A multi-center, randomized controlled trial by the Integrative Management in Japan for Epidemic Disease (IMJEDI study-RCT) on the use of Kampo medicine, kakkonto with shosaikotokakikyosekko, in mild-to-moderate COVID-19 patients for symptomatic relief and prevention of severe stage: a structured summary of a study protocol for a randomized controlled trial.
We aimed to test our hypothesis that additional administration of traditional Japanese (Kampo) medicine, kakkonto (kakkon-to: KT) and shosaikotokakikyosekko (sho-saiko-to-ka-kikyo-sekko: SSKKS), is more effective in relieving symptoms and preventing the onset of severe infection in mild-to-moderate COVID-19 patients compared to those treated only with conventional treatment. The study is designed as a multi-center, interventional, parallel-group, randomized (1:1 ratio), investigator-sponsored, two-arm study. Patients and inpatients will be recruited from 8 Japanese academic and non-academic hospitals. The inclusion and exclusion criteria are as follows: Inclusion criteria: 1. Diagnosed as positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 2. Clinical stages of mild-to-moderate COVID-19 3. Symptomatic 4. ≥ 20 years of age 5. Male or female 6. Ability to communicate in Japanese 7. Outpatients and inpatients 8. Provided informed consent Exclusion criteria: 1. Difficulty in providing informed consent due to dementia, psychosis, or psychiatric symptoms 2. Allergic to Kampo or Western medicines used in this study 3. Pregnant and lactating 4. Unable to follow up 5. Participating in another clinical trial or interventional study 6. Hypokalemic or taking oral furosemide or steroids 7. Determined unsuitable for this study by the physician INTERVENTION AND COMPARATOR: Patients in the control group will receive conventional treatment with antipyretics, painkillers, or antitussives for symptoms that occurred after they contracted the SARS-CoV-2 infection. Patients in the Kampo group will receive 2.5 g of KT (TJ-1@TSUMURA and Co.) and 2.5 g of SSKKS (TJ-109@TSUMURA and Co.) 3 times a day, orally, for 14 days in addition to the conventional treatment as mentioned above. The number of days till at least one of the symptoms (fever, cough, sputum, malaise, shortness of breath) improves in the first 14 days of treatment. To assess the cough, sputum, malaise, and shortness of breath, a numeric rating scale will be used to define improvement in terms of a 2-point decrease in the number of days from the start of treatment for at least 2 days. Fever will be defined as an improvement when the temperature is less than 37 °C. Patients are randomized (1:1 ratio) to each group using the minimization method, with balancing of the arms with severity of disease stage and patient age (< 65, 65 to < 75, or ≥ 75 years). Computer-generated random numbers will be used for the minimization method. Open-label with no blinding NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): The main research hypothesis of this study is that the combination of Kampo medicine and conventional treatment will significantly improve the patients' symptoms (fever, fatigue, cough, sputum, and shortness of breath) during the first 14 days of treatment as compared with conventional treatment alone. Concerning the analysis of the primary endpoint, the duration of time before improvement of at least one of the common cold-like symptoms (fever, malaise, cough, sputum, and shortness of breath) will be estimated using the Kaplan-Meier method, and the survival curves will be compared between groups using the log-rank test. Assuming this method of analysis and based on previous studies reporting the efficacy of Kampo medicine for COVID-19 and H1N1 influenza patients, the median survival time in the Kampo medicine group is estimated as 3 days; this time will be 1.5 times longer in the control group. Assuming a one-sided significance level of 5%, a power of 70%, and an allocation ratio of 1:1, the required sample size is calculated as 126 cases. To compensate for a loss in follow-up, we plan to include 150 cases in both groups (Kampo group = 75, control group = 75). Protocol version 1.2 as of August 20, 2020 Recruitment start (expected): October 1, 2020 Recruitment finish (expected): October 31, 2023 TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) jRCTs021200020 . Registered on August 25, 2020 FULL PROTOCOL: The full protocol is attached as an additional file and is accessible from the Trials website (Additional file 1). In the interest of expediting the dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


[The potential role of microbiota in major psychiatric disorders: Mechanisms, preclinical data, gastro-intestinal comorbidities and therapeutic options].
While forecasts predict an increase in the prevalence of mental health disorders in the worldwide general population, the response rate to classical psychiatric treatment remains unsatisfactory. Resistance to psychotropic drugs can be due to clinical, pharmacological, pharmacokinetic, and pharmacodynamic factors. Among these factors, recent animal findings suggest that microbiota may have an underestimated influence on its host's behavior and on drug metabolism that may explain ineffectiveness or increased side effects of psychiatric medications such as weight gain. The following issues were identified in the present review: (i) microbiota dysbiosis and putative consequences on central nervous system functioning; (ii) chronic microbiota dysbiosis-associated illnesses in humans; (iii) microbiota-oriented treatments and their potential therapeutic applications in psychiatry.


Germline/soma distinction in Drosophila embryos requires regulators of zygotic genome activation.
In Drosophila melanogaster embryos, somatic versus germline identity is the first cell fate decision. Zygotic genome activation (ZGA) orchestrates regionalized gene expression, imparting specific identity on somatic cells. ZGA begins with a minor wave that commences at nuclear cycle (NC)8 under the guidance of chromatin accessibility factors (Zelda, CLAMP, GAF), followed by the major wave during NC14. By contrast, primordial germ cell (PGC) specification requires maternally deposited and posteriorly anchored germline determinants. This is accomplished by a centrosome coordinated release and sequestration of germ plasm during the precocious cellularization of PGCs in NC10. Here, we report a novel requirement for Zelda and CLAMP during the establishment of the germline/soma distinction. When their activity is compromised, PGC determinants are not properly sequestered, and specification is disrupted. Conversely, the spreading of PGC determinants from the posterior pole adversely influences transcription in the neighboring somatic nuclei. These reciprocal aberrations can be correlated with defects in centrosome duplication/separation that are known to induce inappropriate transmission of the germ plasm. Interestingly, consistent with the ability of bone morphogenetic protein (BMP) signaling to influence specification of embryonic PGCs, reduction in the transcript levels of a BMP family ligand, decapentaplegic (dpp), is exacerbated at the posterior pole.


Recognition of sleep-disordered breathing in children.
To determine whether upper airway resistance syndrome (UARS) can be recognized and distinguished from obstructive sleep apnea syndrome (OSAS) in prepubertal children based on clinical evaluations, and, in a subgroup of the population, to compare the efficacy of esophageal pressure (Pes) monitoring to that of transcutaneous carbon dioxide pressure (tcPCO2) and expired carbon dioxide (CO2) measurements in identifying UARS in children. A retrospective study was performed on children, 12 years and younger, seen at our clinic since 1985. Children with diagnoses of sleep-disordered breathing were drawn from our database and sorted by age and initial symptoms. Clinical findings, based on interviews and questionnaires, an orocraniofacial scale, and nocturnal polygraphic recordings were tabulated and compared. If the results of the first polygraphic recording were inconclusive, a second night's recording was performed with the addition of Pes monitoring. In addition, simultaneous measurements of tcPCO2 and endtidal CO2 with sampling through a catheter were performed on this second night in 76 children. These 76 recordings were used as our gold standard, because they were the most comprehensive. For this group, 1848 apneic events and 7040 abnormal respiratory events were identified based on airflow, thoracoabdominal effort, and Pes recordings. We then analyzed the simultaneously measured tcPCO2 and expired CO2 levels to ascertain their ability to identify these same events. The first night of polygraphic recording was inconclusive enough to warrant a second recording in 316 of 411 children. Children were identified as having either UARS (n = 259), OSAS (n = 83), or other sleep disorders (n = 69). Children with small triangular chins, retroposition of the mandible, steep mandibular plane, high hard palate, long oval-shaped face, or long soft palate were highly likely to have sleep-disordered breathing of some type. If large tonsils were associated with these features, OSAS was much more frequently noted than UARS. In the 76 gold standard children, Pes, tcPCO2, and expired CO2 measurements were in agreement for 1512 of the 1848 apneas and hypopneas that were analyzed. Of the 7040 upper airway resistance events, only 2314 events were consonant in all three measures. tcPCO2 identified only 33% of the increased respiratory events identified by Pes; expired CO2 identified only 53% of the same events. UARS is a subtle form of sleep-disordered breathing that leads to significant clinical symptoms and day and nighttime disturbances. When clinical symptoms suggest abnormal breathing during sleep but obstructive sleep apneas are not found, physicians may, mistakenly, assume an absence of breathing-related sleep problems. Symptoms and orocraniofacial information were not useful in distinguishing UARS from OSAS but were useful in distinguishing sleep-disordered breathing (UARS and OSAS) from other sleep disorders. The analysis of esophageal pressure patterns during sleep was the most revealing of the three techniques used for recognizing abnormal breathing patterns during sleep.


Controlled and free-living evaluation of objective measures of sedentary and active behaviors.
Emerging interest in the health impacts of sedentary behaviors has driven the exploration of objective instrumentation capable of capturing these behaviors. The purpose was to compare (under laboratory conditions) outputs from ActiGraph (AG), Intelligent Device for Energy Expenditure and Physical Activity (IDEEA), and activPAL Professional (AP) against direct observation (DO) in sedentary, standing, and active behaviors; and assess convergent validity of instrument outputs under free-living conditions. Participants (13 males/16 females; 28.9 ± 6.2 years) wore instruments concurrently during laboratory and free-living studies. AG cutpoints of ≤50, <100, and ≤259 counts/minute were used to determine time in sedentary behaviors. Laboratory data were evaluated using mean percent error. Free-living data were analyzed using dependent t tests and RM ANOVA. AP precisely measured all identified DO behaviors under laboratory conditions; IDEEA precisely identified sitting and standing. For the free-living study, there was no difference in sedentary time detected by AP and IDEEA but a significant difference was observed in standing time. No difference was apparent between AP and AG259 in sit/lie/stand or ambulatory activity time. In a laboratory setting, the utility of all instruments to classify activities into behavioral categories was confirmed. This may enhance research on sedentary behaviors and health-related outcomes.


