is likely due to the decrease in the number of protonated amino groups and shielding of the positive charges by the PEG chains, thus decreasing the electrostatic interactions of the dendrimers with the negatively-charged bacterial surface. Interestingly, localization of a greater number of amino groups on G5 vs. G3 dendrimers did not improve the potency. Significantly, even a low degree of PEGylation, e.g. 6% with EG(11) on G3 dendrimer, greatly reduced the cytotoxicity towards human corneal epithelial cells while maintaining a high potency against P. aeruginosa. The cytotoxicity of the PEGylated dendrimers to host cells is much lower than that reported for antimicrobial peptides. Furthermore, the MICs of these dendrimers against P. aeruginosa are more than two orders of magnitude lower than other antimicrobial polymers reported to date. These results motivate further exploration of the potential of cationic dendrimers as a new class of antimicrobial agents that may be less likely to induce bacterial resistance than standard antibiotics.


Public health nurses' perception of their roles in relation to psychotropic drug use by adolescents: a phenomenographic study.
The purpose of the paper was to describe the perceptions of public health nurses' roles in relation to psychotropic drug use by adolescents. Mental health problems among adolescents are documented with studies indicating an increased use of psychotropic drugs. In Norway, care for such adolescents may fall naturally into the remit of public health nurses. A phenomenographic approach was used to analyse the data. A qualitative interview study was made of 20 Norwegian public health nurses, strategically chosen using phenomenographic methodology. The public health nurses described three categories: discovering public health nurses who become aware of psychotropic drug use in the health dialogue with adolescents and choose to either act or not act in relation to psychotropic drug use. Those public health nurses who take action are cooperating public health nurses, who cooperate with adolescents, their families, schools and others. If cooperation has been established, supporting public health nurses teach and support the adolescent in relation to psychotropic drug use. The public health nurses who do not act can hinder or delay further treatment. Public health nurses need to acquire knowledge about psychotropic drugs, to fulfil their role in nursing mental health problems among adolescents and the increasing use of psychotropic drugs. The results demonstrated that public health nurses, working in health centres and schools, have the responsibility and the opportunity to identify young people struggling with mental health problems and psychotropic drug use as well as teach and support significant others, e.g. parents and siblings. Intervention studies are needed with regard to health promotion programmes aimed at fortifying young people's mental health.


Polyploidization for the Genetic Improvement of Cannabis sativa.
Cannabis sativa L. is a diploid species, cultivated throughout the ages as a source of fiber, food, and secondary metabolites with therapeutic and recreational properties. Polyploidization is considered as a valuable tool in the genetic improvement of crop plants. Although this method has been used in hemp-type Cannabis, it has never been applied to drug-type strains. Here, we describe the development of tetraploid drug-type Cannabis lines and test whether this transformation alters yield or the profile of important secondary metabolites: Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), or terpenes. The mitotic spindle inhibitor oryzalin was used to induce polyploids in a THC/CBD balanced drug-type strain of Cannabis sativa. Cultured axillary bud explants were exposed to a range of oryzalin concentrations for 24 h. Flow cytometry was used to assess the ploidy of regenerated shoots. Treatment with 20-40 μM oryzalin produced the highest number of tetraploids. Tetraploid clones were assessed for changes in morphology and chemical profile compared to diploid control plants. Tetraploid fan leaves were larger, with stomata about 30% larger and about half as dense compared to diploids. Trichome density was increased by about 40% on tetraploid sugar leaves, coupled with significant changes in the terpene profile and a 9% increase in CBD that was significant in buds. No significant increase in yield of dried bud or THC content was observed. This research lays important groundwork for the breeding and development of new Cannabis strains with diverse chemical profiles, of benefit to medical and recreational users.


BioAssay Research Database (BARD): chemical biology and probe-development enabled by structured metadata and result types.
BARD, the BioAssay Research Database (https://bard.nih.gov/) is a public database and suite of tools developed to provide access to bioassay data produced by the NIH Molecular Libraries Program (MLP). Data from 631 MLP projects were migrated to a new structured vocabulary designed to capture bioassay data in a formalized manner, with particular emphasis placed on the description of assay protocols. New data can be submitted to BARD with a user-friendly set of tools that assist in the creation of appropriately formatted datasets and assay definitions. Data published through the BARD application program interface (API) can be accessed by researchers using web-based query tools or a desktop client. Third-party developers wishing to create new tools can use the API to produce stand-alone tools or new plug-ins that can be integrated into BARD. The entire BARD suite of tools therefore supports three classes of researcher: those who wish to publish data, those who wish to mine data for testable hypotheses, and those in the developer community who wish to build tools that leverage this carefully curated chemical biology resource.


Correction of disease-associated exon skipping by synthetic exon-specific activators.
Differential exon use is a hallmark of alternative splicing, a prevalent mechanism for generating protein isoform diversity. Many disease-associated mutations also affect pre-mRNA splicing, usually causing inappropriate exon skipping. SR proteins are essential splicing factors that recognize exonic splicing enhancers and drive exon inclusion. To emulate this function of SR proteins, we designed small chimeric effectors comprising a minimal synthetic RS domain covalently linked to an antisense moiety that targets an exon by Watson-Crick base pairing. Here we show that such synthetic effectors can mimic the functions of SR proteins and specifically restore wild type splicing when directed to defective BRCA1 or SMN2 pre-mRNA transcripts. This general approach can be used as a tool to investigate splicing mechanisms and modulate alternative splicing of specific genes, and as a therapeutic strategy to correct splicing defects responsible for numerous diseases.


Fall prevention research and practice: a total worker safety approach.
Slips, trips, and falls (STF) represent a serious hazard to workers and occupants in many industries, homes, and communities. Often, the cause of a STF incident is multifactorial, encompassing human, environmental, and task risk factors. A STF-related disability can greatly diminish the occupational capability and quality of life of individuals in both the workplace and the home. Countering STF hazards and risks both on and off the job and on all aspects of control measures is a "total worker safety" matter, a challenging yet tangible undertaking. As the federal organization responsible for conducting research for the prevention of work-related injuries in the United States, the National Institute for Occupational Safety and Health (NIOSH) has been conducting research on STF controls for some decades. Many NIOSH research outcomes have been utilized for STF prevention in workplaces, with potential for prevention in homes as well. This paper summarizes the concept of total worker safety for STF control, NIOSH priority research goals, major activities, and accomplishments, and some emerging issues on STF. The strategic planning process for the NIOSH research goals and some identified research focuses are applicable to the development and implementation of global STF research goals.


Protein crowding on biomembranes: analysis of contour instabilities.
Collective behavior of proteins on biomembranes is usually studied within the spontaneous curvature model. Here we consider an alternative phenomenological approach, which accounts consistently for partial ordering of proteins as well as the anchoring forces exerted on a membrane by layer of proteins. We show analytically that such anisotropic interactions can drive membrane bending, resulting in nontrivial equilibrium morphologies. The predicted instabilities can advance our conceptual understanding of physical mechanisms behind collective phenomena in biological systems, in particular those with inherent anisotropy.


Electrochemical immunosensing of nanovesicles as biomarkers for breast cancer.
Exosomes are nano-sized vesicles, which are currently under intensive study as potential diagnostic biomarkers for many health disorders, including cancer. This paper addresses the study of an electrochemical immunosensor in different formats for the characterization and quantification of exosomes derived from three breast cancer cell lines (MCF7, MDA-MB-231 and SKBR3). To achieve that, the exosomes were preconcentrated from cell-culture supernatant (and eventually in human serum) on magnetic particles modified with antibodies against the general tetraspanins CD9, CD63 and CD81, as well as specific receptors of cancer (CD24, CD44, CD54, CD326 and CD340). The electrochemical immunosensor is able to reach a limit of detection of 105 exosomes μL-1 directly in human serum, when performing the immunomagnetic separation with antiCD81 modified magnetic particles and the labeling based on CD24 and CD340 as cancer-related biomarker, avoiding the interference from free receptors in the serum matrix. Furthermore, the electrochemical immunosensor shows reliable results for the differentiation of healthy donors and breast cancer individuals based on specific epithelial biomarkers. This approach is a highly suitable alternative method for the detection of exosomes in scarce resource settings.


