Tissue and tumor distribution of C-penclomedine in rats.
Penclomedine, a lipophilic alpha-picoline derivative, is undergoing clinical development presently because of its pronounced antitumor activity against intracerebral (i.c.) tumor xenografts. Penclomedine may be metabolized in vivo to a more potent compound. Although it may be useful in the treatment of brain tumors, the drug has caused significant neurotoxicity in early clinical trials. The possibility that antitumor activity and neurotoxicity may be mediated by different mechanisms prompted a study assessing the differential distribution of penclomedine and penclomedine metabolites to brain and i.c.-implanted tumors in rats. In the present study, quantitative autoradiographic analysis demonstrated a homogenous distribution of 14C-penclomedine in all organs within 1 h of administration. Levels of 14C-penclomedine in both i.c. and s.c. tumors were three times higher than in normal brain tissue. High-performance liquid chromatography combined with gas chromatography and mass spectrophotometry demonstrated that two metabolites, O-demethyl penclomedine and penclomic acid, were responsible for most of the plasma radioactivity. Penclomic acid was also the most common urinary metabolite of penclomedine. In liver samples, although a large number of metabolite peaks were detected, no parent compound could be identified. However, in tumors and all other tissues, penclomedine was the main compound detected. The finding of penclomedine in normal brain tissue indicates not only that this drug may be useful in tumors with normal blood-brain barrier function, but also that it may be directly neurotoxic.


Effect of persistent moderate viremia on disease progression during HIV therapy.
Although highly active antiretroviral therapy has been shown to lower plasma HIV-1 RNA in HIV infection, many patients do not reach the target goal of undetectable viremia. We evaluated whether risk of clinical progression varies by level of viral suppression achieved. Patients in the Collaborations in HIV Outcomes Research/United States cohort who maintained stable HIV-1 RNA levels of either <400, 400 to 20,000, or >20,000 copies/mL during a run-in period of at least 6 months were studied. Baseline was the first day after this period. Proportional hazards models were used to quantify the relation between baseline HIV-1 RNA levels and risk of a new AIDS-defining diagnosis or death after adjusting for CD4 count, age, gender, ethnicity, study site, prior AIDS-defining diagnosis, and antiretroviral therapy history. Patients (N = 3010) were followed for up to 4.3 years after the 6-month run-in period, with 343 deaths or AIDS-defining diagnoses reported. The risk of a new AIDS-defining diagnosis or death was not significantly different in the 400 to 20,000- and <400-copies/mL groups (6% vs. 7%, hazard ratio [HR] = 1.0, 95% confidence interval [CI]: 0.7-1.4; P = 0.9) but was significantly higher in the >20,000-copies/mL group (26%, HR = 3.3, 95% CI: 2.5-4.4; P < 0.001 vs. the <400-copies/mL group). Median CD4 count changes during the first year of follow-up showed increases of 75 and 13 cells/mm for the <400- and 400 to 20,000-copies/mL groups, respectively, whereas the >20,000-copies/mL group had a decrease of 23 cells/mm. Patients who maintained baseline HIV-1 RNA levels of 400 to 20,000 copies/mL for at least 6 months preserved immunologic status and were no more likely to die or develop a new AIDS-defining diagnosis in the time frame studied than those with baseline levels <400 copies/mL. Patients with HIV-1 RNA levels >20,000 copies/mL at baseline had greater clinical and immunologic deterioration. These data suggest that maintenance of moderate viremia may confer clinical benefit not seen when viremia exceeds 20,000 copies/mL, and this should be taken into account when considering the risks and benefits of continuing failing therapy.


Human dignity and the creation of human-nonhuman chimeras.
In this work I present a detailed critique of the dignity-related arguments that have been advanced against the creation of human-nonhuman chimeras that could possess human-like mental capacities. My main claim is that the arguments so far advanced are incapable of grounding a principled objection against the creation of such creatures. I conclude that these arguments have one, or more, of the following problems: (a) they confuse the ethical assessment of the creation of chimeras with the ethical assessment of how such creatures would be treated in specific contexts (e.g. in the laboratory), (b) they misrepresent how a being could be treated solely as means towards others' ends,


The challenges of decolonising participatory research in indigenous contexts: the Atautsikut community of practice experience in Nunavik.
Historically, research involving Indigenous peoples has been the scene of power imbalances between Indigenous communities and researchers. Indigenous peoples have often been put in the position of passive subjects of research rather than participants or collaborators with agency, a situation that the current movement of decolonisation of research and practices in the field of Indigenous health aims to counteract. Participatory research seeks a better balance of input, decision-making and power between research participants and research teams and values participants' knowledges. As such, it is a particularly relevant approach for researchers to involve community members and support self-determination of Indigenous people. Yet, if its explicit intentions are aiming at a decolonising approach, the socio-structural context of participatory research initiatives in Indigenous communities brings obstacles to the approach's success. The development and implementation of the participatory project Atautsikut: A Community of Practice in Youth Mental Health and Wellness in Nunavik, has been an occasion to document certain barriers that take place in participatory research. This article describes Atautsikut as a starting point for a reflection on the challenges of decolonising participatory research. It discusses how, despite intentions, structural barriers, blind spots and unexpected contextual elements may challenge the journey towards decolonising research.


The biology of kinetoplastid parasites: insights and challenges from genomics and post-genomics.
Kinetoplastid parasites exhibit a rich and diverse biology which mirrors many of the most interesting topics of current interest and study in the broader biological sciences. These evolutionarily ancient organisms possess intriguing mechanisms for control of gene expression, and exhibit complex patterns of cell morphogenesis orchestrated by an internal cytoskeleton. Their cell shapes change during a set of complex cell type differentiations in their life cycles. These differentiations are intimately linked to interactions with mammalian hosts or insect vectors, and often, these differentiations appear central to the successful transfer of the parasite between vector and host, and host and vector. The basics of this rich and complex cell and life cycle biology were described (with often rather forgotten clarity and prescience) in the early period of the last century. The last 30 years have seen major developments in our understanding of this biology. Ultrastructural differences in the various cells of the life cycle stages of Trypanosoma brucei, Trypanosoma cruzi and the various Leishmania species have been documented, and such studies have proven highly informative in defining important aspects of parasite adaptation. They have also proven to be a rich source of information for defining unusual aspects of parasite cell biology, novel organelles and cell architecture. This ultrastructural cell biology has been mirrored in a set of biochemical explanations defining unusual aspects of metabolism, surface molecules, and organelles. Finally, the application of molecular biology to these parasites revealed fascinating layers of complexity in the control of gene expression. These molecular studies have given us particular insights into polycistronic transcription, trans-splicing, RNA editing and gene rearrangements during antigenic variation. In contrast to other microbial systems, these cell biological, biochemical and molecular studies have not been greatly aided by insights gained from genetics--the diploid nature of the genome has discouraged the application of selectional genetics, mutant isolation and analysis. This is an important fact, since in general, it means that we have only recently started to analyse the phenotypes of mutants produced in the context of reverse genetics. In the following, I will argue that this lack of investment in the analysis of mutant phenotype is just one of the challenges that will need to be met if we are to gain the expected added value from the parasite genome projects. In this presentation, I will use some of the current areas of interest in the biology of T. brucei, T. cruzi and the Leishmania species to rehearse some of the insights and challenges that are likely to stem from the application of genomics and post-genomic studies to the kinetoplastid parasites. In some cases, I will exemplify points by illustrations from my laboratory's work, interests and hypotheses. The presentation slants therefore towards T. brucei biology, however, in each case the reader will, no doubt, see the generalities of application to other kinetoplastid parasites.


Antimicrobial sand via adsorption of cationic Moringa oleifera protein.
Moringa oleifera (Moringa) seeds contain a natural cationic protein (MOCP) that can be used as an antimicrobial flocculant for water clarification. Currently, the main barrier to using Moringa seeds for producing potable water is that the seeds release other water-soluble proteins and organic matter, which increase the concentration of dissolved organic matter (DOM) in the water. The presence of this DOM supports the regrowth of pathogens in treated water, preventing its storage and later use. A new strategy has been established for retaining the MOCP protein and its ability to clarify and disinfect water while removing the excess organic matter. The MOCP is first adsorbed and immobilized onto sand granules, followed by a rinsing step wherein the excess organic matter is removed, thereby preventing later growth of bacteria in the purified water. Our hypotheses are that the protein remains adsorbed onto the sand after the functionalization treatment, and that the ability of the antimicrobial functionalized sand (f-sand) to clarify turbidity and kill bacteria, as MOCP does in bulk solution, is maintained. The data support these hypotheses, indicating that the f-sand removes silica microspheres and pathogens from water, renders adhered Escherichia coli bacteria nonviable, and reduces turbidity of a kaolin suspension. The antimicrobial properties of f-sand were assessed using fluorescent (live-dead) staining of bacteria on the surface of the f-sand. The DOM that can contribute to bacterial regrowth was shown to be significantly reduced in solution, by measuring biochemical oxygen demand (BOD). Overall, these results open the possibility that immobilization of the MOCP protein onto sand can provide a simple, locally sustainable process for producing storable drinking water.


Life on the inside: the intracellular lifestyle of cytosolic bacteria.
Bacterial pathogens exploit a huge range of niches within their hosts. Many pathogens can invade non-phagocytic cells and survive within a membrane-bound compartment. However, only a small number of bacteria, including Listeria monocytogenes, Shigella flexneri, Burkholderia pseudomallei, Francisella tularensis and Rickettsia spp., can gain access to and proliferate within the host cell cytosol. Here, we discuss the mechanisms by which these cytosolic pathogens escape into the cytosol, obtain nutrients to replicate and subvert host immune responses.


