CREATE cornerstone: introduction to scientific thinking, a new course for STEM-interested freshmen, demystifies scientific thinking through analysis of scientific literature.
The Consider, Read, Elucidate hypotheses, Analyze and interpret data, Think of the next Experiment (CREATE) strategy for teaching and learning uses intensive analysis of primary literature to improve students' critical-thinking and content integration abilities, as well as their self-rated science attitudes, understanding, and confidence. CREATE also supports maturation of undergraduates' epistemological beliefs about science. This approach, originally tested with upper-level students, has been adapted in Introduction to Scientific Thinking, a new course for freshmen. Results from this course's initial semesters indicate that freshmen in a one-semester introductory course that uses a narrowly focused set of readings to promote development of analytical skills made significant gains in critical-thinking and experimental design abilities. Students also reported significant gains in their ability to think scientifically and understand primary literature. Their perceptions and understanding of science improved, and multiple aspects of their epistemological beliefs about science gained sophistication. The course has no laboratory component, is relatively inexpensive to run, and could be adapted to any area of scientific study.


Cardiovascular and renin responses to vanadate in the conscious dog: attenuation after calcium channel blockade.
The effects of vanadate on cardiovascular function and on the secretion of renin and vasopressin were investigated by infusing sodium orthovanadate (0.32 mu mole/kg X min) intravenously into five conscious dogs. Vanadate caused significant increases in mean arterial pressure, total peripheral resistance, pulmonary arterial pressure, and cardiac output. These data illustrate that the hemodynamic effects of vanadate in the conscious dog are similar to those of the anesthetized dog but that minor differences do exist. Vanadate significantly suppressed plasma renin activity, but plasma vasopressin was unchanged. The effects of vanadate also were investigated in the same dogs on another day after administration of the calcium channel blocker, verapamil (0.3 mg/kg bolus + 0.01 mg/kg X min). After calcium channel blockade, the increases in arterial pressure and pulmonary arterial pressure induced by vanadate were attenuated, and cardiac output did not increase. Calcium channel blockade also prevented the vanadate-induced decrease in plasma renin activity. These data suggest that the cardiovascular and humoral alterations produced by vanadate in the conscious dog are at least partially mediated by changes in intracellular calcium.


Screening of antidiabetic and antihyperlipidemic potential of oil from Piper longum and piperine with their possible mechanism.
Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycaemia and other symptoms like polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger) which ultimately causes various other complications like retinopathy, neuropathy, nephropathy and microangiopathy. The antidiabetic and antihyperlipidemic potential of oil from Piper longum (PLO) and piperine was investigated with their possible mechanism using α-glucosidase, aldose reductase (AR), and pancreatic lipase inhibitory activity. The biochemical parameters, viz. glucose level, insulin level, liver glycogen content, glycosylated hemoglobin, total plasma cholesterol, triglyceride, and antioxidant parameters, were estimated for all treated groups in acute and chronic antihyperglycemic animal models. PLO (100 and 200 mg/kg), piperine (25 and 50 mg/kg), and glibenclamide (0.6 mg/kg) in respective groups of diabetic animals administered for 28 days reduced the blood glucose level in streptozotocin-induced diabetic rats. There was significant increase in body weight, liver glycogen content, plasma insulin, and high-density lipoprotein and decrease in glycosylated hemoglobin, triglyceride, and total plasma cholesterol in PLO-administered groups as compared to control group. The IC50 value of PLO for α-glucosidase, AR, and pancreatic lipase was found to be 150 ± 2.5, 120 ± 1.2, and 175 ± 1.2 μg/ml, respectively, which was found comparable with the standard drugs acarbose (90 ± 2.3 μg/ml), quercetin (80 ± 2.3 μg/ml), and orlistat (25 ± 0.5 μg/ml), respectively. The investigation done reveals that PLO has significant antidiabetic and antihyperlipidemic activity.


