Sleep disorders and attention-deficit/hyperactivity disorder.
The relationship between attention-deficit/hyperactivity disorder (ADHD) and sleep is complex and poses many challenges in clinical practice. Recent studies have helped to elucidate the nature of the neuromodulator systems underlying the associations among sleepiness, arousal, and attention. Studies of sleep disturbances in children with academic and behavioral problems have also underscored the role that primary sleep disorders play in the clinical presentation of symptoms of inattention and behavioral dysregulation. Recent research has shed further light on the prevalence, type, risk factors for, and impact of sleep disturbances on children with ADHD. The following discussion of the multilevel and bidirectional relationships among sleep, neurobehavioral functioning, and the clinical syndrome of ADHD synthesizes current knowledge about the interaction of sleep and attention/arousal in these children. Guidelines are provided to outline a clinical approach to evaluating and managing children with ADHD and sleep problems.


Prone ventilation in trauma or surgical patients with acute lung injury and adult respiratory distress syndrome: is it beneficial?
To compare the effectiveness of supine versus prone kinetic therapy in mechanically ventilated trauma and surgical patients with acute lung injury (ALI) and adult respiratory distress syndrome (ARDS). A retrospective review of all patients with ALI/ARDS who were placed on either a supine (roto-rest) or prone (roto-prone) oscillating bed was performed. Data obtained included age, revised trauma score (RTS), base deficit, Injury Severity Score (ISS), head Abbreviated Injury Scale score (AIS), chest (AIS), PaO2/FiO2 ratio, FiO2 requirement, central venous pressure (CVP), days on the bed, ventilator days, use of pressors, complications, mortality, and pulmonary-associated mortality. Data are expressed as mean+/-SE with significance attributed to p<0.05. From March 1, 2004 through May 31, 2006, 4,507 trauma patients were admitted and 221 were identified in the trauma registry as having ALI or ARDS. Of these, 53 met inclusion criteria. Additionally, 8 general surgery patients met inclusion criteria. Of these 61 patients, 44 patients were positioned supine, 13 were placed prone, and 4 patients that were initially placed supine were changed to prone positioning. There was no difference between the groups in age, CVP, ISS, RTS, base deficit, head AIS score, chest AIS score, abdominal AIS score, or probability of survival. The PaO2/FiO2 ratios were not different at study entry (149 vs. 153, p=NS), and both groups showed improvement in PaO2/FiO2 ratios. However, the prone group had better PaO2/FiO2 ratios than the supine group by day 5 (243 vs. 200, p=0.066). The prone group had fewer days on the ventilator (13.6 vs. 24.2, p=0.12), and shorter hospital lengths of stay (22 days vs. 40 days, p=0.08). There were four patients who failed to improve with supine kinetic therapy that were changed to prone kinetic therapy. These patients had significant improvements in PaO2/FiO2 ratio, and significantly lower FiO2 requirements. There were 18 deaths (7 pulmonary related) in the supine group and 1 death in the prone group (p < 0.01 by chi test). ALI/ARDS patients who received prone kinetic therapy had greater improvement in PaO2/FiO2 ratio, lower mortality, and less pulmonary-related mortality than did supine positioned patients. The use of a prone-oscillating bed appears advantageous for trauma and surgical patients with ALI/ARDS and a prospective, randomized trial is warranted.


Predicting childhood obesity using electronic health records and publicly available data.
Because of the strong link between childhood obesity and adulthood obesity comorbidities, and the difficulty in decreasing body mass index (BMI) later in life, effective strategies are needed to address this condition in early childhood. The ability to predict obesity before age five could be a useful tool, allowing prevention strategies to focus on high risk children. The few existing prediction models for obesity in childhood have primarily employed data from longitudinal cohort studies, relying on difficult to collect data that are not readily available to all practitioners. Instead, we utilized real-world unaugmented electronic health record (EHR) data from the first two years of life to predict obesity status at age five, an approach not yet taken in pediatric obesity research. We trained a variety of machine learning algorithms to perform both binary classification and regression. Following previous studies demonstrating different obesity determinants for boys and girls, we similarly developed separate models for both groups. In each of the separate models for boys and girls we found that weight for length z-score, BMI between 19 and 24 months, and the last BMI measure recorded before age two were the most important features for prediction. The best performing models were able to predict obesity with an Area Under the Receiver Operator Characteristic Curve (AUC) of 81.7% for girls and 76.1% for boys. We were able to predict obesity at age five using EHR data with an AUC comparable to cohort-based studies, reducing the need for investment in additional data collection. Our results suggest that machine learning approaches for predicting future childhood obesity using EHR data could improve the ability of clinicians and researchers to drive future policy, intervention design, and the decision-making process in a clinical setting.


Expression of the EWS/FLI-1 oncogene in murine primary bone-derived cells Results in EWS/FLI-1-dependent, ewing sarcoma-like tumors.
Ewing sarcoma is the second most common malignant pediatric bone tumor. Over 80% of Ewing sarcoma contain the oncogene EWS/FLI-1, which encodes the EWS/FLI-1 oncoprotein, a hybrid transcription factor comprised of NH2-terminal sequences from the RNA-binding protein EWS and the DNA-binding and COOH-terminal regions of the Ets transcription factor FLI-1. Although numerous genes are dysregulated by EWS/FLI-1, advances in Ewing sarcoma cancer biology have been hindered by the lack of an animal model because of EWS/FLI-1-mediated cytotoxicity. In this study, we have developed conditions for the isolation and propagation of murine primary bone-derived cells (mPBDC) that stably express EWS/FLI-1. Early-passage EWS/FLI-1 mPBDCs were immortalized in culture but inefficient at tumor induction, whereas later-passage cells formed sarcomatous tumors in immunocompetent syngeneic mice. Murine EWS/FLI-1 tumors contained morphologically primitive cells that lacked definitive lineage markers. Molecular characterization of murine EWS/FLI-1 tumors revealed that some but not all had acquired a novel, clonal in-frame p53 mutation associated with a constitutive loss of p21 expression. Despite indications that secondary events facilitated EWS/FLI-1 mPBDC tumorigenesis, cells remained highly dependent on EWS/FLI-1 for efficient transformation in clonogenic assays. This Ewing sarcoma animal model will be a useful tool for dissecting the molecular pathogenesis of Ewing sarcoma and provides rationale for the broader use of organ-specific progenitor cell populations for the study of human sarcoma.


Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation.
Macrophages play a relevant role in innate and adaptive immunity depending on the balance of the stimuli received. From an analytical and functional point of view, macrophage stimulation can be segregated into three main modes, as follows: innate, classic, and alternative pathways. These differential activations result in the expression of specific sets of genes involved in the release of pro- or anti-inflammatory stimuli. In the present work, we have analyzed whether specific metabolic patterns depend on the signaling pathway activated. A [1,2-(13)C(2)]glucose tracer-based metabolomics approach has been used to characterize the metabolic flux distributions in macrophages stimulated through the classic, innate, and alternative pathways. Using this methodology combined with mass isotopomer distribution analysis of the new formed metabolites, the data show that activated macrophages are essentially glycolytic cells, and a clear cutoff between the classic/innate activation and the alternative pathway exists. Interestingly, macrophage activation through LPS/IFN-gamma or TLR-2, -3, -4, and -9 results in similar flux distribution patterns regardless of the pathway activated. However, stimulation through the alternative pathway has minor metabolic effects. The molecular basis of the differences between these two types of behavior involves a switch in the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK2) from the liver type-PFK2 to the more active ubiquitous PFK2 isoenzyme, which responds to Hif-1alpha activation and increases fructose-2,6-bisphosphate concentration and the glycolytic flux. However, using macrophages targeted for Hif-1alpha, the switch of PFK2 isoenzymes still occurs in LPS/IFN-gamma-activated macrophages, suggesting that this pathway regulates ubiquitous PFK2 expression through Hif-1alpha-independent mechanisms.


Triphenylstannyl((arylimino)methyl)benzoates with selective potency that induce G1 and G2/M cell cycle arrest and trigger apoptosis via ROS in human cervical cancer cells.
Metal complexes with organelle specificity and potent but selective cytotoxicity are highly desirable. A novel series of triphenylstannyl 4-((arylimino)methyl)benzoates (2-8) were obtained by the reactions of triphenylstannyl 4-formylbenzoate [Ph3Sn(L1)] 1 with primary aromatic amines. Two representative compounds (10, 11) were also synthesized by reacting aqua-triphenylstannyl 2-formylbenzoate [Ph3Sn(L9)(H2O)] (9) with aniline and p-fluoroaniline, respectively. These compounds were characterized by elemental analysis, IR and 1H, 13C and 119Sn NMR spectroscopy, as well as single-crystal X-ray diffraction for compounds 5, 7-11 and three pro-ligands. The in vitro cytotoxic activities of 1-11 were assessed using the MTT tetrazolium dye assay against HeLa (human cervical) and MDA-MB-231 (breast) cancer cells, with IC50 values revealing high activity. Compared to cisplatin, compounds 1-11 exhibited enhanced cytotoxic efficacy, indicating their potential as potent anticancer agents. Among these, 1 and 5 demonstrated maximum inhibition in HeLa cells, with negligible effect on normal human embryonic kidney (HEK) cells. The combined results of the DCFH-DA dye and Hoechst 33342/PI nuclear staining assays, along with flow cytometry analysis, show that they possess a dual mode of action: They induced apoptotic cell death, attributable to the tin-assisted generation of reactive oxygen species. Cell cycle analyses indicated that compounds 1 and 5 exhibit cell growth inhibition and may cause turbulences in the G1 and G2/M phases.


Evaluation of port wine stain perfusion by laser Doppler imaging and thermography before and after argon laser treatment.
Thirteen patients with port wine stains (PWS) were treated with argon laser therapy. Before and at different points in time following treatment, skin blood perfusion and temperature were mapped with laser Doppler imaging and thermography. In nine patients no elevation in blood perfusion was observed in the PWS in comparison with the surrounding normal skin before treatment. In the remaining four patients a significantly (p less than 0.01) higher blood flow was recorded within the PWS. Immediately after treatment nine patients showed elevated perfusion within the PWS. During the first two days following treatment, all patients showed a gradually decreasing hyperperfusion in the borderline between the PWS lesion and surrounding skin. Immediately after treatment 10 patients had a significantly (p less than 0.01) higher temperature in the PWS than in normal skin. During the first 24 h following treatment, an elevated perfusion was in general accompanied by a tissue temperature increase. Three and a half months after argon laser treatment, three patients showed excellent clinical results with no remaining PWS spots or scarring. Two of these patients had had both elevated perfusion and temperature in the PWS prior to treatment.