Bacterial flavin-containing monooxygenase is trimethylamine monooxygenase.
Flavin-containing monooxygenases (FMOs) are one of the most important monooxygenase systems in Eukaryotes and have many important physiological functions. FMOs have also been found in bacteria; however, their physiological function is not known. Here, we report the identification and characterization of trimethylamine (TMA) monooxygenase, termed Tmm, from Methylocella silvestris, using a combination of proteomic, biochemical, and genetic approaches. This bacterial FMO contains the FMO sequence motif (FXGXXXHXXXF/Y) and typical flavin adenine dinucleotide and nicotinamide adenine dinucleotide phosphate-binding domains. The enzyme was highly expressed in TMA-grown M. silvestris and absent during growth on methanol. The gene, tmm, was expressed in Escherichia coli, and the purified recombinant protein had high Tmm activity. Mutagenesis of this gene abolished the ability of M. silvestris to grow on TMA as a sole carbon and energy source. Close homologs of tmm occur in many Alphaproteobacteria, in particular Rhodobacteraceae (marine Roseobacter clade, MRC) and the marine SAR11 clade (Pelagibacter ubique). We show that the ability of MRC to use TMA as a sole carbon and/or nitrogen source is directly linked to the presence of tmm in the genomes, and purified Tmm of MRC and SAR11 from recombinant E. coli showed Tmm activities. The tmm gene is highly abundant in the metagenomes of the Global Ocean Sampling expedition, and we estimate that 20% of the bacteria in the surface ocean contain tmm. Taken together, our results suggest that Tmm, a bacterial FMO, plays an important yet overlooked role in the global carbon and nitrogen cycles.


Interventions for treating trichomoniasis in women.
Around 120 million women worldwide suffer from Trichomonas vaginalis vaginitis every year. The infection is sexually transmitted and is believed to facilitate HIV transmission. To assess the effects of various treatment strategies for trichomoniasis in women. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE. Trials were also identified from reference lists of reviews, through pharmaceutical companies, and by informal discovery. Only published data were used in this review. Date of the most recent search: November, 2002. Randomised or quasi-randomised trials of different treatment strategies in women with trichomoniasis. Different antitrichomonal drugs or doses were eligible, as were comparisons of treatment with no treatment or placebo. Trial quality was assessed and data extracted by two reviewers independently using standard criteria. Fifty-four trials were included. Nitroimidazole drugs seem to be effective in achieving parasitological cure in short term follow up. Partner treatment can be effective in decreasing longer term reinfection rates. Parasitological cure can be achieved by single oral dose of nitroimidazole. Further research should focus on developing effective partner treatment strategies to prevent reinfections and reduce trichomoniasis prevalence.


Mapping age- and sex-specific HIV prevalence in adults in sub-Saharan Africa, 2000-2018.
Human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS) is still among the leading causes of disease burden and mortality in sub-Saharan Africa (SSA), and the world is not on track to meet targets set for ending the epidemic by the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the United Nations Sustainable Development Goals (SDGs). Precise HIV burden information is critical for effective geographic and epidemiological targeting of prevention and treatment interventions. Age- and sex-specific HIV prevalence estimates are widely available at the national level, and region-wide local estimates were recently published for adults overall. We add further dimensionality to previous analyses by estimating HIV prevalence at local scales, stratified into sex-specific 5-year age groups for adults ages 15-59 years across SSA. We analyzed data from 91 seroprevalence surveys and sentinel surveillance among antenatal care clinic (ANC) attendees using model-based geostatistical methods to produce estimates of HIV prevalence across 43 countries in SSA, from years 2000 to 2018, at a 5 × 5-km resolution and presented among second administrative level (typically districts or counties) units. We found substantial variation in HIV prevalence across localities, ages, and sexes that have been masked in earlier analyses. Within-country variation in prevalence in 2018 was a median 3.5 times greater across ages and sexes, compared to for all adults combined. We note large within-district prevalence differences between age groups: for men, 50% of districts displayed at least a 14-fold difference between age groups with the highest and lowest prevalence, and at least a 9-fold difference for women. Prevalence trends also varied over time; between 2000 and 2018, 70% of all districts saw a reduction in prevalence greater than five percentage points in at least one sex and age group. Meanwhile, over 30% of all districts saw at least a five percentage point prevalence increase in one or more sex and age group. As the HIV epidemic persists and evolves in SSA, geographic and demographic shifts in prevention and treatment efforts are necessary. These estimates offer epidemiologically informative detail to better guide more targeted interventions, vital for combating HIV in SSA.


Tear film, contact lens, and patient-related factors associated with contact lens-related dry eye.
To examine tear film, contact lens, medical, and patient-related factors associated with self-reported contact lens-related dry eye. Four hundred fifteen contact lens wearers were recruited and enrolled in this phase of a larger cross-sectional study. A variety of tear film (e.g., interferometry, osmolality, phenol red thread, meibography, fluorescein, and lissamine green staining), contact lens (i.e., water content, refractive index, material), and patient-related (e.g., gender, sociodemographic, education, income, and medical health) factors were examined in relation to dry eye status. Univariate and multivariate logistic regression models were used to examine the relation between these tear film, contact lens, and patient-related factors associated with dry eye status. Of the 415 enrolled, the data from 360 were used in the analyses. The average age was 31.1 +/- 11.5 years, 245 (68%) participants were female, and 55.3% were classified as having-contact lens-related dry eye via self-report. Overall, 327 (90.8%) were hydrogel lens wearers and 33 (9.2%) were gas-permeable lens wearers. Several factors were shown to be related to dry eye status in multivariate modeling, including female gender (P = 0.007), lenses with higher nominal water content (P = 0.002), rapid prelens tear film thinning time (P = 0.008), frequent usage of over-the-counter pain medication (P = 0.02), limbal injection (P = 0.03), and increased tear film osmolality (P = 0.05). Contact lens-related dry eye may be explained mechanistically by increased tear film thinning times (evaporation or dewetting) resulting in increased tear film osmolality. Other contributing factors include the use of high-water-content lenses, which have traditionally been reported to be associated with less patient comfort than lower-water-content lenses, potentially due to spoilation and deposition. As found in other studies of dry eye, women are more likely to report contact lens-related dry eye than are men.


Dynamic measurement of accommodation and pupil size using the portable Grand Seiko FR-5000 autorefractor.
The purpose of this study was to evaluate the potential of the portable Grand Seiko FR-5000 autorefractor to allow objective, continuous, open-field measurement of accommodation and pupil size for the investigation of the visual response to real-world environments and changes in the optical components of the eye. The FR-5000 projects a pair of infrared horizontal and vertical lines on either side of fixation, analyzing the separation of the bars in the reflected image. The measurement bars were turned on permanently and the video output of the FR-5000 fed into a PC for real-time analysis. The calibration between infrared bar separation and the refractive error was assessed over a range of 10.0 D with a model eye. Tolerance to longitudinal instrument head shift was investigated over a +/-15 mm range and to eye alignment away from the visual axis over eccentricities up to 25.0 degrees . The minimum pupil size for measurement was determined with a model eye. The separation of the measurement bars changed linearly (r2 = 0.99), allowing continuous online analysis of the refractive state at 60 Hz temporal and approximately 0.01 D system resolution with pupils >2 mm. The pupil edge could be analyzed on the diagonal axes at the same rate with a system resolution of approximately 0.05 mm. The measurement of accommodation and pupil size were affected by eccentricity of viewing and instrument focusing inaccuracies. The small size of the instrument together with its resolution and temporal properties and ability to measure through a 2 mm pupil make it useful for the measurement of dynamic accommodation and pupil responses in confined environments, although good eye alignment is important.


The use of antidepressants in alcohol-dependent veterans.
Although some research reports suggest antidepressants may be an effective treatment for alcohol dependence, their clinical use has been controversial. By using comprehensive national administrative data from the Department of Veterans Affairs (VA) documenting psychiatric diagnoses and care under natural conditions in both mental health and non-mental health settings, the use of antidepressants was compared in alcoholic and non-alcoholic veterans. Data were collected from April 1, 2000, to Sept. 30, 2000. Overall, patients with alcohol dependence were significantly more likely to be prescribed antidepressants than individuals without alcoholism (38.9% vs. 31.2%), but multivariate analysis showed that this was attributable to the higher rate of comorbid psychiatric diagnoses in this group. After controlling for diagnosis and other potentially confounding factors, alcohol-dependent individuals treated in specialty mental health clinics were in fact less likely to be prescribed antidepressants (odds ratio = 0.95, p <.0001). Of patients treated with antidepressants, those with alcohol dependence were more likely to be prescribed newer antidepressants (odds ratio = 1.22, p <.0001). Among patients treated in non-mental health clinics, there were no significant differences in rate of antidepressant use between alcohol-dependent and non-alcohol-dependent individuals with mental illness after controlling for other factors. The principal finding is that a diagnosis of alcoholism, independent of other factors, is associated with a decreased likelihood of receiving antidepressant treatment in VA mental health clinics, suggesting that prescribers have not embraced reports of their efficacy in alcohol dependence. In fact, this may reflect a disinclination to use medications to treat alcoholism in specialty mental health clinics but not in non-mental health clinics.


Facial soft-tissue fillers conference: assessing the state of the science.
: The American Society of Plastic Surgeons and the American Academy of Dermatology, with the support of other sister societies, conducted the Facial Soft-Tissue Fillers: Assessing the State of the Science conference in December of 2009. The American Society of Plastic Surgeons and the American Academy of Dermatology established a panel of leading experts in the field of soft-tissue fillers-from researchers to clinicians-and other stakeholders for the conference to examine and discuss issues of patient safety, efficacy, and effectiveness in relation to the approved and off-label use of soft-tissue fillers, and other factors, including the training and level of experience of individuals administering fillers. This report represents the systematic literature review that examines comprehensively the available evidence and gaps in the evidence related to soft-tissue fillers, to inform and support the work of the state-of-the-science conference panel. This evidence-based medicine review will serve as the foundation for future evidence-based medicine reports in this growing field.


