Validity and reliability of the Turkish version of the City Birth Trauma Scale (CityBiTS).
The City Birth Trauma Scale (CityBiTS) was developed to be consistent with the current Diagnostic and Statistical Manual of Mental Disorders-DSM-5. It has been used as a complementary instrument that measures the psychological trauma related to childbirth. The aim of this study was to investigate the validity and reliability of the Turkish version of the CityBiTS. This research is a methodological study. This study was conducted with 315 women who had 6-month-old infants from August to October 2018. The CityBiTS is a 29-item instrument that was developed according to DSM-5 criteria to assess childbirth-related Post-Traumatic Stress Disorder. Test-retest measurements were performed at two-week intervals to evaluate the invariance of the scale over time. Cronbach's alpha coefficient of reliability was used to analyse internal consistency of scale. Cronbach's alpha coefficients were .76 for re-experiencing symptoms, .57 for avoidance symptoms, .77 for negative cognitions and mood, .83 for hyperarousal and .82 for dissociative symptoms. In conclusion, The Turkish version of the CityBiTS, as an instrument developed to be consistent with DSM-5 criteria in assessing childbirth-related trauma symptoms, is a valid and reliable tool.Impact statementWhat is already known on this subject? One of the possible barriers for this is the lack of validated questionnaires that measure the postpartum PTSD.What do the results of this study add? The aim of this study was to investigate the validity and reliability of the Turkish version of the CityBiTS. The City Birth Trauma Scale has good psychometric properties and the two symptom clusters identified are consistent with previous research on symptoms of postpartum PTSD.What are the implications of these findings for clinical practice and/or further research? The City Birth Trauma Scale provides with a measure of birth-related PTSD foruse in research and clinical practice.


Evaluation of Anti-Xa and Activated Partial Thromboplastin Time Monitoring of Heparin in Adult Patients Receiving Extracorporeal Membrane Oxygenation Support.
The approach to monitoring anticoagulation in adult patients receiving heparin on extracorporeal membrane oxygenation (ECMO) support is controversial. The objective of this study was to compare the correlation between anti-Xa and activated partial thromboplastin time (aPTT) with heparin dose and to describe their association with clinical events in adult ECMO patients. We conducted a retrospective single-center study of 34 adult ECMO patients whose heparin was monitored by anti-Xa and/or aPTT. The heparin dose-to-assay correlation coefficient was 0.106 for aPTT and 0.414 for anti-Xa (p < 0.001). Major thrombotic and hemorrhagic events occurred in 14.7% and 26.5% of patients, respectively. The median anti-Xa in patients who experienced a major thrombotic event was 0.09 (0.06-0.25) IU/mL compared with 0.36 (0.26-0.44) IU/mL in patients who did not (p = 0.031), whereas the median aPTT did not differ between these groups. The maximum aPTT in patients who experienced a major bleed was 96.9 (76.0-200) seconds compared with 63.5 (44.4-98.6) seconds in patients who did not (p = 0.049), whereas the maximum anti-Xa did not differ between these groups. Monitoring both anti-Xa and aPTT may be warranted to safely provide understanding of pure heparin activity as well as underlying bleeding diatheses in adult ECMO patients.


Raphides with barbs and grooves in Xanthosoma sagittifolium (Araceae).
Raphides in petioles of Xanthosoma sagittifolium are needlelike crystals about 50 micrometers long. The rectangular cross sections have maximum dimensions of approximately 850 by 250 nanometers. The raphides have two distinct end structures. One end is narrow, acute, and tapered to a point; the other is broad, acute, and abruptly pointed. Barbs, about 750 angstroms long with tips oriented away from the narrow end, occur along the length of the raphide on ridges on either side of two longitudinal grooves. These grooves, located opposite each other, give the raphide cross section an H-shape.


How to Convince Parents to Stop Spanking Their Children.
English- and Spanish-speaking parents of 1- to 5-year-old children were invited to view 5-10 minutes of parent training program, "Play Nicely," as part of the well-child checkup. Key measures were parents' plans to change how they discipline and, if they planned to use less spanking, how the program worked in their situation. Of 197 parents who participated, 128 (65.0%) planned to change how they discipline. Nineteen parents (9.6%) reported that they planned to spank less. The most common reasons for parents to plan to spank less were that the program taught other discipline options (12/19, 63.2%) and that the program taught that spanking was not recommended as a form of discipline (6/19, 31.6%). The majority of parents report that the program works because it offers alternatives to spanking. This study has implications for the development of parent training programs and the primary prevention of child abuse, violence, and other health problems.


The role of machine learning in clinical research: transforming the future of evidence generation.
Interest in the application of machine learning (ML) to the design, conduct, and analysis of clinical trials has grown, but the evidence base for such applications has not been surveyed. This manuscript reviews the proceedings of a multi-stakeholder conference to discuss the current and future state of ML for clinical research. Key areas of clinical trial methodology in which ML holds particular promise and priority areas for further investigation are presented alongside a narrative review of evidence supporting the use of ML across the clinical trial spectrum. Conference attendees included stakeholders, such as biomedical and ML researchers, representatives from the US Food and Drug Administration (FDA), artificial intelligence technology and data analytics companies, non-profit organizations, patient advocacy groups, and pharmaceutical companies. ML contributions to clinical research were highlighted in the pre-trial phase, cohort selection and participant management, and data collection and analysis. A particular focus was paid to the operational and philosophical barriers to ML in clinical research. Peer-reviewed evidence was noted to be lacking in several areas. ML holds great promise for improving the efficiency and quality of clinical research, but substantial barriers remain, the surmounting of which will require addressing significant gaps in evidence.


Discrimination and Calibration of Clinical Prediction Models: Users' Guides to the Medical Literature.
Accurate information regarding prognosis is fundamental to optimal clinical care. The best approach to assess patient prognosis relies on prediction models that simultaneously consider a number of prognostic factors and provide an estimate of patients' absolute risk of an event. Such prediction models should be characterized by adequately discriminating between patients who will have an event and those who will not and by adequate calibration ensuring accurate prediction of absolute risk. This Users' Guide will help clinicians understand the available metrics for assessing discrimination, calibration, and the relative performance of different prediction models. This article complements existing Users' Guides that address the development and validation of prediction models. Together, these guides will help clinicians to make optimal use of existing prediction models.


U-54,669F: a novel hypotensive agent.
U-54,669F, a new antihypertensive agent, administered orally was associated with dose-related hypotensive responses in conscious, spontaneously hypertensive, and normotensive rats (0.015-0.5 mg/kg) and in supine conscious monkeys (1-10 mg/kg). No loss of hypotensive efficacy of U-54,669F was observed after 1 wk of daily repetitive treatment. U-54,669F did not alter electrical postganglionic sympathetic nerve activity or postsynaptic sympathetic function. Hypotensive responses to U-54,669F were blunted in spinal cats. U-54,669F was associated with dose-related decreases in norepinephrine (NE) levels in plasma and in cardiac and splenic tissue, whereas brain NE was unaltered. U-54,669F attenuated vascular responses associated with electrical stimulation of sympathetic nerves. However, at hypotensive doses, U-54,669F did not impair the ability of monkeys to withstand orthostatic stress, or contraction of the nictitating membrane secondary to sympathetic stimulation in the cat. U-54,669F appears to alter peripheral sympathetic neurogenic function, but apparently does not enter the central nervous system and does not impair the ability to withstand orthostatic stress at effective hypotensive doses.


Head segmentation in early cambrian fuxianhuia: implications for arthropod evolution.
The arthropod Fuxianhuia from the Chengjiang fauna displays primitive aspects of cephalic segmentation and trunk limb morphology that indicate a basal position within Euarthropoda. The cephalon consists of an eye-bearing sclerite that articulates with a head shield bearing antennules and subchelate appendages. Eye stalks, antennules, and subchelate appendages are proto-, deuto-, and tritocerebral limbs and organs, respectovely. The anterior position of the eye-bearing sclerite parallels the embryonic origin of arthropod eye lobes. The head of Fuxianhuia includes the acron and one somite and is regarded as a protocephalon. The definitive head of arthropods may have fused separate eye-bearing and appendage-bearing sclerites.


Assessment of the sulfur hexafluoride (SF6) tracer technique for measuring enteric methane emissions from cattle.
A commonly used method of measuring enteric methane (CH4) emissions from ruminants is the SF6 tracer technique that measures respired and eructated CH4. However, within the animal, a small proportion of CH4 is produced post-ruminally and some of this may escape through the rectum. The comparison of emissions using a chamber technique that measures all enteric CH4 losses, and the SF6 tracer technique, could give some insight into the magnitude of post-ruminal emission. The objective of our study was to assess the precision and accuracy of the SF6 tracer technique against a chamber technique for cattle fed a range of diets. Using a repeated-measures design, eight beef heifers were offered a high grain or high forage diet for ad libitum or restricted (65% of ad libitum) feed intake to vary the site of digestion within the gastrointestinal tract (n = 24). The SF6 tracer technique underestimated CH4 emissions on average by 4% relative to the chamber technique. This difference was not significant (P > 0.05) and suggests low post-ruminal CH4 emissions. There was a trend for greater accuracy and precision of the SF6 tracer technique when used with cattle fed a high forage diet at a restricted level of intake. The high forage diet corresponds to the conditions of cattle grazing pasture, suggesting the SF6 tracer technique is most reliable for the grazing system.


Outcomes of patients undergoing edge-to-edge mitral valve repair with the Edwards PASCAL transcatheter valve repair system under conscious sedation.
The development of the PASCAL transcatheter valve repair system for treating mitral regurgitation (MR) greatly extends therapeutic options. To assess the safety, efficacy, and time efficiency of the PASCAL system in transcatheter edge-to-edge repair (TEER) under conscious sedation (CS). This is a retrospective, two-center, German registry study consisting of 211 patients who underwent TEER using the PASCAL system under CS. The endpoints were to assess (1) technical, device, and procedural success as per Mitral Valve Academic Research Consortium (MVARC), (2) conversion rate to general anesthesia (GA), (3) hospital length of stay (LoS), (4) New York Heart Association (NYHA) class, and (5) MR compared to baseline at 30-day. A total of 211 patients with a mean age of 78.4 ± 8.9 years, with 51.4% being female and 86.7% belonging to NYHA functional class III/IV and EuroSCORE II 6.3 ± 4.9%, were enrolled. Procedural success attained was 96.9%, and six patients (2.8%) required conversion from CS to GA. At 30 days follow-up, a significant improvement in MR was found in 96 patients (54.2%) patients with 0/1 grade MR and 45 patients (29.5%) were in NYHA functional class III + IV. Moreover, TEER under CS has a short hospital LoS (6.71 ± 5.29 days) and intensive care unit LoS (1.34 ± 3.49 days) with a 2.8% mortality rate. Performing TEER with the PASCAL system under CS resulted in appreciable (96.9%) procedural success with low mortality and is a safe and promising alternative to GA with positive clinical outcomes.