Ecodevelopmental HIV prevention programs for Hispanic adolescents.
The purpose of this article is to illustrate how an ecodevelopmental perspective on risk and protection can be applied to the study and prevention of unsafe sexual behavior in Hispanic immigrant adolescents. Special attention is given to culturally based ecodevelopmental risk and protective processes that may influence unsafe sexual behavior among Hispanic adolescents. Principles for designing prevention programs to offset these risks are offered on the basis of an ecodevelopmental HIV prevention program that has been developed and is currently being tested.


Knowledge, attitude, and practices of infertility among Saudi couples.
Infertility places a huge psychological burden on infertile couples, especially for women. Greater knowledge of the factors affecting fertility may help to decrease the incidence of infertility by allowing couples to avoid certain risk factors. The aim of our study was (1) to assess the knowledge and attitudes of infertile and fertile Saudi participants on infertility, possible risk factors, and social consequences; and (2) to determine the practices of infertile Saudi couples to promote their fertility before having them attend an in vitro fertilization (IVF) clinic. We conducted a cross-sectional study on 277 fertile participants from outpatient clinics and 104 infertile patients from the IVF clinic at King Abdulaziz Medical City between June 24, 2012 and July 4, 2012, using a previously validated interview questionnaire. Descriptive and analytical statistics were applied with a significance threshold of P ≤ 0.05. A generally poor level of knowledge (59%) and a neutral attitude (76%) toward infertility were reported by participants. Mistaken beliefs commonly held by the study participants regarding the causes of infertility were Djinns and supernatural causes (58.8%), black magic (67.5%), intrauterine devices (71.3%), and contraceptive pills (42.9%). The healer/Sheikh was reported as the primary and secondary preference for infertility treatment by 6.7% and 44.2% of IVF patients, respectively. Compared with fertile patients, IVF patients were significantly less likely to favor divorce (38.5% versus 57.6%; P = 0.001) or marriage to a second wife (62.5% versus 86.2%; P < 0.001), if the woman could not have a baby. The patients with infertility had more favorable attitudes toward fertility drugs (87.5% versus 68.4%; P = 0.003) and having a test tube baby (92.4% versus 70.3%; P < 0.001). Child adoption was accepted as an option for treatment by the majority of IVF patients (60.6%) and fertile outpatients (71.5%). Alternative treatments previously practiced by the IVF patients to improve fertility include practicing Ruqia (61%), using alternative medicine (42%), engaging in physical exercise (39%), eating certain foods (22%), and quitting smoking (12%). These findings have implications for health care providers regarding the reluctance that couples experiencing fertility problems may have, at least initially, to accept some interventions required for the couple to conceive.


Linear morphological stability analysis of the solid-liquid interface in rapid solidification of a binary system.
The interface stability against small perturbations of the planar solid-liquid interface is considered analytically in linear approximation. Following the analytical procedure of Trivedi and Kurz [Acta Metall. 34, 1663 (1986)]], which is advancing the original treatment of morphological stability by Mullins and Sekerka [J. Appl. Phys. 35, 444 (1964)]] to the case of rapid solidification, we extend the model by introducing the local nonequilibrium in the solute diffusion field around the interface. A solution to the heat- and mass-transport problem around the perturbed interface is given in the presence of the local nonequilibrium solute diffusion. Using the developing local nonequilibrium model of solidification, the self-consistent analysis of linear morphological stability is presented with the attribution to the marginal (neutral) and absolute morphological stability of a rapidly moving interface. Special consideration of the interface stability for the cases of solidification in negative and positive thermal gradients is given. A quantitative comparison of the model predictions for the absolute morphological stability is presented with regard to experimental results of Hoglund and Aziz [D. E. Hoglund and M. J. Aziz, in Kinetics of Phase Transformations, edited by M.O. Thompson, M. J. Aziz, and G. B. Stephenson, MRS Symposia Proceedings No. 205 (Materials Research Society, Pittsburgh, 1991), p. 325] on critical solute concentration for the interface breakdown during rapid solidification of Si-Sn alloys.