Cancer-Related Information Seeking Among Cancer Survivors: Trends Over a Decade (2003-2013).
The demonstrated benefits of information seeking for cancer patients, coupled with increases in information availability, underscore the importance of monitoring patient information seeking experiences over time. We compared information seeking among cancer survivors to those with a family history of cancer and those with no history of cancer. We identified characteristics associated with greater information seeking among cancer survivors, key sources of cancer-related information, and changes in information source use over time. Data from five iterations of the Health Information National Trends Survey (HINTS) spanning 2003 to 2013 were merged and analyzed. Frequencies, cross-tabulations, multivariate logistic regression, and multinomial regression analyses were conducted. All data were weighted to provide representative estimates of the adult US population. Cancer information seeking was reported most frequently by cancer survivors (69.8 %). The percentage of cancer survivors who reported information seeking increased from 66.8 % in 2003 to 80.8 % in 2013. Cancer information seeking was independently associated with age, education, and income; seeking was less likely among older adults, those with less education, and those with lower incomes. Compared to respondents in 2003, those in 2005 (odds ratio (OR) = 0.40, 95 % confidence interval (CI) = 0.24-0.65) and 2008 (OR = .43, 95 % CI = 0.26-0.70) were about half as likely to use the Internet as the first source of cancer information compared to a healthcare provider. Despite overall increases in cancer information seeking and access to health information from a variety of sources, healthcare providers remain a key source of health information for cancer survivors.


Effectiveness of a no-sex or safe-sex month in reducing HIV transmission.
To build a deterministic compartmental model for exploring the effects on the transmission of human immunodeficiency virus (HIV) of a population abstaining from sex or practising only "safe" sex for one month each year. A model of HIV transmission was built to simulate the effects of the intervention (i.e. an annual no-sex or safe-sex month in which no transmission occurred) in three countries, under several optimistic assumptions. The reduction in the modelled annual incidence of transmission that was attributable to this "test" intervention was compared with that seen with an alternative intervention. In the latter, monthly incidences of transmission were each reduced by one twelfth, so that, essentially, the month-long interruption was spread evenly across a full year. Over the first modelled year, the test intervention averted only 2.5% (Kenya), 3.3% (South Africa) and 1.6% (Swaziland) more HIV infections than the alternative interruption. According to the model, if the test intervention were repeated each January, it would avert only 2% (Kenya), 2% (South Africa) and 1% (Swaziland) more HIV infections over 5 years than the alternative intervention. Although it did not appear markedly more effective than the alternative intervention, the test intervention may still be more feasible and therefore worthwhile. Before the test intervention can be recommended, the cost-effectiveness and feasibility of such an annual month-long break in HIV transmission need to be assessed and compared with those of other interventions that may reduce new HIV infections, such as circumcision and concurrency-reduction campaigns.


Electron microscopic study of supramolecular liquid crystalline polymers formed by molecular-recognition-directed self-assembly from complementary chiral components.
Electron microscopic observation provides insight into the nature of the polymeric supramolecular liquid crystalline species (TP2, TU2)n formed by polyassociation of the complementary components TP2 and TU2 derived from D-, L-, or meso-tartaric acid (where T is any form of tartaric acid, D is the D species, and L is the L species) and from pyridine (P) and uracil (U) derivatives. Increasing the concentration of equimolecular solutions of (LP2 + LU2) mixtures leads to the progressive assembly of very long supramolecular-polymolecular entities. The process involves successively nucleation to give small nuclei, growth to filaments, and lateral association to tree-like species, strings, and fibers. The species formed are helical; their helicity is right-handed, induced by the chirality of the components and transferred to the larger entities. The data agree with the formulation of the primary filament as a triple-helical species formed by three helically wound supramolecular strands. (DP2 + DU2) mixtures yield left-handed helical species. The helicity of the materials obtained from complementary components having different chirality is imposed by the U component, being, respectively, right- and left-handed for (DP2 + LU2) and (LP2 + DU2). No helicity is found for the meso compounds. The racemic mixture of all four L and D components yields long superhelices of opposite handedness that coexist in the same sample. This points to the occurrence of spontaneous racemate resolution by chiral selection of the components in the self-assembly of these supramolecular liquid crystalline species. The present results illustrate how extended supramolecular-polymolecular entities build up through molecular-recognition-directed polyassociation of complementary components. They also show that molecular chirality is translated into supramolecular helicity that is expressed at the level of the material on nanometric and micrometric scales.


Association of mechanical bowel preparation with oral antibiotics and anastomotic leak following left sided colorectal resection: an international, multi-centre, prospective audit.
The optimal bowel preparation strategy to minimise the risk of anastomotic leak is yet to be determined. This study aimed to determine whether oral antibiotics combined with mechanical bowel preparation (MBP+Abx) was associated with a reduced risk of anastomotic leak when compared to mechanical bowel preparation alone (MBP) or no bowel preparation (NBP). A pre-planned analysis of the European Society of Coloproctology (ESCP) 2017 Left Sided Colorectal Resection audit was performed. Patients undergoing elective left sided colonic or rectal resection with primary anastomosis between 1 January 2017 and 15 March 2017 by any operative approach were included. The primary outcome measure was anastomotic leak. Of 3676 patients across 343 centres in 47 countries, 618 (16.8%) received MBP+ABx, 1945 MBP (52.9%) and 1099 patients NBP (29.9%). Patients undergoing MBP+ABx had the lowest overall rate of anastomotic leak (6.1%, 9.2%, 8.7% respectively) in unadjusted analysis. After case-mix adjustment using a mixed-effects multivariable regression model, MBP+Abx was associated with a lower risk of anastomotic leak (OR 0.52, 0.30-0.92, P = 0.02) but MBP was not (OR 0.92, 0.63-1.36, P = 0.69) compared to NBP. This non-randomised study adds 'real-world', contemporaneous, and prospective evidence of the beneficial effects of combined mechanical bowel preparation and oral antibiotics in the prevention of anastomotic leak following left sided colorectal resection across diverse settings. We have also demonstrated limited uptake of this strategy in current international colorectal practice.


Higher body mass index (BMI) is associated with reduced glucocorticoid inhibition of inflammatory cytokine production following acute psychosocial stress in men.
Body mass index (BMI) and mental stress seem to exert part of their cardiovascular risk by eliciting inflammation. However, the adverse effects of stress on inflammatory activity with BMI are not fully understood. We investigated whether higher BMI is associated with reduced glucocorticoid inhibition of inflammatory cytokine production following stress in men while controlling for age and blood pressure. We measured glucocorticoid inhibition of lipopolysaccharide (LPS)-stimulated release of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha. Forty-two men (age range 21-65 years; BMI range 21-34 kg/m(2)) underwent the Trier Social Stress Test (combination of mock job interview and mental arithmetic task). Whole blood samples were taken immediately before and after stress, and during recovery up to 60 min post-stress. Glucocorticoid sensitivity of LPS-stimulated TNF-alpha expression was assessed in vitro with and without coincubating increasing doses of dexamethasone. Moreover, salivary cortisol was measured during the experiment and on a normal day for assessment of baseline circadian cortisol. Higher BMI was associated with lower glucocorticoid sensitivity of monocyte TNF-alpha production after stress (main effect of BMI: p<0.001) and with more pronounced decreases of glucocorticoid sensitivity following stress (interaction of stress-by-BMI: p=0.002). Neither LPS-stimulated TNF-alpha release nor baseline glucocorticoid sensitivity were associated with BMI. Similarly, BMI was not associated with salivary cortisol, either in reaction to stress or in circadian cortisol secretion. Our data suggest that with increasing BMI, glucocorticoids are less able to inhibit TNF-alpha production following stress. This might suggest a new mechanism linking BMI with elevated risk for adverse cardiovascular outcomes following stress.


Do technical skills correlate with non-technical skills in crisis resource management: a simulation study.
Both technical skills (TS) and non-technical skills (NTS) are key to ensuring patient safety in acute care practice and effective crisis management. These skills are often taught and assessed separately. We hypothesized that TS and NTS are not independent of each other, and we aimed to evaluate the relationship between TS and NTS during a simulated intraoperative crisis scenario. This study was a retrospective analysis of performances from a previously published work. After institutional ethics approval, 50 anaesthesiology residents managed a simulated crisis scenario of an intraoperative cardiac arrest secondary to a malignant arrhythmia. We used a modified Delphi approach to design a TS checklist, specific for the management of a malignant arrhythmia requiring defibrillation. All scenarios were recorded. Each performance was analysed by four independent experts. For each performance, two experts independently rated the technical performance using the TS checklist, and two other experts independently rated NTS using the Anaesthetists' Non-Technical Skills score. TS and NTS were significantly correlated to each other (r=0.45, P<0.05). During a simulated 5 min resuscitation requiring crisis resource management, our results indicate that TS and NTS are related to one another. This research provides the basis for future studies evaluating the nature of this relationship, the influence of NTS training on the performance of TS, and to determine whether NTS are generic and transferrable between crises that require different TS.


Push or pull? Relationships between lung cancer patients' perceptions of quality of care and use of complementary and alternative medicine.
Little is known about relationships between quality of care (QoC) and use of complementary and alternative medicine (CAM) among patients with lung cancer (LC). This study examines CAM-use among patients with LC in Sweden, associations between QoC and CAM-use among these patients, and reported aspects of LC-care perceived as particularly positive and negative by patients, as well as suggestions for improving QoC. Survey data from 94 patient members of the Swedish LC patient organization about CAM-use and QoC as measured by the instrument "Quality from the patient's perspective" were analyzed. Fifty (53%) LC-patients used CAM, with 40 of the CAM-users reporting that CAM helped them. The most common CAMs used were dietary supplements and natural remedies, followed by prayer. Significantly more patients reported using prayer and meditation for cure than was the case for other types of CAM used. Less than half the CAM-users reported having spoken with staff from the biomedical health care system about their CAM-use. Patients provided numerous suggestions for improving LC-care in a variety of areas, aiming at a more effective and cohesive care trajectory. No differences in QoC were found between CAM-users and non-CAM-users, but differences in CAM-use i.e. type of CAM, reasons for using CAM, and CAM-provider consulted could be associated with different experiences of care. It is important to recognize that CAM-users are not a homogeneous group but might seek different types of CAMs and CAM-providers in different situations depending on experiences of care.