Anticoagulant therapy and outcomes in patients with prior or acute heart failure and acute coronary syndromes: Insights from the APixaban for PRevention of Acute ISchemic Events 2 trial.
Clinical outcomes and the effects of oral anticoagulants among patients with acute coronary syndrome (ACS) and either a history of or acute heart failure (HF) are largely unknown. We aimed to assess the relationship between prior HF or acute HF complicating an index ACS event and subsequent clinical outcomes and the efficacy and safety of apixaban compared with placebo in these populations. High-risk patients were randomly assigned post-ACS to apixaban 5.0 mg or placebo twice daily. Median follow-up was 8 (4-12) months. The primary outcome was cardiovascular death, myocardial infarction, or stroke. The main safety outcome was thrombolysis in myocardial infarction major bleeding. Heart failure was reported in 2,995 patients (41%), either as prior HF (2,076 [28%]) or acute HF (2,028 [27%]). Patients with HF had a very high baseline risk and were more often managed medically. Heart failure was associated with a higher rate of the primary outcome (prior HF: adjusted hazard ratio [HR] 1.73, 95% CI 1.42-2.10, P < .0001, acute HF: adjusted HR 1.65, 95% CI 1.35-2.01, P < .0001) and cardiovascular death (prior HF: HR 2.54, 95% CI 1.82-3.54, acute HF: adjusted HR 2.52, 95% CI 1.82-3.50). Patients with acute HF also had significantly higher rates of thrombolysis in myocardial infarction major bleeding (prior HF: adjusted HR 1.22, 95% CI 0.65-2.27, P = .54, acute HF: adjusted HR 1.78, 95% CI 1.03-3.08, P = .04). There was no statistical evidence of a differential effect of apixaban on clinical events or bleeding in patients with or without prior HF; however, among patients with acute HF, there were numerically fewer events with apixaban than placebo (14.8 vs 19.3, HR 0.76, 95% CI 0.57-1.01, interaction P = .13), a trend that was not seen in patients with prior HF or no HF. In high-risk patients post-ACS, both prior and acute HFs are associated with an increased risk of subsequent clinical events. Apixaban did not significantly reduce clinical events and increased bleeding in patients with and without HF; however, there was a tendency toward fewer clinical events with apixaban in patients with acute HF.


Design of an open path near-infrared diode laser sensor: application to oxygen, water, and carbon dioxide vapor detection.
An open path diode laser sensor was constructed with near-infrared diode lasers and two-tone frequency-modulation spectroscopy. The sensor incorporates several novel features (such as digital signal-processing algorithms, a computerized line-locking routine, and discontinuous wavelength scanning) that are important in a field instrument. The sensor was used to monitor oxygen, water, and carbon dioxide in the near-infrared spectral range. For oxygen, an absorbance detection sensitivity of 2 × 10(-6) in a 10-Hz bandwidth was demonstrated with a GaALAs laser at 760.56 nm. The stability of the sensor was 0.1% over a period of 10 h when an absorbance of 6 × 10(-3) was monitored.


Small inhibitor of Bcl-2, HA14-1, selectively enhanced the apoptotic effect of cisplatin by modulating Bcl-2 family members in MDA-MB-231 breast cancer cells.
Inhibition or downregulation of Bcl-2 represents a new therapeutic approach to by-pass chemoresistance in cancer cells. Therefore, we explored the potential of this approach in breast cancer cells. Cisplatin and paclitaxel induced apoptosis in a dose-dependent manner in MCF-7 (drug-sensitive) and MDA-MB-231 (drug-insensitive) cells. Furthermore, when we transiently silenced Bcl-2, both cisplatin and paclitaxel induced apoptosis more than parental cells. Dose dependent induction of apoptosis by drugs was enhanced by the pre-treatment of these cells with HA14-1, a Bcl-2 inhibitor. Although the effect of cisplatin was significant on both cell lines, the effect of paclitaxel was much less potent only in MDA-MB-231 cells. To further understand the distinct role of drugs in MDA-MB-231 cells pretreated with HA14-1, caspases and Bcl-2 family proteins were studied. The apoptotic effect of cisplatin with or without HA14-1 pre-treatment is shown to be caspase-dependent. Among pro-apoptotic Bcl-2 proteins, Bax and Puma were found to be up-regulated whereas Bcl-2 and Bcl-x(L) were down-regulated when cells were pretreated with HA14-1 followed by paclitaxel or cisplatin. Enforced Bcl-2 expression in MDA-MB-231 cells abrogated the sensitizing effect of HA14-1 in cisplatin induced apoptosis. These results suggest that the potentiating effect of HA14-1 is drug and cell type specific and may not only depend on the inhibition of Bcl-2. Importantly, alteration of other pro-apoptotic or anti-apoptotic Bcl-2 family members may dictate the apoptotic response when HA14-1 is combined with chemotherapeutic drugs.


The effectiveness of PMT program on parent-child relationship in parents with ADHD children: A randomized trial.
Background: Attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder in children that creates problems in parents-children relationships. Improving familial and social interactions of these children needs mental and social interventions, and parents' management training (PMT) program is one of these interventions. The present study aimed at determining the effectiveness of PMT program on parent-child relationship of parents with ADHD children. Methods: Through an experimental research, 40 parents with ADHD children were selected based on purposeful sampling. A total of 20 parents were randomly placed in intervention group and received 8 sessions of intervention course (60 minutes per session) and the other 20 parents were grouped in the control group and received no training intervention. Research tools included a researcher-designed demographics questionnaire and Parker's Bonding Instrument (PBI). Data were collected at pretest, posttest, and follow- up stages and analyzed using descriptive and covariance analysis. Results: The results revealed that PMT program was significantly effective in reducing excessive support and increasing parent care index in parents with ADHD children (p<0.05). Conclusion: The results of the present study supported the effectiveness of PMT program on parent-child relationship of the parents with ADHD children.


The development of health law as a way to change traditional attitudes in national legal systems. The influence of international human rights law: what is left for the national legislator?
The development of health law as a sovereign subject of law could be seen as a correlative result of the development of international human rights law. From the perspectives of human rights law, health law gives us a unique possibility to change the traditional point of reference - from the regulation of medical procedures, to the protection of human rights as the main objective of law. At the end of the twentieth and the beginning of this century, human rights law and the most influential international instrument--the European Convention on Human Rights (and the jurisprudence of the ECHR) has influenced health care so much that it has became difficult to draw a line between these subjects. Health law sometimes directly influences and even aspires to change the content of Convention rights that are considered to be traditional. However, certain problems of law linked to health law are decided without influencing the essence of rights protected by the Convention, but just by construing the particularities of application of a certain right. In some cases by further developing the requirements of protection of individual rights that are also regulated by the health law, the ECHR even "codifies" some fields of health law (e.g., the rights of persons with mental disorders). The recognition of worthiness and diversity of human rights and the development of their content raise new objectives for national legislators when they regulate the national legal system. Here the national legislator is often put into a quandary whether to implement the standards of human rights that are recognized by the international community, or to refuse to do so, taking account of the interests of a certain group of the electorate.


The AcrB efflux pump: conformational cycling and peristalsis lead to multidrug resistance.
Antimicrobial resistance of human pathogenic bacteria is an emerging problem for global public health. This resistance is often associated with the overproduction of membrane transport proteins that are capable to pump chemotherapeutics, antibiotics, detergents, dyes and organic solvents out of the cell. In Gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa, tripartite multidrug efflux systems extrude a large variety of cytotoxic substances from the cell membrane directly into the medium bypassing the periplasm and the outer membrane. In E. coli, the tripartite efflux system AcrA/AcrB/TolC is the pump in charge of the efflux of multiple antibiotics, dyes, bile salts and detergents. The trimeric outer membrane factor (OMF) TolC forms a beta-barrel pore in the outer membrane and exhibits a long periplasmic alpha-helical conduit. The periplasmic membrane fusion protein (MFP) AcrA serves as a linker between TolC and the trimeric resistance nodulation cell division (RND) pump AcrB, located in the inner membrane acting as a proton/drug antiporter. The newly elucidated asymmetric structure of trimeric AcrB reveals three different monomer conformations representing consecutive states in a transport cycle. The monomers show tunnels with occlusions at different sites leading from the lateral side through the periplasmic porter (pore) domains towards the funnel of the trimer and TolC. The structural changes create a hydrophobic pocket in one monomer, which is not present in the other two monomers. Minocyclin and doxorubicin, both AcrB substrates, specifically bind to this pocket substantiating its role as drug binding pocket. The energy transduction from the proton motive force into drug efflux includes proton binding in (and release from) the transmembrane part. The conformational changes observed within a triad of essential, titratable residues (Asp407/Asp408/Lys940) residing in the hydrophobic transmembrane domain appear to be transduced by transmembrane helix 8 and associated with the conformational changes seen in the periplasmic domain. From the asymmetric structure a possible peristaltic pump transport mechanism based on a functional rotation of the AcrB trimer has been postulated. The novel transport model merges Jardetzky's alternate access pump mechanism with the rotating site catalysis of F(1)F(0) ATPase and suggests a working hypothesis for the transport mechanism of RND transporters in general.