A facile one-pot preparation of Bi2O2CO3/g-C3N4 composites with enhanced photocatalytic activity.
Bi2O2CO3 modified graphitic carbon nitride (g-C3N4) nanosheets were prepared by a simple one-pot synthetic strategy. In the presence of ammonium nitrate, different mass ratios of bismuth nitrate/melamine were used to fabricate these catalysts, which were characterized by X-ray diffraction (XRD), N2-physisorption, Fourier transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), UV-vis analysis, and photoluminescence (PL). The catalytic properties of composites were evaluated by photodegrading tetracycline hydrochloride (TC) under visible light irradiation. Among these catalysts, Bi2O2CO3(1.5)/g-C3N4 showed the highest catalytic activity, which was more than 16 times greater than the pristine g-C3N4 material. The improved photocatalytic properties of Bi2O2CO3/g-C3N4 may be due to the formation of a heterojunction between Bi2O2CO3 and g-C3N4, leading to the effective separation of photo-induced carriers and the enhanced absorption of visible light. Furthermore, the Bi2O2CO3/g-C3N4 composites had considerable catalytic stability, which was a key element for their potential applications.


Protective effects of Acyl-coA thioesterase 1 on diabetic heart via PPARα/PGC1α signaling.
Using fatty acids (FAs) exclusively for ATP generation was reported to contribute to the development of diabetic cardiomyopathy. We studied the role of substrate metabolism related genes in the heart of the diabetes to find out a novel therapeutic target for diabetic cardiomyopathy. By microarray analysis of metabolic gene expression, acyl-CoA thioesterase 1 (acot1) was clearly upregulated in the myocardia of db/db mice, compared with normal control C57BL/Ks. Therefore, gain-of-function and loss-of-function approaches were employed in db/db mice to investigate the functions of ACOT1 in oxidative stress, mitochondrial dysfunction and heart function. We found that in the hearts of db/db mice which overexpressed ACOT1, H(2)O(2) and malondialdehyde (MDA) were reduced, the activities of ATPases in mitochondria associated with mitochondrial function were promoted, the expression of uncoupling protein 3 (UCP3) contributing to oxygen wastage for noncontractile purposes was decreased, and cardiac dysfunction was attenuated, as determined by both hemodynamic and echocardiographic detections. Consistently, ACOT1 deficiency had opposite effects, which accelerated the cardiac damage induced by diabetes. Notably, by real-time PCR, we found that overexpression of ACOT1 in diabetic heart repressed the peroxisome proliferator-activated receptor alpha/PPARγ coactivator 1α (PPARα/PGC1α) signaling, as shown by decreased expression of PGC1α and the downstream genes involved in FAs use. Our results demonstrated that ACOT1 played a crucial protective role in diabetic heart via PPARα/PGC1α signaling.


Improvement of bone-tendon fixation by porous titanium interference screw: A rabbit animal model.
The interference screw is a widely used fixation device in the anterior cruciate ligament (ACL) reconstruction surgeries. Despite the generally satisfactory results, problems of using interference screws were reported. By using additive manufacturing (AM) technology, we developed an innovative titanium alloy (Ti6 Al4 V) interference screw with rough surface and inter-connected porous structure designs to improve the bone-tendon fixation. An innovative Ti6 Al4 V interference screws were manufactured by AM technology. In vitro mechanical tests were performed to validate its mechanical properties. Twenty-seven New Zealand white rabbits were randomly divided into control and AM screw groups for biomechanical analyses and histological analysis at 4, 8, and 12 weeks postoperatively; while micro-CT analysis was performed at 12 weeks postoperatively. The biomechanical tests showed that the ultimate failure load in the AM interference screw group was significantly higher than that in the control group at all tested periods. These results were also compatible with the findings of micro-CT and histological analyses. In micro-CT analysis, the bone-screw gap was larger in the control group; while for the additive manufactured screw, the screw and bone growth was in close contact. In histological study, the bone-screw gaps were wider in the control group and were almost invisible in the AM screw group. The innovative AM interference screws with surface roughness and inter-connected porous architectures demonstrated better bone-tendon-implant integration, and resulted in stronger biomechanical characteristics when compared to traditional screws. These advantages can be transferred to future interference screw designs to improve their clinical performance. The AM interference screw could improve graft fixation and eventually result in better biomechanical performance of the bone-tendon-screw construct. The innovative AM interference screws can be transferred to future interference screw designs to improve the performance of implants. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2633-2640, 2018.


Cyclic AMP-dependent protein kinase inhibits the activity of myogenic helix-loop-helix proteins.
Differentiation of skeletal muscle cells is inhibited by the cyclic AMP (cAMP) signal transduction pathway. Here we report that the catalytic subunit of cAMP-dependent protein kinase (PKA) can substitute for cAMP and suppress muscle-specific transcription by silencing the activity of the MyoD family of regulatory factors, which includes MyoD, myogenin, myf5, and MRF4. Repression by the PKA catalytic (C) subunit is directed at the consensus sequence CANNTG, the target for DNA binding and transcriptional activation by these myogenic regulators. Phosphopeptide mapping of myogenin in vitro and in vivo revealed two PKA phosphorylation sites, both within the basic region. However, repression of myogenin function by PKA does not require direct phosphorylation of these sites but instead involves an indirect mechanism with one or more intermediate steps. Regulation of the transcriptional activity of the MyoD family by modulation of the cAMP signaling pathway may account for the inhibitory effects of certain peptide growth factors on muscle-specific gene expression and may also determine the responsiveness of different cell types to myogenic conversion by these myogenic regulators.


Severity of leukoaraiosis, leptomeningeal collaterals, and clinical outcomes after intra-arterial therapy in patients with acute ischemic stroke.
Leukoaraiosis (LA) is defined as ischemic white matter lesions associated with increased stroke risk and poor post-stroke outcomes. These lesions are likely the result of diffuse angiopathic changes affecting the cerebral small vessels. We investigated whether pre-existing LA burden is associated with outcomes in patients with large cerebral artery occlusion undergoing intra-arterial therapy (IAT) for acute ischemic stroke (AIS). We analyzed consecutive AIS subjects undergoing IAT from the institutional Get With The Guidelines-Stroke database enrolled between January 1, 2007 and June 30, 2009, who had National Institutes of Health Stroke Scale scores of ≥ 8, baseline diffusion weighted imaging volume ≤ 100 mL, and evidence of proximal artery occlusion (PAO) on pre-IAT computed tomography angiography (CTA). LA volume (LAv) was assessed on fluid attenuated inversion recovery MRI using a validated semi-automated protocol. We used CTA for collateral grade, post-IAT angiogram for recanalization status (Thrombolysis in Cerebral Infarction score ≥ 2b), and the 24 h head CT for symptomatic intracranial hemorrhage. Logistic regression was used to determine independent predictors of 90 day post-stroke good functional outcome (modified Rankin Scale score ≤ 2) and mortality. Increasing LAv independently reduced the odds of good collateral grade (OR 0.85, 95% CI 0.73 to 0.98). Good functional outcome was independently predicted by intravenous tissue plasminogen activator use (OR 12.86, 95% CI 2.20 to 76.28), and recanalization status (OR 6.94, 95% CI 1.56 to 30.86). Mortality was independently associated with recanalization status (OR 0.08, 95% CI 0.01 to 0.51), age (OR 1.08, 95% CI 1.01 to 1.15), and antecedent use of hypoglycemic agents (OR 6.55, 95% CI 1.58 to 54.01). Severity of LA is linked to poor collateral grade in AIS patients undergoing IAT for PAO; however, greater LAv appears not to be a contraindication for acute intervention.


The geriatric clinic: dry and limp: aging queers, zombies, and sexual reanimation.
This essay looks to the omission of aging queer bodies from new medical technologies of sex. We extend the Foucauldian space of the clinic to the mediascape, a space not only of representations but where the imagination is conditioned and different worlds dreamed into being. We specifically examine the relationship between aging queers and the marketing of technologies of sexual function. We highlight the ways queers are excluded from the spaces of the clinic, specifically the heternormative sexual scripts that organize biomedical care. Finally, using recent zombie theory, we gesture toward both the constraints and possibilities of queer inclusion within the discourses and practices that aim to reanimate sexual function. We suggest that zombies usefully frame extant articulations of aging queers with sex and the dangerous lure of medical treatments that promise revitalized, but normative, sexual function at the cost of other, perhaps queerer intimacies.


Bayesian estimation of genetic parameters for multivariate threshold and continuous phenotypes and molecular genetic data in simulated horse populations using Gibbs sampling.
Requirements for successful implementation of multivariate animal threshold models including phenotypic and genotypic information are not known yet. Here simulated horse data were used to investigate the properties of multivariate estimators of genetic parameters for categorical, continuous and molecular genetic data in the context of important radiological health traits using mixed linear-threshold animal models via Gibbs sampling. The simulated pedigree comprised 7 generations and 40000 animals per generation. Additive genetic values, residuals and fixed effects for one continuous trait and liabilities of four binary traits were simulated, resembling situations encountered in the Warmblood horse. Quantitative trait locus (QTL) effects and genetic marker information were simulated for one of the liabilities. Different scenarios with respect to recombination rate between genetic markers and QTL and polymorphism information content of genetic markers were studied. For each scenario ten replicates were sampled from the simulated population, and within each replicate six different datasets differing in number and distribution of animals with trait records and availability of genetic marker information were generated. (Co)Variance components were estimated using a Bayesian mixed linear-threshold animal model via Gibbs sampling. Residual variances were fixed to zero and a proper prior was used for the genetic covariance matrix. Effective sample sizes (ESS) and biases of genetic parameters differed significantly between datasets. Bias of heritability estimates was -6% to +6% for the continuous trait, -6% to +10% for the binary traits of moderate heritability, and -21% to +25% for the binary traits of low heritability. Additive genetic correlations were mostly underestimated between the continuous trait and binary traits of low heritability, under- or overestimated between the continuous trait and binary traits of moderate heritability, and overestimated between two binary traits. Use of trait information on two subsequent generations of animals increased ESS and reduced bias of parameter estimates more than mere increase of the number of informative animals from one generation. Consideration of genotype information as a fixed effect in the model resulted in overestimation of polygenic heritability of the QTL trait, but increased accuracy of estimated additive genetic correlations of the QTL trait. Combined use of phenotype and genotype information on parents and offspring will help to identify agonistic and antagonistic genetic correlations between traits of interests, facilitating design of effective multiple trait selection schemes.