Acute phase response in infectious disease.
In considering the pathology associated with infectious diseases, the most common host response to such infection is inflammation. The mechanism(s) whereby inflammation is initiated and the cell types involved will dictate the kinds of acute phase plasma changes that can be seen associated with the infection. Bacteria seem to initiate the classical type of inflammatory response and plasma protein changes similar to those seen in experimental inflammation induced by chemical means. Viruses, on the other hand, in the absence of cytopathology do not appear to induce the same kind of inflammatory changes and avoid the induction of the acute phase protein response since they may not initiate activation of monocytes and/or macrophages. Those viruses that do cause macrophage activation would be expected to have acute phase protein changes associated with that activation. Parasites, however, appear to initiate the acute phase plasma response only when their migration leads to tissue destruction and local inflammation such as caused by parasitemia with Trypanosoma cruzi in the mouse or with migration of Nippostrongylus brasiliensis in the rodent. Human parasitic diseases require much more investigation in order to clarify the role played by acute phase proteins in the subsequent establishment of the host-parasite relationship. We postulate that the macrophage or monocyte on interaction with the infectious pathogen becomes activated and secretes a number of factors, including interleukin 1 and hepatocyte-stimulating factor, which have a marked effect on the total acute phase reaction. In addition to an effect on phagocytic and immune systems, the mediators cause hepatocytes to markedly increase the secretion of plasma acute phase proteins. Some of these proteins return to the site of inflammation and interact with the infectious pathogen and/or cells and proteins of the host, thereby affecting the final outcome of inflammation. We also propose that the initial interaction of an organism such as a parasite and the mammalian host involves early recognition by the macrophage, thereby initiating both the humoral and cellular acute phase reactions and subsequently affects the immune response against the parasite. Variations in the acute phase reaction may help to explain differences in susceptibility to infectious organisms and the presence or lack of host killing mechanisms for the parasite.


Genetic disorders of nuclear receptors.
Following the first isolation of nuclear receptor (NR) genes, genetic disorders caused by NR gene mutations were initially discovered by a candidate gene approach based on their known roles in endocrine pathways and physiologic processes. Subsequently, the identification of disorders has been informed by phenotypes associated with gene disruption in animal models or by genetic linkage studies. More recently, whole exome sequencing has associated pathogenic genetic variants with unexpected, often multisystem, human phenotypes. To date, defects in 20 of 48 human NR genes have been associated with human disorders, with different mutations mediating phenotypes of varying severity or several distinct conditions being associated with different changes in the same gene. Studies of individuals with deleterious genetic variants can elucidate novel roles of human NRs, validating them as targets for drug development or providing new insights into structure-function relationships. Importantly, human genetic discoveries enable definitive disease diagnosis and can provide opportunities to therapeutically manage affected individuals. Here we review germline changes in human NR genes associated with "monogenic" conditions, including a discussion of the structural basis of mutations that cause distinctive changes in NR function and the molecular mechanisms mediating pathogenesis.


Oral function of older people with mild cognitive impairment or dementia.
The aim of this study was to examine and compare the oral function of older people with mild cognitive impairment (MCI) or dementia. This cross-sectional observational study included participants with MCI or dementia aged 60 years or older. Global cognitive functioning was evaluated with the Mini Mental State Examination (MMSE) and the oral function was evaluated with subjective and objective assessments, including the perceived quality of chewing and swallowing, the function of the prostheses, the number of occluding pairs (OP), the degree of tooth wear and the active and passive maximum mouth opening. The quality of chewing and swallowing was perceived as good in, respectively, 86.0% and 90.9% of the participants. Full or partial prostheses were worn by 63.8% of the participants, and the retention was good in 58.4% of the upper and 50.0% of the lower prostheses. Participants with MCI had a median of 3.0 (Inter Quartile Range [IQR] 0.0-7.5) occluding pairs, while participants with dementia had a median of 0.0 (IQR 0.0-1.0) occluding pairs, U = 3838.50, P < 0.001. There was a weak positive correlation between the number of occluding pairs and the MMSE score, r = 0.267, also when adjusted for age, r = 0.230. The median tooth wear score was 2.0 (IQR 2.0-2.0) in participants with MCI or dementia. The active maximum mouth opening was 45.8 (SD 9.3) mm in participants with dementia, while it was 49.8 (SD 8.1) mm in those with MCI, t(253) = 2.67, P = 0.008. For most participants with MCI or dementia, the swallowing ability and chewing ability were perceived as good. In addition, more than half of the prostheses had good retention and occlusion. Participants with more severe cognitive impairment had fewer occluding pairs and a smaller active mouth opening. The degree of tooth wear was less than one-third of the clinical crown in most participants with MCI or dementia.


Aging mechanisms in arthritic disease.
Arthritic disease is one of the most common age-related pathologies worldwide. The erosion of cartilaginous tissues from articular surfaces within the joint and the failure to efficiently repair and regenerate this region with age lead to debilitating joint destruction, severe pain, and a crippling loss of function. In addition to the accumulative damage brought about by years of mechanical forces acting upon this region of tissue, there are also defects in underlying biological mechanisms which predispose the older population to excessive joint erosion. This occurs as aberrations in normal chondrocyte biology lead to a reduction in crucial matrix proteins and inhibitory molecules, and elevated production of destructive enzymes. The end result is an accelerated loss of articular cartilage and increased erosion of the joint. As a significant global link exists between aging and the onset of arthritis, this review will consider whether factors known to affect lifespan may also play a role in arthritic disease.


The Glucose-lowering Efficacy of Sitagliptin in Obese Japanese Patients with Type 2 Diabetes.
Objective Dipeptidyl peptidase-4 (DPP-4) inhibitors are the most frequently prescribed oral hypoglycemic agents in Japan. Although a relationship between the efficacy of DPP-4 inhibitors and the body mass index (BMI) has been reported, this relationship is controversial. We investigated whether the BMI value affects the glucose-lowering efficacy of sitagliptin in obese Japanese patients with type 2 diabetes. Methods One hundred sixty-two outpatients with inadequate glycemic control were divided into four groups based on their baseline BMI values. They were then treated with sitagliptin (a DPP-4 inhibitor) for 3 months and followed-up for 12 months. Results Sitagliptin significantly reduced the hemoglobin A1c level (HbA1c: -0.71±0.55%) after 3 months, and continued to reduce the HbA1c level until 12 months. There was no significant difference in the efficacy of sitagliptin among the four BMI groups. A multiple linear regression analysis indicated that the factors contributing to the change in the HbA1c level were the baseline level of HbA1c and the homeostasis model assessment of β-cell function (HOMA-β). In terms of the relationship between the baseline BMI value and the efficacy of sitagliptin treatment, the number of patients who responded to sitagliptin treatment after 3 months was lowest in the group of patients with the highest BMI values. A multiple logistic regression analysis revealed that the baseline HOMA-β function and HbA1c level and a baseline BMI value of ≥30 kg/m2 significantly contributed to the response to sitagliptin treatment. Conclusion The results indicated that sitagliptin treatment was effective in controlling glucose metabolism disorder in obese Japanese patients with type 2 diabetes. However, the efficacy of sitagliptin treatment might be attenuated in severely obese patients, such as those with a BMI value of ≥30 kg/m2.


Determination of nitrate and other water quality parameters in groundwater from UV/Vis spectra employing partial least squares regression.
The use of UV/Vis spectroscopy in combination with partial least squares (PLS) regression for the simultaneous prediction of nitrate and non-purgeable organic carbon (NPOC) in groundwaters was evaluated. A model of high quality was obtained using first order derivative spectra in the range 200-300 nm. Inclusion of non-UV-absorbing constituents in the modeling procedure, i.e., chloride, sulfate, fluoride, total carbon (TC), inorganic carbon (IC), alkalinity, pH and conductivity was also evaluated. This model seemed to be useful for prediction of chloride, TC, IC, alkalinity and conductivity, while its ability to predict sulfate, fluoride and pH was poor. In conclusion, application of PLS regression, which requires neither filtration of samples nor addition of chemicals, is a promising alternative for fast interpretation of geochemical patterns of groundwater quality.


Predisposing risk factors for non-contact ACL injuries in military subjects.
The goal of this study was to document the incidence of anterior cruciate ligament (ACL) tears and possible risk factors for these injuries in a large population of young, athletic subjects. The authors retrospectively reviewed the US Naval Academy's database of midshipmen admitted in 1999 and 2000 (n = 2,345) and prospectively followed until graduation 4 years later or disenrollment. Excluded were 658 who had a history of preadmission ACL injury or surgery, those without initial radiographs or documented baseline height and weight, or those who had documented contact ACL injuries. Therefore, 1,687 subjects comprised the study group. Standard radiographic measurements, including condylar width, notch width, and femoral notch width index (notch width divided by condyle width), were obtained for all subjects. Statistical analyses were used to determine differences between injured and uninjured subjects. The overall incidence of non-contact ACL injury was 2.9% (37 men, 12 women). The average BMI was 25.6 and 24.4 kg/m(2) for the injured and uninjured groups, respectively (P < 0.05). Although femoral notch width alone was not associated with non-contact ACL injuries, subjects with higher than average BMI in combination with narrow notch width were at significant risk for ACL injury (P = 0.021). Elevated BMI combined with narrow notch width may predispose young athletes to non-contact ACL injury. Retrospective comparative study, Level III.


Cell surface-associated mucins in signal transduction.
Mucins are heavily glycosylated high molecular weight glycoproteins, which are involved in the protection and lubrication of luminal epithelial surfaces. Transmembrane mucins also engage in signal transduction, through extracellular domain-mediated ligand binding or by interacting with receptors for growth and differentiation factors. The cytoplasmic tail of MUC1 (MUC1CT), the best characterized of the transmembrane mucins, is involved in several signaling pathways, including those involving Ras, beta-catenin, p120 catenin, p53 and estrogen receptor alpha. MUC1CT also forms complexes with transcription factors, and then translocates to the nucleus by an unknown mechanism, where it is believed to influence the transcription of their target genes. MUC1CT has also been proposed to localize to mitochondrial membranes under conditions of genotoxic stress, where it attenuates the apoptotic pathway in response and confers resistance to apoptosis-inducing drugs.


Chemical Indexing: An "Atom Total" Based on Cyclic Features of Structure.
The atom-total of a compound may be obtained from an equation which substitutes cyclic features of structure for hydrogen atoms. This method is useful for checking a compound's molecular formula against its structural formula or systematic name. While it applies to all chemical compounds, it is of most value for compounds with complex ring structures.