[Informed consent in pediatric cardiology and cardiac surgery].
A multidisciplinary study group was established to review and approve the informed consent froms in Pediatric Cardiology and Cardiac Surgery. The work was carried out in several stages, starting with an analysis of what was already in use in several Italian Centers. Subsequently, shared forms for pediatric cardiac surgery and interventional catheterization procedures were developed, pointing to clarity of information, prediction of therapeutic options, quantification for verbal categories of risk associated with cardiac surgery procedures, and provision of information also to young patients. Two versions of informed consent for pediatric cardiac surgery and pediatric interventional catheterization procedures were developed. The work oerformed by the multidisciplinary study group, under the supervision of the Italian Society of Pediatric Cardiology and the Section of Surgery for Congenital Heart Disease of the Italian Society for Cardiac Surgery, resulted in a clear and evolutionary summary of the relationship between available therapeutic options and the patient needs to understand and share the healthcare pathway in terms of risk and perspectives.


Electroneutrality coupling of electron transfer at an electrode surface and ion transfer across the interface between thin-layer of 1-octyl-3-methylimidazolium bis(perfluoroalkylsulfonyl)imide covering the electrode surface and an outer electrolyte solution.
The electrode reaction of decamethylferrocene (DMFc) dissolved in a thin layer of a room-temperature molten salt (RTMS), 1-octyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide (C8mimC1C1N) or 1-octyl-3-methylimidazolium bis(pentafluoroethylsulfonyl)imide (C8mimC2C2N), on a self-assembled monolayer-modified gold electrode is coupled with the ion transfer across the interface between the RTMS and the outer aqueous solution (W) to give a voltammogram whose shape resembles a voltammogram of a simple one-electron transfer process. The electroneutrality of the RTMS layer during the oxidation of DMFc to decamethylferricenium ion is maintained by the concomitant dissolution of C8mim+ ion from the RTMS phase to the W phase, and the reduction of decamethylferricenium ion to DMFc is accompanied by the transfer of either C1C1N- or C2C2N- from RTMS to W. The midpoint potential of the voltammogram varies with the concentration of the salt in the aqueous phase, C8mimCl or LiCnCnN (n = 1 or 2), in a Nernstian manner, showing that the phase-boundary potential between the RTMS and the W is controlled by the partition of these ions. Although the phase-boundary potential across the RTMS / W interface is Nernstian with respect to the ions common to both phases at the equilibrium, the polarization at the RTMS / W interface under current flow distorts the shape of the voltammograms, resulting in a wider peak separation in the voltammogram.


Physical Functioning and Opioid use in Patients with Neuropathic Pain.
To evaluate the association between opioid dosage and ongoing therapy with physical function and disability in patients with neuropathic pain (NeP). Secondary analysis of a prospective cohort. Multicenter clinical NeP registry. Seven hundred eighty-nine patients treated for various NeP diagnoses. The following measures were included: dependent variables. 12-month self-reported physical function (pain disability index [PDI] and medical outcomes study short form-12 physical function [PCSS-12]); independent variables: baseline opioid dose (none, ≤200 mg and >200 mg of morphine equivalent), ongoing opioid use; potential confounding variables: age, sex, baseline pain intensity, and psychological distress (profile of mood states). Analysis of covariance models was created to examine the relationship between opioid therapy and both physical functioning outcomes with adjustment for confounding. Complete data was available for 535 patients (68%). Compared with the lower and high dose opioid groups, NeP patients not taking opioids had statistically lower disability and higher physical functioning scores, after adjusting for disease severity. Compared with patients prescribed opioid therapy on an ongoing basis, NeP patients who were not prescribed had statistically lower disability and higher physical functioning scores, after adjusting for disease severity. Improvements in disability and physical functioning scores from baseline and 12-months in all groups were modest and may not be clinically significant. Physical functioning and disability did not improve in patients with NeP who were prescribed opioids compared with those who are not prescribed, even after adjusting for disease severity.


Subconvulsant doses of pentylenetetrazol uncover the epileptic phenotype of cultured synapsin-deficient Helix serotonergic neurons in the absence of excitatory and inhibitory inputs.
Synapsins are a family of presynaptic proteins related to several processes of synaptic functioning. A variety of reports have linked mutations in synapsin genes with the development of epilepsy. Among the proposed mechanisms, a main one is based on the synapsin-mediated imbalance towards network hyperexcitability due to differential effects on neurotransmitter release in GABAergic and glutamatergic synapses. Along this line, a non-synaptic effect of synapsin depletion increasing neuronal excitability has recently been described in Helix neurons. To further investigate this issue, we examined the effect of synapsin knock-down on the development of pentylenetetrazol (PTZ)-induced epileptic-like activity using single neurons or isolated monosynaptic circuits reconstructed on microelectrode arrays (MEAs). Compared to control neurons, synapsin-silenced neurons showed a lower threshold for the development of epileptic-like activity and prolonged periods of activity, together with the occurrence of spontaneous firing after recurrent PTZ-induced epileptic-like activity. These findings highlight the crucial role of synapsin on neuronal excitability regulation in the absence of inhibitory or excitatory inputs.


Incidence rates of Guillain Barré (GBS), chronic fatigue/systemic exertion intolerance disease (CFS/SEID) and postural orthostatic tachycardia syndrome (POTS) prior to introduction of human papilloma virus (HPV) vaccination among adolescent girls in Finland, 2002-2012.
In Finland a vaccination programme against human papillomavirus (HPV) was introduced in November 2013 for girls aged 11-12 years with a catchup for girls 13-15 years. Allegations that HPV vaccine is causing Guillain Barré syndrome (GBS) and non-specific diagnostic entities, such as chronic fatigue syndrome/systemic exertion intolerance disease (CFS/SEID) and postural orthostatic tachycardia syndrome (POTS), continue to surface. We examined population register-based incidence rates of CFS/SEID, GBS and POTS to provide baseline data for future HPV vaccine safety evaluations. First diagnosis of CFS/SEID, GBS and POTS in girls aged 11-15 years were obtained from the National Hospital Discharge Register during 2002-2012. We considered the following ICD-10 codes: G93.3 for CFS; G61.0 for GBS and G90.9, G90.8, G93.3, I49.8 for POTS. We calculated incidence rates per 100,000 person-years with 95% confidence intervals (CI). In total, 9 CFS/SEID, 19 GBS and 72 POTS cases were identified. The overall incidence rate was 0.53/100,000 (95% CI; 0.27-1.01) for CFS/SEID, 1.11 (95% CI; 0.71-1.74) for GBS and 4.21 (95%CI; 3.34-5.30) for POTS. Significant relative increase in annual incidence rate with a peak in 2012 was observed in CFS/SEID (33% (95% CI; 3.0-70.3: p=0.029) and POTS (16.5% (95% CI; 7.8-25.9: p<0.05), but not in GBS (5.4% (95% CI; -8.4-21.3: p=0.460). Our findings provide baseline estimates of CFS/SEID, GBS and POTS incidences in Finland. However, rates based on register data should be interpreted with caution, especially for non-specific diagnostic entities for which internationally and even nationally agreed criteria are still being discussed. To assess the associations with HPV vaccine, methods using register linkage for cohort and self-controlled case series should be explored in addition to factors contributing to patients seeking care, treating physicians setting the diagnoses, and their preference of using of codes for these clinical entities.


Validation of the Spence Children's Anxiety Scale's obsessive compulsive subscale in a clinical and community sample.
This study describes the validation of the obsessive compulsive subscale on the Spence Children's Anxiety Scale (SCAS OCD) for use as a clinical assessment tool. Data from 196 anxious children (102 males, ages 7-18) and their parent collected during a diagnostic assessment were compared to data from 420 children (206 males, ages 8-13) from the community collected by mail. The validity of the SCAS OCD parent- and child-report forms were supported by correlations with the Children's Yale-Brown Obsessive Compulsive Scale and continuous OCD symptom variables from the Anxiety Disorders Interview Schedule: Child Version. In addition, children with OCD were found to have higher scores on the SCAS OCD subscale than patients without OCD and children from the community without a reported anxiety diagnosis. The sensitivity of the SCAS OCD to treatment effects was also demonstrated in a subset of the clinical sample that received exposure and response prevention therapy. Finally, cut-scores were identified that examine the sensitivity and predictive utility of the scales.


[Dynamics of genetic variation of Sartov cultivars of common wheat Triticum aestivum L. (from the gliadin-coding locus) after a an 80-year period of scientific selection].
Based on analysis of gliadin patterns in common wheat cultivars developed at the Research Institute of Agriculture of the Southeast, profile dynamics in gliadin loci has been surveyed for the period of over eight decades. It was shown that long-term breeding of the wheat cultivars involved gradual replacement of alleles characteristic of ancient cultivars for those widely spread in the world, which are probably linked with alleles that currently confer advantage to their carriers. The process of reduction of inter-population genetic diversity in wheat (with special reference to the allele frequency dynamics at gliadin loci) is discussed. This process is responsible for genetic erosion of the species.


Nemaline myopathy with KLHL40 mutation presenting as congenital totally locked-in state.
We report a case of nemaline myopathy with KLHL40 mutation, presenting as congenital totally locked-in state. At birth, a male patient developed hydrops fetalis, which was diagnosed based on the generalized edema and pleural effusion and could perform no significant spontaneous movements. His eyes were open, without blinking, and the eyeballs were locked in the midposition. He could not express his intentions by vocalization or moving his trunk, extremities, facial muscles, mouth, eyelids, or eyeballs in response to ambient events or personal interactions. Electrophysiological tests and neuroimaging revealed no evidence of visual or auditory impairment that might indicate a lack of sensory perception, and no evidence of impaired consciousness or intellectual disorder(s) that might prevent him from recognizing ambient events or expressing his intentions. He subsequently died at 4 years of age. Our case highlights the fact that severe congenital neuromuscular disorders can present as congenital totally locked-in state, and that special attention should be provided to these patients.