Phylogeny and nucleomorph karyotype diversity of chlorarachniophyte algae.
Chlorarachniophytes are flagellated and/or reticulopod-forming marine algae with chlorophyll a- and b-containing plastids of secondary endosymbiotic origin. They are one of only two algal groups known to possess a "nucleomorph" (i.e. the remnant nucleus of the eukaryotic endosymbiont that donated the plastid). Apart from the recently sequenced nucleomorph genome of Bigelowiella natans, little is known about the size, structure, and composition of chlorarachniophyte nucleomorph genomes. Toward the goal of better understanding nucleomorph genome diversity, as well as establishing a phylogenetic framework with which to interpret variation in chlorarachniophyte morphology, ultrastructure, and life cycle, we are studying a wide range of chlorarachniophyte strains from public culture collections and natural habitats. We have obtained 22 new chlorarachniophyte nuclear and nucleomorph 18S rRNA gene (18S rDNA) sequences and nucleomorph genome size estimates for 14 different strains. Consistent with previous studies, all of the chlorarachniophytes examined appear to possess three nucleomorph chromosomes. However, our results suggest considerable variation in nucleomorph genome size and structure, with individual chromosome sizes ranging from approximately 90 to approximately 210 kbp, and total genome sizes between approximately 330 kbp in Lotharella amoebiformis and approximately 610 kbp in unidentified chlorarachniophyte strain CCMP622. The significance of these phylogenetic and nucleomorph karyotype data is discussed.


Protective mucosal immunity elicited by targeted lymph node immunization with a subunit SIV envelope and core vaccine in macaques.
Prevention of sexually transmitted HIV infection was first investigated in non-human primates by mucosal immunization via the rectal, vaginal or male urethral route. This was compared with subcutaneous targeted iliac lymph node (TILN) and systemic intramuscular immunization in non-human primates. TILN immunization elicited the most consistent mucosal sIgA and IgG antibody response in the rectum, vagina, urine and seminal fluid, as well as in blood. Both mucosal and TILN immunization induced a specific CD4+ T cell proliferative response in the iliac lymph nodes which drain these mucosal surfaces, and in the splenic and circulating T cells. In the next experiment macaques were immunized by the TILN route with SIV gp120 and p27 in alum. Rectal mucosal challenge with SIVmac 32H J5 molecular clone (or cell-free virus) induced total protection in four out of seven macaques, compared with infection in 13 of 14 unimmunized macaques or immunized by other routes (p = 0.025). The remaining three macaques immunized by the TILN route showed either decrease in viral load (> 90%) or transient viraemia, indicating that all seven TILN immunized macaques showed total or partial protection of rectal transmission by SIV (p = 0.001). Protection was associated with significant increase in the iliac lymph nodes IgA antibody secreting cells to p27 (p < 0.02), CD8-suppressor factor inhibiting replication of SIV in CD4+ T cells (p < 0.01) and the chemokines RANTES and MIP-1 beta (p < 0.01). We suggest that administration of gp120 and p27 by the TILN route may elicit protective B and T cell immunity which can significantly prevent rectal transmission of SIV or HIV.


Outcome and Genetic Factors in IgG4-Associated Autoimmune Pancreatitis and Cholangitis: A Single Center Experience.
Introduction. Most investigations on autoimmune pancreatitis (AIP) were published on Asian cohorts while those on Caucasians are limited. However, there might be differences related to the origin. Patients and Methods. We analyzed 36 patients and compared type 1 (AIP1) with type 2 (AIP2). Results. The majority of patients suffered from AIP1 (55.6%). AIP1 patients were significantly older than AIP2 patients (54.4 versus 40.8 years). Moreover, 85.0% of AIP1 patients had concurrent autoimmune cholangitis (AIC) while 18.8% of AIP2 patients suffered from overlap to ulcerative colitis (UC). However, AIP1 patients revealed a cholestatic course and had significantly higher immunoglobulin G4 levels (IgG4). When compared to allele frequencies in healthy controls, in patients with AIP1 HLA-B8 reached statistical significance. Response to steroids was excellent in both groups, but we noticed high rates of relapse especially in AIP1 patients. Finally, 3 patients with AIP1 were diagnosed with cholangiocellular carcinoma (CCC). Conclusion. In contrast to Asian studies, we found an almost equal distribution of AIP1 and AIP2 patients in our German cohort. AIP2 patients were younger and mostly of female gender whereas AIP1 patients revealed higher IgG4 levels and involvement of the biliary tract in sense of IgG4-associated cholangitis.