Adolescents with congenital heart defects: a patient and parental perspective of genetic information and genetic risk.
Congenital heart defects (CHDs) occur in 8 of 1000 live-born children, making them common birth defects in the adolescent population. CHDs may have single gene, chromosomal, or multifactorial causes. Despite evidence that patients with CHD want information on heritability and genetics, no studies have investigated the interest or knowledge base in the adolescent population. This information is necessary as patients in adolescence take greater ownership of their health care and discuss reproductive risks with their physicians. The objectives of this survey-based study were to determine adolescents' recall of their own heart condition, to assess patient and parent perception of the genetic contribution to the adolescent's CHD, and to obtain information about the preferred method(s) for education. The results show that adolescent patients had good recall of their type of CHD. Less than half of adolescents and parents believed their CHD had a genetic basis or was heritable; however, adolescents with a positive family history of CHD were more likely to believe that their condition was genetic (p = 0.0005). The majority of patients were interested in receiving additional genetics education and preferred education in-person and in consultation with both parents and a physician. The adolescents who felt most competent to have discussions with their doctors regarding potential causes of their heart defect previously had a school science course which covered topics in genetics. These results provide insight into adolescents' perceptions and understanding about their CHD and genetic risk and may inform the creation and provision of additional genetic education.


Effects of calcium soaps of long-chain fatty acids on feedlot performance, carcass characteristics and ruminal metabolism of steers.
Two trials were conducted to determine the effects of calcium soaps of long-chain fatty acids (calcium soap) on feedlot performance, diet digestibility, carcass characteristics and ruminal metabolism of steers fed diets (85% concentrate:15% corn silage) containing 0, 2, 4 or 6% calcium soap. In Trial 1, increasing calcium soap decreased (P less than .05) DM, CP and gross energy intake but increased total fatty acid intake. Feed to gain ratio tended to improve with increased calcium soap; gross energy conversion was not affected (P greater than .05) by diet. Average daily gain and hot carcass weight decreased (P less than .05) with addition of calcium soap; other carcass characteristics were not affected (P greater than .05). Apparent digestibilities of DM, N, energy and ash were not affected (P greater than .05) by calcium soap. Neutral detergent fiber digestibility increased linearly (P less than .08) with increasing calcium soap, whereas digestibility of total fatty acids was affected quadratically (P less than .05); fatty acid digestibility was similar among 0, 2 and 4% calcium soap diets but decreased for the 6% calcium soap diet. In Trial 2, increased calcium soap did not affect (P greater than .05) ruminal VFA concentrations, pH or in sacco NDF disappearance of orchardgrass following 12, 24 and 48 h of incubation. Calcium soap increased (P less than .07) ruminal concentrations of calcium soap fatty acids at 1, 2, 4 and 8 h postfeeding. Calcium soap did not improve performance of feedlot cattle fed high-concentrate diets. Further, calcium soap did not affect ruminal fermentation and did not dissociate significantly even when ruminal pH was below 6 for extended periods of time.


An analytical method with a single extraction procedure and two separate high performance liquid chromatographic systems for the determination of artesunate, dihydroartemisinin and mefloquine in human plasma for application in clinical pharmacological studies of the drug combination.
The combination of two sensitive, selective and reproducible reversed phase liquid chromatographic (RP-HPLC) methods was developed for the determination of artesunate (AS), its active metabolite dihydroartemisinin (DHA) and mefloquine (MQ) in human plasma. Solid phase extraction (SPE) of the plasma samples was carried out on Supelclean LC-18 extraction cartridges. Chromatographic separation of AS, DHA and the internal standard, artemisinin (QHS) was obtained on a Hypersil C4 column with mobile phase consisting of acetonitrile-0.05 M acetic acid adjusted to pH 5.2 with 1.0M NaOH (42:58, v/v) at the flow rate of 1.50 ml/min. The analytes were detected using an electrochemical detector operating in the reductive mode. Chromatography of MQ and the internal standard, chlorpromazine hydrochloride (CPM) was carried out on an Inertsil C8-3 column using methanol-acetonitrile-0.05 M potassium dihydrogen phosphate adjusted to pH 3.9 with 0.5% orthophosphoric acid (50:8:42, v/v/v) at a flow rate of 1.00 ml/min with ultraviolet detection at 284 nm. The mean recoveries of AS and DHA over a concentration range of 30-750 ng/0.5 ml plasma and MQ over a concentration of 75-1500 ng/0.5 ml plasma were above 80% and the accuracy ranged from 91.1 to 103.5%. The within-day coefficients of variation were 1.0-1.4% for AS, 0.4-3.4% for DHA and 0.7-1.5% for MQ. The day-to-day coefficients of variation were 1.3-7.6%, 1.8-7.8% and 2.0-3.4%, respectively. Both the lower limit of quantifications for AS and DHA were at 10 ng/0.5 ml and the lower limit of quantification for MQ was at 25 ng/0.5 ml. The limit of detections were 4 ng/0.5 ml for AS and DHA and 15 ng/0.5 ml for MQ. The method was found to be suitable for use in clinical pharmacological studies.


Identification of Fungi and Fungal Pathogens Associated with Hypolixus haerens and Decayed and Cankered Stems of Amaranthus hybridus.
Discoloration, cankers, and decay in branches, stems, and root collars of Amaranthus hybridus were observed in Bloemfontein, South Africa. Examination of symptomatic stems revealed larval galleries of the pigweed weevil (Hypolixus haerens). The objectives of this study were to: identify the most common fungal species associated with this damage, determine if the adult pigweed weevil might be a vector for the fungi, and test if the associated fungi can cause the stem canker disease observed in the field. The most common fungal species isolated were Fusarium subglutinans from discolored tissues adjacent to insect galleries (42%), F. subglutinans from weevil larvae (29%), the Alternaria tenuissima group from adult weevils (31%), and the A. tenuissima group from cankered stems (40%). Three of the seven most common fungal species produced cankers following wounding and inoculation, with F. sambucinum and F. oxysporum being the most aggressive. Although fungal species compositions differed (P < 0.01) among the four tissue/insect stage combinations tested, all four had the same major fungal species, suggesting the pigweed weevil as a vector for the Fusarium pathogens. There is significant potential for yield loss affiliated with this insect-fungal association. The identification of this insect-fungal relationship and the pathogens involved in disease set the stage for further research on the etiology and disease management of this important insect-fungal relationship.


Heat treatment mimics guanosine-5'-triphosphate effects on dopaminergic 3H-ligand binding to bovine caudate membranes.
Exposure of bovine caudate homogenates to 53 degrees rapidly (less than 4 min) abolishes subsequent specific binding of the agonist ligand [3H]dopamine to D-3 sites but not that of the butyrophenone dopaminergic antagonist [3H]spiroperidol to D-2 sites in bovine caudate membranes. It has been suggested that this represents selective heat inactivation of the binding site for [3H]dopamine. However, the binding of the agonist [3H]apomorphine is decreased with a time course and temperature dependence indistinguishable from that of [3H]dopamine, despite the ability of [3H]apomorphine to label D-2 sites as well as D-3 sites in control membranes. Heat treatment thus appears to mimic the effects on dopaminergic binding of guanine nucleotides, which, rather than causing a reduction in the number of binding sites, radically lowers agonist affinity at both D-2 and D-3 sites while leaving antagonist affinity at these sites unchanged. In addition, heat treatment and maximal guanine nucleotide addition (300 microM GTP) cause identical decreases in the affinities of agonists in the displacement of [3H]spiroperidol, and similar increases in pseudo-Hill coefficient of these displacements. The effects of heat treatment and guanine nucleotides are not additive, suggesting that their effects may involve a common mechanism. Thus, it is strongly suggested that brief exposure to 53 degrees inactivates not the D-3 site itself, but rather a guanine nucleotide binding factor that regulates both D-2 and D-3 agonist affinities and, as in the beta-adrenergic system, is essential for formation of high-affinity agonist/receptor complexes.


Fallopian tube and primary peritoneal carcinomas associated with BRCA mutations.
The aims of this study were to determine the incidence of BRCA mutations among Ashkenazi Jewish patients with fallopian tube carcinoma (FTC) or primary peritoneal carcinoma (PPC), to study the clinicopathologic features of these cancers, and to estimate the risks of these cancers in association with a BRCA mutation. A retrospective review at two institutions identified 29 Jewish patients with FTC and 22 Jewish patients with PPC. These patients were genotyped for the three Ashkenazi Jewish BRCA founder mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2). Surgical and pathologic information, family history, and survival data were obtained from hospital records. All statistical tests were two sided. Germline BRCA mutations were identified in five of 29 patients with FTC (17%) and nine of 22 patients with PPC (41%). Mutation carriers had a younger mean age at diagnosis than patients without a mutation (60 v 70 years; P =.002). The overall median survival was 148 months for mutation carriers and 41 months for patients without a mutation (P =.04). For BRCA mutation carriers, the lifetime risks of FTC and PPC were 0.6% and 1.3%, respectively. Substantial proportions of Ashkenazi Jewish patients with FTC or PPC are BRCA mutation carriers. Patients with BRCA-associated FTC or PPC are younger at diagnosis and have improved survival compared with patients without a BRCA mutation. Although the lifetime risks of FTC or PPC for patients with BRCA heterozygotes are greater than those for the general population, the absolute risks seem relatively low.


Beaver-mediated methane emission: The effects of population growth in Eurasia and the Americas.
Globally, greenhouse gas budgets are dominated by natural sources, and aquatic ecosystems are a prominent source of methane (CH(4)) to the atmosphere. Beaver (Castor canadensis and Castor fiber) populations have experienced human-driven change, and CH(4) emissions associated with their habitat remain uncertain. This study reports the effect of near extinction and recovery of beavers globally on aquatic CH4 emissions and habitat. Resurgence of native beaver populations and their introduction in other regions accounts for emission of 0.18-0.80 Tg CH(4) year(-1) (year 2000). This flux is approximately 200 times larger than emissions from the same systems (ponds and flowing waters that became ponds) circa 1900. Beaver population recovery was estimated to have led to the creation of 9500-42 000 km(2) of ponded water, and increased riparian interface length of >200 000 km. Continued range expansion and population growth in South America and Europe could further increase CH(4) emissions.


Transmission and prevention of occupational infections in orthopaedic surgeons.
Microorganisms are transmitted in hospitals mainly by contact, droplet, and airborne routes. Orthopaedic surgeons have a substantial occupational risk of contracting a blood-borne infection because of frequent handling of sharp instruments and objects during operative procedures. Aerosolization means the formation of aerosols and droplets when blood or other body fluids are mechanically disturbed. Smaller particles (<5 microm) will remain suspended in air. Pathogens that can survive in these small airborne particles may cause infection if they are inhaled. Aerosol-generating procedures in patients with tuberculosis or severe acute respiratory syndrome (SARS) may facilitate airborne transmission. The Hospital Infection Control Practices Advisory Committee and the Centers for Disease Control and Prevention have established guidelines for isolation precautions in hospitals.