Evaluation of the SPIRIT Integrated Suicide Prevention Programme: study protocol for a cluster-randomised controlled trial in rural Gujarat, India.
Suicide is a major public health challenge globally and specifically in India where 36.6% and 24.3% of all suicides worldwide occur in women and men, respectively. The United Nations Sustainable Development Goals uses suicide rate as one of two indicators for Target 3.4, aimed at reducing these deaths by one third by 2030. India has no examples of large-scale implementation of evidence-based interventions to prevent suicide; however, there is a sizeable evidence base to draw on for suicide prevention strategies that have been piloted in India or proven to be effective regionally or internationally. The SPIRIT study is designed as a cluster-randomized superiority trial and uses mixed methods to evaluate the implementation, effectiveness and costs of an integrated suicide prevention programme consisting of three integrated interventions including (1) a secondary-school-based intervention to reduce suicidal ideation among adolescents, (2) a community storage facility intervention to reduce access to pesticides and (3) training for community health workers in recognition, management, and appropriate referral of people identified with high suicidal risk. Combining three evidence-based interventions that tackle suicide among high-risk groups may generate a synergistic impact in reducing suicides at the community level in rural areas in India. Examination of implementation processes throughout the trial will also help to prepare a roadmap for policymakers and researchers looking to implement suicide prevention interventions in other countries and at scale. Clinical Trial Registry of Indian Council of Medical Research, India: CTRI/2017/04/008313. Registered on 7 April 2017. http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=18256&EncHid=&userName=SPIRIT Trial registry was last modified on 28 June 2019.


Maturity-Onset Diabetes of the Young: What Do Clinicians Need to Know?
Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes that is characterized by an early onset, autosomal dominant mode of inheritance and a primary defect in pancreatic β-cell function. MODY represents less than 2% of all diabetes cases and is commonly misdiagnosed as type 1 or type 2 diabetes mellitus. At least 13 MODY subtypes with distinct genetic etiologies have been identified to date. A correct genetic diagnosis is important as it often leads to personalized treatment for those with diabetes and enables predictive genetic testing for their asymptomatic relatives. Next-generation sequencing may provide an efficient method for screening mutations in this form of diabetes as well as identifying new MODY genes. In this review, I discuss a current update on MODY in the literatures and cover the studies that have been performed in Korea.


Valorization of biomass polyphenols as potential tyrosinase inhibitors.
Tyrosinases (TYRs; EC 220.127.116.11) catalyze two sequential oxidative reactions of the melanin biosynthesis pathway and play an important role in mammalian pigmentation and enzymatic browning of fruit and vegetables. Inhibition of TYR activity is therefore an attractive target for new drugs and/or food ingredients. In addition, increasing evidence suggests that TYR regulation could be a novel target for treatments of cancer and Parkinson's disease. Biomasses, notably industrial byproducts and biowaste, are good sustainable sources of phytochemicals that may be valorized into bioactive compounds including TYR inhibitors. This review presents potential applications of biomass-derived polyphenols targeting TYR inhibition. Insights into structure-activity relationships of several polyphenols and their glycosides are highlighted. Finally, some remarks and perspectives on research into new TYR inhibitors from biomass waste are provided.


[Treatment response and complications of older patients with ANCA(antineutrophil cytoplasmatic antibody)-associated vasculitis].
ANCA (antineutrophil cytoplasmatic antibody)-associated vasculitis (AAV) mainly affects elderley people but adjusted therapy concepts for this patient group are lacking. The aim of this study was therefore to analyze differences in course and outcome of patients with AAV with respect to age. 62 patients were analyzed for treatment response, of whom 53 (85%) experienced adverse events (AE and SAE) that could be evaluated. Older (> 65 yrs.) versus younger (< 65 yrs.) patients were compared. Treatment response was assessed at 6 months, complications were assessed over 18 months. Treatment response was not seen to differ by age groups. In multiple logistic regression, pulmonary involvement (OR = 6,9; CI = 1,7-27,8, p < 0,01) and ΔGFR [ml/min] (OR = 0,93; CI = 0,89-0,97, p < 0,01) were predictors of SAE. 14 patients had more than 1 SAE. Again, pulmonary involvement (28,2% vs. 78,6%, p < 0,01) was a risk factor and older patients (78,6% vs. 43,6%, p = 0,025) were more frequently affected. Patients with multiple SAEs received glucocorticoids of more than 5 mg/d for longer periods of time (171 ± 65 days vs. 120 ± 70 days, p = 0,03). No differences were found between older and younger patients with regard to treatment response. Multiple SAEs occurred more frequently in elderly patients. There was a correlation between pulmonary manifestation and duration of glucocorticoid therapy with a complicated course. The most frequent SAEs were infections requiring hospitalisation. Therapy for elderly patients should be individualized with the goal of a fast reduction of glucocorticoids. Special monitoring is indicated for elderly patients, especially those with pulmonary involvement.


[Temperature causes structural and functional changes in lactate dehydrogenase from fish skeletal muscles].
Adaptation of fishes to low and high environmental temperatures gives rise to certain changes in kinetic and structural properties of LDH from skeletal muscles. The KM versus temperature plot for pyruvate of the enzyme isolated from fishes adapted to low temperatures has a minimum at low measurement temperatures, whereas adaptation to high temperatures leads to the enzyme showing a minimum at high temperatures. The LDH isolated from fishes adapted to low environmental temperatures is more stable relative to both thermal and urea-induced inactivation. The differences in the kinetic properties of the enzymes from fishes adapted to low and high temperatures disappear after treatment with urea and subsequent reactivation.


Physical Exercise Interventions Targeting Cognitive Functioning and the Cognitive Domains in Nondementia Samples: A Systematic Review of Meta-Analyses.
We investigated whether physical exercise interventions improve cognitive functioning in nondementia populations. We conducted a systematic review of meta-analyses including only randomized controlled trials (RCTs). Two reviewers completed a systematic search of PubMed, Embase, PsychInfo, and Cochrane Controlled Register of Trials. Study characteristics, effect size data, and heterogeneity estimates were extracted and presented in tabular form. Methodological quality was assessed by 2 reviewers using the AMSTAR-2 checklist. The validity of results was considered based on AMSTAR-2 scores and study characteristics. We included 11 meta-analyses: 6 focused on disease-free older adults and 5 on mild cognitive impairment (MCI) excluding dementia. These meta-analyses summarized 97 unique RCTs. Methodological quality ranged from critically low to high. For overall cognitive functioning, which was the outcome of 6 meta-analyses, 1 showed improvement due to exercise interventions in disease-free older adults (g = 0.29, P < .01), while 2 reported nonsignificant effects. In patients with MCI, 3 meta-analyses reported significant benefits of exercise interventions on overall cognitive functioning (g = 0.25-0.57, P < .01). For cognitive domains such as attention and memory, there was limited evidence of beneficial effects of exercise demonstrated in either disease-free or MCI samples. Exercise may improve overall cognitive functioning in disease-free older adults, but there is too little high-quality evidence to conclude whether this is achieved through improvement in any of the specific cognitive domains assessed. There is clearer evidence that exercise may improve cognitive functioning in MCI, but again there is limited evidence across most cognitive domains.


Tensin3 is a negative regulator of cell migration and all four Tensin family members are downregulated in human kidney cancer.
The Tensin family of intracellular proteins (Tensin1, -2, -3 and -4) are thought to act as links between the extracellular matrix and the cytoskeleton, and thereby mediate signaling for cell shape and motility. Dysregulation of Tensin expression has previously been implicated in human cancer. Here, we have for the first time evaluated the significance of all four Tensins in a study of human renal cell carcinoma (RCC), as well as probed the biological function of Tensin3. Expression of Tensin2 and Tensin3 at mRNA and protein levels was largely absent in a panel of diverse human cancer cell lines. Quantitative RT-PCR analysis revealed mRNA expression of all four Tensin genes to be significantly downregulated in human kidney tumors (50-100% reduction versus normal kidney cortex; P<0.001). Furthermore, the mRNA expressions of Tensins mostly correlated positively with each other and negatively with tumor grade, but not tumor size. Immunohistochemical analysis revealed Tensin3 to be present in the cytoplasm of tubular epithelium in normal human kidney sections, whilst expression was weaker or absent in 41% of kidney tumors. A subset of tumor sections showed a preferential plasma membrane expression of Tensin3, which in clear cell RCC patients was correlated with longer survival. Stable expression of Tensin3 in HEK 293 cells markedly inhibited both cell migration and matrix invasion, a function independent of putative phosphatase activity in Tensin3. Conversely, siRNA knockdown of endogenous Tensin3 in human cancer cells significantly increased their migration. Our findings indicate that the Tensins may represent a novel group of metastasis suppressors in the kidney, the loss of which leads to greater tumor cell motility and consequent metastasis. Moreover, tumorigenesis in the human kidney may be facilitated by a general downregulation of Tensins. Therefore, anti-metastatic therapies may benefit from restoring or preserving Tensin expression in primary tumors.


Long-term outcome following radical temporal bone resection for lateral skull base malignancies: a neurosurgical perspective.
Primary temporal bone malignancy is a rare form of tumor for which the therapeutic strategy remains controversial. In this study, the authors reviewed their experience with radical temporal bone resection (TBR) of such lesions and analyzed the long-term results to provide treatment recommendations. Between 1994 and 2006, 17 patients (10 men and 7 women) underwent total or subtotal TBR for primary temporal bone malignancies. Tumors were graded according to the University of Pittsburgh system. The effects of surgical margins and tumor extensions on patient survival were analyzed using the Kaplan-Meier method. All tumors, except 1, were graded T4 (most advanced). Subtotal TBR was performed in 14 patients, and total TBR was performed in 3. The surgical margin was tumor negative in 10 patients and tumor positive in 7. For large tumors extending into the infratemporal fossa or encroaching on the jugular foramen, orbitozygomatic (3 patients) and posterior transjugular (4 patients) approaches were combined with the standard approach, and en bloc resection with a negative margin was achieved in all cases but 1. The follow-up time ranged from 0.3-11.6 years (mean 3.3 years). The 5-year recurrence-free and disease-specific survival rates were 67.5 and 60.1%, respectively. When a negative surgical margin was achieved, the survival rates improved to 100 and 89%, respectively. The neurosurgical skull base technique could improve the probability of en bloc resection with a tumor-free margin for extensive temporal bone malignancies, which would cure a subset of patients. The active participation of neurosurgeons would improve patient care in this field.