Risks of meat: the relative impact of cognitive, affective and moral concerns.
The purpose of the present research was, first, to examine the impact of particular perspectives (Study 1: cognitive and affective; Study 2: moral) on the perception and acceptance of risks associated with meat consumption, and intention to reduce meat consumption in the future. The first study showed that an affective focus generally had a stronger impact on risk perception and acceptance, and intention to reduce meat consumption, than a more cognitive focus. Moreover, moral considerations had a clear impact in all conditions. Results of a second study confirmed that a moral focus has powerful effects on all the dependent variables. The second purpose of the research was to examine the perseverance of the impact of cognitive, affective and moral perspectives. In both studies, a follow-up after three weeks showed increased perception of moral risks and a strong intention to reduce future meat consumption. Moreover, attitude towards meat consumption became less positive in the conditions with an affective and moral focus. There were also significant relations between intention to reduce meat consumption, actual reduction, and intention to adhere to this level in the future. Overall, risk acceptance was mediated by perceived health and moral risks, whereas intention about meat consumption was mediated by risk acceptance.


Narratives of risk in occupational health and safety: why the 'good' boss blames his tradesman and the 'good' tradesman blames his tools.
Risk and its control are important themes in occupational health and safety. In the current regulatory framework, risk is conceptualised as a probabilistic expression of hazard potential. However, social meanings of risk in the workplace may be different. The social context of work shapes the ways that risk is understood in the workplace, yet little research in occupational health and safety acknowledges it. A few studies of risk have used qualitative research methods to elicit understandings of risk at work; however, little research explores the experiences of both employers and employees. This study describes the narratives of risk in occupational health and safety of employers and employees in the Victorian painting industry. Using ethnographic methods, we collected data about the contexts in which risk is experienced and the sources of risk that each group identifies. These narratives reveal that risk in the painting industry is constructed through the interactions of three factors: the social context, the hierarchical structure of the industry and the shared assumptions about risk control through the individual skills and responsibilities. The narratives explain why occupational health and safety strategies focusing solely on individual behaviour change or technical measures will be unsuccessful.


Comparative analysis on the selection of number of clusters in community detection.
We conduct a comparative analysis on various estimates of the number of clusters in community detection. An exhaustive comparison requires testing of all possible combinations of frameworks, algorithms, and assessment criteria. In this paper we focus on the framework based on a stochastic block model, and investigate the performance of greedy algorithms, statistical inference, and spectral methods. For the assessment criteria, we consider modularity, map equation, Bethe free energy, prediction errors, and isolated eigenvalues. From the analysis, the tendency of overfit and underfit that the assessment criteria and algorithms have becomes apparent. In addition, we propose that the alluvial diagram is a suitable tool to visualize statistical inference results and can be useful to determine the number of clusters.