Relationship of Aerial Broad Band Reflectance to Meloidogyne incognita Density in Cotton.
Aerial images were obtained on 22 July 1999 and 4 August 2000 from five cotton sites infested with Meloidogyne incognita. Images contained three broad bands representing the green (500-600 nm), red (600-700 nm), and near-infrared (700-900 nm) spectrum. Soil samples were collected and assayed for nematodes in the fall at these sites. Sampling locations were identified from images, by locating the coordinates of a wide range of light intensity (measured as a digital number) for each single band, and combinations of bands. There was no single band or band combination in which reflectance consistently predicted M. incognita density. In all 10 site-year combinations, the minimum number of samples necessary to estimate M. incognita density within 25% of the population mean was greater when sampling by reflectance-based classes (3 to 4 per site) than sampling based on the entire site as one unit. Two sites were sampled at multiple times during the growing season. At these sites, there was no single time during the growing season optimal to take images for nematode sampling. Aerial infrared photography conducted during the growing season could not be used to accurately determine fall population densities of M. incognita.


Chromosome-level reference genome and alternative splicing atlas of moso bamboo (Phyllostachys edulis).
Bamboo is one of the most important nontimber forestry products worldwide. However, a chromosome-level reference genome is lacking, and an evolutionary view of alternative splicing (AS) in bamboo remains unclear despite emerging omics data and improved technologies. Here, we provide a chromosome-level de novo genome assembly of moso bamboo (Phyllostachys edulis) using additional abundance sequencing data and a Hi-C scaffolding strategy. The significantly improved genome is a scaffold N50 of 79.90 Mb, approximately 243 times longer than the previous version. A total of 51,074 high-quality protein-coding loci with intact structures were identified using single-molecule real-time sequencing and manual verification. Moreover, we provide a comprehensive AS profile based on the identification of 266,711 unique AS events in 25,225 AS genes by large-scale transcriptomic sequencing of 26 representative bamboo tissues using both the Illumina and Pacific Biosciences sequencing platforms. Through comparisons with orthologous genes in related plant species, we observed that the AS genes are concentrated among more conserved genes that tend to accumulate higher transcript levels and share less tissue specificity. Furthermore, gene family expansion, abundant AS, and positive selection were identified in crucial genes involved in the lignin biosynthetic pathway of moso bamboo. These fundamental studies provide useful information for future in-depth analyses of comparative genome and AS features. Additionally, our results highlight a global perspective of AS during evolution and diversification in bamboo.


Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts.
T-cell-based immunotherapies can be effective in the treatment of large vascularized tumors, but they rely on adoptive transfer of substantial numbers ( approximately 20 million) of tumor-specific T cells administered together with vaccination and high-dose interleukin (IL)-2. In this study, we report that approximately 10,000 T cells gene-engineered to express a single-chain IL-12 molecule can be therapeutically effective against established tumors in the absence of exogenous IL-2 and vaccine. Although IL-12-engineered cells did not perist long-term in hosts, they exhibited enhanced functionality and were detected in higher numbers intratumorally along with increased numbers of endogenous natural killer and CD8(+) T cells just before regression. Importantly, transferred T cells isolated from tumors stably overproduced supraphysiologic amounts of IL-12, and the therapeutic effect of IL-12 produced within the tumor microenvironment could not be mimicked with high doses of exogenously provided IL-12. Furthermore, antitumor effects could be recapitulated by engineering wild-type open-repertoire splenocytes to express both the single-chain IL-12 and a recombinant tumor-specific T-cell receptor (TCR), but only when individual cells expressed both the TCR and IL-12, indicating that arrested migration of T cells at the tumor site was required for their activities. Successful tumor eradication was dependent on a lymphodepleting preconditioning regimen that reduced the number of intratumoral CD4(+) Foxp3(+) T regulatory cells. Our findings reveal an approach to genetically modify T cells to reduce the cell number needed, eliminate the need for vaccines or systemic IL-2, and improve immunotherapy efficacy based on adoptive transfer of gene-engineered T cells.


Productivity is a poor predictor of plant species richness.
For more than 30 years, the relationship between net primary productivity and species richness has generated intense debate in ecology about the processes regulating local diversity. The original view, which is still widely accepted, holds that the relationship is hump-shaped, with richness first rising and then declining with increasing productivity. Although recent meta-analyses questioned the generality of hump-shaped patterns, these syntheses have been criticized for failing to account for methodological differences among studies. We addressed such concerns by conducting standardized sampling in 48 herbaceous-dominated plant communities on five continents. We found no clear relationship between productivity and fine-scale (meters(-2)) richness within sites, within regions, or across the globe. Ecologists should focus on fresh, mechanistic approaches to understanding the multivariate links between productivity and richness.


Significantly reduced lymphadenopathy, salivary gland infiltrates and proteinuria in MRL-lpr/lpr mice treated with ultrasoluble curcumin/turmeric: increased survival with curcumin treatment.
Commercial curcumin (CU), derived from food spice turmeric (TU), has been widely studied as a potential therapeutic for a variety of oncological and inflammatory conditions. Lack of solubility/bioavailability has hindered curcumin's therapeutic efficacy in human diseases. We have solubilised curcumin in water applying heat/pressure, obtaining up to 35-fold increase in solubility (ultrasoluble curcumin (UsC)). We hypothesised that UsC or ultrasoluble turmeric (UsT) will ameliorate systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS)-like disease in MRL-lpr/lpr mice. Eighteen female MRL-lpr/lpr (6 weeks old) and 18 female MRL-MpJ mice (6 weeks old) were used. Female MRL-lpr/lpr mice develop lupus-like disease at the 10th week and die at an average age of 17 weeks. MRL-MpJ mice develop lupus-like disease around 47 weeks and typically die at 73 weeks. Six mice of each strain received autoclaved water only (lpr-water or MpJ-water group), UsC (lpr-CU or MpJ-CU group) or UsT (lpr-TU or MpJ-TU group) in the water bottle. UsC or UsT ameliorates SLE in the MRL-lpr/lpr mice by significantly reducing lymphoproliferation, proteinuria, lesions (tail) and autoantibodies. lpr-CU group had a 20% survival advantage over lpr-water group. However, lpr-TU group lived an average of 16 days shorter than lpr-water group due to complications unrelated to lupus-like illness. CU/TU treatment inhibited lymphadenopathy significantly compared with lpr-water group (p=0.03 and p=0.02, respectively) by induction of apoptosis. Average lymph node weights were 2606±1147, 742±331 and 385±68 mg, respectively, for lpr-water, lpr-CU and lpr-TU mice. Transferase dUTP nick end labelling assay showed that lymphocytes in lymph nodes of lpr-CU and lpr-TU mice underwent apoptosis. Significantly reduced cellular infiltration of the salivary glands in the lpr-TU group compared with the lpr-water group, and a trend towards reduced kidney damage was observed in the lpr-CU and lpr-TU groups. These studies show that UsC/UsT could prove useful as a therapeutic intervention in SLE/SS.


Picking up the pieces--applying the DISEASE FILTER to health data.
This contribution presents systematic biases in the process of generating health data by using a step-by-step explanation of the DISEASE FILTER, a heuristic instrument that we designed in order to better understand and evaluate health data. The systematic bias in health data generally varies by data type (register versus survey data) and the operationalization of health outcomes. Self-reported subjective health and disease assessments, for instance, underlie a different selectivity than do data based on medical examinations or health care statistics. Although this is obvious, systematic approaches used to better understand the process of generating health data have been missing until now. We begin with the definitions and classifications of diseases that change (e.g. over time), describe the selective nature of access to and use of medical health care (e.g. depending on health insurance and gender), present biases in diagnoses (e.g. by gender and professional status), report these biases in relation to the decision for or against various treatment (e.g. by age and income), and finally outline the determinants of the treatments (ambulant versus stationary, e.g. via mobility and age). We then show how to apply the DISEASE FILTER to health data and discuss the benefits and shortcomings of our heuristic model. Finally, we give some suggestions on how to deal with biases in health data and how to avoid them.


Laterally transposed pelvis: a new and proper name for an old problem.
There is need for specific terminology for osteopathic findings, including the findings in postural examination. A static test for laterally transposed pelvis is sometimes critical to the establishment of a diagnosis of postural imbalance, particularly in the minor forms of this important clinical entity. There is need for a word or phrase that identifies this clinical finding and nothing else. The phrase laterally transposed pelvis is nominated to indicate a specific finding in the static evaluation of pelvic position in the frontal (coronal) plane in relation to the vertical extension of the midheel line (sagittal plane). The definition of laterally transposed pelvis is: With the patient standing, knees fully extended bilaterally and the feet together on a flat horizontal surface, the median (midsagittal) plane of the pelvis is observed to lie laterally to the vertically extended midheel line (median/midsagittal plane).


Autoinflammatory Diseases in Childhood
Autoinflammatory diseases are characterized by recurrent fevers and clinical findings of impaired natural immunity and can involve various organ systems. The concept of autoinflammatory disease emerged after the definition of familial Mediterranean fever and tumor necrosis factor receptor-associated periodic syndrome. This new disease group was considered to differ from the standard concept of autoimmune diseases, which is relatively better known in terms of basic features, such as defects in innate immunity and the absence of antibodies. A better understanding has been achieved regarding the genetic and pathogenetic mechanisms of this relatively new disease group over the past 20 years since they were first diagnosed, which have led to some changes in the concept of autoinflammatory diseases. The recent definition classifies autoinflammatory disease to be a wide range of diseases with different clinical features, mainly accompanied by changes in innate immune and rarely in humoral immunity. The spectrum of autoinflammatory diseases is rapidly expanding owing to recent developments in molecular sciences and genetics. This review article discusses the clinical features, classification criteria, treatment options, and long-term prognosis of periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome, and other common autoinflammatory diseases in the light of current literature.