Development of an individualized scoring system to predict mid-term survival after carotid endarterectomy.
Carotid endarterectomy (CEA) is a prophylactic surgery focused in preventing stroke in the mid-long term. The purpose of this study was to analyze mid-term mortality in patients undergoing CEA, identify predictors of 3-year mortality and design a score to estimate individual risk of mortality in this population. A retrospective single-center study including consecutive patients undergoing CEA between 1997-2010. Demographic data and comorbidities, postoperative results and patient follow-up data were registered and evaluated. Kaplan Meier analysis was used to analyze survival. After multivariable COX regression analysis, a score based on the calculated Hazards Ratios (HR) was designed. The sum of all points performed the individual score for each patient for estimating 3-years mortality. Population was stratified into four groups according to percentiles of score obtained: Group A (-7 to 4 points), Group B (5-8 points), Group C (9-10 points), Group D (score greater than 11 points). A total of 453 patients with a mean follow-up of 53.4 months were included in the study. Overall 3-year survival was 88.4%. On the univariate analysis the variables associated with significant increasing in 3-year mortality were: female gender (OR 2.32), diabetes mellitus (OR 2.28), COPD (OR 2.98), ischemic heart disease (OR 2.29), critical carotid stenosis >90% (OR 2.16) and antiplatelet therapy as a protective factor (OR 0,23). Factors associated with mortality in multivariate analysis were age (HR 1.14 P=0.001), diabetes mellitus (HR 1.62, P=0.031), COPD (HR 1.88 P=0.022), ischemic heart disease (HR 1.59 P=0.05), critical stenosis >90% (HR 1.70 P=0.015) and antiplatelet therapy as a protective factor (HR 0.23 P=0.027). The scoring system includes the following items: female gender (+2 points), age (50-69 years +7 points, 70-79 years +12 points, >80 years +15 points), diabetes (+4 points), COPD (+5 points), ischemic heart disease (+4 points), carotid stenosis> 90% (+4 points). Antiplatelet (-7 points). The score range from -7 to 26 points. The 3-year mortality range was 5.6% (group A) versus 25.5% (group D). The incidence of stroke at 3-year folllow-up was not correlated with the score (99%, 100%, 97% and 94.5%, respectively groups A-D, P=0.11) CONCLUSIONS: The score developed based on the risk factors of mortality allows individualized risk prediction of 3-year mortality in patients with carotid stenosis. This represents a useful and practical tool for decision-making in the indication of the CEA, allowing surgeons to identify high-risk patients who would benefit from medical treatment due to their limited life expectancy, mainly in asymptomatic patients.


Opioid misuse initiation: Implications for intervention.
The nonmedical use of opioids (e.g., prescription painkillers and heroin) has drastically increased over the past two decades. Despite the popular media narrative suggesting initiation often begins with misused personal prescriptions, there has been surprisingly little investigation into how persons initiate their misuse of opioids. Inattention to initiation patterns is an important limitation because understandings of onset directly inform prevention and treatment interventions. The primary goals of this study, therefore, were to: (1) describe the age patterns of opioid misuse initiation, (2) identify the opioid most commonly used at initiation and the source of the initial opioids, and (3) explore the narrative accounts of the circumstances surrounding opioid misuse onset. Surveys (n = 125) and in-depth interviews (n = 30) were conducted with nonmedical opioid users currently residing in southwest Pennsylvania between July 2017 and July 2018. Survey results show that initiation of opioid misuse (both heroin and prescription opioids) tends to occur prior to age 25, peaking between the ages of 18-25, with most (81%) initiating with prescription opioids. Qualitative findings provided additional context regarding the timing of initiation, acquiring opioids at initiation, and motivations for initiating. This study adds to the limited research on opioid misuse initiation and provides insights to drug treatment providers, prescribers, and public health professionals in identifying who is at risk for opioid misuse initiation, and more importantly, when and how to intervene most effectively.


Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes.
Polymorphisms in tamoxifen metabolizing genes affect the plasma concentration of tamoxifen metabolites, but their effect on clinical outcome is unknown. We determined cytochrome P450 (CYP)2D6 (*4 and *6) and CYP3A5 (*3) genotype from paraffin-embedded tumor samples and buccal cells (living patients) in tamoxifen-treated women enrolled onto a North Central Cancer Treatment Group adjuvant breast cancer trial. The relationship between genotype and disease outcome was determined using the log-rank test and Cox proportional hazards modeling. Paraffin blocks were obtained from 223 of 256 eligible patients, and buccal cells were obtained from 17 living women. CYP2D6 (*4 and *6) and CYP3A5 (*3) genotypes were determined from 190, 194, and 205 patient samples and in 17 living women. The concordance rate between buccal and tumor genotype was 100%. Women with the CYP2D6 *4/*4 genotype had worse relapse-free time (RF-time; P = .023) and disease-free survival (DFS; P = .012), but not overall survival (P = .169) and did not experience moderate to severe hot flashes relative to women heterozygous or homozygous for the wild-type allele. In the multivariate analysis, women with the CYP2D6 *4/*4 genotype still tended to have worse RFS (hazard ratio [HR], 1.85; P = .176) and DFS (HR, 1.86; P = .089). The CYP3A5*3 variant was not associated with any of these clinical outcomes. In tamoxifen-treated patients, women with the CYP2D6 *4/*4 genotype tend to have a higher risk of disease relapse and a lower incidence of hot flashes, which is consistent with our previous observation that CYP2D6 is responsible for the metabolic activation of tamoxifen to endoxifen.


Efficacy and safety of left atrial appendage electrical isolation during catheter ablation of atrial fibrillation: an updated meta-analysis.
Left atrial appendage electrical isolation (LAAEI) has been shown to improve freedom from all-atrial arrhythmia recurrence in patients with non-paroxysmal atrial fibrillation (AF). The aim of this study is to investigate the long-term efficacy and safety outcomes of LAAEI in patients with non-paroxysmal AF undergoing catheter ablation. A systematic review of Medline, Cochrane, and Embase was performed for clinical studies evaluating the benefit of LAAEI in non-paroxysmal AF. Nine studies with a total of 2336 patients were included (mean age: 65 ± 9 years, 63% male). All studies included patients with persistent AF, long-standing persistent AF, or both. At a mean follow-up of 40.5 months, patients who underwent LAAEI had significantly higher freedom from all-atrial arrhythmia recurrence than patients who underwent standard ablation alone [69.3% vs. 46.4%; risk ratio (RR) 0.54; 95% confidence interval (CI) 0.42-0.69; P < 0.0001]. A 46% relative risk reduction and 22.9% absolute risk reduction in atrial-arrhythmia recurrence was noted with LAAEI. Rates of cerebral thromboembolism were not significantly different between the two groups (LAAEI 3% vs. standard ablation 1.6%, respectively; RR 1.76; 95% CI 0.61-5.04; P = 0.29). Furthermore, there was no significant difference in the acute procedural complication rates between the two groups (LAAEI 4% vs. standard ablation 3%, respectively; RR 1.29; 95% CI 0.83-2.02; P = 0.26). At long-term follow-up, LAAEI led to a significantly higher improvement in freedom from all-atrial arrhythmia recurrence in patients with non-paroxysmal AF, when compared to standard ablation alone. Importantly, this benefit was achieved without an increased risk of acute procedural complications or cerebral thromboembolic events.


Incorporating single molecules into electrical circuits. The role of the chemical anchoring group.
Constructing electronic circuits containing singly wired molecules is at the frontier of electrical device miniaturisation. When a molecule is wired between a pair of electrodes, the two points of contact are determined by the chemical anchoring groups, located at the ends of the molecule. At this point, when a bias is applied, electrons are channelled from a metallic environment through an extremely narrow constriction, essentially a single atom, into the molecule. The fact that this is such an abrupt change in the electron pathway makes the nature of the chemical anchoring groups critically important regarding the propagation of electrons from the electrode across the molecule. A delicate interplay of phenomena can occur when a molecule binds to the electrodes, which can produce profound differences in conductance properties depending on the anchoring group. This makes answering the question "what is the best anchoring group for single molecule studies" far from straight forward. In this review, we firstly take a look at techniques developed to 'wire-up' single molecules, as understanding their limitations is key when assessing a molecular wire's performance. We then analyse the various chemical anchoring groups, and discuss their merits and disadvantages. Finally we discuss some theoretical concepts of molecular junctions to understand how transport is affected by the nature of the chemical anchor group.


Topical Timolol for Infantile Hemangiomas: Evidence for Efficacy and Degree of Systemic Absorption.
Topical use of timolol for infantile hemangiomas has recently emerged with promising results. It is unknown whether topical β-blockers act locally or if their effect is partly due to systemic absorption. This study investigates whether topically applied timolol is absorbed and reports on the efficacy of this treatment. We treated 40 infants with small proliferating hemangiomas with topical timolol gel 0.5% twice daily and assessed urinary excretion and serum levels in a proportion of patients. Clinical response was evaluated on a visual analog scale of standardized photographs after 1, 2, 3, and 5 months. Forty infants with a median age of 18 weeks (range 2-35 wks) were included; 23 (58%) had superficial and 17 (42%) mixed-type hemangiomas. The median size was 3 cm(2) (range 0.1-15 cm(2) ) and nine hemangiomas were ulcerated. The hemangiomas improved significantly during treatment, with a median increase in visual analog scale of 7 points after 5 months (p < 0.001). Urinalysis for timolol was performed in 24 patients and was positive in 20 patients (83%). In three infants, serum levels of timolol were also measured and were all positive (median 0.16 ng/mL [range 0.1-0.18 ng/mL]). No significant side effects were recorded. Topical therapy with timolol is effective for infantile hemangiomas, but systemic absorption occurs. Serum levels in our patients were low, suggesting that using timolol for small hemangiomas is safe, but caution is advised when treating ulcerated or large hemangiomas, very young infants, or concomitantly using systemic propranolol.