Providing practical estimates of malaria burden for health planners in resource-poor countries.
In many countries in sub-Saharan Africa, estimates of malaria occurrence used by health planners at all levels are based on data from formal sector health facilities. Since the majority of fever episodes are treated at home and within the community, the burden estimates obtained this way are the tips of the iceberg. A case study from Ghana comparing household data on acute morbidity and treatment-seeking behavior in two districts with health facility data is used as an illustration. For every case of febrile illness seen in the health facilities, there were approximately 4-5 in the community. Many sub-Saharan African countries recommend that all febrile episodes, especially in children, be treated with an antimalarial. Since several countries extend malaria treatment to include the community and the home through public and private, formal and informal sectors, the need for more comprehensive burden estimates becomes urgent.


Vision impairment, ocular conditions, and vision-specific function: the Singapore Malay Eye Study.
To validate the VF-11, a vision-specific function scale and determine the relationship among vision impairment, ocular conditions, and vision-specific functioning in an Asian Malay population. Population-based cross-sectional study. Persons aged 40 to 80 years of Malay ethnicity in Singapore. Of the 3280 participants, 3267 answered the VF-11 scale. Participants underwent an extensive and standardized examination procedure, which included visual acuity testing. Sociodemographic and medical data were recorded using a standardized questionnaire. Rasch analysis was initially used to validate the VF-11 and determine its measurement characteristics. Analyses were performed to explore the relationship between the overall functioning score and the presenting unilateral and bilateral vision and ocular conditions using linear regression models. Vision-specific functioning score. The mean presenting visual acuity values in the better and worse eyes were 0.21 (+/-0.23) and 0.36 (+/-0.27) logarithm of the minimum angle of resolution, respectively. Some 46.4% of participants had some form of visual impairment in either eye, and 1.8% of participants had severe visual impairment in both eyes. By using Rasch analysis, it was shown that a modified VF-11 is a unidimensional, reliable, and valid scale to assess vision-specific functioning in this population. Participants with unilateral or bilateral visual impairment had significantly lower vision functioning scores. The independent association between severe vision loss in one or both eyes and functioning was considered to be clinically meaningful. Eye conditions were not independently associated with overall visual function with bilateral visual impairment in the model with the exception of glaucoma (P<0.05 and beta = -1.08). Compared with people with normal vision, people with mild/moderate visual impairment were 1.6 (95% confidence intervals [CI], 1.2-2.2; P = 0.01) and 2.2 (95% CI, 1.6-3.0; P = 0.007) times more likely to have moderate and poor vision function, respectively. Similarly, participants with severe visual impairment were 3.5 (95% CI, 1.1-12.7; P<0.001) and 13.6 (CI, 4.0-45.4; P<0.001) times more likely to have moderate and poor vision function, respectively. Presenting unilateral and bilateral vision impairment is significantly associated with poor vision-specific functioning across the spectrum of mild to severe vision impairment in this Asian Malay population.


Knowledge, attitudes and practices of mothers and knowledge of health workers regarding care of the newborn umbilical cord.
To determine the knowledge, attitudes and practices (KAP) of mothers and the knowledge of health workers regarding care of the newborn umbilical cord. Cross-sectional survey. Mothers with infants less than three months of age attending well child clinics and health workers (HW) in the clinics, maternity and newborn units of public health, facilities serving an urban slum area in Nairobi, Kenya. Of the 307 mothers interviewed, 91% and 28% of mothers knew of the need for hygiene whilst cutting and tying the cord, respectively. Regarding postnatal cord care, 40% had good knowledge and 66% good practice. Fifty-one percent of mothers knew and 54% practised postnatal cord care for the appropriate duration of time. Seventy-nine percent of mothers were afraid of handling an unhealed cord. After multivariate analysis, the following variables showed significant independent association with good maternal KAP; increased level of education (OR 2.3, p < 0.001), living in middle class areas rather than slums (OR 1.5, p < 0.03), increased maternal age (OR 1.8, p < 0.001), acquisition of knowledge from a HW rather than from other sources (OR 1.5, p < 0.001), and living in stone/brick houses rather than mud houses (p = 0.01). Fifty per cent of HW had correct knowledge on type of postnatal cord care, and 79% had correct knowledge on duration required for the same. The knowledge of 50% on type of care was incorrect by international standards, but was in keeping with Nursing Council of Kenya teaching. Mothers had good knowledge on the need for hygiene when cutting the cord, had poor knowledge and practice in other aspects of cord care, and were afraid of handling the cord. Poor KAP was associated with young, poor mothers of low education, who had acquired their knowledge from sources other than HW. The knowledge of a large proportion of HW was incorrect and outdated. We recommend that health education on cord care be given at all levels of contact with mothers and that knowledge of all primary HW on cord care be updated.


The third-stimulus temporal discrimination threshold: focusing on the temporal processing of sensory input within primary somatosensory cortex.
The somatosensory temporal discrimination threshold (STDT) has been used in recent years to investigate time processing of sensory information, but little is known about the physiological correlates of somatosensory temporal discrimination. The objective of this study was to investigate whether the time interval required to discriminate between two stimuli varies according to the number of stimuli in the task. We used the third-stimulus temporal discrimination threshold (ThirdDT), defined as the shortest time interval at which an individual distinguishes a third stimulus following a pair of stimuli delivered at the STDT. The STDT and ThirdDT were assessed in 31 healthy subjects. In a subgroup of 10 subjects, we evaluated the effects of the stimuli intensity on the ThirdDT. In a subgroup of 16 subjects, we evaluated the effects of S1 continuous theta-burst stimulation (S1-cTBS) on the STDT and ThirdDT. Results show that ThirdDT is shorter than STDT. We found a positive correlation between STDT and ThirdDT values. As long as the stimulus intensity was within the perceivable and painless range, it did not affect ThirdDT values. S1-cTBS significantly affected both STDT and ThirdDT, although the latter was affected to a greater extent and for a longer period of time. We conclude that the interval needed to discriminate between time-separated tactile stimuli is related to the number of stimuli used in the task. STDT and ThirdDT are encoded in S1, probably by a shared tactile temporal encoding mechanism whose performance rapidly changes during the perception process. ThirdDT is a new method to measure somatosensory temporal discrimination.NEW & NOTEWORTHY To investigate whether the time interval required to discriminate between stimuli varies according to changes in the stimulation pattern, we used the third-stimulus temporal discrimination threshold (ThirdDT). We found that the somatosensory temporal discrimination acuity varies according to the number of stimuli in the task. The ThirdDT is a new method to measure somatosensory temporal discrimination and a possible index of inhibitory activity at the S1 level.


Low number of mitochondrial pseudogenes in the chicken (Gallus gallus) nuclear genome: implications for molecular inference of population history and phylogenetics.
Mitochondrial DNA has been detected in the nuclear genome of eukaryotes as pseudogenes, or Numts. Human and plant genomes harbor a large number of Numts, some of which have high similarity to mitochondrial fragments and thus may have been inadvertently included in population genetic and phylogenetic studies using mitochondrial DNA. Birds have smaller genomes relative to mammals, and the genome-wide frequency and distribution of Numts is still unknown. The release of a preliminary version of the chicken (Gallus gallus) genome by the Genome Sequencing Center at Washington University, St. Louis provided an opportunity to search this first avian genome for the frequency and characteristics of Numts relative to those in human and plants. We detected at least 13 Numts in the chicken nuclear genome. Identities between Numts and mitochondrial sequences varied from 58.6 to 88.8%. Fragments ranged from 131 to 1,733 nucleotides, collectively representing only 0.00078% of the nuclear genome. Because fewer Numts were detected in the chicken nuclear genome, they do not represent all regions of the mitochondrial genome and are not widespread in all chromosomes. Nuclear integrations in chicken seem to occur by a DNA intermediate and in regions of low gene density, especially in macrochromosomes. The number of Numts in chicken is low compared to those in human and plant genomes, and is within the range found for most sequenced eukaryotic genomes. For chicken, PCR amplifications of fragments of about 1.5 kilobases are highly likely to represent true mitochondrial amplification. Sequencing of these fragments should expose the presence of unusual features typical of pseudogenes, unless the nuclear integration is very recent and has not yet been mutated. Metabolic selection for compact genomes with reduced repetitive DNA and gene-poor regions where Numts occur may explain their low incidence in birds.


Identification and analysis of man-made geological product particles to aid forensic investigation of provenance in the built environment.
Small (sub-mm) fragments of construction materials derived from geological products are common components of soil and dust samples from urban and industrial environments. These particles increase the complexity of a soil through the admixture of man-made materials with natural minerals within the soil matrix. One application of such indicators is in nuclear security investigations, where there is a requirement to determine the origin and process history of a nuclear material discovered outside of regulatory control. In such cases, analysis of trace environmental materials accumulated from locations where the material was produced, transported and stored may help to establish material provenance. Given a suitable sample, the recognition of particles derived from construction materials can aid such investigations by helping to determine potentially distinctive properties of the originating environment, such as types and potential sources of building materials. Correct identification of man-made particles is also necessary to prevent misidentification of soil mineral particle profiles, and therefore enable determination of the natural mineralogy of associated soil material. In this paper the application of automated mineralogy (based on scanning electron microscopy) analysis for the characterisation of sub-mm particles of man-made construction materials is tested. Thirty-three examples of concrete, construction blocks, cement, brick, plaster and render were analysed. Based on both the particle texture and the minerals/chemical phases present, it is shown that the different construction materials can be readily recognised and characterised. Comparison of natural and artificial cemented particles derived from sedimentary rocks and concrete, and of natural and artificial fine-grained particles derived from mudstone and brick fragments highlights how salient features can be recognised from automated mineralogy data to distinguish man-made geological products from soil mineral assemblages.


Concomitants of atherosclerotic carotid artery stenosis.
To identify metabolic and other concomitants of a single important type of atherosclerotic cerebrovascular disease, 75 patients with angiographically and surgically proven internal carotid stenosis were compared with age and sex matched control subjects with respect to plasma cholesterol, triglycerides and glucose. They were also compared for blood pressure, cigarette smoking, evidence of ischemic heart disease, peripheral vascular disease and for a family history of these diseases. Patients with carotid stenosis had higher systolic and diastolic blood pressures and higher plasma cholesterol and triglyceride concentrations than the control groups. They had, as well, a far greater likelihood of being cigarette smokers and a greater likelihood of having diabetes mellitus and previous evidence of coronary and peripheral vascular disease. Patients with carotid stenosis were far more likely to have 2 or more of these common concomitants of atherosclerosis than were the control subjects. The data suggest that the precursors of carotid stenosis are similar to those of coronary atherosclerosis and raise the hope that modification of these factors may decrease the incidence of this highly prevalent form of cerebrovascular disease.