The Chiropractic Outcome Study: pain, functional ability and satisfaction with care.
To examine changes in pain experienced, changes in functional ability and degree of patient satisfaction with chiropractic care. Patient characteristics influencing these parameters were also explored. A follow-up study consisting of a questionnaire to be completed at the beginning of treatment and a mailed questionnaire 6 wk later. Non-random sample of 13 chiropractic practices in Calgary and Red Deer, Alberta, Canada. Three hundred sixty-nine patients presenting with neck and/or back pain who saw a chiropractor for the first time or who had not seen a chiropractor for a period for 6 months before the first visit. Pain relief and changes in functional ability were greatest among patients whose initial pain or disability level was moderate or severe. No significant improvement was found among those whose initial level of pain or disability was mild. Pain relief and improved functional ability was greatest among those with an acute condition and those who saw no one other than the chiropractor during treatment. In addition, pain relief was highest among men, those who perceived themselves to be in good or excellent health and those who had completed treatment in 6 wk. Patients positively endorsed all items on the satisfaction questionnaire, indicating a high level of satisfaction with the care they received. Patients were most satisfied with access to chiropractic care and least satisfied with financial aspects. Improvement in pain and in back and neck disability were significantly related to general satisfaction. Based on these results, it seems that patients suffering from back and/or neck complaints experience chiropractic care as an effective means of resolving or ameliorating pain and functional impairments, thus reinforcing previous results showing the benefits of chiropractic treatment for back and neck pain.


The development of attention skills in action video game players.
Previous research suggests that action video game play improves attentional resources, allowing gamers to better allocate their attention across both space and time. In order to further characterize the plastic changes resulting from playing these video games, we administered the Attentional Network Test (ANT) to action game players and non-playing controls aged between 7 and 22 years. By employing a mixture of cues and flankers, the ANT provides measures of how well attention is allocated to targets as a function of alerting and orienting cues, and to what extent observers are able to filter out the influence of task irrelevant information flanking those targets. The data suggest that action video game players of all ages have enhanced attentional skills that allow them to make faster correct responses to targets, and leaves additional processing resources that spill over to process distractors flanking the targets.


Changing pattern in malignant mesothelioma survival.
Survival for mesothelioma has been shown to be poor, with marginal improvement over time. Recent advances in the understanding of pathophysiology and treatment of mesothelioma may impact therapy to improve survival that may not be evident from available clinical trials that are often small and not randomized. Therapies may affect survival differently based on mesothelioma location (pleural vs peritoneal). Data are conflicting regarding the effect of asbestos exposure on mesothelioma location. We examined survival in a large cohort of mesothelioma subjects analyzed by tumor location and presence and mode of asbestos exposure. Data were analyzed from cases (n = 380) diagnosed with mesothelioma from 1992 to 2012. Cases were either drawn from treatment referrals, independent medical evaluation for medical legal purposes, or volunteers who were diagnosed with mesothelioma. Subjects completed an occupational medical questionnaire, personal interview with the examining physician, and physician review of the medical record. This study reports better survival for mesothelioma than historical reports. Survival for peritoneal mesothelioma was longer than that for pleural mesothelioma (hazard ratio = 0.36, 95% confidence interval = 0.24-0.54, P < .001) after adjusting for gender and age at diagnosis. Non-occupational cases were more likely to be 1) diagnosed with peritoneal mesothelioma, 2) female, 3) exposed, and 4) diagnosed at a younger age and to have a 5) shorter latency compared to occupational cases (P < .001). Peritoneal mesothelioma was more likely associated with non-occupational exposure, thus emphasizing the importance of exposure history in enhancing early diagnosis and treatment impact.


Prompt mental health care, the Norwegian version of IAPT: clinical outcomes and predictors of change in a multicenter cohort study.
Prompt mental health care (PMHC) is a Norwegian initiative, inspired by the English 'Improving Access to Psychological Therapy' (IAPT), aimed to provide low-threshold access to primary care treatment for persons with symptoms of anxiety and depression. The objectives of the present study are to describe the PMHC service, to examine changes in symptoms of anxiety and depression following treatment and to identify predictors of change, using data from the 12 first pilot sites. A prospective cohort design was used. All participants were asked to complete questionnaires at baseline, before each treatment session and at the end of treatment. Effect sizes (ES) for pre-post changes and recovery rates were calculated based on the Patient Health Questionnaire and the Generalized Anxiety Disorder scale. Multiple imputation (MI) was used in order to handle missing data. We examined predictors through latent difference score models and reported the contribution of each predictor level in terms of ES. In total, N = 2512 clients received treatment at PMHC between October 2014 and December 2016, whereof 61% consented to participate. The changes from pre- to post-treatment were large for symptoms of both depression (ES = 1.1) and anxiety (ES = 1.0), with an MI-based reliable recovery rate of 58%. The reliable recovery rate comparable to IAPT based on last-observation-carried-forward was 48%. The strongest predictors for less improvement were having immigrant background (ES change depression - 0.27, ES change anxiety - 0.26), being out of work at baseline (ES change depression - 0.18, ES change anxiety - 0.35), taking antidepressants (ES change anxiety - 0.36) and reporting bullying as cause of problems (ES change depression - 0.29). Taking sleep medication did on the other hand predict more improvement (ES change depression 0.23, ES change anxiety 0.45). Results in terms of clinical outcomes were promising, compared to both the IAPT pilots and other benchmark samples. Though all groups of clients showed substantial improvements, having immigrant background, being out of work, taking antidepressant medication and reporting bullying as cause stood out as predictors of poorer treatment response. Altogether, PMHC was successfully implemented in Norway. Areas for improvement of the service are discussed.


Melatonin, cardiolipin and mitochondrial bioenergetics in health and disease.
Melatonin is a natural occurring compound with well-known antioxidant properties. Melatonin is ubiquitously distributed and because of its small size and amphiphilic nature, it is able to reach easily all cellular and subcellular compartments. The highest intracellular melatonin concentrations are found in mitochondria, raising the possibility of functional significance for this targeting with involvement in situ in mitochondrial activities. Mitochondria, the powerhouse of the cell, are considered to be the most important cellular organelles to contribute to degenerative processes mainly through respiratory chain dysfunction and formation of reactive oxygen species, leading to damage to mitochondrial proteins, lipids and DNA. Therefore, protecting mitochondria from oxidative damage could be an effective therapeutic strategy against cellular degenerative processes. Many of the beneficial effects of melatonin administration may depend on its effect on mitochondrial physiology. Cardiolipin, a phospholipid located at the level of inner mitochondrial membrane is known to be intimately involved in several mitochondrial bioenergetic processes as well as in mitochondrial-dependent steps of apoptosis. Alterations to cardiolipin structure, content and acyl chain composition have been associated with mitochondrial dysfunction in multiple tissues in several physiopathological situations and aging. Recently, melatonin was reported to protect the mitochondria from oxidative damage by preventing cardiolipin oxidation and this may explain, at least in part, the beneficial effect of this molecule in mitochondrial physiopathology. In this review, we discuss the role of melatonin in preventing mitochondrial dysfunction and disease.


Assessment of Allergic and Anaphylactic Reactions to mRNA COVID-19 Vaccines With Confirmatory Testing in a US Regional Health System.
As of May 2021, more than 32 million cases of COVID-19 have been confirmed in the United States, resulting in more than 615 000 deaths. Anaphylactic reactions associated with the Food and Drug Administration (FDA)-authorized mRNA COVID-19 vaccines have been reported. To characterize the immunologic mechanisms underlying allergic reactions to these vaccines. This case series included 22 patients with suspected allergic reactions to mRNA COVID-19 vaccines between December 18, 2020, and January 27, 2021, at a large regional health care network. Participants were individuals who received at least 1 of the following International Statistical Classification of Diseases and Related Health Problems, Tenth Revision anaphylaxis codes: T78.2XXA, T80.52XA, T78.2XXD, or E949.9, with documentation of COVID-19 vaccination. Suspected allergy cases were identified and invited for follow-up allergy testing. FDA-authorized mRNA COVID-19 vaccines. Allergic reactions were graded using standard definitions, including Brighton criteria. Skin prick testing was conducted to polyethylene glycol (PEG) and polysorbate 80 (P80). Histamine (1 mg/mL) and filtered saline (negative control) were used for internal validation. Basophil activation testing after stimulation for 30 minutes at 37 °C was also conducted. Concentrations of immunoglobulin (Ig) G and IgE antibodies to PEG were obtained to determine possible mechanisms. Of 22 patients (20 [91%] women; mean [SD] age, 40.9 [10.3] years; 15 [68%] with clinical allergy history), 17 (77%) met Brighton anaphylaxis criteria. All reactions fully resolved. Of patients who underwent skin prick tests, 0 of 11 tested positive to PEG, 0 of 11 tested positive to P80, and 1 of 10 (10%) tested positive to the same brand of mRNA vaccine used to vaccinate that individual. Among these same participants, 10 of 11 (91%) had positive basophil activation test results to PEG and 11 of 11 (100%) had positive basophil activation test results to their administered mRNA vaccine. No PEG IgE was detected; instead, PEG IgG was found in tested individuals who had an allergy to the vaccine. Based on this case series, women and those with a history of allergic reactions appear at have an elevated risk of mRNA vaccine allergy. Immunological testing suggests non-IgE-mediated immune responses to PEG may be responsible in most individuals.


Systems level metabolic phenotype of methotrexate administration in the context of non-alcoholic steatohepatitis in the rat.
Adverse drug reactions (ADRs) represent a significant clinical challenge with respect to patient morbidity and mortality. We investigated the hepatotoxicity and systems level metabolic phenotype of methotrexate (MTX) in the context of a prevalent liver disease; non-alcoholic steatohepatitis (NASH). A nuclear magnetic resonance spectroscopic-based metabonomic approach was employed to analyze the metabolic consequences of MTX (0, 10, 40, and 100 mg/kg) in the urine and liver of healthy rats (control diet) and in a model of NASH (methionine-choline deficient diet). Histopathological analysis confirmed baseline (0 mg/kg) liver necrosis, liver inflammation, and lipid accumulation in the NASH model. Administration of MTX (40 and 100 mg/kg) led to liver necrosis in the control cohort, whereas the NASH cohort also displayed biliary hyperplasia and liver fibrosis (100 mg/kg), providing evidence of the synergistic effect of MTX and NASH. The complementary hepatic and urinary metabolic phenotypes of the NASH model, at baseline, revealed perturbation of multiple metabolites associated with oxidative and energetic stress, and folate homeostasis. Administration of MTX in both diet cohorts showed dose-dependent metabolic consequences affecting gut microbial, energy, nucleobase, nucleoside, and folate metabolism. Furthermore, a unique panel of metabolic changes reflective of the synergistic effect of MTX and NASH was identified, including the elevation of hepatic phenylalanine, urocanate, acetate, and both urinary and hepatic formiminoglutamic acid. This systems level metabonomic analysis of the hepatotoxicity of MTX in the context of NASH provided novel mechanistic insight of potential wider clinical relevance for further understanding the role of liver pathology as a risk factor for ADRs.