Early enteral nutrition within 24 hours of lower gastrointestinal surgery versus later commencement for length of hospital stay and postoperative complications.
This is an update of the review last published in 2011. It focuses on early postoperative enteral nutrition after lower gastrointestinal surgery. Traditional management consisted of 'nil by mouth', where patients receive fluids followed by solids after bowel function has returned. Although several trials have reported lower incidence of infectious complications and faster wound healing upon early feeding, other trials have shown no effect. The immediate advantage of energy intake (carbohydrates, protein or fat) could enhance recovery with fewer complications, and this warrants a systematic evaluation. To evaluate whether early commencement of postoperative enteral nutrition (within 24 hours), oral intake and any kind of tube feeding (gastric, duodenal or jejunal), compared with traditional management (delayed nutritional supply) is associated with a shorter length of hospital stay (LoS), fewer complications, mortality and adverse events in patients undergoing lower gastrointestinal surgery (distal to the ligament of Treitz). We searched the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library 2017, issue 10), Ovid MEDLINE (1950 to 15 November 2017), Ovid Embase (1974 to 15 November 2017). We also searched for ongoing trials in ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform (15 November 2017). We handsearched reference lists of identified studies and previous systematic reviews. We included randomised controlled trials (RCT) comparing early commencement of enteral nutrition (within 24 hours) with no feeding in adult participants undergoing lower gastrointestinal surgery. Two review authors independently assessed study quality using the Cochrane 'Risk of bias' tool tailored to this review and extracted data. Data analyses were conducted according to the Cochrane recommendations.We rated the quality of evidence according to GRADE.Primary outcomes were LoS and postoperative complications (wound infections, intraabdominal abscesses, anastomotic dehiscence, pneumonia).Secondary outcomes were: mortality, adverse events (nausea, vomiting), and quality of life (QoL).LoS was estimated using mean difference (MD (presented as mean +/- SD). For other outcomes we estimated the common risk ratio (RR) and calculated the associated 95% confidence intervals. For analysis, we used an inverse-variance random-effects model for the primary outcome (LoS) and Mantel-Haenszel random-effects models for the secondary outcomes. We also performed Trial Sequential Analyses (TSA). We identified 17 RCTs with 1437 participants undergoing lower gastrointestinal surgery. Most studies were at high or unclear risk of bias in two or more domains. Six studies were judged as having low risk of selection bias for random sequence generation and insufficient details were provided for judgement on allocation concealment in all 17 studies. With regards to performance and deception bias; 14 studies reported no attempt to blind participants and blinding of personnel was not discussed either. Only one study was judged as low risk of bias for blinding of outcome assessor. With regards to incomplete outcome data, three studies were judged to be at high risk because they had more than 10% difference in missing data between groups. For selective reporting, nine studies were judged as unclear as protocols were not provided and eight studies had issues with either missing data or incomplete reporting of results.LOS was reported in 16 studies (1346 participants). The mean LoS ranged from four days to 16 days in the early feeding groups and from 6.6 days to 23.5 days in the control groups. Mean difference (MD) in LoS was 1.95 (95% CI, -2.99 to -0.91, P < 0.001) days shorter in the early feeding group. However, there was substantial heterogeneity between included studies (I2 = 81, %, Chi2 = 78.98, P < 0.00001), thus the overall quality of evidence for LoS is low. These results were confirmed by the TSA showing that the cumulative Z-curve crossed the trial sequential monitoring boundary for benefit.We found no differences in the incidence of postoperative complications: wound infection (12 studies, 1181 participants, RR 0.99, 95%CI 0.64 to 1.52, very low-quality evidence), intraabdominal abscesses (6 studies, 554 participants, RR 1.00, 95%CI 0.26 to 3.80, low-quality evidence), anastomotic leakage/dehiscence (13 studies, 1232 participants, RR 0.78, 95%CI 0.38 to 1.61, low-quality evidence; number needed to treat for an additional beneficial outcome (NNTB) = 100), and pneumonia (10 studies, 954 participants, RR 0.88, 95%CI 0.32 to 2.42, low-quality evidence; NNTB = 333).Mortality was reported in 12 studies (1179 participants), and showed no between-group differences (RR = 0.56, 95%CI, 0.21 to 1.52, P = 0.26, I2 = 0%, Chi2 = 3.08, P = 0.96, low-quality evidence). The most commonly reported cause of death was anastomotic leakage, sepsis and acute myocardial infarction.Seven studies (613 participants) reported vomiting (RR 1.23, 95%CI, 0.96 to 1.58, P = 0.10, I2 = 0%, Chi2 = 4.98, P = 0.55, low-quality evidence; number needed to treat for an additional harmful outcome (NNTH) = 19), and two studies (118 participants) reported nausea (RR 0.95, 0.71 to 1.26, low-quality evidence). Four studies reported combined nausea and vomiting (RR 0.94, 95%CI 0.51 to 1.74, very low-quality evidence). One study reported QoL assessment; the scores did not differ between groups at 30 days after discharge on either QoL scale EORTC QLQ-C30 or EORTC QlQ-OV28 (very low-quality evidence). This review suggests that early enteral feeding may lead to a reduced postoperative LoS, however cautious interpretation must be taken due to substantial heterogeneity and low-quality evidence. For all other outcomes (postoperative complications, mortality, adverse events, and QoL) the findings are inconclusive, and further trials are justified to enhance the understanding of early feeding for these. In this updated review, only a few additional studies have been included, and these were small and of poor quality.To improve the evidence, future trials should address quality issues and focus on clearly defining and measuring postoperative complications to allow for better comparison between studies. However due to the introduction of fast track protocols which already include an early feeding component, future trials may be challenging. A more feasible trial may be to investigate the effect of differing postoperative energy intake regimens on relevant outcomes.


Floating light-activated microelectrical stimulators tested in the rat spinal cord.
Microelectrodes of neural stimulation utilize fine wires for electrical connections to driving electronics. Breakage of these wires and the neural tissue response due to their tethering forces are major problems encountered with long-term implantation of microelectrodes. The lifetime of an implant for neural stimulation can be substantially improved if the wire interconnects are eliminated. Thus, we proposed a floating light-activated microelectrical stimulator (FLAMES) for wireless neural stimulation. In this paradigm, a laser beam at near infrared (NIR) wavelengths will be used as a means of energy transfer to the device. In this study, microstimulators of various sizes were fabricated, with two cascaded GaAs p-i-n photodiodes, and tested in the rat spinal cord. A train of NIR pulses (0.2 ms, 50 Hz) was sent through the tissue to wirelessly activate the devices and generate the stimulus current. The forces elicited by intraspinal stimulation were measured from the ipsilateral forelimb with a force transducer. The largest forces were around 1.08 N, a significant level of force for the rat forelimb motor function. These in vivo tests suggest that the FLAMES can be used for intraspinal microstimulation even for the deepest implant locations in the rat spinal cord. The power required to generate a threshold arm movement was investigated as the laser source was moved away from the microstimulator. The results indicate that the photon density does not decrease substantially for horizontal displacements of the source that are in the same order as the beam radius. This gives confidence that the stimulation threshold may not be very sensitive to small displacement of the spinal cord relative to the spine-mounted optical power source.


Perineurioma -a rare cause of proptosis.
Perineurioma is a rare benign soft tissue tumor arising from the peripheral nerve sheath. To date only two cases of orbital perineurioma have been reported in literature. A 45-year-old, with no comorbidities, presented with protrusion of the right eye since one-year. Examination revealed 8mm proptosis of the right eye. Dilated fundoscopy of the right eye showed a pale optic disc with choroidal folds temporal to it. Computerised Tomogram (CT) of the orbit showed a well-defined intraconal mass in the inferotemporal part of the orbit. A trans conjunctival orbitotomy with lateral canthotomy was performed and the tumor was removed en bloc. On immunohistochemistry, the tumour was negative for S-100 and showed patchy weak Epithelial Membrane Antigen positivity which was suggestive of a soft tissue perineurioma.


Detection of Pathogenic and Non-pathogenic Bacteria in Drinking Water and Associated Biofilms on the Crow Reservation, Montana, USA.
Private residences in rural areas with water systems that are not adequately regulated, monitored, and updated could have drinking water that poses a health risk. To investigate water quality on the Crow Reservation in Montana, water and biofilm samples were collected from 57 public buildings and private residences served by either treated municipal or individual groundwater well systems. Bacteriological quality was assessed including detection of fecal coliform bacteria and heterotrophic plate count (HPC) as well as three potentially pathogenic bacterial genera, Mycobacterium, Legionella, and Helicobacter. All three target genera were detected in drinking water systems on the Crow Reservation. Species detected included the opportunistic and frank pathogens Mycobacterium avium, Mycobacterium gordonae, Mycobacterium flavescens, Legionella pneumophila, and Helicobacter pylori. Additionally, there was an association between HPC bacteria and the presence of Mycobacterium and Legionella but not the presence of Helicobacter. This research has shown that groundwater and municipal drinking water systems on the Crow Reservation can harbor potential bacterial pathogens.