Red Meat and Processed Meat Consumption and Nasopharyngeal Carcinoma Risk: A Dose-response Meta-analysis of Observational Studies.
The purpose of this study is to clarify and quantify the potential dose-response association between the intake of total red and total processed meat and risk of nasopharyngeal carcinoma (NPC). Relevant studies were identified by searching PubMed, EMBASE, and Chinese databases (CNKI and Wanfang). The summary relative risk (RR) with 95% confidence interval (95%CI) was calculated. A total of 15 independent studies with 12,735 subjects were identified. Compared with the low-rank intake, the summary RR of NPC was 1.35 (95%CI, 1.21-1.51) for total red meat and 1.46 (95%CI, 1.34-1.64) for total processed meat. For the moderate-rank intake, the summary RR of NPC was 1.54 (95%CI, 1.36-1.79) for total red meat and 1.59 (95%CI, 1.3-1.90) for total processed meat. The summary RR for high-rank intake was 1.71 (95%CI, 1.14-2.55) for total red meat and 2.11 (95%CI, 1.31-3.42) for total processed meat. The combined estimates showed obvious evidence of statistically significant association between total red and total processed meat consumption dose and risk of NPC (Ptrend< 0.01). In conclusion, our data suggest that a high intake of total red or total processed meat is associated with a significantly increased risk of NPC.


Monitoring Acute Stroke Progression: Multi-Parametric OCT Imaging of Cortical Perfusion, Flow, and Tissue Scattering in a Mouse Model of Permanent Focal Ischemia.
Cerebral ischemic stroke causes injury to brain tissue characterized by a complex cascade of neuronal and vascular events. Imaging during the early stages of its development allows prediction of tissue infarction and penumbra so that optimal intervention can be determined in order to salvage brain function impairment. Therefore, there is a critical need for novel imaging techniques that can characterize brain injury in the earliest phases of the ischemic stroke. This paper examined optical coherence tomography (OCT) for imaging acute injury in experimental ischemic stroke in vivo. Based on endogenous optical scattering signals provided by OCT imaging, we have developed a single, integrated imaging platform enabling the measurement of changes in blood perfusion, blood flow, erythrocyte velocity, and light attenuation within a cortical tissue, during focal cerebral ischemia in a mouse model. During the acute phase (from 5 min to the first few hours following the blood occlusion), the multi-parametric OCT imaging revealed multiple hemodynamic and tissue scattering responses in vivo, including cerebral blood flow deficits, capillary non-perfusion, displacement of penetrating vessels, and increased light attenuation in the cortical tissue at risk that are spatially correlated with the infarct core, as determined by postmortem staining with triphenyltetrazolium chloride. The use of multi-parametric OCT imaging may aid in the comprehensive evaluation of ischemic lesions during the early stages of stroke, thereby providing essential knowledge for guiding treatment decisions.


Fine mapping of epitopes by intradomain Kd/Dd recombinants.
11 intradomain recombinants between H-2Kd and H-2Dd were produced using an original technique based on in vivo recombination in Escherichia coli. After transfection into mouse L cells, all these recombinants were expressed at high levels on the cell surface. The specificities of 77 mAbs were examined on these cell lines. mAbs could be organized in 12 groups. In each group, a small number of amino acids participating in the recognized epitope(s) were identified. In a few instances, noncontinuous epitopes comprising amino acids belonging to different domains of the antigen were found. The data thus obtained are compatible with those produced in previous exon-shuffling experiments, but permit a much more precise definition of recognized epitope(s).


Suppression of Th2-driven airway inflammation by allergen immunotherapy is independent of B cell and Ig responses in mice.
Allergen-specific immunotherapy (IT) uniquely renders long-term relief from allergic symptoms and is associated with elevated serum levels of allergen-specific IgG and IgA. The allergen-specific IgG response induced by IT treatment was shown to be critical for suppression of the immediate phase of the allergic response in mice, and this suppression was partially dependent on signaling through FcγRIIB. To investigate the relevance of the allergen-specific IgG responses for suppression of the Th2-driven late-phase allergic response, we performed IT in a mouse model of allergic asthma in the absence of FcγRIIB or FcγRI/FcγRIII signaling. We found that suppression of Th2 cell activity, allergic inflammation, and allergen-specific IgE responses is independent of FcγRIIB and FcγRI/FcγRIII signaling. Moreover, we show that the IT-induced allergen-specific systemic IgG or IgA responses and B cell function are dispensable for suppression of the late-phase allergic response by IT treatment. Finally, we found that the secretory mucosal IgA response also is not required for suppression of the Th2-driven allergic inflammation by IT. These data are in contrast to the suppression of the immediate phase of the allergic response, which is critically dependent on the induced allergen-specific serum IgG response. Hence, IT-induced suppression of the immediate and late phases of the allergic response is governed by divergent and independent mechanisms. Our data show that the IT-induced suppression of the Th2 cell-dependent late-phase allergic response is independent of the allergen-specific IgG and IgA responses that are associated with IT treatment.


GenomicTools: a computational platform for developing high-throughput analytics in genomics.
Recent advances in sequencing technology have resulted in the dramatic increase of sequencing data, which, in turn, requires efficient management of computational resources, such as computing time, memory requirements as well as prototyping of computational pipelines. We present GenomicTools, a flexible computational platform, comprising both a command-line set of tools and a C++ API, for the analysis and manipulation of high-throughput sequencing data such as DNA-seq, RNA-seq, ChIP-seq and MethylC-seq. GenomicTools implements a variety of mathematical operations between sets of genomic regions thereby enabling the prototyping of computational pipelines that can address a wide spectrum of tasks ranging from pre-processing and quality control to meta-analyses. Additionally, the GenomicTools platform is designed to analyze large datasets of any size by minimizing memory requirements. In practical applications, where comparable, GenomicTools outperforms existing tools in terms of both time and memory usage. The GenomicTools platform (version 2.0.0) was implemented in C++. The source code, documentation, user manual, example datasets and scripts are available online at http://code.google.com/p/ibm-cbc-genomic-tools.


Nanotechnology and glaucoma: a review of the potential implications of glaucoma nanomedicine.
The purpose of this review is to discuss the evolution of nanotechnology and its potential diagnostic and therapeutic applications in the field of ophthalmology, particularly as it pertains to glaucoma. We reviewed literature using MEDLINE and PubMed databases with the following search terms: glaucoma, nanotechnology, nanomedicine, nanoparticles, ophthalmology and liposomes. We also reviewed pertinent references from articles found in this search. A brief history of nanotechnology and nanomedicine will be covered, followed by a discussion of the advantages and concerns of using this technology in the field of glaucoma. We will look at various studies concerning the development of nanomedicine, its potential applications in ocular drug delivery, diagnostic and imaging modalities and, surgical techniques. In particular, the challenges of assuring safety and efficacy of nanomedicine will be examined. We conclude that nanotechnology offers a novel approach to expanding diagnostic, imaging and surgical modalities in glaucoma and may contribute to the knowledge of disease pathogenesis at a molecular level. However, more research is needed to better elucidate the mechanism of cellular entry, the potential for nanoparticle cytotoxicity and the assurance of clinical efficacy.


A rare missense variant in the ATP2C2 gene is associated with language impairment and related measures.
At least 5% of children present unexpected difficulties in expressing and understanding spoken language. This condition is highly heritable and often co-occurs with other neurodevelopmental disorders such as dyslexia and ADHD. Through an exome sequencing analysis, we identified a rare missense variant (chr16:84405221, GRCh38.p12) in the ATP2C2 gene. ATP2C2 was implicated in language disorders by linkage and association studies, and exactly the same variant was reported previously in a different exome sequencing study for language impairment (LI). We followed up this finding by genotyping the mutation in cohorts selected for LI and comorbid disorders. We found that the variant had a higher frequency in LI cases (1.8%, N = 360) compared with cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24 046 gnomAD controls). Additionally, we observed that carriers of the rare variant identified from a general population cohort (N = 42, ALSPAC cohort) presented, as a group, lower scores on a range of reading and language-related measures compared to controls (N = 1825; minimum P = 0.002 for non-word reading). ATP2C2 encodes for an ATPase (SPCA2) that transports calcium and manganese ions into the Golgi lumen. Our functional characterization suggested that the rare variant influences the ATPase activity of SPCA2. Thus, our results further support the role of ATP2C2 locus in language-related phenotypes and pinpoint the possible effects of a specific rare variant at molecular level.


Hard convex lens-shaped particles: Densest-known packings and phase behavior.
By using theoretical methods and Monte Carlo simulations, this work investigates dense ordered packings and equilibrium phase behavior (from the low-density isotropic fluid regime to the high-density crystalline solid regime) of monodisperse systems of hard convex lens-shaped particles as defined by the volume common to two intersecting congruent spheres. We show that, while the overall similarity of their shape to that of hard oblate ellipsoids is reflected in a qualitatively similar phase diagram, differences are more pronounced in the high-density crystal phase up to the densest-known packings determined here. In contrast to those non-(Bravais)-lattice two-particle basis crystals that are the densest-known packings of hard (oblate) ellipsoids, hard convex lens-shaped particles pack more densely in two types of degenerate crystalline structures: (i) non-(Bravais)-lattice two-particle basis body-centered-orthorhombic-like crystals and (ii) (Bravais) lattice monoclinic crystals. By stacking at will, regularly or irregularly, laminae of these two crystals, infinitely degenerate, generally non-periodic in the stacking direction, dense packings can be constructed that are consistent with recent organizing principles. While deferring the assessment of which of these dense ordered structures is thermodynamically stable in the high-density crystalline solid regime, the degeneracy of their densest-known packings strongly suggests that colloidal convex lens-shaped particles could be better glass formers than colloidal spheres because of the additional rotational degrees of freedom.


Use of the KTP laser in the treatment of rosacea and solar lentigines.
Numerous techniques have evolved in facial plastic surgery to treat rosacea and solar lentigines. The treatment regimens range from avoidance of causative factors to the use of topical agents or other modalities that target the superficial layers of the skin. Of the modalities that target the epidermis, lasers offer the physician and patient the ability to target specific chromophores in the skin. Advances in laser technology led to the implementation of targeting certain characteristic pigments of abnormal areas with minimal damage to surrounding normal tissue. Rosacea and solar lentigines have characteristic cells that are targeted by a potassium-titanyl-phosphate (KTP) laser. The lesions are different in their origins but share the ability to be treated successfully with the KTP laser. A review of both conditions and other treatment options is discussed.