Bilirubin conjugates in bile of man, rat and dog. Semi-quantitative analysis of bile composition by thin-layer chromatography.
1. Conjugated bile pigments, separated in two fractions by semi-quantitative t.l.c. performed on silicic acid with phenol/water as the developing solvent, were treated with diazotized ethyl anthranilate. Resulting dipyrrylazo derivatives were analysed by quantitative t.l.c. 2. The tentative structure elucidation of tetrapyrrolic bilirubin conjugates and semi-quantitative evaluation of rat bile, post-obstructive human bile and dog bile composition is presented. 3. Homogeneous and mixed hexuronic acid diesters of bilirubin containing glucuronic acid constitute 51% of the total conjugates in normal rat bile, 45% of those in human post-obstructive bile and 38% of those in obstructed rat biles. 4. Monoconjugated bilirubin amounts to 33% of total conjugated bile pigments in normal rat bile, and 17 and 14% in post-obstructive hepatic human bile and gall-bladder bile of dog respectively. After loading with unconjugated bilirubin a greater amount of monoconjugates (56%) occur in the rat bile, whereas bilirubin diglucuronide excretion is decreased (34%). 5. In gall-bladder bile of normal dog, 40% of glucose-containing diconjugates, 32% of homogeneous and/or mixed hexuronic acid (mainly glucuronic acid) diesters of bilirubin and 14% of xylose-containing diconjugates are estimated. 6. Increased amounts of bilirubin conjugates, including some with unidentified uronic acid groups, were observed in cholestatic rat biles and quantities of conjugates with glucuronic acid were decreased.


Activity Coefficients and Solubilities of NaCl in Water-Methanol Solutions from Molecular Dynamics Simulations.
We obtain activity coefficients and solubilities of NaCl in water-methanol solutions at 298.15 K and 1 bar from molecular dynamics (MD) simulations with the Joung-Cheatham, SPC/E, and OPLS-AA force fields for NaCl, water, and methanol, respectively. The Lorentz-Berthelot combining rules were adopted for the unlike-pair interactions of Na+, Cl-, and the oxygen site in SPC/E water, and geometric combining rules were utilized for the remainder of the cross interactions. We found that the selection of appropriate combining rules is important in obtaining physically realistic solubilities. The solvent compositions studied range from pure water to pure methanol. Several salt concentrations were investigated at each solvent composition, from the lowest concentrations permitted by the system size used up to the experimental solubilities. We first calculated individual ion activity coefficients (IIACs) for Na+ and Cl- from the free energy change due to the gradual insertion of a single cation or anion into the solution, accompanied by a neutralizing background. We obtained the salt solubilities by comparing the chemical potentials in solution with solid NaCl chemical potentials calculated previously using the Einstein crystal method. Mean ionic activity coefficients obtained from the IIACs are in reasonable agreement with experimental data, with deviations increasing for solutions of higher methanol content. Predictions for the salt solubility are in surprisingly good agreement with experimental data, despite well-known challenges in the simultaneous calculation of activity coefficients and solubilities with classical MD simulations. The present study demonstrates that good predictions for these two important phase equilibrium properties can be obtained for mixed-solvent electrolyte solutions using existing nonpolarizable models and further suggests that the previously proposed single ion insertion technique can be extended to complex mixed-solvent solutions as well.


Sexual activity and vaginal symptoms in the postintervention phase of the Women's Health Initiative Hormone Therapy Trials.
To assess the impact of discontinuing oral hormone therapy (HT) on sexual activity, vaginal symptoms, and sexual activity components among participants in the estrogen-progestin therapy (EPT) and estrogen therapy (ET) trial of the Women's Health Initiative. Surveys were sent postintervention to those who were still taking study pills and agreed to continue in the study when the trials were stopped. Comparisons between former HT and placebo users were accomplished with chi-square tests for categorical variables and t tests for continuous variables. In all, 13,902 women with mean age at survey 69.9 years (EPT trial, women with intact uterus) and 71.7 years (ET trial, women with history of hysterectomy) responded. Prevalence of sexual activity postintervention was not significantly different between former EPT and placebo users (36.0% vs 34.2%; P = 0.37). Sexual activity of former ET users was 5.6% higher than placebo users (27.6% vs 22.0%; P = 0.001). The majority of sexually active women overall maintained orgasmic capacity and sexual satisfaction. Former EPT users were 10% to 12% more likely than former placebo users to report decreased desire, arousal, intercourse, climax, and satisfaction with sexual activity, and also increased dryness and dyspareunia upon discontinuing study drugs (P < 0.001). Former ET users were more likely than placebo users to report rare to no desire or arousal postintervention (P < 0.001). Postintervention ET trial participants formerly assigned to ET were significantly more likely to report sexual activity than those formerly assigned to placebo. Women who discontinued EPT were significantly more likely to report negative vaginal and sex-related effects.


Secondary fracture prevention with osteoporosis medication after a fragility fracture in Sweden remains low despite new guidelines.
This national register study investigated osteoporosis medication prescriptions for secondary fracture prevention among older Swedish adults. Although prescription proportions are increasing for both men and women, they remain low, especially among individuals aged 90 and older. Improved Fracture Liaison Services could increase the prescription proportions and should be bolstered. Despite clear guidelines for secondary fracture prevention among older adults, it seems undertreatment persists. We aimed to describe secondary fracture prevention with medical osteoporosis treatment in the older Swedish population. Specifically, how prescription has changed over time and if these patterns differ in sociodemographic subgroups. Between 2007 and 2020, osteoporosis medication use was studied among all Swedish residents aged 70 and older who had a fragility fracture in the previous 5 years. Previous fragility fractures were defined as fractures of the humerus, wrist, hip, or vertebrae. Osteoporosis medication was defined as any prescription of bone-enhancing medications (including bisphosphonates and denosumab). Osteoporosis medication increased over the study period, especially among men. Prescription among individuals 90 + was consistently two- to threefold lower compared to 70-79- and 80-89-year-olds. In 2018-2020, 8-17% of women and 5-9% of men, depending on age, received osteoporosis medication. At the beginning of the study period, women with higher education were more likely to be prescribed osteoporosis medication, though this difference decreased over time. Prescription of vitamin D and/or calcium as the only treatment was more common than osteoporosis medications throughout the study period. Despite increasing prescription proportions, medical treatment for secondary fracture prevention remains low. In addition, it is more common to be prescribed vitamin D or calcium than osteoporosis medication after a fragility fracture, contrary to current guidelines. These results indicate that there is room for improvement for Fracture Liaison Services in Sweden.


Electrical wire explosion process of copper/silver hybrid nano-particle ink and its sintering via flash white light to achieve high electrical conductivity.
In this work, combined silver/copper nanoparticles were fabricated by the electrical explosion of a metal wire. In this method, a high electrical current passes through the metal wire with a high voltage. Consequently, the metal wire evaporates and metal nanoparticles are formed. The diameters of the silver and copper nanoparticles were controlled by changing the voltage conditions. The fabricated silver and copper nano-inks were printed on a flexible polyimide (PI) substrate and sintered at room temperature via a flash light process, using a xenon lamp and varying the light energy. The microstructures of the sintered silver and copper films were observed using a scanning electron microscope (SEM) and a transmission electron microscope (TEM). To investigate the crystal phases of the flash-light-sintered silver and copper films, x-ray diffraction (XRD) was performed. The absorption wavelengths of the silver and copper nano-inks were measured using ultraviolet-visible spectroscopy (UV-vis). Furthermore, the resistivity of the sintered silver and copper films was measured using the four-point probe method and an alpha step. As a result, the fabricated Cu/Ag film shows a high electrical conductivity (4.06 μΩcm), which is comparable to the resistivity of bulk copper (1.68 μΩcm). In addition, the fabricated Cu/Ag nanoparticle film shows superior oxidation stability compared to the Cu nanoparticle film.


Comparison of seven enzyme immunoassay systems for measurement of cytomegalovirus.
The relative sensitivities of seven different enzyme immunoassay (EIA) systems for the measurement of cytomegalovirus (CMV) were compared. Methods which used two separate antisera to CMV provided the greatest degree of sensitivity. Equivalent sensitivity was noted with the use of either enzyme-labeled antiglobulin or unlabeled staphylococcal protein A and rabbit enzyme-antienzyme complex to measure the second anti-CMV antibody bound to the solid phase. Single-antibody methods were less sensitive than the double-antibody methods but were more sensitive than an inhibition EIA. However, the sensitivity of the inhibition EIA was improved when CMV-antibody complexes were separated from unreacted antibody by means of precipitation with polyethylene glycol. Double-antibody EIA systems are preferable when antisera prepared in two different animal species are obtainable. However, a number of single-antibody EIA systems can be formulated for use in situations where only a single antiserum is available.


Vitamin D supplementation in the prevention and management of major chronic diseases not related to mineral homeostasis in adults: research for evidence and a scientific statement from the European society for clinical and economic aspects of osteoporosis and osteoarthritis (ESCEO).
Optimal vitamin D status promotes skeletal health and is recommended with specific treatment in individuals at high risk for fragility fractures. A growing body of literature has provided indirect and some direct evidence for possible extraskeletal vitamin D-related effects. Members of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis have reviewed the main evidence for possible proven benefits of vitamin D supplementation in adults at risk of or with overt chronic extra-skeletal diseases, providing recommendations and guidelines for future studies in this field. Robust mechanistic evidence is available from in vitro studies and in vivo animal studies, usually employing cholecalciferol, calcidiol or calcitriol in pharmacologic rather than physiologic doses. Although many cross-sectional and prospective association studies in humans have shown that low 25-hydroxyvitamin D levels (i.e., <50 nmol/L) are consistently associated with chronic diseases, further strengthened by a dose-response relationship, several meta-analyses of clinical trials have shown contradictory results. Overall, large randomized controlled trials with sufficient doses of vitamin D are missing, and available small to moderate-size trials often included people with baseline levels of serum 25-hydroxyvitamin D levels >50 nmol/L, did not simultaneously assess multiple outcomes, and did not report overall safety (e.g., falls). Thus, no recommendations can be made to date for the use of vitamin D supplementation in general, parental compounds, or non-hypercalcemic vitamin D analogs in the prevention and treatment of extra-skeletal chronic diseases. Moreover, attainment of serum 25-hydroxyvitamin D levels well above the threshold desired for bone health cannot be recommended based on current evidence, since safety has yet to be confirmed. Finally, the promising findings from mechanistic studies, large cohort studies, and small clinical trials obtained for autoimmune diseases (including type 1 diabetes, multiple sclerosis, and systemic lupus erythematosus), cardiovascular disorders, and overall reduction in mortality require further confirmation.