Characterization of Fibrinogen as a Key Modulator in Patients with Wilson's Diseases with Functional Proteomic Tools.
Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism caused by defects in the ATPase gene (ATP7B). The various clinical features result from the massive accumulation of copper in the liver, cornea and basal ganglia. Although WD can be effectively treated with proper medicine, this disease is difficult to clearly diagnose due to its indefinite symptoms. In the current study, we achieved a positive correlation between clinical symptoms and the enzymatic activity of ceruloplasmin in WD patients. Furthermore, proteome profiles of plasma as well as network analysis demonstrated that fibrinogen is a critical indicator which is significantly unregulated in WD subjects in comparison to healthy donors and closely linked to pathogenesis of WD. Here, we applied 2DE-immunoblots and immunohistochemistry to verify the protein level and localization in situ. The enhanced expression of fibrinogen in the plasma of WD subjects with respect to that of healthy controls and patients with distinct disorders was also confirmed by utilizing clinical samples. As expected, application of high dose of copper induced expression of fibrinogen, while knockdown of ceruloplasmin also resulted in upregulation of fibrinogen as well as elimination of superoxide dismutase (SOD), leading to increased oxidative stress in cells. In summary, the liver injury or oxidative stress induced by the progression of WD may account for the obvious increase of fibrinogen, which in turn triggers inflammatory responses and interferes coagulation cascades; this finding sheds light on the early detection and diagnosis of WD.


Combined prolonged-release oxycodone and naloxone improves bowel function in patients receiving opioids for moderate-to-severe non-malignant chronic pain: a randomised controlled trial.
This randomised, double-blind, double-dummy, parallel-group multicentre study assessed the impact of a total daily dose of 60-80 mg oral oxycodone prolonged-release (PR)/naloxone PR (OXN PR) as fixed-ratio combination for patients with opioid-induced constipation (OIC) having moderate-to-severe, non-malignant pain. During pre-randomisation patients receiving opioids for moderate-to-severe non-malignant pain were converted to oxycodone PR (OXY PR) and titrated to an effective analgesic dose. During randomisation 265 patients on a stable OXY PR dose (60-80 mg/day) and with OIC were included in the full analysis population to receive OXN PR or OXY PR alone. Primary outcome was improvement in symptoms of constipation as measured by the Bowel Function Index (BFI). Secondary/exploratory outcomes examined analgesic efficacy and other bowel function parameters. After 4 weeks of treatment, patients receiving OXN PR showed a significant improvement in bowel function compared with those in the OXY PR group (-14.9; 95% CI: -17.9, -11.9; p<0.0001) as measured by BFI which was seen after only 1 week of treatment continuing to the end of the study. After 4 weeks of treatment, patients receiving OXN PR had a median number of 3.0 complete spontaneous bowel movements (CSBM) per week compared with only 1.0 for OXY PR alone. Laxative intake was lower in the OXN PR than the OXY PR group. Furthermore, improvements in bowel function were achieved without loss of analgesic efficacy; pain intensity scores were comparable between the groups and consistent for duration of the study. Most frequently reported adverse events were consistent with those reported for opioid analgesics; no new or unexpected adverse reactions attributable to OXN PR used in higher doses were observed. This study shows that the fixed-ratio combination of OXN PR is superior to OXY PR alone in terms of bowel function, while providing effective equivalent analgesia.


A systematic review of the influence of skin pigmentation on changes in the concentrations of vitamin D and 25-hydroxyvitamin D in plasma/serum following experimental UV irradiation.
Defining whether skin pigmentation influences vitamin D photosynthesis is important for delivering accurate public health messages. Current evidence is contradictory. We undertook a systematic review of the published literature to examine the association between skin pigmentation and change in blood concentrations of vitamin D and 25-hydroxyvitamin D following experimental UV irradiation. Twelve studies fulfilled the inclusion criteria: human study in vivo with non-diseased participants; controlled artificial UV radiation; vitamin D or 25-hydroxyvitamin D measured in serum or plasma; full text in English. In seven studies, vitamin D photosynthesis was reduced in dark-skinned compared with fairer-skinned individuals. In the remaining five studies, only one of which was published after 1990, there was no difference in vitamin D photosynthesis according to skin type. The disparities in these results may be due to small sample sizes and variations in study methodology, including the source, dose and frequency of UV irradiation, phototype classification, and analysis of vitamin D and 25-hydroxyvitamin D. Of these, the spectrum emitted by the UV lamps may be significant. No study considered potential modifying factors, such as relevant genetic polymorphisms. On balance, we conclude that pigmented skin has less effective photoproduction of vitamin D and 25-hydroxyvitamin D. The quantity of sun exposure needed for dark-skinned, compared with light-skinned, people to achieve vitamin D sufficiency remains uncertain.


Genetic insights into biological mechanisms governing human ovarian ageing.
Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.


Tracing the associations between sex, the atypical and the combined atypical-melancholic depression subtypes: A path analysis.
Numerous studies have examined determinants leading to preponderance of women in major depressive disorder (MDD), which is particularly accentuated for the atypical depression subtype. It is thus of interest to explore the specific indirect effects influencing the association between sex and established depression subtypes. The data of 1624 subjects with a lifetime diagnosis of MDD derived from the population-based PsyCoLaus data were used. An atypical (n=256), a melancholic (n=422), a combined atypical and melancholic features subtype (n=198), and an unspecified MDD group (n=748) were constructed according to the DSM-IV specifiers. Path models with direct and indirect effects were applied to the data. Partial mediation of the female-related atypical and combined atypical-melancholic depression subtypes was found. Early anxiety disorders and high emotion-orientated coping acted as mediating variables between sex and the atypical depression subtype. In contrast, high Body Mass Index (BMI) served as a suppression variable, also concerning the association between sex and the combined atypical-melancholic subtype. The latter association was additionally mediated by an early age of MDD onset and early/late anxiety disorders. The use of cross-sectional data does not allow causal conclusions. This is the first study that provides evidence for a differentiation of the general mechanisms explaining sex differences of overall MDD by depression subtypes. Determinants affecting the pathways begin early in life. Since some of them are primarily of behavioral nature, the present findings could be a valuable target in mental health care.


Ir6In32S21, a polar, metal-rich semiconducting subchalcogenide.
Subchalcogenides are uncommon, and their chemical bonding results from an interplay between metal-metal and metal-chalcogenide interactions. Herein, we present Ir6In32S21, a novel semiconducting subchalcogenide compound that crystallizes in a new structure type in the polar P31m space group, with unit cell parameters a = 13.9378(12) Å, c = 8.2316(8) Å, α = β = 90°, γ = 120°. The compound has a large band gap of 1.48(2) eV, and photoemission and Kelvin probe measurements corroborate this semiconducting behavior with a valence band maximum (VBM) of -4.95(5) eV, conduction band minimum of -3.47(5) eV, and a photoresponse shift of the Fermi level by ∼0.2 eV in the presence of white light. X-ray absorption spectroscopy shows absorption edges for In and Ir do not indicate clear oxidation states, suggesting that the numerous coordination environments of Ir6In32S21 make such assignments ambiguous. Electronic structure calculations confirm the semiconducting character with a nearly direct band gap, and electron localization function (ELF) analysis suggests that the origin of the gap is the result of electron transfer from the In atoms to the S 3p and Ir 5d orbitals. DFT calculations indicate that the average hole effective masses near the VBM (1.19m e) are substantially smaller than the average electron masses near the CBM (2.51m e), an unusual feature for most semiconductors. The crystal and electronic structure of Ir6In32S21, along with spectroscopic data, suggest that it is neither a true intermetallic nor a classical semiconductor, but somewhere in between those two extremes.


Dectin-1 Binding to Annexins on Apoptotic Cells Induces Peripheral Immune Tolerance via NADPH Oxidase-2.
Uptake of apoptotic cells (ACs) by dendritic cells (DCs) and induction of a tolerogenic DC phenotype is an important mechanism for establishing peripheral tolerance to self-antigens. The receptors involved and underlying signaling pathways are not fully understood. Here, we identify Dectin-1 as a crucial tolerogenic receptor binding with nanomolar affinity to the core domain of several annexins (annexin A1, A5, and A13) exposed on ACs. Annexins bind to Dectin-1 on a site distinct from the interaction site of pathogen-derived β-glucans. Subsequent tolerogenic signaling induces selective phosphorylation of spleen tyrosine kinase (SYK), causing activation of NADPH oxidase-2 and moderate production of reactive oxygen species. Thus, mice deficient for Dectin-1 develop autoimmune pathologies (autoantibodies and splenomegaly) and generate stronger immune responses (cytotoxic T cells) against ACs. Our data describe an important immunological checkpoint system and provide a link between immunosuppressive signals of ACs and maintenance of peripheral immune tolerance.