Different types of smooth muscle hypertrophy.
Smooth muscles respond to changes in their working situation by rapid and pronounced adjustments of functional and structural properties. We have examined the effects of experimental portal hypertension on the smooth muscle of the rat portal vein in a series of studies that are summarized in this review. Within one week following partial ligation of the hepatic branches of the vein, the cross-sectional area of its muscle coat increased about twofold owing to increase in the size of the individual muscle cells. The hypertrophy was associated with membrane hyperpolarization, inhibition of spontaneous electrical and mechanical activity, and reduced sensitivity to exogenous norepinephrine. Active force per unit of cross-sectional area decreased, but metabolic studies indicated improved tension economy compared with normal portal veins. The literature on different types of hypertrophy in intestinal smooth muscle, urinary bladder, and uterus is briefly reviewed. The importance of mechanical distention and chemical trophic factors as stimuli for the growth processes is discussed.


Impact of symptoms on quality of life before and after diagnosis of coeliac disease: results from a UK population survey.
Coeliac disease is a common chronic autoimmune disorder. Underdiagnosis is common and the quality of life impact of symptoms may be severe. We report a study of symptom duration and quality of life before and after diagnosis in a representative sample of people with diagnosed coeliac disease in the UK. Postal questionnaire of 2000 people with diagnosed coeliac disease, requesting information on date of diagnosis, type and duration of symptoms, and quality of life before and after diagnosis using the EQ-5D instrument. The survey response rate was 40% (788/2000). Mean duration of symptoms prior to diagnosis was 13.2 years, with some evidence of shorter duration in recent years. Respondents reported a mean of 13 consultations with their GP about their symptoms prior to diagnosis. The mean utility value of pre-diagnosis quality of life was 0.56, compared to 0.84 at time of survey, a highly statistically significant improvement of 0.27 (95% c.i. 0.25, 0.30). The symptoms of undiagnosed coeliac disease are associated with a prolonged and substantial decrement to quality of life. These results strengthen the case for detailed examination of the cost-effectiveness of improved methods of detection and diagnosis, including population screening.


PGC-1{alpha} is required for AICAR-induced expression of GLUT4 and mitochondrial proteins in mouse skeletal muscle.
We tested the hypothesis that repeated activation of AMP-activated protein kinase (AMPK) induces mitochondrial and glucose membrane transporter mRNA/protein expression via a peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha)-dependent mechanism. Whole body PGC-1alpha-knockout (KO) and littermate wild-type (WT) mice were given either single or repeated subcutaneous injections of the AMPK activator AICAR or saline. Skeletal muscles were removed either 1 or 4 h after the single AICAR treatment or 24 h after the last injection following repeated AICAR treatment. Repeated AICAR treatment increased GLUT4, cytochrome (cyt) c oxidase I, and (cyt) c protein expression approximately 10-40% relative to saline in white muscles of WT but not of PGC-1alpha-KO mice, whereas fatty acid translocase/CD36 (FAT/CD36) protein expression was unaffected by AICAR treatment in both genotypes. GLUT4, cyt c, and FAT/CD36 mRNA content increased 30-60% 4 h after a single AICAR injection relative to saline in WT, and FAT/CD36 mRNA content decreased in PGC-1alpha-KO mice. One hour after a single AICAR treatment, phosphorylation of AMPK and the downstream target acetyl-coenzyme A carboxylase increased in all muscles investigated independent of genotype, indicating normal AICAR-induced AMPK signaling in the absence of PGC-1alpha. The hexokinase II (HKII) mRNA and protein response was similar in muscles of WT and PGC-1alpha-KO mice after single and repeated AICAR treatments, respectively, confirming that HKII is regulated independently of PGC-1alpha in response to AICAR. In conclusion, here we provide genetic evidence for a role of PGC-1alpha in AMPK-mediated regulation of mitochondrial and glucose membrane transport protein expression in skeletal muscle.


Gold Nanoparticles Radio-Sensitize and Reduce Cell Survival in Lewis Lung Carcinoma.
It has been suggested that particle size plays an important role in determining the genotoxicity of gold nanoparticles (GNPs). The purpose of this study was to compare the potential radio-sensitization effects of two different sized GNPs (3.9 and 37.4 nm) fabricated and examined in vitro in Lewis lung carcinoma (LLC) as a model of non-small cell lung cancer through use of comet and clonogenic assays. After treatment with 2Gy X-ray irradiation, both particle sizes demonstrated increased DNA damage when compared to treatment with particles only and radiation alone. This radio-sensitization was further translated into a reduction in cell survival demonstrated by clonogenicity. This work indicates that GNPs of both sizes induce DNA damage in LLC cells at the tested concentrations, whereas the 37.4 nm particle size treatment group demonstrated greater significance in vitro. The presented data aids in the evaluation of the radiobiological response of Lewis lung carcinoma cells treated with gold nanoparticles.


Infrared absorption cross section of arsenic in silicon in the impurity band region of concentration.
The spectral dependence of the infrared absorption cross section of As in Si near 0 K has been determined from infrared transmission measurements for three As concentrations (5.3, 8.4, and 15.9 x 10(17) cm(-3)) in the impurity band regime. The results demonstrate some features of physical interest. With increasing As concentration, the lines associated with the intra-atomic transitions broaden asymmetrically, while the integral of the total absorption cross section over photon energy is conserved as required by the oscillator strength sum rule. It thus appears that the cross section for the intra-atomic transitions is conserved as the lines hybridize with the continuum. Comparison of our results with photoionization cross-sectional data suggests that the lines contribute to the cross section for photoionization through field and thermally assisted transitions when they are near the threshold for photoionization.


Socioeconomic costs of open surgery and gamma knife radiosurgery for benign cranial base tumors.
The aim of this study was to evaluate the relative socioeconomic costs of benign cranial base tumors treated with open surgery and gamma knife radiosurgery. In a retrospective study, we studied 174 patients with benign cranial base tumors, less than 3 cm in diameter (or volume less than 30 ml), admitted in the past 5 years. Group A (n = 94) underwent open surgery for removal of the tumors, whereas Group B (n = 80) underwent gamma knife radiosurgery. The socioeconomic costs were evaluated by both direct and indirect cost. The direct costs comprised intensive care unit cost, ward cost, operating room cost, and outpatient visiting cost. The indirect costs included loss of workdays and mortality. The length of hospital stay, the number of lost workdays, surgical complications, mortality, and cost-effectiveness analysis were calculated as well. Student t test and chi test were used for statistical analysis. The mean length of hospital stay for open surgery was 18.2 +/- 30.4 days including 5.0 +/- 14.7 days of intensive care unit stay and 13.0 +/- 15.2 days of ward stay, P < 0.01. The mean hospital stay for gamma knife was 2.2 +/- 0.9 days with no need of intensive care unit stay, P < 0.01. The mean loss of workdays for open surgery was 160 +/- 158 days and 8.0 +/- 9.0 days for gamma knife, P < 0.01. The gamma knife cost per hour (1435 US dollars) is higher than the open surgery cost per hour (450 US dollars), P < 0.01. The direct cost for gamma knife (9677 US dollars +/- 6700 US dollars) is higher than that for open surgery (5837 US dollars +/- 6587 US dollars), P < 0.01. Open surgery had more complication rates (31.2%) than gamma knife (3.8%). Open surgery had a mortality rate of 5.3%; there was no mortality for gamma knife. The indirect costs, including loss of workdays and mortality, were significantly higher for open surgery than for gamma knife, P < 0.01. Finally, the socioeconomic cost (34,453 US dollars +/- 97,277 US dollars) is higher for open surgery than for gamma knife (10,044 US dollars +/- 7481 US dollars), P < 0.01. The CEA is significantly higher in gamma knife (3762 US dollars/quality-adjusted life year) than in open surgery (8996 US dollars/quality-adjusted life year), P < 0.01. Most of the socioeconomic loss with open surgery for benign cranial base tumors comes from the indirect costs of workdays lost and mortality. Gamma knife radiosurgery is a worthwhile treatment to our patients and to our society because it may shorten hospital stays and workdays lost and reduce complications, mortality, socioeconomic loss, and achieve better cost-effectiveness.


Examining surface and bulk structures using combined nonlinear vibrational spectroscopies.
We combined sum-frequency generation (SFG) vibrational spectroscopy with coherent anti-Stokes Raman scattering (CARS) spectroscopy in one system to examine both surface and bulk structures of materials with the same geometry and without the need to move the sample. Poly(methyl methacrylate) (PMMA) and polystyrene (PS) thin films were tested before and after plasma treatment. The sensitivities of SFG and CARS were tested by varying polymer film thickness and using a lipid monolayer.


Bile acids are "homeotrophic" sensors of the functional hepatic capacity and regulate adaptive growth during liver regeneration.
Liver mass depends on one or more unidentified humoral signals that drive regeneration when liver functional capacity is diminished. Bile acids are important liver products, and their levels are tightly regulated. Here, we identify a role for nuclear receptor-dependent bile acid signaling in normal liver regeneration. Elevated bile acid levels accelerate regeneration, and decreased levels inhibit liver regrowth, as does the absence of the primary nuclear bile acid receptor FXR. We propose that FXR activation by increased bile acid flux is a signal of decreased functional capacity of the liver. FXR, and possibly other nuclear receptors, may promote homeostasis not only by regulating expression of appropriate metabolic target genes but also by driving homeotrophic liver growth.