Evaluation of antioxidant and antimicrobial activities of Bergenia ciliata Sternb (Rhizome) crude extract and fractions.
Biologically, screening of medicinal plants extracts have been since pre-historic to determine the antioxidants and antimicrobial profile. The present study was aimed to investigate and evaluate crude extract and different fractions of Bergenia ciliata Sternb (rhizome) for bioactivity which is most considerable medicinal plants. The chloroform fraction was found to be highly anti-oxidative with the IC50 value (4.15±0.82) as compare to ethyl acetate and n-hexane fraction. In addition, neither crude extract nor any fraction showed inhibition against fungal strains, i.e. Aspergillus flavus and Aspergillus niger. Furthermore, the crude extract and fractions of B. ciliata (rhizome) exhibiting promising activities against Bacillus atrophoeus, Bacillus subtilis, Kleibsiella pneumonia and Pseudomonas aeruginosa strains. In summary, B. ciliata is recommended as a source of bioactive compounds which might be used against oxidative stress and drug resistance bacteria.


Australian general practitioner chlamydia testing rates among young people.
To describe the proportion of 16-29-year-olds tested for chlamydia by Australian general practitioners in a 12-month period. Between October 2007 and September 2008, the national chlamydia testing rate in 16-29-year-olds was calculated by dividing the number of Medicare-reimbursed chlamydia tests by two denominators: (i) Medicare-reimbursed GP consultations; and (ii) estimated resident populations adjusted for the proportion who were sexually active. GP chlamydia testing rates in 16-29-year-olds per 100 patients attending a GP consultation and per 100 sexually active population, by patient age and sex, state/territory of residence, and remoteness area. Among the estimated Australian population of 16-29-year-olds, 85.6% of females and 64.4% of males had at least one GP consultation in the 12-month period. The national GP chlamydia testing rate per 100 patients was 8.9% (95% CI, 8.88%-8.94%). The national GP chlamydia testing rate per 100 sexually active population was 8.0% (95% CI, 7.92%-7.98%). The rate per 100 sexually active population was higher in females (12.5%) compared with males (3.7%) (P < 0.01); higher in 20-24-year-olds (9.0%) compared with 16-19-year-olds (8.7%) and 25-29-year-olds (6.6%) (P < 0.01); higher in those living in non-metropolitan areas (11.0%) compared with metropolitan areas (8.4%) (P < 0.01); and highest in those living in the Northern Territory (21.4%) compared with other jurisdictions (P < 0.01). Despite clinical guidelines recommending annual chlamydia testing for sexually active 15-29-year-olds, our analysis showed that a high proportion of young people aged 16-29 years attend a GP each year, but few of the sexually active population in this age group were tested for chlamydia in general practice. Strategies are needed to support GPs to enhance chlamydia testing in young people.


Can strand displacement take place in DNA triplexes?
This work studies strand displacement in the context of DNA triplexes. We observed that toehold-mediated strand displacement could proceed in DNA triplexes, but at a much slower rate than in DNA duplexes. In this study, strand displacement was studied with native polyacrylamide gel electrophoresis (PAGE) for two molecular systems. While both systems were involved in branch migration in a DNA triplex, the toehold forms either a duplex or a triplex. This study provides a new strategy for sequence-specific strand displacement and it is useful for the construction of dynamic DNA nanostructures and control of smart DNA nanodevices.


Postprandial effect of dietary fat quantity and quality on arterial stiffness and wave reflection: a randomised controlled trial.
Arterial stiffness is a component of vascular function and an established risk factor for cardiovascular disease. There is a lack of conclusive evidence on the effect of a meal rich in monounsaturated fat (MUFA) compared with an isoenergetic meal rich in saturated fat (SFA) on postprandial vascular function and specifically on arterial stiffness. Twenty healthy, non-smoking males (BMI 24 ± 2 kg/m2; age 37.7 ± 14.4 y) participated in this single-blind, randomised, cross-over dietary intervention study. Each subject was randomised to receive a high-fat test-meal (3 MJ; 56 ± 2 g fat) at breakfast on 2 separate occasions, one rich in oleic acid (MUFA-meal) and one rich in palmitic acid (SFA-meal), and the meals were isoenergetic. Blood pressure (BP), arterial stiffness (PWV) and arterial wave reflection (augmentation index, AIx) were measured using applanation tonometry at baseline and every 30 minutes up to 4 hours after the ingestion of the test-meals. All subjects completed both arms of the dietary intervention. There was no significant difference in BP parameters, PWV or AIx at baseline between the two treatments (P > 0.05). There was a significant increase in brachial and aortic BP, mean arterial pressure (MAP), heart rate and PVW (time, P < 0.05) over the four hours after consumption of the fat-rich test-meal although the increase in PWV was no longer significant when adjusted for the increase in MAP. There was no difference in PWV between the two treatments (treatment*time, P > 0.05). There was a significant reduction in AIx (time, P < 0.05) over the four hour postprandial period although this was no longer significant when adjusted for the increase in heart rate and MAP (time, P > 0.05). There was no difference in AIx between the two treatments (treatment*time, P > 0.05). However, the reduction in heart rate corrected augmentation index (AIx75) was significant when corrected for the increase in MAP (time, P < 0.01) with no differential effect of the treatments (treatment*time, P > 0.05). This study has demonstrated a BP dependent increase in PWV and a decrease in arterial wave reflection in the four hour period in response to a high-fat meal. There was no evidence however that replacement of some of the SFA with MUFA had a differential effect on these parameters. The study highlights the need for further research to understand the effects of the substitution of SFA with MUFA on non-serum, new and emerging risk factors for CVD such as arterial stiffness.


Marine-Derived Anticancer Agents: Clinical Benefits, Innovative Mechanisms, and New Targets.
The role of the marine environment in the development of anticancer drugs has been widely reviewed, particularly in recent years. However, the innovation in terms of clinical benefits has not been duly emphasized, although there are important breakthroughs associated with the use of marine-derived anticancer agents that have altered the current paradigm in chemotherapy. In addition, the discovery and development of marine drugs has been extremely rewarding with significant scientific gains, such as the discovery of new anticancer mechanisms of action as well as novel molecular targets. Approximately 50 years since the approval of cytarabine, the marine-derived anticancer pharmaceutical pipeline includes four approved drugs and eighteen agents in clinical trials, six of which are in late development. Thus, the dynamic pharmaceutical pipeline consisting of approved and developmental marine-derived anticancer agents offers new hopes and new tools in the treatment of patients afflicted with previously intractable types of cancer.


Natural Course of Frailty Components in People Who Develop Frailty Syndrome: Evidence From Two Cohort Studies.
Frailty is an important geriatric syndrome, but little is known about its development in the years preceding onset of the syndrome. The aim of this study was to examine the progression of frailty and compare the trajectories of each frailty component prior to frailty onset. Repeat data were from two cohort studies: the Longitudinal Aging Study Amsterdam (n = 1440) with a 15-year follow-up and the InCHIANTI Study (n = 998) with a 9-year follow-up. Participants were classified as frail if they had >3 frailty components (exhaustion, slowness, physical inactivity, weakness, and weight loss). Transitions between frailty components were examined with multistate modeling. Trajectories of frailty components were compared among persons who subsequently developed frailty to matched nonfrail persons by using mixed effects models. The probabilities were 0.43, 0.40, and 0.36 for transitioning from 0 to 1 frailty component, from 1 component to 2 components, and from 2 components to 3-5 components (the frail state). The transition probability from frail to death was 0.13. Exhaustion separated frail and nonfrail groups already 9 years prior to onset of frailty (pooled risk ratio [RR] = 1.53, 95% confidence interval [CI] 1.04-2.24). Slowness (RR = 1.94, 95% CI 1.44-2.61), low activity (RR = 1.59, 95% CI 1.19-2.13), and weakness (RR = 1.39, 95% CI 1.10-1.76) separated frail and nonfrail groups 6 years prior to onset of frailty. The fifth frailty component, weight loss, separated frail and nonfrail groups only at the onset of frailty (RR = 3.36, 95% CI 2.76-4.08). Evidence from two cohort studies suggests that feelings of exhaustion tend to emerge early and weight loss near the onset of frailty syndrome.


Modeling 3D facial shape from DNA.
Human facial diversity is substantial, complex, and largely scientifically unexplained. We used spatially dense quasi-landmarks to measure face shape in population samples with mixed West African and European ancestry from three locations (United States, Brazil, and Cape Verde). Using bootstrapped response-based imputation modeling (BRIM), we uncover the relationships between facial variation and the effects of sex, genomic ancestry, and a subset of craniofacial candidate genes. The facial effects of these variables are summarized as response-based imputed predictor (RIP) variables, which are validated using self-reported sex, genomic ancestry, and observer-based facial ratings (femininity and proportional ancestry) and judgments (sex and population group). By jointly modeling sex, genomic ancestry, and genotype, the independent effects of particular alleles on facial features can be uncovered. Results on a set of 20 genes showing significant effects on facial features provide support for this approach as a novel means to identify genes affecting normal-range facial features and for approximating the appearance of a face from genetic markers.


A research agenda for malaria eradication: modeling.
Malaria modeling can inform policy and guide research for malaria elimination and eradication from local implementation to global policy. A research and development agenda for malaria modeling is proposed, to support operations and to enhance the broader eradication research agenda. Models are envisioned as an integral part of research, planning, and evaluation, and modelers should ideally be integrated into multidisciplinary teams to update the models iteratively, communicate their appropriate use, and serve the needs of other research scientists, public health specialists, and government officials. A competitive and collaborative framework will result in policy recommendations from multiple, independently derived models and model systems that share harmonized databases. As planned, modeling results will be produced in five priority areas: (1) strategic planning to determine where and when resources should be optimally allocated to achieve eradication; (2) management plans to minimize the evolution of drug and pesticide resistance; (3) impact assessments of new and needed tools to interrupt transmission; (4) technical feasibility assessments to determine appropriate combinations of tools, an associated set of target intervention coverage levels, and the expected timelines for achieving a set of goals in different socio-ecological settings and different health systems; and (5) operational feasibility assessments to weigh the economic costs, capital investments, and human resource capacities required.