The cytoskeletal system of nucleated erythrocytes. I. Composition and function of major elements.
We have studied the dogfish erythrocyte cytoskeletal system, which consists of a marginal band of microtubules (MB) and trans-marginal band material (TBM). The TBM appeared in whole mounts as a rough irregular network and in thin sections as a surface-delimiting layer completely enclosing nucleus and MB. In cells incubated at 0 degrees C for 30 min or more, the MB disappeared but the TBM remained. MB reassembly occurred with rewarming, and was inhibited by colchicine. Flattened elliptical erythrocyte morphology was retained even when MBs were absent. Total solubilization of MB and TBM at low pH, or dissolution of whole anucleate cytoskeletons, yielded components comigrating with actin, spectrin, and tubulin standards during gel electrophoresis. Mass-isolated MBs, exhibiting ribbonlike construction apparently maintained by cross-bridges, contained four polypeptides in the tubulin region of the gel. Only these four bands were noticeably increased in the soluble phase obtained from cells with 0 degrees C-disassembled MBs. The best isolated MB preparations contained tubulin but no components comigrating with high molecular weight microtubule-associated proteins, spectrin, or actin. Actin and spectrin therefore appear to be major TBM constituents, with tubulin localized in the MB. The results are interpreted in terms of an actin- and spectrin-containing subsurface cytoskeletal layer (TBM), related to that of mammalian erythrocytes, which maintains cell shape in the absence of MBs. Observations on abnormal pointed erythrocytes containing similarly pointed MBs indicate further that the MB can deform the TBM from within so as to alter cell shape. MBs may function in this manner during normal cellular morphogenesis and during blood flow in vivo.


A scalable memetic algorithm for simultaneous instance and feature selection.
Instance selection is becoming increasingly relevant due to the huge amount of data that is constantly produced in many fields of research. At the same time, most of the recent pattern recognition problems involve highly complex datasets with a large number of possible explanatory variables. For many reasons, this abundance of variables significantly harms classification or recognition tasks. There are efficiency issues, too, because the speed of many classification algorithms is largely improved when the complexity of the data is reduced. One of the approaches to address problems that have too many features or instances is feature or instance selection, respectively. Although most methods address instance and feature selection separately, both problems are interwoven, and benefits are expected from facing these two tasks jointly. This paper proposes a new memetic algorithm for dealing with many instances and many features simultaneously by performing joint instance and feature selection. The proposed method performs four different local search procedures with the aim of obtaining the most relevant subsets of instances and features to perform an accurate classification. A new fitness function is also proposed that enforces instance selection but avoids putting too much pressure on removing features. We prove experimentally that this fitness function improves the results in terms of testing error. Regarding the scalability of the method, an extension of the stratification approach is developed for simultaneous instance and feature selection. This extension allows the application of the proposed algorithm to large datasets. An extensive comparison using 55 medium to large datasets from the UCI Machine Learning Repository shows the usefulness of our method. Additionally, the method is applied to 30 large problems, with very good results. The accuracy of the method for class-imbalanced problems in a set of 40 datasets is shown. The usefulness of the method is also tested using decision trees and support vector machines as classification methods.


Randomized, controlled trial of video self-instruction versus traditional CPR training.
We conducted a prospective, randomized, controlled trial to test the hypothesis that a 34-minute video self-instruction (VSI) training program for adult CPR would yield comparable or better CPR performance than the current community standard, the American Heart Association Heartsaver course. Incoming freshman medical students were randomly assigned to VSI or the Heartsaver CPR course. Two to 6 months after training, we tested subjects to determine their ability to perform CPR in a simulated cardiac arrest setting. Blinded observers used explicit criteria to assess our primary outcome, CPR performance skill. In addition, we assessed secondary outcomes including sequential performance of individual skills, ventilation and chest compression characteristics, and written tests of CPR-related knowledge and attitudes. VSI trainees displayed superior overall performance compared with traditional trainees. Twenty of 47 traditional trainees (43%) were judged not competent in their performance of CPR, compared with only 8 of 42 VSI trainees (19%; absolute difference, 24%; 95% confidence interval, 5% to 42%). In a group of incoming freshman medical students, we found that a half-hour of VSI resulted in superior overall CPR performance compared with that in traditional trainees. If validated by further research, VSI may provide a simple, quick, and inexpensive alternative to traditional CPR instruction for health care workers and, perhaps, the general population.


Evaluation of aspartate aminotransferase to platelet ratio index and fibrosis 4 scores for hepatic fibrosis assessment compared with transient elastography in chronic hepatitis C patients.
Fibrotic stage (FS) assessment is essential in chronic hepatitis C treatment cascade. Liver stiffness measurement (LSM) using transient elastography (TE) is reliable and correlated with liver biopsy. However, TE may not be widely available. This study aimed to evaluate the diagnostic performances of aspartate aminotransferase to platelet ratio index (APRI) and fibrosis 4 (FIB-4) scores compared with TE. We conducted a multicenter, cross-sectional study, including all chronic hepatitis C virus (HCV) monoinfection patients with successful and reliable LSM, at 10 centers in Thailand from 2012 to 2017. Characteristics and laboratory data within 3 months of TE were retrospectively reviewed. Using TE as a reference standard, the diagnostic performances of APRI and FIB-4 were evaluated. TE cut-off levels of 7.1 and 12.5 kPa represented significant fibrosis (SF) and cirrhosis, respectively. The distribution of FS by TE in 2000 eligible patients was as follows: no SF 28.3%, SF 31.4%, and cirrhosis 40.3%. APRI ≥ 1 provided 70.1% sensitivity and 80.6% specificity, with an area under the receiver operator characteristics curve (AUROC) of 0.834 for cirrhosis. The specificity increased to 96.3% when using a cut-off level of APRI ≥ 2. FIB-4 ≥ 1.45 provided a sensitivity, specificity, and AUROC of 52.4%, 91.0%, and 0.829 for cirrhosis, respectively. For SF, APRI performed better than FIB-4, with an AUROC of 0.84 versus 0.80 (P < 0.001). APRI score < 0.5 and FIB-4 score > 1.45 yielded sensitivities of 82.3% and 74.4% and specificities of 65.4% and 69.8%, respectively. APRI and FIB-4 scores had good diagnostic performances for FS assessment compared with TE, especially for cirrhosis. APRI may be used as the noninvasive assessment in resource-limited settings for HCV patients' management.


Effects of intensive medical therapy on microemboli and cardiovascular risk in asymptomatic carotid stenosis.
To assess the effect of more intensive medical therapy on the rate of transcranial Doppler (TCD) microemboli and cardiovascular events in patients with asymptomatic carotid stenosis (ACS). A prospective study. A teaching hospital. Four hundred sixty-eight patients with ACS greater than 60% by Doppler peak velocity. We compared (1) the proportion of ACS patients who had microemboli on TCD, (2) cardiovascular events, (3) rate of carotid plaque progression, and (4) baseline medical therapy, before and since 2003. Among 468 ACS patients, 199 were enrolled between January 1, 2000, and December 31, 2002; and 269 were enrolled between January 1, 2003, and July 30, 2007. Microemboli were present in 12.6% before 2003 and 3.7% since 2003 (P < .001). The decline in microemboli coincided with better control of plasma lipids and slower progression of carotid total plaque area. Since 2003, there have been significantly fewer cardiovascular events among patients with ACS: 17.6% had stroke, death, myocardial infarction, or carotid endarterectomy for symptoms before 2003, vs 5.6% since 2003 (P < .001). The rate of carotid plaque progression in the first year of follow-up has declined from 69 mm(2) (SD, 96 mm(2)) to 23 mm(2) (SD, 86 mm(2)) (P < .001). Cardiovascular events and microemboli on TCD have markedly declined with more intensive medical therapy. Less than 5% of patients with ACS now stand to benefit from revascularization; patients with ACS should receive intensive medical therapy and should only be considered for revascularization if they have microemboli on TCD.


Comprehensive gene expression profiling of Peyer's patch M cells, villous M-like cells, and intestinal epithelial cells.
Separate populations of M cells have been detected in the follicle-associated epithelium of Peyer's patches (PPs) and the villous epithelium of the small intestine, but the traits shared by or distinguishing the two populations have not been characterized. Our separate study has demonstrated that a potent mucosal modulator cholera toxin (CT) can induce lectin Ulex europaeus agglutinin-1 and our newly developed M cell-specific mAb NKM 16-2-4-positive M-like cells in the duodenal villous epithelium. In this study, we determined the gene expression of PP M cells, CT-induced villous M-like cells, and intestinal epithelial cells isolated by a novel approach using FACS. Additional mRNA and protein analyses confirmed the specific expression of glycoprotein 2 and myristoylated alanine-rich C kinase substrate (MARCKS)-like protein by PP M cells but not CT-induced villous M-like cells. Comprehensive gene profiling also suggested that CT-induced villous M-like cells share traits of both PP M cells and intestinal epithelial cells, a finding that is supported by their unique expression of specific chemokines. The genome-wide assessment of gene expression facilitates discovery of M cell-specific molecules and enhances the molecular understanding of M cell immunobiology.