Training substance abuse clinicians in motivational interviewing using live supervision via teleconferencing.
Training through traditional workshops is relatively ineffective for changing counseling practices. Teleconferencing supervision (TCS) was developed to provide remote, live supervision for training motivational interviewing (MI). Ninety-seven drug treatment counselors completed a 2-day MI workshop and were randomized to live supervision via teleconferencing (TCS; n = 32), standard tape-based supervision (tape; n = 32), or workshop alone (workshop; n = 33). Supervision conditions received 5 weekly supervision sessions at their sites using actors as standard patients. Sessions with clients were rated for MI skill with the Motivational Interviewing Treatment Integrity (MITI) Coding System pre-workshop and 1, 8, and 20 weeks post-workshop. Mixed-effects linear models were used to test training condition on MI skill at 8 and 20 weeks. TCS scored better than workshop on the MITI for spirit (mean difference = 0.76; p < .0001; d = 1.01) and empathy (mean difference = 0.68; p < .001; d = 0.74). TCS was superior to workshop in reducing MI non-adherence and was superior to workshop and tape in increasing reflection to question ratio. Tape was superior to TCS in increasing complex reflections. Percentage of counselors meeting proficiency differed significantly between training conditions for the most stringent threshold (spirit and empathy scores ≥ 6). TCS shows promise for promoting new counseling behaviors following participation in workshop training. However, further work is needed to improve supervision methods to bring more clinicians to high levels of proficiency and facilitate dissemination of evidence-based practices.


Demographic, clinical and lifestyle-related correlates of accelerometer assessed physical activity and fitness in newly diagnosed patients with head and neck cancer.
Introduction: Objective measurements of levels of physical activity and fitness in patients with head and neck cancer (HNC) are lacking. Furthermore, demographic, clinical and lifestyle-related correlates of low levels of physical activity and fitness in patients with HNC are unknown. This study aims to investigate the levels of accelerometer that assessed physical activity and fitness in patients with HNC and to identify their demographical, clinical and lifestyle-related correlates.Methods: Two hundred and fifty-four patients who were recently diagnosed with HNC and participated in the NETherlands QUality of life and Biomedical cohort studies In head and neck Cancer (NET-QUBIC) study were included. Physical activity (accelerometer), cardiorespiratory fitness (Chester Step Test), hand grip strength (hand dynamometer) and lower body muscle function (30-second chair-stand test) were assessed. Multivariable linear regression analyses with a stepwise forward selection procedure were used.Results: Patients spent 229 min/d in physical activity of which 18 min/d in moderate-to-vigorous physical activity. The mean predicted VO2max was 27.9 ml/kg/min, the mean hand grip strength was 38.1 kg and the mean number of standings was 14.3. Patients with lower educational level, more comorbidity and higher tumor stage spent significantly less time in physical activity. Older patients, females and patients with a higher tumor stage had significantly lower cardiorespiratory fitness levels. Older patients, females, patients with more comorbidity, patients with normal weight and patients who have never smoked had significantly lower hand grip strength. Older patients, patients with lower educational level, smokers and patients with more comorbidity had a significantly lower function of lower body muscle.Conclusions: Pre-treatment levels of physical activity, cardiorespiratory fitness and lower body muscle function are low in patients with HNC. Based on this study, exercise programs targeted and tailored to patients with low levels of physical activity and fitness can be developed.


A new method for computer-assisted detection, definition and differentiation of the urinary calculi.
Urinary stones are common and can be diagnosed with computed tomography (CT) easily. In this study, we aimed to specify the opacity characteristics of various types of calcified foci that develop through the urinary system by using an image analysis program. With this method, we try to differentiate the calculi from the non-calculous opacities and also we aimed to present how to identify the characteristic features of renal and ureteral calcules. We obtained the CT studies of the subjects (n = 48, mean age = 41 years) by using a dual source CT imaging system. We grouped the calculi detected in the dual-energy CT sections as renal (n = 40) or ureteric (n = 45) based on their locations. Other radio-opaque structures that were identified outside but within close proximity of the urinary tract were recorded as calculi "mimickers". We used ImageJ program for morphological analysis. All the acquired data were analyzed statistically. According to thorough morphological parameters, there were statistically significant differences in the angle and Feret angle values between calculi and mimickers (p < 0.001). Multivariate logistical regression analysis showed that Minor Axis and Feret angle parameters can be used to distinguish between ureteric (p = 0.003) and kidney (p = 0.001) stones. Computer-based morphologic parameters can be used simply to differentiate between calcular and noncalcular densities on CT and also between renal and ureteric stones.


Serial Imaging Surveillance for Patients With a History of Intracranial Aneurysm: Risk of De Novo Aneurysm Formation.
Although rare, de novo intracranial aneurysms (DNIAs) may develop in patients with a history of intracranial aneurysms (IAs). To evaluate the benefit of routine radiographic screening for DNIAs. Data for 2153 patients with IAs were retrospectively analyzed. A total of 185 patients underwent screening for DNIAs at frequent intervals. Overall, DNIAs were detected in 26 patients (1.2%). Of the 185 patients with surveillance, DNIAs developed in 9 (4.9%). The risk of DNIA detection was 1.14% per person-year of follow-up (95% confidence interval: 0.6%-2.2%). Patients with imaging follow-up had a significantly higher rate of DNIA detection compared with patients without regular imaging surveillance (4.9% vs 0.86%; P < .001), but surveillance was associated with smaller lesions (with surveillance: 3.8 ± 1.8 mm, without: 7.0 ± 4.4 mm, mean ± standard deviation; P = .026). A unimodal distribution of time to detection was found in those with surveillance, with a peak between 0 and 2 years. There was a trend toward an association of cigarette smoking and DNIA detection within 10 years (P = .06); 6 of the 26 patients (23.1%) with DNIAs had a history of cigarette smoking, with all 6 patients continuing to smoke up to the detection of the DNIAs, which were detected in 2.5 ± 1.8 years. The low 1.14% per-person year risk of DNIA detection and small DNIA size at detection cannot justify routine screening for DNIAs in all patients with a personal history of IAs. If imaging follow-up is considered for selected patients, early screening will likely yield the most benefit in patients who continue to smoke cigarettes.


How active gaze informs the hand in sequential pointing movements.
Visual information is vital for fast and accurate hand movements. It has been demonstrated that allowing free eye movements results in greater accuracy than when the eyes maintain centrally fixed. Three explanations as to why free gaze improves accuracy are: shifting gaze to a target allows visual feedback in guiding the hand to the target (feedback loop), shifting gaze generates ocular-proprioception which can be used to update a movement (feedback-feedforward), or efference copy could be used to direct hand movements (feedforward). In this experiment we used a double-step task and manipulated the utility of ocular-proprioceptive feedback from eye to head position by removing the second target during the saccade. We confirm the advantage of free gaze for sequential movements with a double-step pointing task and document eye-hand lead times of approximately 200 ms for both initial movements and secondary movements. The observation that participants move gaze well ahead of the current hand target dismisses foveal feedback as a major contribution. We argue for a feedforward model based on eye movement efference as the major factor in enabling accurate hand movements. The results with the double-step target task also suggest the need for some buffering of efference and ocular-proprioceptive signals to cope with the situation where the eye has moved to a location ahead of the current target for the hand movement. We estimate that this buffer period may range between 120 and 200 ms without significant impact on hand movement accuracy.


Docking-based comparative intermolecular contacts analysis as new 3-D QSAR concept for validating docking studies and in silico screening: NMT and GP inhibitors as case studies.
The significant role played by docking algorithms in drug discovery combined with their serious pitfalls prompted us to envisage a novel concept for validating docking solutions, namely, docking-based comparative intermolecular contacts analysis (dbCICA). This novel approach is based on the number and quality of contacts between docked ligands and amino acid residues within the binding pocket. It assesses a particular docking configuration on the basis of its ability to align a set of ligands within a corresponding binding pocket in such a way that potent ligands come into contact with binding site spots distinct from those approached by low-affinity ligands and vice versa. In other words, dbCICA evaluates the consistency of docking by assessing the correlation between ligands' affinities and their contacts with binding site spots. Optimal dbCICA models can be translated into valid pharmacophore models that can be used as 3-D search queries to mine structural databases for new bioactive compounds. dbCICA was implemented to search for new inhibitors of candida N-myristoyl transferase as potential antifungal agents and glycogen phosphorylase (GP) inhibitors as potential antidiabetic agents. The process culminated in five selective micromolar antifungal leads and nine GP inhibitory leads.


Executable biochemical space for specification and analysis of biochemical systems.
Computational systems biology provides multiple formalisms for modelling of biochemical processes among which the rule-based approach is one of the most suitable. Its main advantage is a compact and precise mechanistic description of complex processes. However, state-of-the-art rule-based languages still suffer several shortcomings that limit their use in practice. In particular, the elementary (low-level) syntax and semantics of rule-based languages complicate model construction and maintenance for users outside computer science. On the other hand, mathematical models based on differential equations (ODEs) still make the most typical used modelling framework. In consequence, robust re-interpretation and integration of models are difficult, thus making the systems biology paradigm technically challenging. Though several high-level languages have been developed at the top of rule-based principles, none of them provides a satisfactory and complete solution for semi-automated description and annotation of heterogeneous biophysical processes integrated at the cellular level. We present the second generation of a rule-based language called Biochemical Space Language (BCSL) that combines the advantages of different approaches and thus makes an effort to overcome several problems of existing solutions. BCSL relies on the formal basis of the rule-based methodology while preserving user-friendly syntax of plain chemical equations. BCSL combines the following aspects: the level of abstraction that hides structural and quantitative details but yet gives a precise mechanistic view of systems dynamics; executable semantics allowing formal analysis and consistency checking at the level of the language; universality allowing the integration of different biochemical mechanisms; scalability and compactness of the specification; hierarchical specification and composability of chemical entities; and support for genome-scale annotation.


A survey of trauma alert criteria and handover practice in England and Wales.
Appropriate alerting of patients with trauma and informative handover are necessary to allow a smooth transition of care between the prehospital and hospital teams. To identify current practice and areas that need to be improved to facilitate the transition from prehospital care to emergency department resuscitation. A questionnaire postal study of 100 emergency departments and all 32 ambulance service trusts in England and Wales. Emergency departments returned 34 (34%) completed questionnaires, and ambulance trusts returned 16 (50%) completed questionnaires. In all, 56.8% of emergency department responders stated that trauma alert information was relayed through ambulance control, 48.5% stated that alert messages were standardised and 18.5% felt that ambulance crews used the trauma severity scoring system during alerting. 64.7% stated that handover was broadcast to the trauma team and 9.1% routinely received digital photographic images. All ambulance service responders included injury mechanism in their alerting criteria and 53.3% used a standard handover structure with 86.7% familiar with the mnemonic ASHICE (Age, Sex, History, Injuries, Condition, Expected time of arrival) for rapid information transmission. Greater cooperation between regional emergency departments and ambulance services is necessary to refine the alerting and handover process, producing a pathway through which vital information is collected by trained personnel and communicated without distortion to the resuscitation room, where it may be utilised to inform life-saving decisions.