The denominator problem: estimating MSM-specific incidence of sexually transmitted infections and prevalence of HIV using population sizes of MSM derived from Internet surveys.
Measuring prevalence and incidence of sexually transmitted infections in hard to reach populations like men who have sex with men (MSM) is hampered by unknown size and regional distribution of this population. Community sample- and study-based measurements are often fraught with participation biases and do not allow generalization of the results for other regions or the whole population group of MSM. We used the proportional regional distribution of participants of large internet-based surveys among MSM from Germany together with a general population survey-derived estimate of the MSM population to estimate regional population sizes. Based on transmission group category from surveillance data and regional MSM population size we calculated regional population-specific incidence rates of newly diagnosed HIV infection and syphilis. For HIV prevalence we compared estimates of prevalent HIV infections in MSM from a surveillance data-based model with a mixed model in which we used the proportional regional distribution of HIV positive participants from surveys and the estimated total number of prevalent HIV infections from the surveillance based model. Assuming a similar regional distribution of survey participants and the MSM population as a whole, the regional proportion of MSM in the general population can be estimated. Regional incidence calculated with the estimated MSM population as denominator and national surveillance data as numerator results in regional peak incidence rates of 7-8 per 1,000 MSM for newly diagnosed HIV infection and syphilis. The gradient between metropolitan and rural areas narrows considerably compared with calculations which use the total (male) population as denominator. Regional HIV prevalence estimates are comparable in the two models. Considering the difficulties to obtain regionally representative data by other sampling methods for MSM, in Western post-industrialized countries internet-based surveys may provide an easy and low cost tool to estimate regional population distributions. With national surveillance data, which categorize transmission groups, regional population-specific incidence rates for reportable sexually transmitted infections can be estimated. HIV prevalence estimates for regional MSM populations show differences related to the level of urbanization, MSM concentration, and starting points of the HIV epidemic in western and eastern Germany.


Modular repeat protein sculpting using rigid helical junctions.
The ability to precisely design large proteins with diverse shapes would enable applications ranging from the design of protein binders that wrap around their target to the positioning of multiple functional sites in specified orientations. We describe a protein backbone design method for generating a wide range of rigid fusions between helix-containing proteins and use it to design 75,000 structurally unique junctions between monomeric and homo-oligomeric de novo designed and ankyrin repeat proteins (RPs). Of the junction designs that were experimentally characterized, 82% have circular dichroism and solution small-angle X-ray scattering profiles consistent with the design models and are stable at 95 °C. Crystal structures of four designed junctions were in close agreement with the design models with rmsds ranging from 0.9 to 1.6 Å. Electron microscopic images of extended tetrameric structures and ∼10-nm-diameter "L" and "V" shapes generated using the junctions are close to the design models, demonstrating the control the rigid junctions provide for protein shape sculpting over multiple nanometer length scales.


Design, synthesis and pharmacological evaluation of 4-hydroxyphenylglycine and 4-hydroxyphenylglycinol derivatives as GPR88 agonists.
The orphan receptor GPR88 is an attractive therapeutic target because of its implications in a number of basal ganglia-associated disorders. To date, pharmacological characterization of GPR88 has been limited due to the lack of potent and selective agonists and antagonists appropriate for CNS investigations. We have previously reported that GPR88 couples to Gαi proteins and modulates cAMP levels upon treatment with a small molecule agonist 2-PCCA. Recently, another chemotype of GPR88 agonist, represented by 2-AMPP [(2S)-N-((1R)-2-amino-1-(4-(2-methylpentyloxy)-phenyl)ethyl)-2-phenylpropanamide], has also been discovered. In this report, a new series of 2-AMPP structurally related 4-hydroxyphenylglycine and 4-hydroxyphenylglycinol derivatives have been designed and evaluated for agonist activity at GPR88. The structure-activity relationship (SAR) studies suggest that the amine group in 2-AMPP can be replaced by hydroxyl, ester and amide groups, resulting in analogues with good to moderate potency, whereas the phenyl group on the amide cap is essential for activity and has limited size, shape and electronic tolerance.


Interaction of HLA-DR with an acidic face of HLA-DM disrupts sequence-dependent interactions with peptides.
HLA-DM (DM) edits major histocompatibility complex class II (MHCII)-bound peptides in endocytic compartments and stabilizes empty MHCII molecules. Crystal structures of DM have revealed similarity to MHCII but not how DM and MHCII interact. We used mutagenesis to map a MHCII-interacting surface on DM. Mutations on this surface impair DM action on HLA-DR and -DP in cells and DM-dependent peptide loading in vitro. The orientation of DM and MHCII predicted by these studies guided design of soluble DM and DR molecules fused to leucine zippers via their beta chains, resulting in stable DM/DR complexes. Peptide release from the complexes was fast and only weakly sequence dependent, arguing that DM diminishes the selectivity of the MHCII groove. Analysis of soluble DM action on soluble DR/peptide complexes corroborates this conclusion.


The patient-reported outcome content of international ovarian cancer randomised controlled trial protocols.
Patient-reported outcomes (PROs) provide the patient's perspective of the impact of treatment. Evidence suggests that PRO content of randomised controlled trials (RCTs) protocols is generally sub-optimal. This study aimed to describe and evaluate the PRO-specific content of ovarian cancer RCT protocols. Published, phase III, ovarian cancer RCTs with PRO endpoints were identified following a systematic search of Medline and Cochrane databases (Jan 2000 to Feb 2016). Corresponding RCT protocols were downloaded (if published) or obtained by contacting authors. Two investigators independently assessed adherence of PRO-specific content of included protocols to a checklist of 58 recommended PRO protocol items currently being developed by the International Society for Quality of Life Research. Discrepancies were resolved with a third investigator. Of 41 eligible trials identified, 26 protocols were assessed (developed 1995-2010). We were unable to obtain the remaining 15 protocols. Protocols addressed a mean of 28 % PRO checklist items (range 8-66 %). Fifteen (58 % of assessed protocols) provided a rationale for PRO assessment, 8 (31 %) described a PRO objective, 24 (92 %) included a PRO assessment schedule, but only 6 (23 %) justified timing of PRO assessments. Twelve protocols (46 %) provided staff data collection instructions, 4 (15 %) included plans for monitoring PRO compliance, and 16 (62 %) included a PRO analysis plan. On average, protocols addressed less than one-third of PRO protocol checklist items. In some cases, key guidance regarding PRO administration was lacking, which may lead to inconsistent and sub-optimal PRO methodology. Efforts are needed to improve PRO protocol content in cancer trials.


Acetogenic and sulfate-reducing bacteria inhabiting the rhizoplane and deep cortex cells of the sea grass Halodule wrightii.
Recent declines in sea grass distribution underscore the importance of understanding microbial community structure-function relationships in sea grass rhizospheres that might affect the viability of these plants. Phospholipid fatty acid analyses showed that sulfate-reducing bacteria and clostridia were enriched in sediments colonized by the sea grasses Halodule wrightii and Thalassia testudinum compared to an adjacent unvegetated sediment. Most-probable-number analyses found that in contrast to butyrate-producing clostridia, acetogens and acetate-utilizing sulfate reducers were enriched by an order of magnitude in rhizosphere sediments. Although sea grass roots are oxygenated in the daytime, colorimetric root incubation studies demonstrated that acetogenic O-demethylation and sulfidogenic iron precipitation activities were tightly associated with washed, sediment-free H. wrightii roots. This suggests that the associated anaerobes are able to tolerate exposure to oxygen. To localize and quantify the anaerobic microbial colonization, root thin sections were hybridized with newly developed (33)P-labeled probes that targeted (i) low-G+C-content gram-positive bacteria, (ii) cluster I species of clostridia, (iii) species of Acetobacterium, and (iv) species of Desulfovibrio. Microautoradiography revealed intercellular colonization of the roots by Acetobacterium and Desulfovibrio species. Acetogenic bacteria occurred mostly in the rhizoplane and outermost cortex cell layers, and high numbers of sulfate reducers were detected on all epidermal cells and inward, colonizing some 60% of the deepest cortex cells. Approximately 30% of epidermal cells were colonized by bacteria that hybridized with an archaeal probe, strongly suggesting the presence of methanogens. Obligate anaerobes within the roots might contribute to the vitality of sea grasses and other aquatic plants and to the biogeochemistry of the surrounding sediment.


Plasma concentrations of micronutrients during a nine-month clinical trial of beta-carotene in women with precursor cervical cancer lesions.
The effects of oral supplementation of a 30-mg dose of beta-carotene on the plasma levels of carotenoids, tocopherols, and retinol were studied sequentially in 69 patients participating in a nine-month randomized placebo controlled trial conducted to examine efficacy of beta-carotene to induce regression of cervical intraepithelial neoplasia. At each visit (baseline and 1.5, 3, 6, 9, 10.5, and 15 mo), blood samples were collected and the levels of six micronutrients were determined by high-performance liquid chromatography. No limitations or changes were introduced in each participant's dietary habits. Cervico-vaginal lavage samples were also obtained at the same visit and assayed for the presence of human papillomavirus DNA by Southern blot hybridization and polymerase chain reaction. In the supplemented group, mean plasma beta-carotene levels were significantly higher (p = 0.0001) than baseline and remained markedly elevated for 15 months. In the longitudinal analysis of the placebo group, there were no variations among individual mean plasma levels of beta-carotene, alpha-carotene, lycopene, retinol, gamma-tocopherol, or alpha-tocopherol, suggesting absence of seasonal or dietary changes. In the placebo group, cigarette smoking and steroid contraceptive use were significantly associated with low levels of plasma beta-carotene (p = 0.05 and p = 0.012, respectively). However, in contrast, in the beta-carotene-supplemented group, steroid contraceptive use had no influence on the plasma beta-carotene levels. An additional noteworthy finding was that beta-carotene supplementation did not reverse the depletion effect in smokers. There was no association between the plasma levels of these six micronutrients in women with cervical intraepithelial neoplasia and persistent human papillomavirus infection status in the placebo or the supplemented groups. Functional sequential nutrient interactions with each other or with other essential micronutrients and possible long-term toxicity need to be addressed in clinical trials.