[Morphological peculiarities of mesenteric lymph nodes in hypokinesia modeling].
Using histological methods, qualitative and quantitative changes in cell composition were studied in mesenteric lymph nodes in 20 male Wistar rats after experimental 30 days-long hypokinesia, and in 10 rats 1 month following the cessation of mobility restriction. Hypokinesia was found to result in massive destruction of lymphoid cells in the structural organ zones, suppression of lymphocytopoiesis, reduction in plasma cell and macrophage numbers, indicating the dampening of the immune reactions, however the full restoration of the cytoarchitectonics in the structural zones of lymph nodes did not take part 30 days following the cessation of hypokinesia.


Induction of actin disruption and downregulation of P-glycoprotein expression by solamargine in multidrug-resistant K562/A02 cells.
Solamargine (SM), a steroidal glycoalkaloid isolated from the Chinese herb Solanum incanum, has been shown to inhibit the growth of some cancer cell lines and induce significant apoptosis. However, the effects of SM on multidrug-resistant (MDR) cells and the molecular mechanisms involved are poorly understood. The purpose of this study was to evaluate the anti-MDR effects of SM and the associated mechanisms in MDR K562/A02 cells. The cytotoxicity of SM was measured by 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT) assay. The 14',6-diamidino-2-phenylindole (DAPI) nuclear staining and flow cytometry were used to detect SM-induced apoptosis. The mRNA expression of P-glycoprotein (P-gp) was investigated by real-time PCR (RT-PCR). Western blotting was used to determine the expression of Bcl-2, Bax, and actin. The changes in the morphology of actin were examined with immunofluorescence staining. MTT results showed that SM effectively killed the MDR sublines K562/A02, KB/VCR, and H460/paclitaxel (Taxol), and their parental cell lines K562, KB, and H460 to an equivalent or more sensitive degree. Based on the results by flow cytometry and immunostaining, the pro-apoptotic effects of SM were observed in MDR K562/A02 cells. Furthermore, the RT-PCR results showed that SM induced the downregulation of MDR1 mRNA. In addition, the expression of P-gp and actin was decreased in the SM-treated cells, as measured by western blotting and immunostaining. These results demonstrate that SM effectively triggers apoptosis in MDR tumor cells, which is associated with actin disruption and downregulation of MDR1 expression. This compound may merit further investigation as a potential therapeutic agent that bypasses the MDR mechanism for the treatment of MDR tumors.


Phosphate removal by hydrothermally modified fumed silica and pulverized oyster shell.
A calcined and hydrothermally annealed material for phosphate removal was prepared in a hollow cylindrical shape from fumed silica generated by a ferroalloy factory, and pulverized oyster shell. Phosphorus removal from wastewater by this material calcined at a range of temperatures (700-900 degrees C) and hydrothermally annealed at temperatures from 130 to 180 degrees C, for 8-16 h, was investigated and the most suitable physicochemical conditions were determined. XRD, SEM, EDS, and XRF techniques were used to characterize the microstructures and compositions of the materials produced, and UV-Vis spectrophotometry using the ammonium phosphomolybdate blue method was used to determine the phosphate concentration in the wastewater. The results indicate that calcium carbonate in oyster shell reacted with SiO(2) in fumed silica and formed hydrated calcium silicate after hydrothermal treatment, and the hydrated calcium silicate reacted with phosphate ions in wastewaters to form hydroxyapatite precipitate. The optimal conditions for material production were calcination at 800 degrees C, and hydrothermal annealing at 150 degrees C for 12 h. Materials made under these conditions showed 74% or 92% phosphate removal after 2 or 4 h, respectively.


A mathematical model on germinal center kinetics and termination.
We devise a mathematical model to study germinal center (GC) kinetics. Earlier models for GC kinetics are extended by explicitly modeling 1) the cell division history of centroblasts, 2) the Ag uptake by centrocytes, and 3) T cell dynamics. Allowing for T cell kinetics and T-B cell interactions, we study the role of GC T cells in GC kinetics, GC termination, and B cell selection. We find that GC T cells play a major role in GC formation, but that the maintenance of established GC reactions requires very few T cells only. The results therefore suggest that the termination of a GC reaction is largely caused by lack of Ag on the follicular dendritic cells and is hardly influenced by Th cells. Ag consumption by centrocytes is the major factor determining the decay rate of the antigenic stimulus during a GC reaction. Investigating the effect of the Ag dose on GC kinetics, we find that both the total size of the GC and its duration are hardly influenced by the initial amount of Ag. In the model this is due to a buffering effect by competition for limited T cell help and/or competition between proliferating centroblasts.


Marihuana: studies on the disposition and metabolism of delta-9-tetrahydrocannabinol in man.
Delta(9)-Tetrahydrocannabinol (the major active component of marihuana) administered intravenously to normal human volunteers persists in plasma for more than 3 days (t(1/2) = 56 hours). Its metabolites appear in plasma within 10 minutes after administration and persist along with the precursor compound. Delta(9)-Tetrahydrocannabinol is completely metabolized in man, and the radioactive metabolites are excreted in urine and feces for more than 8 days.


Linking medical and dental health record data: a partnership with the Rochester Epidemiology Project.
The purpose of this project was to expand the Rochester Epidemiology Project (REP) medical records linkage infrastructure to include data from oral healthcare providers. The goal of this linkage is to facilitate research studies examining the role of oral health in overall health and quality of life. Eight dental practices joined the REP between 2011 and 2015. The REP study team has linked oral healthcare information with medical record information from local healthcare providers for 31 750 participants who have resided in Olmsted County, Minnesota. Overall, 17 718 (56%) participants are women, 14 318 (45%) are 40 years of age or older and 26 090 (82%) are white. A first study using this new information was recently completed. This resource was used to determine whether the 2007 guidelines from the American Heart Association affected prescription rates of antibiotics to patients with moderate-risk cardiac conditions prior to dental procedures. The REP infrastructure was used to identify a series of patients diagnosed with moderate-risk cardiac conditions by the local healthcare providers (n=1351), and to abstract antibiotic prescriptions from dental records both pre-2007 and post-2007. Antibiotic prescriptions prior to dental procedures declined from 62% to 7% following the change in guidelines. Dental data from participating practitioners will be updated on an annual basis, and new dental data will be linked to patient medical records. In addition, we will continue to invite new dental practices to participate in the REP. Finally, we will continue to use this research infrastructure to investigate associations between oral and medical health, and will present findings at conferences and in the scientific literature.


Mobile health assisted self-monitoring is acceptable for supporting weight loss in rural men: a pragmatic randomized controlled feasibility trial.
Addressing overweight and obesity among men at-risk for obesity-related diseases and disability in rural communities is a public health issue. Commercial smartphone applications (apps) that promote self-monitoring for weight loss are widely available. Evidence is lacking regarding what support is required to enhance user engagement with and effectiveness of those technologies. Pragmatically comparing these apps effectiveness, including rural men's desired forms of support when using them, can lead to greater weight loss intervention impact and reach. This study assessed the feasibility and acceptability of a mobile technology application applied differently across two groups for weight loss. In a two-armed, pragmatic pilot feasibility study, 80 overweight and obese men aged 40-69 were randomized using a 1:1 ratio to either an enhanced Mobile Technology Plus (MT+) intervention or a basic Mobile Technology (MT) intervention. The MT+ group had an enhanced smartphone app for self-monitoring (text messaging, discussion group, Wi-Fi scale) whereas the MT group received a basic app that allowed self-monitoring logging only. Assessments were collected at baseline, 3 and 6 months. App logs were analyzed to track engagement and adherence to self-monitoring. Acceptability was assessed via focus groups. Analysis included descriptive statistics and qualitative content analysis. Of 80 men recruited, forty were allocated to each arm. All were included in the primary analysis. Recruitment ended after 10 months with a 97.5 and 92.5% (3 month, 6 month) retention rate. Over 90% of men reported via survey and focus groups that Lose-It app and smart scale (MT+) was an acceptable way to self-monitor weight, dietary intake and physical activity. Adherence to daily app self-monitoring of at least 800 dietary calories or more (reported respectively as MT+, MT) was positive with 73.4, 51.6% tracking at least 5 days a week. Adherence to tracking activity via recorded steps four or more days weekly was positive, 87.8, 64.6%. Men also adhered to self-weighing at least once weekly, 64, 46.3%. At 6 months, an observed mean weight loss was 7.03 kg (95% CI: 3.67, 10.39) for MT+ group and 4.14 kg (95% CI: 2.22, 6.06) for MT group, with 42.9 and 34.2% meeting ≥5% weight loss, respectively. No adverse events were reported. This National Institutes of Health-funded pilot study using mobile technologies to support behavior change for weight loss was found to be feasible and acceptable among midlife and older rural men. The interventions demonstrated successful reductions in weight, noting differing adherence to lifestyle behaviors of eating, monitoring and activity between groups, with men in the MT+ having more favorable results. These findings will be used to inform the design of a larger scale, clinical trial. The trial was prospectively registered with ClinicalTrials NCT03329079 . 11/1/2017.