Innate signals compensate for the absence of PKC-{theta} during in vivo CD8(+) T cell effector and memory responses.
PKC- is central to T-helper (Th) 2 cell differentiation and effector function; however, its importance for antiviral effector, and in particular memory CD8(+) T cell responses, remains unclear. We have investigated the role of PKC- during in vivo and in vitro responses against influenza virus, lymphocytic choriomeningitis virus, vaccinia virus, and replication-deficient virus-like particles. In the absence of PKC-, antiviral CD8(+) T cells presented an unresponsive phenotype in vitro, which could be restored with exogenous IL-2 or by Toll-like receptor ligand-activated dendritic cells. In striking contrast, PKC- appeared to be superfluous for in vivo antiviral responses irrespective of whether the virus infected systemically, was localized to the lung, or did not replicate. In addition, CD8(+) CCR7-effector memory responses were normal in PKC--deficient mice, both in lymphoid and peripheral tissues. Our data show that increased activation signals delivered in vivo by highly activated dendritic cells, as present during viral infections, overcome the requirement for PKC- during CD8(+) T cell antiviral responses.


The impact of aging and oxidative stress in metabolic and nervous system disorders: programmed cell death and molecular signal transduction crosstalk.
Life expectancy is increasing throughout the world and coincides with a rise in non-communicable diseases (NCDs), especially for metabolic disease that includes diabetes mellitus (DM) and neurodegenerative disorders. The debilitating effects of metabolic disorders influence the entire body and significantly affect the nervous system impacting greater than one billion people with disability in the peripheral nervous system as well as with cognitive loss, now the seventh leading cause of death worldwide. Metabolic disorders, such as DM, and neurologic disease remain a significant challenge for the treatment and care of individuals since present therapies may limit symptoms but do not halt overall disease progression. These clinical challenges to address the interplay between metabolic and neurodegenerative disorders warrant innovative strategies that can focus upon the underlying mechanisms of aging-related disorders, oxidative stress, cell senescence, and cell death. Programmed cell death pathways that involve autophagy, apoptosis, ferroptosis, and pyroptosis can play a critical role in metabolic and neurodegenerative disorders and oversee processes that include insulin resistance, β-cell function, mitochondrial integrity, reactive oxygen species release, and inflammatory cell activation. The silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), AMP activated protein kinase (AMPK), and Wnt1 inducible signaling pathway protein 1 (WISP1) are novel targets that can oversee programmed cell death pathways tied to β-nicotinamide adenine dinucleotide (NAD+), nicotinamide, apolipoprotein E (APOE), severe acute respiratory syndrome (SARS-CoV-2) exposure with coronavirus disease 2019 (COVID-19), and trophic factors, such as erythropoietin (EPO). The pathways of programmed cell death, SIRT1, AMPK, and WISP1 offer exciting prospects for maintaining metabolic homeostasis and nervous system function that can be compromised during aging-related disorders and lead to cognitive impairment, but these pathways have dual roles in determining the ultimate fate of cells and organ systems that warrant thoughtful insight into complex autofeedback mechanisms.


Safety and Complications of Double-Lumen Tunnelled Cuffed Central Venous Dialysis Catheters: Clinical and radiological perspective from a tertiary centre in Oman.
This study aimed to assess the technical success, safety and immediate and delayed complications of double-lumen tunnelled cuffed central venous catheters (TVCs) at the Sultan Qaboos University Hospital (SQUH), Muscat, Oman. This retrospective study took place between January 2012 and October 2013. The clinical records and radiological data of all patients who underwent ultrasound- and fluoroscopy-guided TVC placement at SQUH during the study period were reviewed. Demographic data and information regarding catheter placement, technical success and peri- and post-procedure complications (such as catheter-related infections or thrombosis) were collected. A total of 204 TVCs were placed in 161 patients. Of these, 68 were female (42.2%) and 93 were male (57.8%). The mean age of the patients was 54.4 ± 17.3 years. The most common reason for catheter placement was the initiation of dialysis (63.4%). A total of 203 procedures were technically successful (99.5%). The right internal jugular vein was the most common site of catheter placement (74.9%). Mild haemorrhage which resolved spontaneously occurred in 11 cases (5.4%). No other complications were observed. Subsequent follow-up data was available for 132 catheters (65.0%); of these, thrombosis-related catheter malfunction was observed in 22 cases (16.7%) and catheter-related infection in 29 cases (22.0%). Radiological-guided placement of tunnelled haemodialysis catheters can be performed safely with excellent technical success. The success rate of catheter insertion at SQUH was favourable in comparison with other studies reported in the literature.


Models of Care Delivery for Families of Critically Ill Children: An Integrative Review of International Literature.
Critical illness in children is a life changing event for the child, their parents, caregivers and wider family. There is a need to design and evaluate models of care that aim to implement family-centred care to support more positive outcomes for critically ill children and their families. Due to a gap in knowledge on the impact of such models, the present review was conducted. Primary research articles written in English that focused on children hospitalised for an acute, unexpected, sudden critical illness, such as that requiring an intensive care admission; and addressed the implementation of a model of care in a paediatric acute care hospital setting. Thirteen studies met the inclusion criteria. The models of care implemented were associated with positive changes such as reduced parental anxiety and improved communication between parents/caregivers and health professionals. However, no model provided intervention throughout each phase of care to (or post) hospital discharge. Models of care applying family-centred care principles targeting critically ill children and their families can create positive changes in care delivery for the family. However a model which provides continuity across the span of care is required. There is need to describe how best to design, implement and sustain models of care for critically ill children and their families. The success of any intervention implementation will be dependent on the comprehensiveness of the strategy for implementation, the relevance to the context and setting, and engagement with key stakeholders.


Dehydroepiandrosterone supplementation in women with adrenal failure: impact on twenty-four hour GH secretion and IGF-related parameters.
In women, GH secretion is strongly influenced by oestrogen status, whereas the role of androgens is unclear. We, therefore, examined GH secretory dynamics during low vs. normalized androgen levels in women with adrenal failure. Ten females with adrenal failure (AF), mean age of 42 years (range 22-54 years). The effects of 8 days of oral dehydroepiandrosterone (DHEA; 50 mg/day) were studied in a double-blind placebo-controlled, cross-over design. A control group of healthy women was studied once without any treatment. Before and after each treatment period, blood was sampled for measurement of androgens, IGF-I, IGFBP-3 and GHBP. A 24-h GH profile with measurements every 20 min was performed at the end of each period. DHEA supplementation normalized the mean circulating levels of testosterone and androgen precursors. The secretory pattern of GH was unaltered during DHEA [placebo vs. DHEA; half-life 22.83 +/- 1.24 vs. 21.45 +/- 1.19 (min), P = 0.429; pulse frequency 9.9 +/- 0.7 vs. 10.5 +/- 0.5 (/24 h), P = 0.502; total production rate 62.27 +/- 13.44 vs. 52.61 +/- 7.06 (microg/l/day), P = 0.317]. Subgroup analysis, however, indicated that DHEA treatment increased GH secretion in patients not receiving oestrogen (n = 5), whereas the opposite was observed among patients receiving exogenous oestrogen derivatives (n = 5). Compared to the control group (CON), GH half-life was longer in AF (half-life CON: 16.48 +/- 0.91, P = 0.001). The additional features of GH secretion were similar. Unexpectedly, the levels of IGF-I, IGFBP-3 and GHBP were elevated in the patients as compared to controls, without significant effects of DHEA [AF vs. CON. IGF-I: 186 +/- 20 vs. 144 +/- 7 (microg/l), P = 0.04; IGFBP-3: 5196 +/- 224 vs. 3687 +/- 212 (microg/l), P = 0.001; GHBP: 2.27 +/- 0.25 vs. 1.41 +/- 0.13 (nmol/l), P = 0.002]. (1) Short-term DHEA administration in women with adrenal failure normalizes the circulating levels of androgens without uniformly affecting the GH-IGF axis; (2) The observation that exogenous oestradiol may mask a stimulatory effect of DHEA on GH secretion merits future investigation.


Effect of orthognathic surgery on the temporomandibular joint in patients with anterior open bite.
This study examined the prevalence of temporomandibular joint (TMJ) signs and symptoms in patients with anterior open bite. The influence of orthognathic surgery on the TMJ in these patients and the interaction of occlusal and psychologic variables on the presence and/or persistence of pain was studied. A retrospective survey of 83 patients with an anterior open bite who underwent orthognathic surgery was carried out. Records were examined for the prevalence of abnormal TMJ signs and symptoms, including pain. A survey was mailed to these patients that consisted of: (1) the TMJ Scale, (2) the Symptom Checklist 90 (SCL90), (3) the Spielberger State-Trait Anxiety Inventory (STAI), and (4) a visual analog scale on which patients indicated their degree of satisfaction with the procedure. Thirty-seven (42%) patients responded to the survey, and 13 (15%) also attended a clinical and radiographic examination. Multiple regression analysis was used for statistical analysis of the factors contributing to the presence and/or persistence of pain. In the preoperative group, the prevalence of pain was 32%, dysfunction 40%, and limitation of opening 7%. Age and gender were significantly associated with the presence of pain. The overall prevalence of abnormal TMJ signs and symptoms was not significantly different after orthognathic surgery. An abnormal psychologic profile was the most significant factor associated with the presence and/or persistence of pain. It is concluded that that the prevalence of temporomandibular disorders in anterior open bite patients increases with age, is significantly higher in females, and is not influenced by other occlusal variables. Furthermore, orthognathic surgery does not significantly influence temporomandibular disorders in patients with anterior open bite. Female patients, particularly those with an abnormal psychologic profile, are at a higher risk of persistent postoperative TMJ pain.