Acousto-optic cyclostationary signal processing.
Cyclostationary signal-processing techniques implemented by means of acousto-optics are considered. Cyclic-processing methods are reviewed and motivated, such as the cyclic correlation and the cyclic spectrum. It is shown that the cyclic correlation can be computed at cycle frequencies of interest by use of one-dimensional time-integrating correlators in additive or multiplicative configurations. Detection of cycle frequencies is briefly considered, and a one-dimensional acousto-optic spectrum-analysis approach is described that is effective for amplitude-modulated signals. The problem of computing the two-dimensional cyclic correlation for all cycle frequencies and lags is then considered. This is accomplished by means of an acousto-optic triple-product processor configured in a manner similar to that used for ambiguity-function generation. The cyclic spectrum can be obtained in a postprocessing step by Fourier transformation of the cyclic correlation in one dimension. Higher-order extensions of the cyclic correlation are also discussed, and it is shown how a two-dimensional slice of the three-dimensional cyclic triple correlation can be computed by use of an acousto-optic four-product processor.


Learning end-of-life care in ICU: strategies for nurses new to ICU.
The experience of critical care nurses caring for patients and families during the withdrawal of life support has recently been explored (Vanderspank-Wright, Fothergill Bourbonnais, Brajtman, & Gagnon, 2011). In that study, the nurses were able to find, using their developing knowledge and experience, their own way, over time, through the process of withdrawing life support. Challenges in caring for patients and families were described by the participants in themes such as "the runaway train of technology," which explored nurses' experience of caring in a technologically complex environment. In this current article, the authors will explore the importance of providing "good care" in relation to withdrawal of life-sustaining treatment. The principles of providing "good care" such as patient comfort, open and frequent communication with families, support by fellow co-workers and time to reflect on the care given are fundamental to the overall experience of providing quality end-of-life care in the critical care environment. Practical solutions will be offered to help both new graduates and nurses who are new to ICU, find their way to care for patients and families within this context.


Dexmedetomidine for Sedation During Noninvasive Ventilation in Pediatric Patients.
To describe the use of dexmedetomidine for sedation in a large cohort of nonintubated children with acute respiratory insufficiency receiving noninvasive ventilatory support. Single-center, retrospective, observational cohort study. A large quaternary-care PICU. The study cohort included 202 children receiving noninvasive ventilatory and a dexmedetomidine infusion within 48 hours of PICU admission over a 6-month period. None. The primary respiratory diagnoses in the cohort (median age, 2 yr) included status asthmaticus (60%) and bronchiolitis (29%). Dexmedetomidine was infused for a median of 35 hours with a median hourly dose across the patient cohort of 0.61 μg/kg/hr (range, 0.4-0.8 μg/kg/hr). The target sedation level was achieved in 168 patients (83%) in the cohort for greater than or equal to 80% of the recorded values over the entire noninvasive ventilatory course, with dexmedetomidine as the only continuously administered sedative agent. While vital signs were frequently abnormal relative to age-based norms, clinical interventions were needed rarely to treat bradycardia (13%), hypotension (20%), and hypopnea (5%). The most frequently used of these interventions was a dexmedetomidine dose reduction, fluid bolus, and titration of noninvasive ventilatory support. Five patients (2.5%) required endotracheal intubation: three due to progression of their respiratory illness, one with septic shock, and one with apnea requiring resuscitation. In 194 of 202 patients (96%), the outcome of the noninvasive ventilatory course was successful with the patient being weaned from noninvasive respiratory support to nasal cannula or room air. Dexmedetomidine was often effective as a single continuous sedative infusion during pediatric noninvasive ventilatory. Cardiorespiratory events associated with its use were typically mild and/or reversible with dose reduction, fluid administration, and/or noninvasive ventilatory titration. Prospective studies comparing dexmedetomidine with other agents in this setting are warranted.


Estrogenic compounds, estrogen receptors and vascular cell signaling in the aging blood vessels.
The cardiovascular benefits of menopausal hormone therapy (MHT) remain controversial. The earlier clinical observations that cardiovascular disease (CVD) was less common in MHT users compared to non-users suggested cardiovascular benefits of MHT. Also, experimental studies have identified estrogen receptors ERalpha, ERbeta and GPR30, which mediate genomic or non-genomic effects in vascular endothelium, smooth muscle, and extracellular matrix (ECM). However, data from randomized clinical trials (RCTs), most notably the Women's Health Initiative (WHI) study, have challenged the cardiovascular benefits and highlighted adverse cardiovascular events with MHT. The discrepancies have been attributed to the design of RCTs, the subjects' advanced age and preexisting CVD, and the form of estrogen used. The discrepancies may also stem from age-related changes in vascular ER amount, distribution, integrity, and post-receptor signaling pathways as well as structural changes in the vasculature. Age-related changes in other sex hormones such as testosterone may also alter the hormonal environment and influence the cardiovascular effects of estrogen. Investigating the chemical properties, structure-activity relationship and pharmacology of natural and synthetic estrogens should improve the effectiveness of conventional MHT. Further characterization of phytoestrogens, selective estrogen-receptor modulators (SERMs), and specific ER agonists may provide substitutes to conventional MHT. Conditions with excess or low estrogen levels such as polycystic ovary syndrome (PCOS) and Turner syndrome may provide insight into the development and regulation of ER and the mechanisms of aberrant estrogen-ER interactions. The lessons learned from previous RCTs have led to more directed studies such as the Kronos Early Estrogen Prevention Study (KEEPS). Careful design of experimental models and RCTs, coupled with the development of specific ER modulators, hold the promise of improving the actions of estrogen in the aging blood vessels and thereby enhancing the efficacy and safety of MHT in postmenopausal CVD.


Angina pectoris and acute myocardial infarction due to "slow-flow phenomenon" in nonatherosclerotic coronary arteries: a case report.
A 51 year-old White woman with angina pectoris and nonatheromatous coronary artery disease is presented. Cardiac catheterization demonstrated a "slow-flow phenomenon" in the left coronary artery accompanied by severe angina pectoris and anterolateral ST-segment elevation and culminating in an acute nontransmural myocardial infarction. At repeat coronary arteriography, ergonovine maleate provocation proved negative. This patient is unique, since the previously documented 6 cases with this coronary cineangiographic response did not exhibit angina pectoris or ECG evidence of myocardial ischemia during the "slow-flow phenomenon," and none was complicated by an acute myocardial infarction. Various aspects of the pathophysiology of angina pectoris in this patient, including the recently described "reduced vasodilator reserve" concept, are briefly outlined.


Colestipol, clofibrate, and phytosterols in combined therapy of hyperlipidemia.
Studies were carried out to determine effects of combined chemotherapy in patients with hyperlipidemia. In one study, 14 patients were treated first with colestipol and then with the combination of colestipol and clofibrate. In a second study, six patients were given clofibrate followed by addition of phytosterols. The following measurements were made in most patients: (1) plasma lipid concentrations, (2) fecal excretions of neutral steroids and bile acids, and (3) lipid composition of gallbladder bile. In six patients of the first study, hepatic secretion rates of biliary lipids and pool sizes of bile acids were also estimated. In the first study, colestipol alone caused a marked increase in fecal bile acids that resulted in a sizable decrease in plasma cholesterol concentrations (average 21 percent). In several patients, however, triglycerides were increased somewhat by colestipol. Despite interruption of the enterohepatic circulation of bile acids, the bile acid pool was not reduced, since a compensatory increase took place in bile acid synthesis. Also, except in one patient who developed gallstones following institution of colestipol, saturation of gallbladder bile with cholesterol was not markedly increased by this drug alone. Addition of clofibrate frequently produced a further decrement in plasma cholesterol, and the mild hypertriglyceridemia induced by colestipol was reversed. However, colestipol plus clofibrate usually caused a striking increase in saturation of gallbladder bile. Previous studies have shown that clofibrate causes a flux of cholesterol from tissue pools by simultaneously decreasing cholesterol synthesis and increasing its excretion. To further increase cholesterol excretion, phytosterols, which block cholesterol absorption, were added to clofibrate in the second study. Although phytosterols did not cause a further reduction in plasma cholesterol in these particular patients, they nevertheless greatly enhanced cholesterol excretion.


Fat-specific protein 27 modulates nuclear factor of activated T cells 5 and the cellular response to stress.
Fat-specific protein 27 (FSP27), a member of the cell death-inducing DNA fragmentation factor α-like effector (Cide) family, is highly expressed in adipose tissues and is a lipid droplet (LD)-associated protein that induces the accumulation of LDs. Using a yeast two-hybrid system to examine potential interactions of FSP27 with other proteins, a direct interaction with the N-terminal region of nuclear factor of activated T cells 5 (NFAT5) was identified. NFAT5 is a transcription factor that induces osmoprotective and inflammatory genes after its translocation to the nucleus. The interaction between FSP27 and NFAT5 was confirmed by bimolecular fluorescence complementation and coimmunoprecipitation. Using immunocytochemistry, NFAT5 is detected in the cytoplasm and in the nucleus under isotonic conditions; however, overexpression of FSP27 inhibited the hypertonic-induced nuclear translocation of NFAT5. Consistent with the suppression of NFAT5 nuclear translocation, in cells transfected with a reporter construct containing the NFAT5 response element from the monocyte chemoattractant protein 1 (MCP1) promoter, FSP27 overexpression repressed hypertonic-induced luciferase activity and the expression of NFAT5 target genes. Knockdown of FSP27 in differentiated 3T3-L1 adipocytes increased the NFAT5-mediated rise in MCP1. These results suggest that FSP27 not only modulates LD homeostasis but also modulates the response to osmotic stress via a physical interaction with NFAT5 at the LD surface.


Effectiveness of low-level laser therapy combined with an exercise program to reduce pain and increase function in adults with shoulder pain: a critically appraised topic.
Shoulder pain is a common musculoskeletal condition that affects up to 25% of the general population. Shoulder pain can be caused by any number of underlying conditions including Subacromial impingement syndrome, rotator-cuff tendinitis, and biceps tendinitis. Regardless of the specific pathology, pain is generally the number 1 symptom associated with shoulder injuries and can severely affect daily activities and quality of life of patients with these conditions. Two of the primary goals in the treatment of these conditions are reducing pain and increasing shoulder range of motion (ROM). Conservative treatment has traditionally included a therapeutic exercise program targeted at increasing ROM, strengthening the muscles around the joint, proprioceptive training, or some combination of those activities. In addition, these exercise programs have been supplemented with other interventions including nonsteroidal anti-inflammatory drugs, corticosteroid injections, manual therapy, activity modification, and a wide array of therapeutic modalities (eg, cryotherapy, EMS, ultrasound). Recently, low-level laser therapy (LLLT) has been used as an additional modality in the conservative management of patients with shoulder pain. However, the true effectiveness of LLLT in decreasing pain and increasing function in patients with shoulder pain is unclear. Is low-level laser therapy combined with an exercise program more effective than an exercise program alone in the treatment of adults with shoulder pain?