Mutations in CIZ1 cause adult onset primary cervical dystonia.
Primary dystonia is usually of adult onset, can be familial, and frequently involves the cervical musculature. Our goal was to identify the causal mutation in a family with adult onset, primary cervical dystonia. Linkage and haplotype analyses were combined with solution-based whole-exome capture and massively parallel sequencing in a large Caucasian pedigree with adult onset, primary cervical dystonia to identify a cosegregating mutation. High-throughput screening and Sanger sequencing were completed in 308 Caucasians with familial or sporadic adult onset cervical dystonia and matching controls for sequence variants in this mutant gene. Exome sequencing led to the identification of an exonic splicing enhancer mutation in exon 7 of CIZ1 (c.790A>G, p.S264G), which encodes CIZ1, Cip1-interacting zinc finger protein 1. CIZ1 is a p21(Cip1/Waf1) -interacting zinc finger protein expressed in brain and involved in DNA synthesis and cell-cycle control. Using a minigene assay, we showed that c.790A>G altered CIZ1 splicing patterns. The p.S264G mutation also altered the nuclear localization of CIZ1. Screening in subjects with adult-onset cervical dystonia identified 2 additional CIZ1 missense mutations (p.P47S and p.R672M). Mutations in CIZ1 may cause adult onset, primary cervical dystonia, possibly by precipitating neurodevelopmental abnormalities that manifest in adults and/or G1/S cell-cycle dysregulation in the mature central nervous system.


New insights into the coagulopathy of liver disease and liver transplantation.
The liver is an essential player in the pathway of coagulation in both primary and secondary haemostasis. Only von Willebrand factor is not synthetised by the liver, thus liver failure is associated with impairment of coagulation. However, recently it has been shown that the delicate balance between pro and antithrombotic factors synthetised by the liver might be reset to a lower level in patients with chronic liver disease. Therefore, these patients might not be really anticoagulated in stable condition and bleeding may be caused only when additional factors, such as infections, supervene. Portal hypertension plays an important role in coagulopathy in liver disease, reducing the number of circulating platelets, but platelet function and secretion of thrombopoietin have been also shown to be impaired in patients with liver disease. Vitamin K deficiency may coexist, so that abnormal clotting factors are produced due to lack of gamma carboxylation. Moreover during liver failure, there is a reduced capacity to clear activated haemostatic proteins and protein inhibitor complexes from the circulation. Usually therapy for coagulation disorders in liver disease is needed only during bleeding or before invasive procedures. When end stage liver disease occurs, liver transplantation is the only treatment available, which can restore normal haemostasis, and correct genetic clotting defects, such as haemophilia or factor V Leiden mutation. During liver transplantation haemorrage may occur due to the pre-existing hypocoagulable state, the collateral circulation caused by portal hypertension and increased fibrinolysis which occurs during this surgery.


Age-associated cardiovascular changes in health: impact on cardiovascular disease in older persons.
In the United States, cardiovascular disease, e.g., atherosclerosis and hypertension, that lead to heart failure and stroke, is the leading cause of mortality, accounting for over 40 percent of deaths in those aged 65 years and above. Over 80 percent of all cardio-vascular deaths occur in the same age group. Thus, age, per se, is the major risk factor for cardiovascular disease. Clinical manifestations and prognosis of these cardiovascular diseases likely become altered in older persons with advanced age because interactions occur between age-associated cardiovascular changes in health and specific pathophysiologic mechanisms that underlie a disease. A fundamental understanding of age-associated changes in cardiovascular structure and function ranging in scope from humans to molecules is required for effective and efficient prevention and treatment of cardiovascular disease in older persons. A sustained effort over the past two decades has been applied to characterize the multiple effects of aging in health on cardiovascular structure and function in a single study population, the Baltimore Longitudinal Study on Aging. In these studies, community dwelling, volunteer participants are rigorously screened to detect both clinical and occult cardiovascular disease and characterized with respect to lifestyle, e.g. exercise habits, in an attempt to deconvolute interactions among lifestyle, cardiovascular disease and the aging process in health. This review highlights some specific changes in resting cardiovascular structure and function and cardiovascular reserve capacity that occur with advancing age in healthy humans. Observations from relevant experiments in animal models have been integrated with those in humans to provide possible mechanistic insight.


All Trans Retinoic Acid, Transforming Growth Factor β and Prostaglandin E2 in Mouse Plasma Synergize with Basophil-Secreted Interleukin-4 to M2 Polarize Murine Macrophages.
In previous studies we found that macrophages (MФs) from SH2-containing inositol-5'-phosphatase (SHIP) deficient mice are M2 polarized while their wild type (WT) counterparts are M1 polarized and that this difference in MФ phenotype can be recapitulated during in vitro derivation from bone marrow if mouse plasma (MP), but not fetal calf serum, is added to standard M-CSF-containing cultures. In the current study we investigated the mechanism by which MP skews SHIP-/- but not +/+ MФs to an M2 phenotype. Our results suggest that SHIP-/- basophils constitutively secrete higher levels of IL-4 than SHIP+/+ basophils and this higher level of IL-4 is sufficient to skew both SHIP+/+ and SHIP-/- MФs to an M2 phenotype, but only when MP is present to increase the sensitivity of the MФs to this level of IL-4. MP increases the IL-4 sensitivity of both SHIP+/+ and -/- MФs not by increasing cell surface IL-4 or CD36 receptor levels, but by triggering the activation of Erk and Akt and the production of ROS, all of which play a critical role in sensitizing MФs to IL-4-induced M2 skewing. Studies to identify the factor(s) in MP responsible for promoting IL-4-induced M2 skewing suggests that all-trans retinoic acid (ATRA), TGFβ and prostaglandin E2 (PGE2) all play a role. Taken together, these results indicate that basophil-secreted IL-4 plays an essential role in M2 skewing and that ATRA, TGFβ and PGE2 within MP collaborate to dramatically promote M2 skewing by acting directly on MФs to increase their sensitivity to IL-4.


[Extracorporeal shockwave lithotripsy in cholecystolithiasis using a new type of minilithotripter].
Extracorporeal shock wave lithotripsy (ESWL) of gallstones has until now required fixed, nearly room-sized and expensive equipment. It has become even less cost-effective with an increase in the number of laparoscopic cholecystectomies. The authors have technically modified a mini-lithotripter, used for dissolving salivary stones, for application against gallstones (by changing the energy spectrum and depth of focus). 125 consecutive patients with solitary gallstone underwent lithotripsy according to a standard protocol (including oral litholysis), 64 of them (average age 42.5 +/- 9.3 years; 44 women, 20 men) by conventional ESWL (with the Modulith), 62 (average age 41.6 +/- 10.1 years; 43 women, 13 men) with a modified mini-lithotripter (Minilith). Clinical and sonographic follow-up took place at 1, 3, 6 and 12 months. Quality of life was documented according to a point score (GIQL), developed specially for patients with gastrointestinal conditions. The mini-lithotripter applied significantly lower voltage and more shock-wave impulses per treatment than the conventional ESWL (p < 0.01), while patient tolerance, measured with a visual analogue scale, was the same. Application of the mini-lithotripter was easier and quicker than with conventional ESWL, namely 31 +/- 8 min vs 41 +/- 12 min (p < 0.01). Frequency of adequate stone fragmentation per patient was the same for both methods, 2.2 +/- 0.5 applications with the mini-lithotripter vs 1.6 +/- 0.3 with conventional ESWL (p < 0.01). There was no significant difference between the methods with regard to improved quality of life (increase of GIQL scale of 16% with the conventional ESWL, 14% with the mini-lithotripter) or freedom from stone at 1 year after lithotripsy (conventional ESWL: 80%, mini-lithotripter: 82%). Colics recurred in 15 of 64 patients receiving conventional ESWL, and in 13 of 61 in the mini-lithotripter group (difference not significant). There were no other complications. The cheaper mini-lithotripter, costing only a third of the conventional ESWL, is equally effective in the dissolution of gallstones.


Increased CD4+Foxp3+ T cells in BAFF-transgenic mice suppress T cell effector responses.
The cytokine B cell activation factor of the TNF family (BAFF) is considered to perform a proinflammatory function. This paradigm is particularly true for B cell-dependent immune responses; however the exact role for BAFF in regulating T cell immunity is ill-defined. To directly assess the effect of BAFF upon T cells, we analyzed T cell-dependent immune responses in BAFF-transgenic (Tg) mice. We found that T cell responses in BAFF-Tg mice are profoundly compromised, as indicated by their acceptance of islet allografts and delayed skin graft rejection. However, purified BAFF-Tg effector T cells could reject islet allografts with a normal kinetic, suggesting that the altered response did not relate to a defect in T cell function per se. Rather, we found that BAFF-Tg mice harbored an increased number of peripheral CD4+Foxp3+ T cells. A large proportion of the BAFF-expanded CD4+CD25+Foxp3+ regulatory T cells (Tregs) were CD62LlowCD103high and ICAM-1high, a phenotype consistent with an ability to home to inflammatory sites and prevent T cell effector responses. Indeed, depletion of the endogenous BAFF-Tg Tregs allowed allograft rejection to proceed, demonstrating that the increased Tregs were responsible for preventing alloimmunity. The ability of BAFF to promote Treg expansion was not T cell intrinsic, as Tregs did not express high levels of BAFF receptor 3, nor did excessive BAFF trigger NF-kappaB2 processing in Tregs. In contrast, we found that BAFF engendered Treg expansion through an indirect, B cell-dependent mechanism. Thus, under certain conditions, BAFF can play a surprising anti-inflammatory role in T cell biology by promoting the expansion of Treg cells.