Poor capacity for proliferation of pancreatic beta-cells in Otsuka-Long-Evans-Tokushima Fatty rat: a model of spontaneous NIDDM.
Otsuka-Long-Evans-Tokushima Fatty (OLETF) rat, a genetic model of spontaneous development of NIDDM, exhibits hyperglycemic obesity with hyperinsulinemia and insulin resistance similar to that in humans. It is still unclear whether a defect in the beta-cell proliferation per se is the primary pathogenetic event in OLETF rat. To determine whether it is, we used partially pancreatectomized rats as a model, with administration of phlorizin to control blood glucose level, to examine whether the capacity for proliferation of beta-cells during hyperglycemia or normoglycemia differs between OLETF and their diabetes-resistant counterparts, Long-Evans-Tokushima-Otsuka (LETO) rats. We also examined whether such a defect, if present, could be improved by nicotinamide. Male rats, 6 weeks of age, were allocated at random to two groups: 70% pancreatectomy (Px) and sham-pancreatectomy (sham). Each group was divided into four subgroups by date of killing after surgery: 3-day, 7-day, 28-day (treated with phlorizin, nicotinamide, or saline), and 91-day. A sustained hyperglycemia was evident in the Px OLETF rats after surgery, which was associated with insufficient proliferation of beta-cells, characterized by decrease in beta-cell labeling index in proportion to decrease in beta-cell mass and reduction in insulin content in the remnant pancreas. This defect was unaffected by restoration of normoglycemia induced by phlorizin injection. Administration of nicotinamide, however, ameliorated the sustained hyperglycemia by increasing beta-cell proliferation. These findings suggest that OLETF rats have poor capacity for proliferation of pancreatic beta-cells and that this change may be the critical pathogenetic event before the onset of overt diabetes.


An in vitro airway wall model of remodeling.
Recent studies have shown that mechanical forces on airway epithelial cells can induce upregulation of genes involved in airway remodeling in diseases such as asthma. However, the relevance of these responses to airway wall remodeling is still unclear since 1). mechanotransduction is highly dependent on environment (e.g., matrix and other cell types) and 2). inflammatory mediators, which strongly affect remodeling, are also present in asthma. To assess the effects of mechanical forces on the airway wall in a relevant three-dimensional inflammatory context, we have established a tissue culture model of the human airway wall that can be induced to undergo matrix remodeling. Our model contains differentiated human bronchial epithelial cells characterized by tight junctions, cilia formation, and mucus secretion atop a collagen gel embedded with human lung fibroblasts. We found that addition of activated eosinophils and the application of 50% strain to the same system increased the epithelial thickness compared with either condition alone, suggesting that mechanical strain affects airway wall remodeling synergistically with inflammation. This integrated model more closely mimics airway wall remodeling than single-cell, conditioned media, or even two-dimensional coculture systems and is relevant for examining the importance of mechanical strain on airway wall remodeling in an inflammatory environment, which may be crucial for understanding and treating pathologies such as asthma.


An actin barrier to resealing.
Plasma membrane disruption is a common form of cell injury in many normal biological environments, including many mammalian tissues. Survival depends on the initiation of a rapid resealing response that is mounted only in the presence of physiological levels of extracellular Ca(2+). Vesicle-vesicle and vesicle-plasma membrane fusion events occurring in cortical cytoplasm surrounding the defect are thought to be a crucial element of the resealing mechanism. However, in mammalian cells, the vesicles used in this fusion reaction (endosomes/lysosomes) are not present in a 'pre-docked' configuration and so must be brought into physical contact with one another and with the plasma membrane. We propose that a requisite prelude to fusion is the disassembly in local cell cortex of the physical barrier constituted by filamentous actin. Consistent with this hypothesis, we found that rat gastric epithelial (RGM1) cell cortical staining with phalloidin was apparently reduced at presumptive disruption sites. Moreover, flow cytofluorometric analysis of wounded RGM1 populations revealed a small, but significant, Ca(2+)-dependent reduction in whole cell phalloidin staining. The functional significance of this disruption-induced depolymerization response was confirmed in several independent tests. Introduction into RGM1 cells of the filamentous actin-depolymerizing agent, DNase1, enhanced resealing, although cytochalasin treatment, by itself, had no effect. By contrast, when the filamentous actin cytoskeleton was stabilized experimentally, using phalloidin or jasplakinolide, resealing was strongly inhibited. Cells in wounded cultures displayed an enhanced cortical array of filamentous actin, and resealing by such cells was enhanced strongly by both cytochalasin and DNase 1, demonstrating the specific reversibility of a biologically mediated, polymerization-induced inhibition of resealing. We conclude that localized filamentous actin disassembly removes a cortical barrier standing in the way of membrane-membrane contacts leading to resealing-requisite homotypic and exocytotic fusion events.


Candida esophagitis: risk factors in non-HIV population in Pakistan.
Candida esophagitis is a frequent infection in immunocompromised patients. This study was designed to determine its characteristics in non- human immune deficiency virus (HIV) infected patients attending a teaching hospital. Clinical records of all patients coded by international classification of diseases 9th revision with clinical modifications' (ICD-9-CM), with candida esophagitis diagnosed by esophagogastroduodenoscopy (EGD) and histopathology over a period of 5 years were studied. Fifty-one patients (27 males, 24 females, range 21-77 years old and mean age 52.9 years) fulfilled the criteria (0.34% of the EGD). The common predisposing factors were carcinoma (OR 3.87, CI 1.00-14.99) and diabetes mellitus (OR 4.39, CI 1.34-14.42). The frequent clinical symptoms were retrosternal discomfort, dysphagia and epigastric abdominal pain with endoscopic appearance of scattered mucosal plaques. Another endoscopic lesion was associated with candida esophagitis in 15% patients. Carcinomas, diabetes mellitus, corticosteroid and antibiotic therapy are major risk factors for candida esophagitis in Pakistan. It is an easily managed complication that responds to treatment with nystatin.


Nutrient Restriction has Limited Short-Term Effects on Gut, Immunity, and Brain Development in Preterm Pigs.
Extrauterine growth restriction (EUGR) in preterm infants is associated with higher morbidity and impaired neurodevelopment. Early nutrition support may prevent EUGR in preterm infants, but it is not known if this improves organ development and brain function in the short and long term. Using pigs as models for infants, we hypothesized that diet-induced EUGR impairs gut, immunity, and brain development in preterm neonates during the first weeks after birth. Forty-four preterm caesarean-delivered pigs (Danish Landrace × Large White × Duroc, birth weight 975 ± 235 g, male:female ratio 23:21) from 2 sows were fed increasing volumes [32-180 mL/(kg·d)] of dilute bovine milk (EUGR group) or the same diet fortified with powdered bovine colostrum for 19 d (CONT group, 50-100% higher protein and energy intake than the EUGR group). The EUGR pigs showed reduced body growth (-39%, P < 0.01), lower plasma albumin, phosphate, and creatine kinase concentrations (-35 to 14%, P < 0.05), increased cortisol and free iron concentrations (+130 to 700%, P < 0.05), and reduced relative weights of the intestine, liver, and spleen (-38 to 19%, all P < 0.05). The effects of EUGR on gut structure, function, microbiota, and systemic immunity were marginal, although EUGR temporarily increased type 1 helper T cell (Th1) activity (e.g. more blood T cells and higher Th1-related cytokine concentrations on day 8) and reduced colon nutrient fermentation (lower SCFA concentration; -45%, P < 0.01). Further, EUGR pigs showed increased relative brain weights (+19%, P < 0.01), however, memory and learning, as tested in a spatial T-maze, were not affected. Most of the measured organ growth, and digestive, immune, and brain functions showed limited effects of diet-induced EUGR in preterm pigs during the first weeks after birth. Likewise, preterm infants may show remarkable physiological adaptation to deficient nutrient supply during the first weeks of life although early life malnutrition may exert negative consequences later.


Appetite suppressants in pregnancy.
Both, obesity as well as anorexia may be associated with infertility and other complications of pregnancy. Weight loss during pregnancy is therefore considered a risk factor. Weight loss and appetite suppressant are contraindicated during pregnancy, but the unintended exposure is probably not associated with higher risk. Our work was focused on trends in the appetite suppressants use in the Czech Republic and their embryotoxicity. The pregnancies exposed to various appetite suppressants were followed prospectively in the years 1997-2012. The study group was compared to the comparison group which enrolled pregnant women exposed to non-teratogenic drugs. Drugs used as appetite suppressants were sibutramine and phentermine. Number of calls for this type of exposure was rare till 2005. Their number started to increase until 2009. Later, number of calls decreased because both drugs were withdrawn from the market. This finding reflects increasing tendency for the weight control in the group of fertile women in the Czech Republic. In our study, we did not reveal differences in pregnancy outcomes between study and comparison groups. However, we should be aware of the increasing food supplements exposure, that could be used as alternative to the appetite suppressants. Their potential risk results from the limited or completely absent control of their origin. Some of them have probably only placebo effect, but some of them could represent the risk.


Effect of beam defocus on the efficiency of planar waveguide grating couplers.
Results of theoretical calculations and experimental measurements of variation of grating coupling efficiency with beam-defocus position are presented. Our results indicate that (1) coupling efficiency is not necessarily maximum at the beam waist, (2) coupling efficiency as a function of defocus position shows oscillatory behavior particularly for a tightly focused beam. The effect of beam size alone cannot account for the observed behavior of variation of coupling efficiency with defocus position. The results of measured angular dependence of coupling efficiency for various defocus conditions are also presented.


Severe diverticulitis after heart, lung, and heart-lung transplantation.
In this study, we reviewed our experience with severe diverticulitis in patients who have undergone heart and/or lung transplantation to assess whether transplant recipients are at increased risk of having severe diverticulitis compared with the general population. We reviewed the records of patients who underwent heart and/or lung transplantation from 1984 to 2000, inclusive, and identified patients with severe diverticulitis that required surgery or that resulted in death. We compared this incidence with the incidence of such complications in the general population, served by the same institution during a 2-year period, 1999 to 2000. A total of 953 patients underwent transplantation in the study period. The mean follow-up was 57 months, a total follow-up of 4528 patient-years. Nine patients (mean age, 54 years) had severe diverticulitis that required surgical intervention (8 patients) or that resulted in death (1 patient died without surgical intervention). During 1999 to 2000, 16 patients (mean age, 66 years) from the general population were treated for severe diverticulitis that required surgical intervention, 3 of whom died. From census and area health data, we found that the study institution serves approximately 90000 people older than 40 years, with a total follow-up of 180000 patient-years. The incidence rate ratio for severe diverticulitis when comparing the transplant with the non-transplant groups was 22.2 (95% confidence interval; 9.9-50.0; p < 0.001). Patients with severe diverticulitis who have undergone heart and/or lung transplantation can be treated surgically with a small mortality rate. Transplant recipients probably are at substantially increased risk of experiencing severe diverticulitis.