Mercury concentrations in tidal marsh sparrows and their use as bioindicators in Delaware Bay, USA.
Mercury (Hg) contamination from industrial sources is pervasive throughout North America and is recognized by the US Environmental Protection Agency as a health hazard for wildlife and humans. Avian species are commonly used as bioindicators of Hg because they are sensitive to contaminants in the environment and are relatively easy to sample. However, it is important to select the appropriate avian species to use as a bioindicator, which should be directly related to the project objectives. In this study, we tested the utility of two tidal marsh sparrows, Seaside (Ammodramus maritimus) and Saltmarsh (Ammodramus caudacutus) sparrows, as bioindicator species of the extent of Hg contamination in tidal marshes along the Delaware Bay. To determine the possibility of using one or both of these species, we estimated sparrow blood Hg burden in five Delaware watersheds. We found no difference in Hg concentrations between species (F (1,133) < 0.01, P=0.99), but Saltmarsh Sparrows had limited sample size from each site and were, therefore, not appropriate for a Delaware Bay-wide Hg indicator. Seaside Sparrows, however, were abundant and relatively easy to sample in the five watersheds. Seaside Sparrow blood Hg levels ranged from 0.15 to 2.12 ppm, differed among drainages, and were greatest in two drainages distant from the Delaware Bay shoreline (F (4,95) =2.51, P=0.05). Based on a power analysis for Seaside Sparrow blood Hg, we estimated that 16 samples would be necessary to detect differences among sites. Based on these data, we propose that Seaside Sparrows may be used as a tidal marsh Hg bioindicator species given their habitat specificity, relative abundance, widespread distribution in marsh habitats, ease of sampling, and limited variation in blood Hg estimates within a sampling area. In Delaware Bay, Saltmarsh Sparrows may be too rare (making them difficult to sample) to be a viable tidal marsh Hg bioindicator.


Description, Prediction, and Causation in Sport and Exercise Medicine Research: Resolving the Confusion to Improve Research Quality and Patient Outcomes.
SYNOPSIS: Researchers often assign a label (such as a risk factor or predictor) to a characteristic that is statistically associated with an outcome (such as future injury). Labeling signifies that the characteristic has an established clinical value. More often than not, these labels are assigned prematurely and haphazardly. The rampant practice conflates research goals, the ultimate clinical value of the findings, and many risk factors/predictors that may not warrant the label. To address these issues and improve injury prevention research, we (1) outline the problem; (2) clarify the key differences between the research goals of description, causation, and prediction/prognosis (along with labeling conventions); (3) differentiate the clinical implications for each label; and (4) frame an appropriate scientific process to follow before applying a label. J Orthop Sports Phys Ther 2023;53(7):1-7. Epub: 26 April 2023. doi:10.2519/jospt.2023.11773.


Implicit perception and level of processing in object-substitution masking.
Object-substitution masking (OSM) refers to reduced target discrimination when the target is surrounded by a sparse mask that does not overlap with the target in space but trails it in time. In four experiments, we used a novel paradigm to investigate the extent of processing of a masked target in OSM. We measured response-compatibility effects between target and mask, both when the offsets were simultaneous and when the offset of the mask was delayed. Evidence for both OSM and a dissociation between perception and awareness was found when detecting the match between the target and the mask required feature but not categorical analyses. Our results suggest that the locus of disruption in OSM is likely to be beyond feature analysis of the unreported target.


Yoga and hypertension: a systematic review.
Lifestyle modification is a cornerstone of hypertension (HPT) treatment, yet most recommendations currently focus on diet and exercise and do not consider stress reduction strategies. Yoga is a spiritual path that may reduce blood pressure (BP) through reducing stress, increasing parasympathetic activation, and altering baroreceptor sensitivity; however, despite reviews on yoga and cardiovascular disease, diabetes, metabolic syndrome, and anxiety that suggest yoga may reduce BP, no comprehensive review has yet focused on yoga and HPT. A systematic review of all published studies on yoga and HPT was performed revealing 39 cohort studies, 30 nonrandomized, controlled trials (NRCTs), 48 randomized, controlled trials (RCTs), and 3 case reports with durations ranging from 1 wk to 4 y and involving a total of 6693 subjects. Most studies reported that yoga effectively reduced BP in both normotensive and hypertensive populations. These studies suggest that yoga is an effective adjunct therapy for HPT and worthy of inclusion in clinical guidelines, yet the great heterogeneity of yoga practices and the variable quality of the research makes it difficult to recommend any specific yoga practice for HPT. Future research needs to focus on high quality clinical trials along with studies on the mechanisms of action of different yoga practices.


Analysis of KIR3DP1 Polymorphism Provides Relevant Information on Centromeric KIR Gene Content.
Four killer cell Ig-like receptor (KIR) genes, collectively referred to as framework genes, characterize almost all KIR haplotypes. In particular, KIR3DL3 and KIR3DL2 mark the ends of the locus, whereas KIR3DP1 and KIR2DL4 are located in the central part. A recombination hot spot, mapped between KIR3DP1 and KIR2DL4, splits the haplotypes into two regions: a centromeric (Cen) region (spanning from KIR3DL3 to KIR3DP1) and a telomeric region (from KIR2DL4 to KIR3DL2), both varying in KIR gene content. In this study, we analyzed KIR3DP1 polymorphism in a cohort of 316 healthy, unrelated individuals. To this aim, we divided KIR3DP1 alleles into two groups by the use of a sequence-specific primer- PCR approach. Our data clearly indicated that KIR3DP1 alleles present on haplotypes carrying Cen-A or Cen-B1 regions differ from those having Cen-B2 motifs. Few donors (∼3%) made exceptions, and they were all, except one, characterized by uncommon haplotypes, including either KIR deletions or KIR duplications. Consequently, as KIR2DL1 is present in Cen-A and Cen-B1 regions but absent in Cen-B2 regions, we demonstrated that KIR3DP1 polymorphism might represent a suitable marker for KIR2DL1 gene copy number analysis. Moreover, because Cen-B1 and Cen-B2 regions are characterized by different KIR3DP1 alleles, we showed that KIR3DP1 polymorphism analysis also provides information to dissect between Cen-B1/Cen-B1 and Cen-B1/Cen-B2 donors. Taken together, our data suggest that the analysis of KIR3DP1 polymorphism should be included in KIR repertoire evaluation.


Gender, technology and jobs.
Men have traditionally gained more than women from access to technologies at work which bring prestige, job security, more satisfying work and higher pay. Typically female jobs have centred on technologies, if they have at all, which tend towards routine and possibly deskilled work. Typing is a prime example. It is possible that this is changing through computerization, which is extensive but also equally distributed by gender. Does the wage premium, which use of a computer has been found to confer on users, benefit women sufficiently to suggest some sort of equalization through technology, or possibly even a female advantage? This is tested using data from four European countries. There is no across-the-board benefit from the use of computers. For both men and women it depends on the nature of their occupation. Some, more routine usages of computers are associated with a negative outcome. However, this occupational balance itself varies by gender.


Immune-evasive gene switch enables regulated delivery of chondroitinase after spinal cord injury.
Chondroitinase ABC is a promising preclinical therapy that promotes functional neuroplasticity after CNS injury by degrading extracellular matrix inhibitors. Efficient delivery of chondroitinase ABC to the injured mammalian spinal cord can be achieved by viral vector transgene delivery. This approach dramatically modulates injury pathology and restores sensorimotor functions. However, clinical development of this therapy is limited by a lack of ability to exert control over chondroitinase gene expression. Prior experimental gene regulation platforms are likely to be incompatible with the non-resolving adaptive immune response known to occur following spinal cord injury. Therefore, here we apply a novel immune-evasive dual vector system, in which the chondroitinase gene is under a doxycycline inducible regulatory switch, utilizing a chimeric transactivator designed to evade T cell recognition. Using this novel vector system, we demonstrate tight temporal control of chondroitinase ABC gene expression, effectively removing treatment upon removal of doxycycline. This enables a comparison of short and long-term gene therapy paradigms in the treatment of clinically-relevant cervical level contusion injuries in adult rats. We reveal that transient treatment (2.5 weeks) is sufficient to promote improvement in sensory axon conduction and ladder walking performance. However, in tasks requiring skilled reaching and grasping, only long term treatment (8 weeks) leads to significantly improved function, with rats able to accurately grasp and retrieve sugar pellets. The late emergence of skilled hand function indicates enhanced neuroplasticity and connectivity and correlates with increased density of vGlut1+ innervation in spinal cord grey matter, particularly in lamina III-IV above and below the injury. Thus, our novel gene therapy system provides an experimental tool to study temporal effects of extracellular matrix digestion as well as an encouraging step towards generating a safer chondroitinase gene therapy strategy, longer term administration of which increases neuroplasticity and recovery of descending motor control. This preclinical study could have a significant impact for tetraplegic individuals, for whom recovery of hand function is an important determinant of independence, and supports the ongoing development of chondroitinase gene therapy towards clinical application for the treatment of spinal cord injury.


The cortisol awakening response and the metabolic syndrome in a population-based sample of middle-aged men and women.
The objective was to explore the relationship between the cortisol awakening response (CAR) and the metabolic syndrome (MetS) as defined by the National Cholesterol Education Program criteria. The final study sample consisted of 91 women (14 with MetS) and 84 men (15 with MetS), aged 45 to 70 years, from a general population sample. The only exclusion criteria were no consent, pregnancy, or insufficient cortisol testing. On the day of measurement (weekday), salivary cortisol was sampled at awakening and 15 minutes after awakening. Relative CAR (CAR%) and the MetS were the main variables studied. Results showed that, in women with the MetS, cortisol at awakening was significantly lower (mean, 8.92 vs 12.33 nmol/L; P = .05) and the CAR was significantly higher (91.4% vs 36.5%, P < .001) than in women without the syndrome. Significant difference in the relative CAR was also present between men and women with MetS (38.5% and 91.4%, respectively; P = .02). No difference was seen in the awakening response comparing men with and without the MetS. In a regression model, the response to awakening was dependent on the MetS in women (F(1,89) = 13.19, P < .001); but the model was not significant in men. Furthermore, the awakening response was associated with more depressive symptoms in women (F(1,80) = 8.12, P = .01) and with weekday/weekend cortisol sampling in men (F(1,82) = 4.63, P = .03). The association between the relative CAR and the MetS remained significant but somewhat attenuated after adjusting for depressive symptoms (P = .01). Results indicate a sex difference in the CAR% in the presence of the MetS independent of depressive symptoms, a known correlate of the MetS.