Establishment a real-time reverse transcription PCR based on host biomarkers for the detection of the subclinical cases of Mycobacterium avium subsp. paratuberculosis.
Bovine paratuberculosis (PTB) is a chronic enteric inflammatory disease of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP) that causes large economic losses in the dairy industry. Spread of PTB is mainly provoked by a long subclinical stage during which MAP is shed into the environment with feces; accordingly, detection of subclinical animals is very important to its control. However, current diagnostic methods are not suitable for detection of subclinical animals. Therefore, the current study was conducted to develop a diagnostic method for analysis of the expression of genes of prognostic potential biomarker candidates in the whole blood of cattle naturally infected with MAP. Real-time PCR with nine potential biomarker candidates was developed for the diagnosis of MAP subclinical infection. Animals were divided into four groups based on fecal MAP PCR and serum ELISA. Eight genes (Timp1, Hp, Serpine1, Tfrc, Mmp9, Defb1, Defb10, and S100a8) were up-regulated in MAP-infected cattle (p <0.05). Moreover, ROC analysis revealed that eight genes (Timp1, Hp, Serpine1, Tfrc, Mmp9, Defb1, Defb10, and S100a8) showed fair diagnostic performance (AUC≥0.8). Four biomarkers (Timp1, S100a8, Defb1, and Defb10) showed the highest diagnostic accuracy in the PCR positive and ELISA negative group (PN group) and three biomarkers (Tfrc, Hp, and Serpine1) showed the highest diagnostic accuracy in the PCR negative and ELISA positive group (NP group). Moreover, three biomarkers (S100a8, Hp, and Defb10) were considered the most reliable for the PCR positive and ELISA positive group (PP group). Taken together, our data suggest that real-time PCR based on eight biomarkers (Timp1, Hp, Serpine1, Tfrc, Mmp9, Defb1, Defb10, and S100a8) might be useful for diagnosis of JD, including subclinical stage cases.


Lack of association of dengue activity with haze.
Dengue activity depends on fluctuations in Aedes populations which in turn are known to be influenced by climate factors including temperature, humidity and rainfall. It has been hypothesized that haze may reduce dengue transmission. Due to its geographical location Singapore suffers almost every year from hazes caused by wildfires from Indonesia. Such hazes have a significant impact on pollution indexes in Singapore. We set out to study the relationship of dengue activity and haze (measured as pollution standard index) in Singapore, using ARIMA models. We ran different univariate models, each encompassing a different lag period for the effects of haze and temperature (from lag 0 to lag 12 weeks). We analysed the data on a natural logarithmic scale to stabilize the variance and improve the estimation. No association between dengue activity and haze was found. Our findings do not lend support to the hypothesis that haze is associated with reduced dengue activity in Singapore.


In vitro development of cloned embryos derived from miniature pig somatic cells after activation by ultrasound stimulation.
The present study was carried out to examine the activation and development of cloned embryos produced by transferring miniature pig somatic cells into enucleated farm pig oocytes after exposing to ultrasound. The rates of the pronucleus-like structure formation and polar body-like structure extrusion in embryos exposed to ultrasound did not differ from those applied electric pulses. Although there was no significant difference in the blastocyst formation rates between different activation methods, the mean number of cells in the blastocysts developed from embryos activated by exposing to ultrasound was significantly (p < 0.05) higher than that obtained by applying electric pulses. The results of the present study showed that ultrasound stimulation can induce the activation and in vitro development of cloned embryos derived from miniature pig somatic cells.


Aesthetic preference is related to organized complexity.
There is extensive evidence today linking exposure to natural environments to favorable changes in mental and even physical health. There is also a growing body of work indicating that there are specific geometric properties of natural scenes that mediate these effects, and that these properties can also be found in artificial structures like buildings, especially those designed before the emergence of modernism. These geometries are also associated with aesthetic preference-we seem to like what is good for us. Here, using a questionnaire-based survey, we have tried to elucidate some of the parameters that play a role in formulating a preference for one form over the other. The images used were nature scenes from the Alpine landscape with various manipulations to alter their complexity, or with additions of computer graphics or various buildings. In all cases, the presence of a natural scaling hierarchy and of either fractal graphics or of ornate, non-local pre-modern buildings was always preferable to the alternative. We discuss these findings under the light of recent evidence in the field and conclude that they support the idea of the existence of a preference of our perceptive system for certain types of visual organization.