PROTON GRADIENT REGULATION5 is essential for proper acclimation of Arabidopsis photosystem I to naturally and artificially fluctuating light conditions.
In nature, plants are challenged by constantly changing light conditions. To reveal the molecular mechanisms behind acclimation to sometimes drastic and frequent changes in light intensity, we grew Arabidopsis thaliana under fluctuating light conditions, in which the low light periods were repeatedly interrupted with high light peaks. Such conditions had only marginal effect on photosystem II but induced damage to photosystem I (PSI), the damage being most severe during the early developmental stages. We showed that PROTON GRADIENT REGULATION5 (PGR5)-dependent regulation of electron transfer and proton motive force is crucial for protection of PSI against photodamage, which occurred particularly during the high light phases of fluctuating light cycles. Contrary to PGR5, the NAD(P)H dehydrogenase complex, which mediates cyclic electron flow around PSI, did not contribute to acclimation of the photosynthetic apparatus, particularly PSI, to rapidly changing light intensities. Likewise, the Arabidopsis pgr5 mutant exhibited a significantly higher mortality rate compared with the wild type under outdoor field conditions. This shows not only that regulation of PSI under natural growth conditions is crucial but also the importance of PGR5 in PSI protection.


Androgen receptor-dependent and independent atheroprotection by testosterone in male mice.
The atheroprotective effect of testosterone is thought to require aromatization of testosterone to estradiol, but no study has adequately addressed the role of the androgen receptor (AR), the major pathway for the physiological effects of testosterone. We used AR knockout (ARKO) mice on apolipoprotein E-deficient background to study the role of the AR in testosterone atheroprotection in male mice. Because ARKO mice are testosterone deficient, we sham operated or orchiectomized (Orx) the mice before puberty, and Orx mice were supplemented with placebo or a physiological testosterone dose. From 8 to 16 wk of age, the mice consumed a high-fat diet. In the aortic root, ARKO mice showed increased atherosclerotic lesion area (+80%, P < 0.05). Compared with placebo, testosterone reduced lesion area both in Orx wild-type (WT) mice (by 50%, P < 0.001) and ARKO mice (by 24%, P < 0.05). However, lesion area was larger in testosterone-supplemented ARKO compared with testosterone-supplemented WT mice (+57%, P < 0.05). In WT mice, testosterone reduced the presence of a necrotic core in the plaque (80% among placebo-treated vs. 12% among testosterone-treated mice; P < 0.05), whereas there was no significant effect in ARKO mice (P = 0.20). In conclusion, ARKO mice on apolipoprotein E-deficient background display accelerated atherosclerosis. Testosterone treatment reduced atherosclerosis in both WT and ARKO mice. However, the effect on lesion area and complexity was more pronounced in WT than in ARKO mice, and lesion area was larger in ARKO mice even after testosterone supplementation. These results are consistent with an AR-dependent as well as an AR-independent component of testosterone atheroprotection in male mice.


Genetic services and attitudes in primary care pediatrics.
Given the integral role primary care pediatricians (PCPs) play in caring for children with genetic conditions, we aimed to identify current practices of PCPs regarding genetic patients, their attitudes toward genetic medical care and their choices regarding family history taking. We conducted an on-line survey of a national convenience sample of PCPs associated with the American Academy of Pediatrics' Quality Improvement Innovation Networks. Eighty-eight respondents (29% response rate) were included in the analysis. Seventy-four (86%) reported ordering genetic based tests three or less times annually. Eleven (13%) strongly agreed that they discuss with patients the potential risks, benefits, and limitations of genetic tests. Forty-three (49%) agreed or strongly agreed that they feel competent in providing healthcare to patients related to genetics and genomics. Perceived competence was not associated with more recent training (P = 0.29), number of genetic tests ordered annually (P = 0.84) or mean number of weekly patient encounters (P = 0.15). 100% of participants stated that taking a family history is important. 27 (31%) agreed or strongly agreed that they gather a minimum of a three-generation family history. Forty-one of the 63 participants with an electronic health record (65%) reported their system was fair or poor in its ability to easily capture a three-generation family history. PCPs interested in quality improvement reported variation in care practices for children with genetic diseases and a majority did not feel competent to provide genetic related healthcare. Research should focus on improving the care and diagnosis of children with genetic disorders and enhanced integration of genetic medicine into routine primary preventative care.


Heterogeneous expression of gamma-aminobutyric acid and gamma-aminobutyric acid-associated receptors and transporters in the rat suprachiasmatic nucleus.
The hypothalamic suprachiasmatic nucleus (SCN) is the primary mammalian circadian clock that regulates rhythmic physiology and behavior. The SCN is composed of a diverse set of neurons arranged in a tight intrinsic network. In the rat, vasoactive intestinal peptide (VIP)- and gastrin-releasing peptide (GRP)-containing neurons are the dominant cell phenotypes of the ventral SCN, and these cells receive photic information from the retina and the intergeniculate leaflet. Neurons expressing vasopressin (VP) are concentrated in the dorsal and medial aspects of the SCN. Although the VIP/GRP and VP cell groups are concentrated in different regions of the SCN, the separation of these cell groups is not absolute. The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is expressed in most SCN neurons irrespective of their location or peptidergic phenotype. In the present study, immunoperoxidase labeling, immunofluorescence confocal microscopy, and ultrastructural immunocytochemistry were used to examine the spatial distribution of several markers associated with SCN GABAergic neurons. Glutamate decarboxylase, a marker of GABA synthesis, and vesicular GABA transporter were more prominently observed in the ventral SCN. KCC2, a K(+)/Cl(-) cotransporter, was highly expressed in the ventral SCN in association with VIP- and GRP-producing neurons, whereas VP neurons in the dorsal SCN were devoid of KCC2. On the other hand, GABA(B) receptors were observed predominantly in VPergic neurons dorsally, whereas, in the ventral SCN, GABA(B) receptors were associated almost exclusively with retinal afferent fibers and terminals. The differential expression of GABAergic markers within the SCN suggests that GABA may play dissimilar roles in different SCN neuronal phenotypes.


Three-color flow cytometric study on lymphocytes derived from thymic diseases.
Anterior mediastinal masses derive from a variety of diseases. Thymomas have been shown to commonly hold CD4(+)CD8(+) double-positive (DP) lymphocytes, and identification of this subset by two-color flow cytometric study was suggested to help diagnosis of thymoma. Several other thymic diseases, however, possibly hold CD4(+)CD8(+) DP lymphocytes. In this study, we utilized the three-color flow cytometric method for further examination of the phenotypes of lymphocytes in the thymic diseases. One hundred eight specimens (77 primary and 10 metastatic thymomas, 10 thymic carcinomas, 2 thymic carcinoids, 4 malignant lymphomas, 2 seminomas, an inflammatory pseudotumor, and 2 nonneoplastic thymic hyperplasias) were subjected to the study. The expressions of CD3, CD4, and CD8 on tumor-associated lymphocytes were evaluated by three-color flow cytometric study. The proportion of the CD4(+)CD8(+) DP subset was more than 30% in all 78 lymphocyte-rich thymomas, in 2 malignant lymphomas, and in both thymic hyperplasias. CD3 expression of the CD4(+)CD8(+) DP subset ranged from a negative to a high level in thymomas and thymic hyperplasias, while it was restricted to a particular level in CD4(+)CD8(+) DP-type malignant lymphomas. The proportion of CD3(+) cells in the CD4(+)CD8(-) single-positive subset was consistently less than 90% in the lymphocyte-rich thymomas, while it was more than 90% in the thymic hyperplasias. Although identification of the CD4(+)CD8(+) DP subset in the tumor-associated lymphocytes does not necessarily indicate thymoma, a further characterization of thymic neoplasms possessing the CD4(+)CD8(+) DP subset was enabled by three-color flow cytometric study, suggesting the utility of this method as an ancillary tool for differential diagnosis of these diseases.


Age- and gender-specific mortality risk profiles for depressive outpatients with major chronic medical diseases.
As leading causes of death, chronic medical diseases, particularly common cardiovascular diseases, are associated with depression. The combination of depression and chronic medical disease in turn is linked with poorer health and premature death. Despite numerous studies on mortality in people with depression and chronic medical disease, the effects of age and gender were not consistently considered. To appropriately estimate mortality in the clinical setting, we aimed to analyse age- and gender-specific mortality profiles in outpatients with depression and chronic medical disease by considering depression severity. We examined data from N=327,018 outpatients with depression aged 18 years and older (mean=60 years), which we obtained from German electronic health-insurance claims data covering the years 2007-2010. We considered major chronic medical disease groups: cardiovascular diseases, diabetes, diseases of the respiratory system and cancer. To analyse both adjusted mortality risk and rates over one year in a comprehensive manner, we calculated General Estimation Equation (GEE) Poisson models for binary data. The mortality risk increased with age and was higher for males. Especially patients below 60 years of age with cancer or diabetes had an increased mortality risk, but not patients with cardiovascular disease. Mortality was comparably increased in patients with severe depression, diabetes or respiratory disease. We did not have data from a control group without depression. Notably, not cardiovascular diseases but cancer and, to a lesser extent, diabetes, both in younger patients, respiratory diseases and severity of depression require particular attention in outpatient care to reduce mortality.