Influence of multiple stents on periprocedural stroke after carotid artery stenting in the Carotid Revascularization Endarterectomy versus Stent Trial (CREST).
In the Carotid Revascularization Endarterectomy versus Stent Trial (CREST), carotid artery atherosclerotic lesion length and nature of the lesions were important factors that predicted the observed difference in stroke rates between carotid endarterectomy and carotid artery stenting (CAS). Additional patient-related factors influencing CAS outcomes in CREST included age and symptomatic status. The importance of the operator's proficiency and its influence on periprocedural complications have not been well defined. We evaluated data from CREST to determine the impact of use of multiple stents, which we speculate may be related to technical proficiency. CREST includes CAS performed for symptomatic ≥50% carotid stenosis and asymptomatic ≥70% stenosis. Both symptomatic and asymptomatic patients were enrolled in the trial and in the lead-in registry. Data from patients enrolled in the CREST registry and randomized trial from 2000 to 2008 were reviewed for patient- and lesion-related characteristics along with number of stents deployed. The occurrence of 30-day stroke and demographic and clinical features were recorded. Odds ratios for 30-day stroke associated with the use of multiple stents were calculated in univariate analysis and on multivariable analysis after adjustment for demographics (age, sex, symptomatic status), lesion characteristics (length, ulceration, eccentric, percentage stenosis), and risk factors (diabetes, hypertension, dyslipidemia, and smoking). The registry (n = 1531) and trial (n = 1121) enrolled 2652 patients undergoing CAS. The mean age was 69 years; 36% were women, and 38% were symptomatic. The mean diameter stenosis was 78%, and the mean lesion length was 18 mm (±standard deviation, 8 mm). Risk factors included hypertension (85%), diabetes (32%), dyslipidemia (84%), and smoking (23%). All patients received Acculink stents (Abbott Vascular, Abbott Park, Ill) that were 20, 30, or 40 mm in length (straight or tapered) and Accunet (Abbot Vascular) embolic protection when possible. Most patients received one stent (n = 2545), whereas 98 patients received two stents and 9 patients received three stents (P < .001) to treat the lesion. Patients receiving more than one stent were older (P = .01) but did not differ in other demographic or risk factors. Strokes occurred in 118 (4.5%) of all CAS procedures, in 102 (4%) with the use of one stent, and in 16 (15%) with the use of two or three stents. After adjustment for demographics, lesion characteristics, and risk factors, the use of more than one stent resulted in 2.90 odds (95% confidence interval, 1.49-5.64) for a stroke. Although we know that lesion characteristics (length, ulceration) play an important role in CAS outcomes, in this early experience with carotid stenting, a significant and independent relationship existed between the number of stents used and procedural risk of CAS. We postulate that this was an indicator of the operator's inexperience with the procedure.


'Quantal' calcium release operated by membrane voltage in frog skeletal muscle.
1. Ca2+ transients and Ca2+ release flux were determined optically in cut skeletal muscle fibres under voltage clamp. 'Decay' of release during a depolarizing pulse was defined as the difference between the peak value of release and the much lower steady level reached after about 100 ms of depolarization. Using a double-pulse protocol, the inactivating effect of release was measured by 'suppression', the difference between the peak values of release in the test pulse, in the absence and presence of a conditioning pulse that closely preceded the test pulse. 2. The relationship between decay and suppression was found to follow two simple arithmetic rules. Whenever the conditioning depolarization was less than or equal to the test depolarization, decay in the conditioning release was approximately equal to suppression of the test release. Whenever the conditioning depolarization was greater than that of the test, suppression was complete, i.e. test release was reduced to a function that increased monotonically to a steady level. The steady level was the same with or without conditioning. 3. These arithmetic rules suggest that inactivation of Ca2+ release channels is strictly and fatally linked to their activation. More than a strict linkage, however, is required to explain the arithmetic properties. 4. The arithmetic rules of inactivation result in three other properties that are inexplicable with classical models of channel gating: constant suppression, incremental inactivation and increment detection. These properties were first demonstrated for inositol trisphosphate (IP3)-sensitive channels and used to define IP3-induced release as quantal. In this sense, it can now be stated that skeletal muscle Ca2+ release is activated by membrane voltage in a quantal manner. 5. For both classes of intracellular Ca2+ channels, one explanation of the observations is the existence of subsets of channels with different sensitivities (to voltage or agonist dose). In an alternative explanation, channels are identical, but have a complex repertoire of voltage- or dose-dependent responses.


Antithrombotic Therapy Practices in Older Adults Residing in the Long-Term Care Setting.
To explore physician practice patterns with regard to antithrombotic therapy, including antiplatelets and anticoagulants, in long-term care residents and compare resulting embolic complications. Conducted between August 2012 and March 2013, this study was a retrospective chart review of 400 residents of a long-term care facility. Electronic charts from October 2005 through January 2013 were selected using systematic random sampling. Approximately one-third of residents (29.6%) received anticoagulants, 27.3% received antiplatelets, 15.8% received both, and 27.3% did not receive any antithrombotic therapy. The most commonly prescribed antithrombotic drugs were aspirin (37.5%) and warfarin (22.1%). The type of antithrombotic therapy was significantly associated with medical history, including deep vein thrombosis (P = 0.03), the presence of atrial fibrillation (P = 0.001) and other nonsurgical medical conditions (P = 0.0001). Weight (P = 0.009) and body mass index (P = 0.007) also were significantly associated with type of antithrombotic therapy, indicating that heavier residents and those with a higher body mass index were more likely to receive both anticoagulants and antiplatelets. There was no difference in the number of embolic complications among groups. Physicians are more disposed to initiate and maintain residents on aspirin while being more cautious when prescribing anticoagulants such as warfarin, dabigatran, heparin, and enoxaparin. In some residents, anticoagulants were not used at all, even when residents had particular risk factors, demonstrating that at times physicians may err on the side of overcautiousness. Antithrombotic therapy should be individualized for each resident based on bleeding risk, comorbidities, and benefits of a particular therapy for our most vulnerable populations.


Health promotion in specialist and community care: how a broadly applicable health promotion intervention influences patient's sense of coherence.
Chronic illness health interventions aim to strengthen individuals' wellness resources, in addition to their ability to handle their condition. This presupposes a partnership between patients and professionals and flexibility in care organization. This study aims to investigate possible changes in individuals' sense of coherence while living with long-term illness as they engage in a broadly applicable health promotion intervention developed in specialist care settings that was later implemented in the community care context. This study had a pre-postdesign. Sense of coherence was measured using the SOC-29 questionnaire at baseline and within 14 days of programme completion. The total baseline sample included 108 Norwegian adults (aged 21-89) with chronic illness. Data were analysed using paired samples t-tests. In both clinical sites, the total sample's mean SOC score changed positively from the baseline to the follow-up 4 months later. This change was larger for the participants in the community care context. Manageability increased significantly for women. Significant positive changes in SOC score and the manageability dimension were also identified among participants who had children. Similar findings were found for those who were living with a partner, as well as for public transfer payment recipients. The intervention contributed to a positive change in participants' SOC while living with illness. The findings revealed that the intervention is a flexible health promotion tool across age, diagnostic categories and clinical sites. The community participants' SOC changed the most, which indicates that the intervention is especially relevant in the follow-up of persons living with long-term illness within the community. The intervention contributes to a shift of perspectives in health care towards strenght-based care and health within illness.


FMRFamide regulates oscillatory activity of the olfactory center in the slug.
In the olfactory center of terrestrial animals, changes in the oscillatory frequency of the local field potential (LFP) are thought to be involved in olfaction-based behavior and olfactory memory. The terrestrial slug Limax has a highly developed olfactory center, the procerebrum, in which the LFP spontaneously oscillates. Although changes in the oscillatory frequency are thought to correspond to the preference for specific odors, our knowledge about the mechanism of this frequency regulation is limited. To clarify the mechanism of the bidirectional frequency changes in the procerebrum, we focused on the neuropeptide Phe-Met-Arg-Phe-NH₂ (FMRFamide), which is known to have neuromodulatory functions in invertebrate nervous systems. Application of FMRFamide decreased the oscillatory frequency via G-protein-mediated cascades. Immunohistochemistry showed that FMRFamide-like-immunoreactive neuronal cell bodies are located in the cell mass layer of the procerebrum, projecting their neurites to the neuropile layers. The procerebrum was shown to also receive innervation from other regions of the cerebral ganglion. Furthermore, according to their morphological and projection characteristics, FMRFamide-containing neurons belong to the subpopulations of both bursting and nonbursting neurons in the procerebrum. The mRNA splice variant encoding multiple copies of canonical FMRFamide was specifically expressed in the procerebrum. Taking into account previous results showing that serotonin increases the oscillatory frequency, our results indicate that FMRFamide and serotonin both regulate the LFP frequency but in exactly the opposite direction in the olfactory center of the terrestrial slug.


A Gene Regulatory Program for Meiotic Prophase in the Fetal Ovary.
The chromosomal program of meiotic prophase, comprising events such as laying down of meiotic cohesins, synapsis between homologs, and homologous recombination, must be preceded and enabled by the regulated induction of meiotic prophase genes. This gene regulatory program is poorly understood, particularly in organisms with a segregated germline. We characterized the gene regulatory program of meiotic prophase as it occurs in the mouse fetal ovary. By profiling gene expression in the mouse fetal ovary in mutants with whole tissue and single-cell techniques, we identified 104 genes expressed specifically in pre-meiotic to pachytene germ cells. We characterized the regulation of these genes by 1) retinoic acid (RA), which induces meiosis, 2) Dazl, which is required for germ cell competence to respond to RA, and 3) Stra8, a downstream target of RA required for the chromosomal program of meiotic prophase. Initial induction of practically all identified meiotic prophase genes requires Dazl. In the presence of Dazl, RA induces at least two pathways: one Stra8-independent, and one Stra8-dependent. Genes vary in their induction by Stra8, spanning fully Stra8-independent, partially Stra8-independent, and fully Stra8-dependent. Thus, Stra8 regulates the entirety of the chromosomal program but plays a more nuanced role in governing the gene expression program. We propose that Stra8-independent gene expression enables the stockpiling of selected meiotic structural proteins prior to the commencement of the chromosomal program. Unexpectedly, we discovered that Stra8 is required for prompt down-regulation of itself and Rec8. Germ cells that have expressed and down-regulated Stra8 are refractory to further Stra8 expression. Negative feedback of Stra8, and subsequent resistance to further Stra8 expression, may ensure a single, restricted pulse of Stra8 expression. Collectively, our findings reveal a gene regulatory logic by which germ cells prepare for the chromosomal program of meiotic prophase, and ensure that it is induced only once.