Heterologous Humoral Response against H5N1, H7N3, and H9N2 Avian Influenza Viruses after Seasonal Vaccination in a European Elderly Population.
Avian influenza viruses are currently one of the main threats to human health in the world. Although there are some screening reports of antibodies against these viruses in humans from Western countries, most of these types of studies are conducted in poultry and market workers of Asian populations. The presence of antibodies against avian influenza viruses was evaluated in an elderly European population. An experimental study was conducted, including pre- and post-vaccine serum samples obtained from 174 elderly people vaccinated with seasonal influenza vaccines of 2006-2007, 2008-2009, 2009-2010, and 2010-2011 Northern Hemisphere vaccine campaigns. The presence of antibodies against A/H5N1, A/H7N3, and A/H9N2 avian influenza viruses were tested by using haemaglutination inhibition assays. Globally, heterotypic antibodies were found before vaccination in 2.9% of individuals against A/H5N1, 1.2% against A/H7N3, and 25.9% against A/H9N2. These pre-vaccination antibodies were present at titers ≥1/40 in 1.1% of individuals against A/H5N1, in 1.1% against H7N3, and in 0.6% against the A/H9N2 subtype. One 76 year-old male showed pre-vaccine antibodies (Abs) against those three avian influenza viruses, and another three individuals presented Abs against two different viruses. Seasonal influenza vaccination induced a significant number of heterotypic seroconversions against A/H5N1 (14.4%) and A/H9N2 (10.9%) viruses, but only one seroconversion was observed against the A/H7N3 subtype. After vaccination, four individuals showed Abs titers ≥1/40 against those three avian viruses, and 55 individuals against both A/H5N1 and A/H9N2. Seasonal vaccination is able to induce some weak heterotypic responses to viruses of avian origin in elderly individuals with no previous exposure to them. However, this response did not accomplish the European Medicament Agency criteria for influenza vaccine efficacy. The results of this study show that seasonal vaccines induce a broad response of heterotypic antibodies against avian influenza viruses, albeit at a low level.


Investigating Research Gaps of Pharmaceutical take back Events: An Analysis of take back Program Participants' Socioeconomic, Demographic, and Geographic Characteristics and the Public Health Benefits of take back Programs.
Research continues to show that pharmaceutical environmental contamination causes adverse effects to aquatic life. There are also public health risks associated with pharmaceuticals because in-home reserves of medications provide opportunities for accidental poisoning and intentional medication abuse. Pharmaceutical take back programs have been seen as a potential remedy for these issues; however, a thorough review of past programs indicates limited research has been conducted on take back programs. Furthermore, there are significant gaps in take back program research. To address these gaps and ultimately determine if take back programs could improve public health, research was conducted in conjunction with the take back program Denton drug disposal days held in Denton, Texas. Socioeconomic, demographic, and geographic characteristics of Denton drug disposal days participants were investigated using surveys and Geographic Information Systems. Potential impacts of the Denton drug disposal days program on public health were determined by comparing data from Denton drug disposal days events with data supplied by the North Texas Poison Center. Results suggest that Denton drug disposal days events may have prevented accidental poisonings or intentional abuse, however only qualitative comparisons support this statement and there was insufficient empirical evidence to support the conclusion that Denton drug disposal days events were exclusively responsible for public health improvements. An interesting finding was that there was a definitive travel threshold that influenced participation in Denton drug disposal days events. Overall, this study fills some geographic, socioeconomic, and demographic data gaps of take back programs and proposes methods to analyze and improve participation in future take back programs. These methods could also be applied to improve participation in other local environmentally-focused programs such as household hazardous collection events.