Improving Generalization via Attribute Selection on Out-of-the-Box Data.
Zero-shot learning (ZSL) aims to recognize unseen objects (test classes) given some other seen objects (training classes) by sharing information of attributes between different objects. Attributes are artificially annotated for objects and treated equally in recent ZSL tasks. However, some inferior attributes with poor predictability or poor discriminability may have negative impacts on the ZSL system performance. This letter first derives a generalization error bound for ZSL tasks. Our theoretical analysis verifies that selecting the subset of key attributes can improve the generalization performance of the original ZSL model, which uses all the attributes. Unfortunately, previous attribute selection methods have been conducted based on the seen data, and their selected attributes have poor generalization capability to the unseen data, which is unavailable in the training stage of ZSL tasks. Inspired by learning from pseudo-relevance feedback, this letter introduces out-of-the-box data-pseudo-data generated by an attribute-guided generative model-to mimic the unseen data. We then present an iterative attribute selection (IAS) strategy that iteratively selects key attributes based on the out-of-the-box data. Since the distribution of the generated out-of-the-box data is similar to that of the test data, the key attributes selected by IAS can be effectively generalized to test data. Extensive experiments demonstrate that IAS can significantly improve existing attribute-based ZSL methods and achieve state-of-the-art performance.


Multi-order Stokes output based on intra-cavity KTiOAsO₄ Raman crystal.
We report efficient multi-Stokes Raman output of a KTiOAsO4 (KTA) crystal driven by a laser diode end-pumped acousto-optic Q-switched Nd:YAG laser. The Raman outputs of two x-cut KTA crystals, one with a length of 20 mm and the other one of 25-mm, were experimentally compared. Under an incident pump power of 10.9 W, a maximum output power of 1.12 W with a pulse width of 7.6 ns and a pulse repetition frequency of 15 kHz were obtained. The conversion efficiency and slope efficiency with respect to the incident diode pump power were 10.3% and 15.2%, respectively. The laser output contains multiple Raman Stokes lines with different spectral strengths that varied with the pump power.


Contrasting Sex-and Caste-Dependent piRNA Profiles in the Transposon Depleted Haplodiploid Honeybee Apis mellifera.
Protecting genome integrity against transposable elements is achieved by intricate molecular mechanisms involving PIWI proteins, their associated small RNAs (piRNAs), and epigenetic modifiers such as DNA methylation. Eusocial bees, in particular the Western honeybee, Apis mellifera, have one of the lowest contents of transposable elements in the animal kingdom, and, unlike other animals with a functional DNA methylation system, appear not to methylate their transposons. This raises the question of whether the PIWI machinery has been retained in this species. Using comparative genomics, mass spectrometry, and expressional profiling, we present seminal evidence that the piRNA system is conserved in honeybees. We show that honey bee piRNAs contain a 2'-O-methyl modification at the 3' end, and have a bias towards a 5' terminal U, which are signature features of their biogenesis. Both piRNA repertoire and expression levels are greater in reproductive individuals than in sterile workers. Haploid males, where the detrimental effects of transposons are dominant, have the greatest piRNA levels, but surprisingly, the highest expression of transposons. These results show that even in a transposon-depleted species, the piRNA system is required to guard the vulnerable haploid genome and reproductive castes against transposon-associated genomic instability. This also suggests that dosage plays an important role in the regulation of transposons and piRNAs expression in haplo-diploid systems.


Impact of Multiple Chronic Conditions on Activity Limitations Among Older Mexican-American Care Recipients.
Older Mexican Americans are living longer with multiple chronic conditions (MCCs). This has placed greater demands on caregivers to assist with basic activities of daily living (ADL) or instrumental activities of daily living (IADL). To understand the needs of older Mexican-American care recipients, we examined the impact of MCC on ADL and IADL limitations. We analyzed data from 485 Mexican American care-receiving/caregiving dyads. Selected MCCs in the analysis were diabetes, hypertension, stroke, heart disease, arthritis, emphysema/chronic obstructive pulmonary disease, cognitive impairment, depression, and cancer. Care recipients were dichotomized as having 3 or more conditions or as having 2 or fewer conditions. Three comorbidity clusters were established on the basis of the most prevalent health conditions among participants with comorbid arthritis and hypertension. These clusters included arthritis and hypertension plus: diabetes (cluster 1), cognitive impairment (cluster 2), and heart disease (cluster 3). Care recipients with 3 or more chronic conditions (n = 314) had higher odds of having mobility limitations (OR = 1.98; 95% CI, 1.34-2.94), self-care limitations (OR = 2.53; 95% CI, 1.70-3.81), >3 ADL limitations (OR = 2.00; 95% CI, 1.28-3.17), and >3 IADL limitations (OR = 1.88; 95% CI, 1.26-2.81). All clusters had increased odds of ADL and severe ADL limitations. Of care recipients in cluster 2, those with arthritis, hypertension, and cognitive impairment had significantly higher odds of mobility limitations (OR = 2.33; 95% CI, 1.05-5.24) than those with just arthritis and hypertension. MCCs were associated with more ADL and IADL limitations among care recipients, especially for those with hypertension and arthritis plus diabetes, cognitive impairment, or heart disease. These findings can assist in developing programs to meet the needs of older Mexican-American care recipients.


High prevalence of late presentation of ART-naïve perinatally infected children for care in Pune, India.
Delayed presentation to care of perinatally infected children in India continues to be a hindrance to achieving the "end pediatric HIV by 2020" goal. In this study, we characterize this issue by describing the prevalence, risk factors and temporal trends of delayed presentation to care of perinatally infected, antiretroviral therapy (ART) - naïve children using programmatic data from a tertiary care center in western India. Delayed presentation was defined as children presenting in moderate or severe WHO immunodeficiency categories. Of 269 children eligible for inclusion in the analysis, the median age at presentation was 4 years (IQR: 3-6 years) and prevalence of delayed presentation was 52%. Multivariable logistic regression identified domicile distance ≥20km from the ART center (OR: 2.2, 95% CI: 1.02-4.7) to be a risk factor for delayed presentation. An inverse association with increasing age (OR: 0.8, 95% CI: 0.7-0.9) was also seen. The proportion of children with delayed presentation between 2006 and 2016 remained unchanged (p = 0.36), although the median age at presentation over the same time period increased significantly (p < 0.001). Our results indicate the urgency of identifying strategies to improve linkage of perinatally infected ART-naïve children to care, earlier than what is currently observed.


Acupuncture as treatment of hot flashes and the possible role of calcitonin gene-related Peptide.
The mechanisms behind hot flashes in menopausal women are not fully understood. The flashes in women are probably preceded by and actually initiated by a sudden downward shift in the set point for the core body temperature in the thermoregulatory center that is affected by sex steroids, β-endorphins, and other central neurotransmitters. Treatments that influence these factors may be expected to reduce hot flashes. Since therapy with sex steroids for hot flashes has appeared to cause a number of side effects and risks and women with hot flashes and breast cancer as well as men with prostate cancer and hot flashes are prevented from sex steroid therapy there is a great need for alternative therapies. Acupuncture affecting the opioid system has been suggested as an alternative treatment option for hot flashes in menopausal women and castrated men. The heat loss during hot flashes may be mediated by the potent vasodilator and sweat gland activator calcitonin gene-related peptide (CGRP) the concentration of which increases in plasma during flashes in menopausal women and, according to one study, in castrated men with flushes. There is also evidence for connections between the opioid system and the release of CGRP. In this paper we discuss acupuncture as a treatment alternative for hot flashes and the role of CGRP in this context.


Selection and combustion of Ni-hyperaccumulators for the phytomining process.
Ni recovery from serpentine soils by phytomining has proved feasible. Phytomining involves the crop of hyperaccumulating plants with high Ni contents and the valorization of Ni by pyro or hydrometallurgical process. In order to evaluate the Ni content of different plants, we analyzed the organs of 14 hyperaccumulators from three genera: Alyssum, Leptoplax and Bornmuellera. The highest concentration was recorded in the leaves of Leptoplax (34.3 +/- 0.7 mg g(-1)DM). Additionally, we investigated biomass combustion which is the first step of the process we designed to obtain a nickel salt. We showed that temperature and duration were important parameters to ensure a good quality of ashes. At the bench scale, the best conditions were 550 degrees C and 3 h. In this way, we obtained ashes in which Ni could reach 20 wt%. Biomass ashes can be considered as a bio-ore for recovering metal value.


Disruption of microtubules alters polarity of basement membrane proteoglycan secretion in epithelial cells.
Basement membrane proteins such as the heparan sulfate proteoglycan (HSPG) are secreted in a polarized fashion from the basolateral membrane of epithelial cells. We have used the microtubule-disrupting drug colchicine to study the role of the microtubule network in directing constitutive secretion to the basolateral membrane of LLC-PK1 renal epithelial cells. Microtubule depolymerization induced by colchicine resulted in fragmentation and redistribution of fluorescently labeled trans-Golgi membranes. Increased immunofluorescent staining of HSPG was associated with these dispersed Golgi cisternae. The biosynthetic processing of HSPG was not significantly altered by the loss of microtubules or by the dispersal of the Golgi elements. The most striking effect of microtubule disruption was the loss of polarity of HSPG secretion. Immunoprecipitation studies showed that HSPG was secreted from both apical and basolateral surfaces of LLC-PK1 cells treated with colchicine, and a similar result was found for the delivery of laminin, another basement membrane protein. In contrast, there was no change in the distribution of an integral basolateral membrane protein, Na(+)-K(+)-ATPase, following colchicine treatment. Our results provide the first demonstration that microtubules are involved in the constitutive trafficking of basolateral secretory proteins. These data also suggest that there may be an inherent difference in the targeting or delivery of membrane and secretory proteins to the basolateral cell surface.


The diagnostic accuracy of questions about past experiences of being mechanically restrained in a population of psychiatric patients.
Information about stressful life experiences obtained from patients during diagnostic interviews is an important foundation for clinical decision making. In this study self-reports from 115 committed psychiatric patients of experiences of mechanical restraint were compared with medical records. The sensitivity of patient self-reports was 73% (11/15) and the specificity was 92% (92/100). No clear relationship between psychiatric symptoms and reliability of self-reports was identified. The results highlight the subjective qualities of narratives about past experiences.