Evaluation of resequencing on number of tag SNPs of 13 atherosclerosis-related genes in Thai population.
In the candidate gene approach, information about the distribution of single nucleotide polymorphisms (SNPs) is a crucial requirement for choosing efficient markers necessary for a case-control association study. To obtain such information, we discovered SNPs in 13 genes related to atherosclerosis by resequencing exon-flanking regions of 32 healthy Thai individuals. In total, 194 polymorphisms were identified, 184 of them SNPs, four insertions, and the rest deletions. Fifty-nine of the SNPs were characterized as novel polymorphisms, and these accounted for 30% of the identified SNPs. Comparing allele frequency distributions of the Thai population with other Asian populations shows similar patterns. In contrast, a low correlation pattern (r = 0.521) was found when comparing with either Caucasian or African populations. However, some rare alleles (rs11574541 and rs10874913) are found in the Thai population but not in other Asian populations. Most of the novel SNPs found were located outside the haplotype blocks generated by known SNPs in the Thai population. Only 5.77% of the novel SNPs lies in these defined haplotype blocks. The selection of haplotype-tagging SNPs shows that 8 of 13 genes benefited from the ethnic-specific genotype information. That is, when at least one novel SNP was present, the tagging SNPs chosen were altered. Functional prediction of 16 nonsynonymous SNPs (nsSNPs) by three different algorithm tools demonstrated that five nsSNPs possibly alter their corresponding protein functions. These results provide necessary information for conducting further genetic association studies involving the Thai population and demonstrate that resequencing of candidate genes provides more complete information for full genetic studies.


Optical injection and spectral filtering of high-power ultraviolet laser diodes.
We demonstrate injection locking of high-power laser diodes operating at 397 nm. We achieve stable operation with an injection power of ∼100 μW and a slave laser output power of up to 110 mW. We investigate the spectral purity of the slave laser light via photon scattering experiments on a single trapped (40)Ca(+) ion. We show that it is possible to achieve a scattering rate indistinguishable from that of monochromatic light by filtering the laser light with a diffraction grating to remove amplified spontaneous emission.


Cigarette taxes and the transition from youth to adult smoking: smoking initiation, cessation, and participation.
Many policy makers continue to advocate and adopt cigarette taxes as a public health measure. Most previous individual-level empirical studies of cigarette demand are essentially static analyses of the relationship between the level of taxes and smoking behavior at a point in time. In this study, we use longitudinal data to examine the dynamics of young adults' decisions about smoking initiation and cessation. We develop a simple model to highlight the distinctions between smoking initiation, cessation, and participation. We show that because smoking participation reflects past decisions regarding initiation and cessation, the price elasticity of smoking participation is a weighted average of corresponding initiation and cessation elasticities, a finding that applies more broadly to other addictive substances as well. The paper's remaining contributions are empirical. We use data from the 1992 wave of the National Education Longitudinal Study, when most of the cohort were high school seniors, and data from the 2000 wave, when they were about 26 years old. The results show that the distinction between initiation and cessation is empirically useful. We also contribute new estimates on the tax-responsiveness of young adult smoking, paying careful attention to the possibility of bias if hard-to-observe differences in anti-smoking sentiment are correlated with state cigarette taxes. We find no evidence that higher taxes prevent smoking initiation, but some evidence that higher taxes are associated with increased cessation.


Trial Watch: Oncolytic viro-immunotherapy of hematologic and solid tumors.
Oncolytic viruses selectively target and kill cancer cells in an immunogenic fashion, thus supporting the establishment of therapeutically relevant tumor-specific immune responses. In 2015, the US Food and Drug Administration (FDA) approved the oncolytic herpes simplex virus T-VEC for use in advanced melanoma patients. Since then, a plethora of trials has been initiated to assess the safety and efficacy of multiple oncolytic viruses in patients affected with various malignancies. Here, we summarize recent preclinical and clinical progress in the field of oncolytic virotherapy.


Can flavonoids from honey alter multidrug resistance?
Cancer is one of the deadly diseases that burdens the society since long-time. Although design of chemotherapy is well-advanced, still it could not prevent the cancer death by hundred percent. One of the major stumbling blocks for cancer chemotherapy is multidrug resistance (MDR) developed by cancer cells. Role of ABC family of transporter proteins is well recognized in MDR. P-glycoprotein (P-gp), member of ABC transporter family, has been described for drug resistance and a low bioavailability of drugs by pumping structurally unrelated drugs out of the cells at the cost of ATP hydrolysis. Recently various P-gp inhibitors (chemosensitizers) are studied extensively to reverse MDR. In this scenario, we propose honey with multitude of polyphenolic flavonoids as a plausible candidate for inhibiting the P-gp proteins. Common flavonoids of honey like chrysin, genistein, biochanin, quercetin, kaempferol, and naringenin have found to interact with P-gp transporters. Generally chemosensitizers bind with transmembrane domain (TMD) in the P-gp transporter but flavonoids are bi-functional in reversing the MDR. Flavonoids can inhibit the ATPases activity involved in drug efflux and also it may serve as substrates for P-gp transporters, thereby causing competitive inhibition towards other substrates. This dual-mode of flavonoids interaction with P-gp transporter enhances the therapeutic index. Hence we promulgate honey with rich flavonoid content as a potential candidate for reversing MDR. If our hypothesis is true, honey a novel chemosensitizer will reduce the huge amount invested in developing new chemosensitizers to overcome the burden of chemo-resistance.


A Case of Two Sisters Suffering from 46,XY Gonadal Dysgenesis and Carrying a Mutation of a Novel Candidate Sex-Determining Gene STARD8 on the X Chromosome.
Identification of novel genes involved in sexual development is crucial for understanding disorders of sex development (DSD). Here, we propose a member of the START domain family, the X chromosome STARD8, as a DSD candidate gene. We have identified a missense mutation of this gene in 2 sisters with 46,XY gonadal dysgenesis, inherited from their heterozygous mother. Gonadal tissue of one of the sisters contained Leydig cells overloaded with cholesterol droplets, i.e., structures previously identified in 46,XY DSD patients carrying mutations in the STAR gene encoding another START domain family member, which is crucial for steroidogenesis. Based on the phenotypes of our patients, we propose a dual role of STARD8 in sexual development, namely in testes determination and testosterone synthesis. However, further studies are needed to confirm the involvement of STARD8 in sexual development.


Predictors of mental health and substance use disorder treatment use over 3 years among rural adults using stimulants.
Background: Persons using substances, living in rural communities, tend to underutilize mental health (MH) and substance use disorder (SUD) treatment compared with their urban peers. However, no studies have examined longitudinal predictors of MH and SUD treatment use among rural persons using stimulants. Methods: Data were collected through interviews conducted between 2002 and 2008 from a natural history study of 710 adults using stimulants and living in rural counties of Arkansas, Kentucky, and Ohio. Each study site recruited participants using respondent-driven sampling (RDS). Participants were adults, not in drug treatment, and reporting past-30-day use of methamphetamine, crack cocaine, or powder cocaine. Study participants completed face-to-face baseline assessments and follow-up interviews using computer-assisted personal interviews. Follow-up interviews were conducted at 6-month intervals for 3 years. Results: Our results show that being male, nonwhite, and having a prior lifetime history of MH or SUD treatment use were associated with lower odds of using MH and SUD treatment over time; having medical insurance and living in a state with potentially greater availability of MH and SUD treatment were associated with higher odds of using MH and SUD treatment over the 3-year period. Further, reporting greater legal problems and alcohol severity were associated with greater odds of using MH and SUD care, whereas greater employment problems was associated with higher odds of SUD but not MH treatment use. Conclusions: Findings from this study could be used to inform clinical and public health strategies for improving linkage to MH and SUD care in this population. Our findings also highlight the importance of having medical insurance as a potential facilitator to utilizing SUD care in this population and support the need for health care policies that increase the ability of rural adults who use stimulants to pay for such services.


Reproducibility of importance extraction methods in neural network based fMRI classification.
Recent advances in machine learning allow faster training, improved performance and increased interpretability of classification techniques. Consequently, their application in neuroscience is rapidly increasing. While classification approaches have proved useful in functional magnetic resonance imaging (fMRI) studies, there are concerns regarding extraction, reproducibility and visualization of brain regions that contribute most significantly to the classification. We addressed these issues using an fMRI classification scheme based on neural networks and compared a set of methods for extraction of category-related voxel importances in three simulated and two empirical datasets. The simulation data revealed that the proposed scheme successfully detects spatially distributed and overlapping activation patterns upon successful classification. Application of the proposed classification scheme to two previously published empirical fMRI datasets revealed robust importance maps that extensively overlap with univariate maps but also provide complementary information. Our results demonstrate increased statistical power of importance maps compared to univariate approaches for both detection of overlapping patterns and patterns with weak univariate information.


Systemic chemotherapy for urothelial cancer in patients with ureteric obstruction.
The aims of this study were to document the toxicity of systemic chemotherapy and response rates in patients with ureteric obstruction caused by urothelial cancer. The study group included 91 patients who received cisplatin and methotrexate; 36 (40%) had upper tract dilatation, 9 of whom had drainage by stenting or nephrostomy and 55 (60%) had normal upper tracts. The response rate was documented in 65 patients (71%) who had measurable primary or metastatic disease. No significant differences were found between the dilated/drained group, the dilated/undrained group and the normal group in biochemical measurements of renal function during or after the courses of chemotherapy. Serious haematological toxicity occurred in 10% (10/104 cycles) of the dilated/undrained group and in 6% (12/200 cycles) of the normal group. The complete response rate in the dilated group was 15% compared with 41% in the normal group. No increased chemotherapy toxicity was observed in patients with upper tract dilatation and a significant complete response rate was found in patients with upper tract dilatation without renal impairment.