Advances in pancreatic islet monolayer culture on glass surfaces enable super-resolution microscopy and insights into beta cell ciliogenesis and proliferation.
A robust and reproducible method for culturing monolayers of adherent and well-spread primary islet cells on glass coverslips is required for detailed imaging studies by super-resolution and live-cell microscopy. Guided by an observation that dispersed islet cells spread and adhere well on glass surfaces in neuronal co-culture and form a monolayer of connected cells, we demonstrate that in the absence of neurons, well-defined surface coatings combined with components of neuronal culture media collectively support robust attachment and growth of primary human or rat islet cells as monolayers on glass surfaces. The islet cell monolayer cultures on glass stably maintain distinct mono-hormonal insulin+, glucagon+, somatostatin+ and PP+ cells and glucose-responsive synchronized calcium signaling as well as expression of the transcription factors Pdx-1 and NKX-6.1 in beta cells. This technical advance enabled detailed observation of sub-cellular processes in primary human and rat beta cells by super-resolution microscopy. The protocol is envisaged to have broad applicability to sophisticated analyses of pancreatic islet cells that reveal new biological insights, as demonstrated by the identification of an in vitro protocol that markedly increases proliferation of primary beta cells and is associated with a reduction in ciliated, ostensibly proliferation-suppressed beta cells.


An efficient Agrobacterium-mediated transformation system for poplar.
Poplar is a model system for the regeneration and genetic transformation of woody plants. To shorten the time required for studies of transgenic poplar, efforts have been made to optimize transformation methods that use Agrobacterium tumefaciens. In this study, an Agrobacterium infective suspension was treated at 4 °C for at least 10 h before infecting explants. By transforming the Populus hybrid clone "Nanlin895" (Populus deltoides×P. euramericana) with Agrobacterium harboring the PBI121:CarNAC6 binary vector, we showed that the transformation efficiency was improved significantly by multiple independent factors, including an Agrobacterium infective suspension with an OD600 of 0.7, an Agrobacterium infection for 120 min, an Agrobacterium infective suspension at a pH of 5.0, an acetosyringone concentration of 200 µM, a cocultivation at 28 °C, a cocultivation for 72 h and a sucrose concentration of 30 g/L in the cocultivation medium. We also showed that preculture of wounded leaf explants for two days increased the regeneration rate. The integration of the desired gene into transgenic poplars was detected using selective medium containing kanamycin, followed by southern blot analysis. The expression of the transgene in the transgenic lines was confirmed by northern blot analysis.


Dynamics of unidirectional drying of colloidal dispersions.
We investigate the dynamics of unidirectional drying of silica dispersions. For small colloids (radii a < 15 nm), the minute recession of the drying interface inside the growing solid leads to a slowing down of the evaporation rate, as recently proposed by Wallenstein and Russel [J. Phys.: Condens. Matter, 2011, 23, 194104]. We first propose that Kelvin's effect, i.e. the reduction of the partial pressure of water in the presence of highly curved nanomenisci at the drying air-dispersion interface, has to be taken into account, notably for such small colloids. Our model can fit qualitatively the literature measurements, but with a crossover between the linear regime and the slowing down regime that scales as a(2), as compared to the model of Wallenstein and Russel that predicts a linear scaling. We then also present careful measurements of the dynamics of solidification, which clearly demonstrate that both models (taking into account or not Kelvin's effect) do not fit correctly the slowing down. This is consistent with a brief review of similar recent measurements. Nevertheless, the dynamics can be correctly estimated with a significantly lower effective permeability of the solid region. We suggest that this result may come from the polydispersity of the suspensions, and from the inhomogeneity of the flow within the fracturated solid region, as illustrated by infiltration experiments of a coloured dye.


Acute undifferentiated fever in India: a multicentre study of aetiology and diagnostic accuracy.
The objectives of this study were to determine the proportion of malaria, bacteraemia, scrub typhus, leptospirosis, chikungunya and dengue among hospitalized patients with acute undifferentiated fever in India, and to describe the performance of standard diagnostic methods. During April 2011-November 2012, 1564 patients aged ≥5 years with febrile illness for 2-14 days were consecutively included in an observational study at seven community hospitals in six states in India. Malaria microscopy, blood culture, Dengue rapid NS1 antigen and IgM Combo test, Leptospira IgM ELISA, Scrub typhus IgM ELISA and Chikungunya IgM ELISA were routinely performed at the hospitals. Second line testing, Dengue IgM capture ELISA (MAC-ELISA), Scrub typhus immunofluorescence (IFA), Leptospira Microscopic Agglutination Test (MAT), malaria PCR and malaria immunochromatographic rapid diagnostic test (RDT) Parahit Total™ were performed at the coordinating centre. Convalescence samples were not available. Case definitions were as follows: Leptospirosis: Positive ELISA and positive MAT. Scrub typhus: Positive ELISA and positive IFA. Dengue: Positive RDT and/or positive MAC-ELISA. Chikungunya: Positive ELISA. Bacteraemia: Growth in blood culture excluding those defined as contaminants. Malaria: Positive genus-specific PCR. Malaria was diagnosed in 17% (268/1564) and among these 54% had P. falciparum. Dengue was diagnosed in 16% (244/1564). Bacteraemia was found in 8% (124/1564), and among these Salmonella typhi or S. paratyphi constituted 35%. Scrub typhus was diagnosed in 10%, leptospirosis in 7% and chikungunya in 6%. Fulfilling more than one case definition was common, most frequent in chikungunya where 26% (25/98) also had positive dengue test. Malaria and dengue were the most common causes of fever in this study. A high overlap between case definitions probably reflects high prevalence of prior infections, cross reactivity and subclinical infections, rather than high prevalence of coinfections. Low accuracy of routine diagnostic tests should be taken into consideration when approaching the patient with acute undifferentiated fever in India.


Compact, portable, automatic sample changer stick for cryostats and closed-cycle refrigerators.
Beamlines are facilities that produce and deliver highly focused and intense beams of radiation, typically x rays, synchrotron radiation, or neutrons, for scientific research purposes. Millions of dollars are spent annually to maintain and operate these scientific beamlines, oftentimes running continuously between cycles. To reduce human intervention and improve productivity, mechanical sample changers are often commissioned for use. Designing sample changers is difficult because mechanical parts can be bulky, expensive, and challenging to design for instruments with low volume access, high radiation, and cryogenic environments. We present a portable and inexpensive sample changer stick that can hold and manipulate up to four samples, specifically designed for use with cryogenic closed-cycle refrigerators. The sample changer stick enables rapid and efficient exchange of samples without manual intervention, and is compatible with standard sample mounts such as vanadium cans. The sample changer stick includes a motorized rotation and lancing mechanism, which enables the precise positioning of each sample in the neutron beam, while ensuring compatibility with the operating temperatures and vacuum conditions required for closed-cycle refrigerators. The design has been successfully tested at the VISION beamline at the Spallation Neutron Source. The mechanical action and software controls are detailed. The sample changer stick is a valuable tool for scientists working with cryogenic closed-cycle refrigerators.


Mitochondrial Reactive Oxygen Species Are Essential for the Development of Psoriatic Inflammation.
Psoriasis is a common immune-mediated, chronic, inflammatory skin disease that affects approximately 2-3% of the population worldwide. Although there is increasing evidence regarding the essential roles of the interleukin (IL)-23/IL-17 axis and dendritic cell (DC)-T cell crosstalk in the development of skin inflammation, the contributions of mitochondrial function to psoriasis are unclear. In a mouse model of imiquimod (IMQ)-induced psoriasiform skin inflammation, we found that hematopoietic cell-specific genetic deletion of p32/C1qbp, a regulator of mitochondrial protein synthesis and metabolism, protects mice from IMQ-induced psoriatic inflammation. Additionally, we demonstrate that p32/C1qbp is an important regulator of IMQ-induced DC activation, both in vivo and in vitro. We also found that p32/C1qbp-deficient DCs exhibited impaired production of IL-1β, IL-23, and mitochondrial reactive oxygen species (mtROS) after IMQ stimulation. Because the inhibition of mtROS suppressed IMQ-induced DC activation and psoriatic inflammation, we presume that p32/C1qbp and mtROS can serve as therapeutic targets in psoriasis.


Glutathione-responsive PROTAC for targeted degradation of ERα in breast cancer cells.
ERα (estrogen receptor-α)-targeting PROTACs (PROteolysis TArgeting Chimeras) have emerged as a novel and promising modality for breast cancer therapeutics. However, ERα PROTACs-induced degradation in normal tissues raises concerns about potential off-tissue toxicity. Tumor microenvironment-responsive strategy provides potential for specific control of the PROTAC's on-target degradation activity. The glutathione (GSH) level has been reported to be significantly increased in tumor cells. Here, we designed a GSH-responsive ERα PROTAC, which is generated by conjugating an o-nitrobenzenesulfonyl group to the hydroxyl group of VHL-based ERα PROTAC through a nucleophilic substitution reaction. The o-nitrobenzenesulfonyl group as a protecting group blocks the bioactivity of ERα PROTAC (ER-P1), and that can be specifically recognized and removed by highly abundant GSH in cancer cells. Consequently, the GSH-responsive ERα PROTAC (GSH-ER-P1) exhibits significantly enhanced degradation of ERα in cancer cells compared to that in normal cells, leading to a remarkable inhibition of breast cancer cell proliferation and less toxic effects on normal cells. This study provides a potentially valuable strategy for breast cancer treatment using tumor microenvironment-responsive PROTACs.


Phosphatidylinositol 4-kinase III beta regulates cell shape, migration, and focal adhesion number.
Cell shape is regulated by cell adhesion and cytoskeletal and membrane dynamics. Cell shape, adhesion, and motility have a complex relationship and understanding them is important in understanding developmental patterning and embryogenesis. Here we show that the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIβ) regulates cell shape, migration, and focal adhesion (FA) number. PI4KIIIβ generates phosphatidylinositol 4-phosphate (PI4P) from phosphatidylinositol and is highly expressed in a subset of human breast cancers. PI4KIIIβ and the PI4P it generates regulate a variety of cellular functions, ranging from control of Golgi structure, fly fertility, and Akt signaling. Here, we show that loss of PI4KIIIβ expression decreases cell migration and alters cell shape in NIH3T3 fibroblasts. The changes are accompanied by an increase in the number of FA in cells lacking PI4KIIIβ. Furthermore, we find that PI4P-containing vesicles move to the migratory leading edge during migration and that some of these vesicles tether to and fuse with FA. Fusion is associated with FA disassembly. This suggests a novel regulatory role for PI4KIIIβ and PI4P in cell adhesion and cell shape maintenance.