Tomato flower abnormalities induced by stolbur phytoplasma infection are associated with changes of expression of floral development genes.
Tomato (Lycopersicon esculentum cv. Micro-Tom) plants infected by the stolbur phytoplasma (isolate PO) display floral abnormalities, including sepal hypertrophy, virescence, phyllody, and aborted reproductive organs, which are reminiscent of those observed in Arabidopsis thaliana mutants affected in flower development genes. Semiquantitative reverse transcription-polymerase chain reaction and in situ RNA hybridization were used to compare expressions of meristem and flower development genes in healthy and stolbur phytoplasma-infected tomatoes. In infected plants, FALSIFLORA (FA), controlling the identity of the inflorescence meristem, was up-regulated, whereas LeWUSCHEL (LeWUS) and LeCLAVATA1 (LeCLV1), regulating the meristem development, and LeDEFICIENS (LeDEF), responsible for the organ (petals and stamens) identity within the flower, were down-regulated regardless of the development stage of the flower bud. In contrast, expression of TAG1, which regulates stamen and carpel identities and negatively controls LeWUS, was up-regulated at the early stages and down-regulated at the late stages. In situ RNA hybridization analyses revealed that TAG1 transcripts were restricted to the same floral meristem territories in healthy and infected tomatoes, indicating that tissue-specific expression of TAG1 was not affected by the stolbur phytoplasma infection. Taken together, these data indicate that flower malformations of stolbur phytoplasma-infected tomatoes are associated with early changes in the expression of key flower development genes. The possible mechanisms by which the multiplication of stolbur phytoplasma in tomato sieve tubes deregulates floral development are discussed.


Revisiting the insanity defense: contested or consensus?
The author assesses the accuracy of both the public's opinion and researchers' conclusions regarding the method of adjudication of insanity cases and investigates the impact of the various types of reforms enacted in the 1980s on the degree to which insanity cases are contested. Data from seven states are analyzed. The public's view that insanity cases are typically resolved by a jury trial is inaccurate. Only 14.4 percent of the 7,299 insanity cases involved a jury trial. Likewise, scholars' views that most cases are resolved through plea-bargained insanity acquittals are inaccurate. Only 42.9 percent of all insanity cases are plea bargains, and 87.9 percent of all plea bargains are to a conviction. Jury trials are most likely to occur when the case involves a violent crime such as murder and the defendant has not been diagnosed with a major mental illness. Public fears that defendants easily "fool" juries into an inappropriate insanity acquittal are also unfounded. Only 16.1 percent of all jury trials result in an insanity acquittal. In three states, the figure is 10 percent or less. Contrary to the conclusions drawn by some scholars, this author finds that several types of reforms enacted in the 1980s affected the processing of insanity cases.


An exploratory multilevel analysis of income, income inequality and self-rated health of the elderly in China.
In the last three decades, China has experienced rapid economic development and growing economic inequality, such that economic disparities between rural and urban areas, as well as coastal and interior areas have deepened. Since the late 1990s China has also experienced an ageing population which has attracted attention to the wellbeing of the rapidly growing number of elderly. This research aims to characterise province differences in health and to explore the effects of individual income and economic disparity in the form of income inequality on health outcomes of the elderly. The study is based on the Chinese Longitudinal Healthy Longevity Survey data collected in 2008 for 23 provinces. Multilevel logistic models are employed to investigate the relationship between income, income inequality and self-rated health for the elderly using both individual and province-level variables. Results are presented as relative odds ratios, and for province differentials as Median Odds Ratios. The analysis is deliberately exploratory so as to find evidence of income effects if they exist and particular attention is placed on how province-level inequality (contemporaneous and lagged) may moderate individual relationships. The results show that the health of the elderly is not only affected by individual income (the odds of poor health are 3 times greater for the elderly with the lowest income compared to those at the upper quartile) but also by a small main effect for province-level income inequality (odds ratio of 1.019). There are significant cross-level interactions such that where inequality is high there are greater differences between those with and without formal education, and between men and women with the latter experiencing poorer health.


Mapping Post-Glacial expansions: The Peopling of Southwest Asia.
Archaeological, palaeontological and geological evidence shows that post-glacial warming released human populations from their various climate-bound refugia. Yet specific connections between these refugia and the timing and routes of post-glacial migrations that ultimately established modern patterns of genetic variation remain elusive. Here, we use Y-chromosome markers combined with autosomal data to reconstruct population expansions from regional refugia in Southwest Asia. Populations from three regions in particular possess distinctive autosomal genetic signatures indicative of likely refugia: one, in the north, centered around the eastern coast of the Black Sea, the second, with a more Levantine focus, and the third in the southern Arabian Peninsula. Modern populations from these three regions carry the widest diversity and may indeed represent the most likely descendants of the populations responsible for the Neolithic cultures of Southwest Asia. We reveal the distinct and datable expansion routes of populations from these three refugia throughout Southwest Asia and into Europe and North Africa and discuss the possible correlations of these migrations to various cultural and climatic events evident in the archaeological record of the past 15,000 years.


Etiology of anemia in pregnancy in south Malawi.
Anemia in pregnancy is a major public health problem in developing countries. In sub-Saharan Africa, such anemia is generally accepted as resulting from nutritional deficiencies, particularly iron deficiency. We comprehensively assessed the full spectrum of nutritional and nonnutritional factors associated with pregnancy anemia. Iron, folate, vitamin B-12, and vitamin A were measured in serum in a cross-sectional study of 150 pregnant women in Blantyre, Malawi. Bone marrow aspirates were evaluated, peripheral blood films were examined for malaria parasites, stool and urine samples were examined for helminthic infection, and tests were done for genetic disorders and for HIV infection. C-reactive protein (CRP) concentrations and erythrocyte sedimentation rates were measured as markers of inflammation. Of the 150 anemic women, 23% were iron deficient with no evidence of folate, vitamin B-12, or vitamin A deficiencies; 32% were deficient in iron and one or more of the other micronutrients; 26% were not iron deficient but had evidence of one of the other micronutrient deficiencies, most often vitamin A; and 19% were not deficient in any of the micronutrients studied. CRP concentrations were notably high in 54% of the anemic women with no nutritional deficiencies and in 73.5% of the anemic women who were iron replete by bone marrow assessment. The role of chronic inflammation as a possible contributing factor to anemia in pregnancy has important implications for the clinical evaluation and treatment of women.


Optical properties of the South pole ice at depths between 0.8 and 1 kilometer.
The optical properties of the ice at the geographical South Pole have been investigated at depths between 0.8 and 1 kilometer. The absorption and scattering lengths of visible light ( approximately 515 nanometers) have been measured in situ with the use of the laser calibration setup of the Antarctic Muon and Neutrino Detector Array (AMANDA) neutrino detector. The ice is intrinsically extremely transparent. The measured absorption length is 59 +/- 3 meters, comparable with the quality of the ultrapure water used in the Irvine-Michigan-Brookhaven and Kamiokande proton-decay and neutrino experiments and more than twice as long as the best value reported for laboratory ice. Because of a residual density of air bubbles at these depths, the trajectories of photons in the medium are randomized. If the bubbles are assumed to be smooth and spherical, the average distance between collisions at a depth of 1 kilometer is about 25 centimeters. The measured inverse scattering length on bubbles decreases linearly with increasing depth in the volume of ice investigated.


Dose dependent cytotoxicity of pranoprofen in cultured human corneal endothelial cells by inducing apoptosis.
Pranoprofen (PPF), a non-steroidal anti-inflammatory drugs (NSAIDs), is often used in keratitis treatment in clinic. Several studies have assessed in vitro the cytotoxicity of topical NSAIDs to corneal epithelial cells due to its importance for predicting human corneal toxicity. Damage by cytotoxic drugs can result in excessive loss of human corneal endothelial (HCE) cells which lead to decompensation of the endothelium and eventual loss of visual acuity. However, the endothelial cytotoxicity of PPF has not yet been reported using an in vitro model of HCE cells. This study assessed the cytotoxicity of PPF to HCE cells and its underlying mechanism. Cellular viability was determined using inverted phase contrast light microscopy, and plasma membrane permeability, genomic DNA fragmentation, and ultrastructure were detected by acridine orange/ethidium bromide staining, DNA agarose gel electrophoresis, and transmission electron microscopy (TEM), respectively. The results on cellular viability showed that PPF at concentrations ranging from 0.0625 to 1.0 g/l had poignant cytotoxicity to HCE cells, and the extent of its cytotoxicity was dose- and time-dependent. Further characterization indicated that PPF induced plasma membrane permeability elevation, DNA fragmentation, and apoptotic body formation, proving its apoptosis inducing effect on HCE cells. In conclusion, PPF above 0.0625 g/l has poignant cytotoxicity on HCE cells in vitro by inducing cell apoptosis, and should be carefully employed in eye clinic.