Design, synthesis, and biological evaluation of CXCR4 ligands.
A combination of the CXCR4 inverse agonist T140 with N-terminal CXCL12 oligopeptides has produced the first nanomolar synthetic CXCR4 agonists. In these agonists, the inverse agonistic portion provides affinity whereas the N-terminal CXCL12 sequence induces receptor activation. Several CXCR4 crystal structures exist with either CVX15, an inverse agonist closely related to T140 and IT1t, a small molecule; we therefore attempted to produce another CXCL12 oligopeptide combination with IT1t. For this purpose, a primary amino group was introduced by total synthesis into one of the methyl groups of IT1t, serving as an anchoring point for the oligopeptide graft. The introduction of the oligopeptides on this analog however yielded antagonists, one compound displaying high affinity. On the other hand, the amino-substituted analogue itself proved to be an inverse agonist with a binding affinity of 2.6 nM compared to 11.5 nM for IT1t. This IT1t-like analog is hitherto one of the most potent non-peptidic CXCR4 inverse agonists reported.


Effects of ocean acidification on the physiological performance and carbon production of the Antarctic sea ice diatom Nitzschia sp. ICE-H.
Ocean acidification (OA) resulting from increasing atmospheric CO2 strongly influences marine ecosystems, particularly in the polar ocean due to greater CO2 solubility. Here, we grew the Antarctic sea ice diatom Nitzschia sp. ICE-H in a semicontinuous culture under low (~400ppm) and high (1000ppm) CO2 levels. Elevated CO2 resulted in a stimulated physiological response including increased growth rates, chlorophyll a contents, and nitrogen and phosphorus uptake rates. Furthermore, high CO2 enhanced cellular particulate organic carbon production rates, indicating a greater shift from inorganic to organic carbon. However, the cultures grown in high CO2 conditions exhibited a decrease in both extracellular and intracellular carbonic anhydrase activity, suggesting that the carbon concentrating mechanisms of Nitzschia sp. ICE-H may be suppressed by elevated CO2. Our results revealed that OA would be beneficial to the survival of this sea ice diatom strain, with broad implications for global carbon cycles in the future ocean.


Climate change enhances the mobilisation of naturally occurring metals in high altitude environments.
Manmade climate change has expressed a plethora of complex effects on Earth's biogeochemical compartments. Climate change may also affect the mobilisation of natural metal sources, with potential ecological consequences beyond mountains' geographical limits; however, this question has remained largely unexplored. We investigated this by analysing a number of key climatic factors in relationship with trace metal accumulation in the sediment core of a Pyrenean lake. The sediment metal contents showed increasing accumulation trend over time, and their levels varied in step with recent climate change. The findings further revealed that a rise in the elevation of freezing level, a general increase in the frequency of drier periods, changes in the frequency of winter freezing days and a reducing snow cover since the early 1980s, together are responsible for the observed variability and augmented accumulation of trace metals. Our results provide clear evidence of increased mobilisation of natural metal sources - an overlooked effect of climate change on the environment. With further alterations in climate equilibrium predicted over the ensuing decades, it is likely that mountain catchments in metamorphic areas may become significant sources of trace metals, with potentially harmful consequences for the wider environment.


PC-FACS.
PC-FACS(FastArticleCriticalSummaries for Clinicians inPalliativeCare) provides hospice and palliative care clinicians with concise summaries of the most important findings from more than 100 medical and scientific journals. If you have colleagues who would benefit from receiving PC-FACS, please encourage them to join the AAHPM at aahpm.org. Comments from readers are welcomed at email@example.com.


Imaging through scattering media by interferometric techniques.
Imaging through scattering media such as fog is a problem with few known viable solutions. Holographic techniques have been demonstrated successfully in the laboratory, but their usefulness is often limited in field conditions by the requirement of a separate coherent reference beam. In this paper, an interferometric imaging technique that utilizes a grating interferometer is presented. Experimental results obtained with this technique show substantial improvement in image contrast over that obtained via direct imaging.


Assessing the likely effectiveness of multispecies management for imperiled desert fishes with niche overlap analysis.
A critical decision in species conservation is whether to target individual species or a complex of ecologically similar species. Management of multispecies complexes is likely to be most effective when species share similar distributions, threats, and response to threats. We used niche overlap analysis to assess ecological similarity of 3 sensitive desert fish species currently managed as an ecological complex. We measured the amount of shared distribution of multiple habitat and life history parameters between each pair of species. Habitat use and multiple life history parameters, including maximum body length, spawning temperature, and longevity, differed significantly among the 3 species. The differences in habitat use and life history parameters among the species suggest they are likely to respond differently to similar threats and that most management actions will not benefit all 3 species equally. Habitat restoration, frequency of stream dewatering, non-native species control, and management efforts in tributaries versus main stem rivers are all likely to impact each of the species differently. Our results demonstrate that niche overlap analysis provides a powerful tool for assessing the likely effectiveness of multispecies versus single-species conservation plans.


Association of the cytochrome P450 and arylamine N-acetyltransferase gene polymorphisms with the incidence of head and neck cancer in Polish population.
Head and neck cancer (HNC) is one of the most common cancers. Most exogenous HNC is head and neck squamous cell carcinomas. Scientists are striving to develop diagnostic tests that will allow the prognosis of HNC. The aim of the study was to determine the risk of HNC. The research concerned changes caused by polymorphisms in genes encoding proteins responsible for the metabolism of xenobiotics. In group of 280 patients with HNC, the occurrence of polymorphic variants in NAT1(rs72554606), NAT2(rs1799930), CYP1A(rs1799814), CYP2D(rs3892097) were studied with TaqMan technique. The control group consisted of 260 cancer free people. The TNM scale was analyzed. Gene interactions of genotyped polymorphisms were investigated. The effects of smoking and alcohol consumption on HNC were assessed. The results indicated an increased risk of HNC in NAT1 polymorphisms in the GC genotype (OR = 1.772, 95% CI: 1.184-2.651, p = 0.005) and NAT2 polymorphism in the GA genotype (OR = 1.506, 95% CI: 1.023-2.216, p = 0.037). The protective phenomenon in the CYP1A polymorphism the GT genotype (OR = 0.587, 95% CI: 0.381-0.903, p = 0.015) and the TT genotype (OR = 0.268, 95% CI: 0.159-0.452, p = 0.001). The coexistence of GA-GC polymorphisms (OR = 2.687, 95% CI: 1.387-5.205, p = 0.003) in NAT2-NAT1 genes increases the risk of HNC. Risk-reducing effect in the polymorphism GG-GT (OR = 0.340, 95% CI: 0.149-0.800, p = 0.011), GG-TT (OR = 0.077, 95% CI: 0.028-0.215, p < 0.0001), GA-TT (OR = 0.250, 95% CI: 0.100-0.622, p = 0.002), AA-GT (OR = 0.276, 95% CI: 0.112-0.676, p = 0.002) in NAT2-CYP1A genes. In the CYP2D-CYP1A genes in the polymorphisms CT-CC (OR = 0.338, 95% CI: 0.132-0.870, p = 0.020), TT-GG (OR = 0.100, 95% CI: 0.027-0.359, p = 0.001), TT-GC (OR = 0.190, 95% CI: 0.072-0.502, p = 0.0004), TT-CC (OR = 0.305, 95% CI: 0.107-0.868, p = 0.024). Correlation was noted between cigarette smoking and HNC (OR = 7.297, 95% CI: 4.989-10.674, p < 0.0001) and consuming alcohol (OR = 1.572, 95% CI: 1.003-2.464, p = 0.047). The CYP1A polymorphism shows a protective association with HNC. On the other hand, NAT2, NAT1 polymorphism influence the susceptibility to developing HNC. The coexistence of the NAT2-NAT1 genotypes increases the risk of HNC. In contrast, NAT1-CYP1A and CYP1A-CYP2D reduce this risk. Smoking and alcohol consumption increase the incidence of HNC. Int J Occup Med Environ Health. 2023;36(6):812-24.


Educational quality of YouTube videos on knee arthrocentesis.
Knee arthrocentesis is a commonly performed diagnostic and therapeutic procedure in rheumatology and orthopedic surgery. Classic teaching of arthrocentesis skills relies on hands-on practice under supervision. Video-based online teaching is an increasingly utilized educational tool in higher and clinical education. YouTube is a popular video-sharing Web site that can be accessed as a teaching source. The objective of this study was to assess the educational value of YouTube videos on knee arthrocentesis posted by health professionals and institutions during the period from 2008 to 2012. The YouTube video database was systematically searched using 5 search terms related to knee arthrocentesis. Two independent clinical reviewers assessed videos for procedural technique and educational value using a 5-point global score, ranging from 1 = poor quality to 5 = excellent educational quality. As validated international guidelines are lacking, we used the guidelines of the Swiss Society of Rheumatology as criterion standard for the procedure. Of more than thousand findings, 13 videos met the inclusion criteria. Of those, 2 contained additional animated video material: one was purely animated, and one was a check list. The average length was 3.31 ± 2.28 minutes. The most popular video had 1388 hits per month. Our mean global score for educational value was 3.1 ± 1.0. Eight videos (62 %) were considered useful for teaching purposes. Use of a "no-touch" procedure, meaning that once disinfected the skin remains untouched before needle penetration, was present in all videos. Six videos (46%) demonstrated full sterile conditions. There was no clear preference of a medial (n = 8) versus lateral (n = 5) approach. A discreet number of YouTube videos on knee arthrocentesis appeared to be suitable for application in a Web-based format for medical students, fellows, and residents. The low-average mean global score for overall educational value suggests an improvement of future video-based instructional materials on YouTube would be necessary before regular use for teaching could be recommended.


Visualizing SNP statistics in the context of linkage disequilibrium using LD-Plus.
Often in human genetic analysis, multiple tables of single nucleotide polymorphism (SNP) statistics are shown alongside a Haploview style correlation plot. Readers are then asked to make inferences that incorporate knowledge across these multiple sets of results. To better facilitate a collective understanding of all available data, we developed a Ruby-based web application, LD-Plus, to generate figures that simultaneously display physical location of SNPs, binary SNP attributes (such as coding/non-coding or presence on genotyping platforms), common haplotypes and their frequencies and continuously scaled values (such as F(st), minor allele frequency, genotyping efficiency or P-values), all in the context of the D' and r(2) linkage disequilibrium structures. Combining these results into one comprehensive figure reduces dereferencing between figures and tables, and can provide unique insights into genetic features that are not clearly seen when results are partitioned across multiple figures and tables.