County-Level Variation in Emergency Department Admission Rates Among US Medicare Beneficiaries.
Hospital-based emergency departments (EDs) are the gateway to hospital admissions for many Americans. Approximately half of all US hospital admissions originate from EDs, and more than 3 in 4 are among Medicare beneficiaries. Recent literature has demonstrated nearly 2-fold variation in both physician- and hospital-level ED admission rates. We study geographic variation at the county level in ED admission rates among Medicare fee-for-service beneficiaries. Using the 100% population data from the Centers for Medicare & Medicaid Services (CMS), we analyzed beneficiaries continuously enrolled in Medicare fee-for-service Parts A and B who resided in the 50 states and the District of Columbia in 2012. The ED admission rate was aggregated to the county level. ED admission rates were adjusted with the CMS Hierarchical Condition Categories (HCC) risk score. The resulting HCC adjusted ED admission rate was mapped to display the variation by county. The average county HCC adjusted ED admission rate was 30.8% in the Medicare population. Counties in the lowest quintile had an ED admission rate of 19.9% or lower. By comparison, counties in the highest quintile had an ED admission rate of 40.3% or higher. Among Medicare beneficiaries, county-level ED admission rates varied 2-fold between counties in the lowest and highest quintiles. Future work should focus on exploring causes for this variation, such as racial ethnic composition, socioeconomic status, and health care delivery system characteristics and the research of effectiveness of policies that affect ED admission decisions.


The Indiana Prenatal Substance Use Prevention Program: its impact on smoking cessation among high-risk pregnant women.
The Indiana Prenatal Substance Use Prevention Program (PSUPP) was established in 1988 to help pregnant women quit cigarette smoking as well as alcohol and drugs. PSUPP directors implement the Screen, Intervene and Follow-up (SIF) model to assess substance use and provide services to help clients stop smoking. During fiscal year 1995, almost 25,000 individuals were impacted directly or indirectly by the PSUPP. Of these, 1,334 pregnant women were screened for substance use by PSUPP. Of the 987 women identified with a known substance use risk factor, 42.4% (418) were high-risk smokers (more than five cigarettes per day) and 9.9% (98) were medium-risk smokers (smoking between one and four cigarettes per day). PSUPP directors counseled their high/medium risk smokers an average of four times during their pregnancy. The PSUPP appears to be effective in getting high-risk smokers to change their smoking behavior during their pregnancy. Approximately one-half (49.9%) of the 516 high- or medium-risk smokers decreased or quit smoking while participating in the PSUPP. When surveyed, about 80% of the PSUPP participants stated that the knowledge they gained through PSUPP relative to tobacco use was "very helpful." Only two-thirds of the PSUPP clients responded that they "strongly agreed" with the statement that tobacco use causes babies to have a lower birth weight. While pregnancy may provide the "teachable moment" for women who smoke, more attention needs to be placed on making women more aware of the risks involved with smoking during pregnancy.


Exploring the temperature-stress metabolome of Arabidopsis.
Metabolic profiling analyses were performed to determine metabolite temporal dynamics associated with the induction of acquired thermotolerance in response to heat shock and acquired freezing tolerance in response to cold shock. Low-M(r) polar metabolite analyses were performed using gas chromatography-mass spectrometry. Eighty-one identified metabolites and 416 unidentified mass spectral tags, characterized by retention time indices and specific mass fragments, were monitored. Cold shock influenced metabolism far more profoundly than heat shock. The steady-state pool sizes of 143 and 311 metabolites or mass spectral tags were altered in response to heat and cold shock, respectively. Comparison of heat- and cold-shock response patterns revealed that the majority of heat-shock responses were shared with cold-shock responses, a previously unknown relationship. Coordinate increases in the pool sizes of amino acids derived from pyruvate and oxaloacetate, polyamine precursors, and compatible solutes were observed during both heat and cold shock. In addition, many of the metabolites that showed increases in response to both heat and cold shock in this study were previously unlinked with temperature stress. This investigation provides new insight into the mechanisms of plant adaptation to thermal stress at the metabolite level, reveals relationships between heat- and cold-shock responses, and highlights the roles of known signaling molecules and protectants.


Implantable cardioverter-defibrillators in patients hospitalized for heart failure with chronically reduced left ventricular ejection fraction.
The aim of this study was to investigate the association between implantable cardioverter-defibrillator (ICD) status at the time of hospitalization for worsening heart failure (HF) with postdischarge events in patients with reduced left ventricular ejection fraction. We conducted an analysis of 4133 patients hospitalized for HF with left ventricular ejection fraction 40% or less in EVEREST. The final analysis included patients without an electrophysiological device (n = 3102) and those with an ICD (n = 600) at the time of enrollment. During a median follow-up of 300 days, all-cause mortality was 22.9% in the no device group and 35.2% in the ICD group (hazard ratio [HR], 1.62; 95% confidence interval [CI], 1.39-1.89). Rehospitalization for HF was 27.0% in the no device group and 46.8% in the ICD group (HR, 2.20; 95% CI, 1.92-2.52). After adjustment for multiple variables, the rates for all-cause mortality were similar (HR, 1.01; 95% CI, 0.83-1.22), but the ICD group had elevated rates of HF hospitalizations compared with the no device group (HR, 1.35; 95% CI, 1.14-1.60). In patients with reduced left ventricular ejection fraction, an ICD at presentation for hospitalization for worsening HF was associated with similar rates of death but higher rates of rehospitalization for HF. Given our findings, further studies should investigate optimization of care in patients already implanted with an ICD as well as the role of ICD implantation during or soon after hospitalization for HF in patients not yet implanted.


Betamethasone pharmacokinetics after two prodrug formulations in sheep: implications for antenatal corticosteroid use.
Maternal administration of betamethasone to enhance fetal lung maturation for women who threaten preterm labor is common clinical practice. However, recommendations regarding the choice of betamethasone formulations for perinatal use are vague. The disposition of betamethasone from two commonly used antenatal formulations is poorly understood. We therefore designed a study to capture the true pharmacokinetic profiles of betamethasone from these fast acting and dual-release formulations. Betamethasone in sheep plasma was measured by a newly designed, highly sensitive liquid chromatography/tandem mass spectrometry assay after intramuscular injection (n = 4) of 0.25 mg/kg betamethasone phosphate and 0.5 mg/kg betamethasone phosphate/acetate formulations. Compartmental modeling was performed using the ADAPT II program. Betamethasone pharmacokinetics could be captured for 24 h for the phosphate and for 5 days for the phosphate/acetate formulations. The phosphate formulation profile had the appearance of a traditional Bateman function with a terminal half-life of 4 h, whereas the phosphate/acetate formulation produced a biexponential decline with a terminal half-life of 14 h. The latter is much longer than is commonly reported and has been missed in the literature due to assay limitations. Extrapolations to humans indicate that although both formulations might have similar therapeutic indices, the dual formulation might be associated with a lower safety profile. In light of this newly identified long terminal half-life for the betamethasone dual formulation, dosing practices for betamethasone in pregnancy need to be reassessed.


The effect of lung biopsy on lung function in diffuse lung disease.
The aim of this study was to investigate the effect on lung function of lung biopsy used in the diagnosis of diffuse lung disease carried out by an open procedure or by video-assisted thoracoscopy. One hundred and sixteen patients with diffuse lung disease who attended the Royal Brompton Hospital were studied retrospectively. Thirty five patients underwent open lung biopsy, and 33 video-assisted thoracoscopic biopsy and 48 had their diagnosis made without biopsy. All patients underwent lung function tests before and after surgery, or at an interval of 3-6 months in those who did not undergo biopsy. No significant differences were found in changes in lung function between those who had and had not undergone biopsy, and the proportions of patients whose lung function improved or deteriorated were similar. Lung biopsy by an open procedure or by video-assisted thoracoscopy did not differ in its effects on lung function. The results for older patients, those with severe disease and those with fibrosing alveolitis were the same as for the whole group. Open lung biopsy for the diagnosis of diffuse lung disease does not deleteriously affect lung function whether carried out by an open or a minimally invasive procedure.


Potential interactions between alternative therapies and warfarin.
Potential and documented interactions between alternative therapy agents and warfarin are discussed. An estimated one third of adults in the United States use alternative therapies, including herbs. A major safety concern is potential interactions of alternative medicine products with prescription medications. This issue is especially important with respect to drugs with narrow therapeutic indexes, such as warfarin. Herbal products that may potentially increase the risk of bleeding or potentiate the effects of warfarin therapy include angelica root, arnica flower, anise, asafoetida, bogbean, borage seed oil, bromelain, capsicum, celery, chamomile, clove, fenugreek, feverfew, garlic, ginger ginkgo, horse chestnut, licorice root, lovage root, meadowsweet, onion, parsley, passionflower herb, poplar, quassia, red clover, rue, sweet clover, turmeric, and willow bark. Products that have been associated with documented reports of potential interactions with warfarin include coenzyme Q10, danshen, devil's claw, dong quai, ginseng, green tea, papain, and vitamin E. Interpretation of the available information on herb-warfarin interactions is difficult because nearly all of it is based on in vitro data, animal studies, or individual case reports. More study is needed to confirm and assess the clinical significance of these potential interactions. There is evidence that a wide range of alternative therapy products have the potential to interact with warfarin. Pharmacists and other health care professionals should question all patients about use of alternative therapies and report documented interactions to FDA's MedWatch program.


Risk Factors Associated With Recurrent Clostridium difficile Infection.
Recurrence of Clostridium difficile infection (CDI) is a problem that can cost up to $20,000 each year in the United States. Studies have reported risk factors that may be associated with a higher incidence of recurrent CDI. We studied additional risk factors, including history of partial colectomy, chemotherapy use and hospitalization in the intensive care unit (ICU). We conducted a retrospective chart review of all outpatients and inpatients at our institution to determine risk factors associated with recurrent CDI. Frequencies were compared using Fisher's exact test and continuous data were compared using Wilcoxon ranks sums test. Recurrent CDI was determined for all patients and risk factors were analyzed using single and multiple logistic regression. A P < 0.05 was used to determine significance. This study included 435 patients and found that advanced age significantly increased the odds of recurrent CDI by 2.3% per year (OR = 1.023, 95% CI = 1.009 - 1.037, P < 0.05). Patients with prior partial colectomy were found to have 3.2 times increased odds of recurrence compared to those without history of partial colectomy (OR = 3.168, 95% CI = 1.324 - 7.579, P < 0.05). Patients receiving chemotherapy or hospitalized in the ICU were not found to have a significantly higher rate of recurrent CDI (P > 0.05). Advanced age and history of partial colectomy were associated with a significantly higher recurrence rate of CDI. Contrary to prior studies, chemotherapy use or hospitalization in the ICU were not found to be associated with a higher rate of recurrent CDI.