Optimizing the use of frequency doubling technology perimetry in community vision screenings.
In recent years, Frequency Doubling Technology perimetry (FDT) has been added to traditional ocular health testing in screening for glaucoma. This study examines a number of strategies to employ FDT in an effort to determine its optimal use in large community screenings. In Part I, 1253 persons participated in a free, community vision screening in a large metropolitan area. FDT testing was limited to those in a high-risk group, defined as individuals over age 45 and either black or having a family history of glaucoma that passed the eye health part of the screening. In Part II, a simulated screening performed at the same location examined four different strategies for utilizing FDT: (1) FDT limited to the high risk group passing eye health testing; (2) FDT on all persons passing eye health testing; (3) FDT and eye health testing on all persons; and (4) FDT on all persons, without eye health testing. In the community screening, 1043 persons (83.2%) passed the eye health testing. 159 (15.2%) of the 1043 were in the high risk group and were tested with FDT. 19 (1.5%) of these tests resulted in failure. There were few unreliable tests (5.0%). For the simulated screening, specificity and sensitivity with 95% confidence intervals for strategies one through four were, respectively, 83.3% (64.5 to 93.7) and 77.8% (51.9 to 92.6); 80.0% (60.9 to 91.6) and 88.9% (63.9 to 98.1); 76.7% (57.3 to 89.4) and 94.4% (70.6 to 99.7); 90.0% (72.3 to 97.4) and 38.9% (18.3 to 63.9). In the community screening, FDT performed reliably and identified abnormalities in a significant number of persons in the high-risk group passing the eye health part of the screening. However, with the exception of the poor sensitivity shown by strategy 4, results from the simulated screening did not support the usefulness of one strategy over another.


Antioxidants Attenuate Oxidative Stress-Induced Hidden Blood Loss in Rats.
Hidden blood loss (HBL), commonly seen after total knee or hip arthroplasty, causes postoperative anemia even after reinfusion or blood transfusion based on the visible blood loss volume. Recent studies demonstrated that oxidative stress might be involved in HBL. However, whether the antioxidants proanthocyanidin (PA) or hydrogen water (HW) can ameliorate HBL remains poorly understood. The aim of this study was to evaluate the effects of PA and HW on HBL. A rat HBL model was established through administration of linoleic acid with or without treatment with PA or HW. The levels of hemoglobin (Hb), red blood cell (RBC) count, superoxide dismutase (SOD) activity, glutathione peroxidase (GSH-PX) activity, malondialdehyde (MDA), and ferryl Hb were measured. RBC and Hb values as well as the activity of SOD and GSH-PX were reduced after administration of linoleic acid, which was ameliorated by treatment with PA or HW. In addition, the quantity of MDA was significantly decreased with the administration of PA or HW. PA and HW could ameliorate HBL in a rat model by reducing oxidative stress, suggesting that they might be used as a novel therapeutic approach in the prophylaxis or treatment of HBL in clinics.


Utilization of a preoperative assessment clinic in a tertiary care centre.
To describe the utilization of a preoperative assessment clinic (PAC) by various surgical divisions, and the types of consultations sought by those divisions. Cross-sectional descriptive study of PAC utilization. A large university-affiliated tertiary care centre. All patients who underwent surgical procedures by selected surgical divisions between July 1, 1996, and Mar. 31, 1998. The number of patients referred to the centre's PAC, utilization by surgical division, and the types of consultation obtained (general internal medicine, anesthesia, cardiology, intensive care). Adjusted rates of consultations were determined by logistic regression, controlling for age, sex, comorbidity and major versus minor procedure. Of 9603 surgical cases, 5725 (60%) were referred to the PAC. The adjusted rates of PAC utilization ranged from a low of 46% for cardiovascular and thoracic surgery to a high of 72% for general surgery. The adjusted rates of general internal medicine consultations ranged from 5% for oral surgery to 33% for otolaryngology. For anesthesia consultations, the rates ranged from 6% for orthopedics to 39% for general surgery. Increasing age (odds ratio [OR] = 1.14 for 10-year age increments), female sex (OR = 1.23), major surgery (OR = 1.94) and a number of comorbidity variables were significant predictors of PAC referral on multivariable analysis. PAC utilization varies across surgical divisions and in the types of consultation sought, even when controlling for age, sex, comorbidity and type of procedure. The potential exists for standardized PAC referral guidelines to reduce these variations.


[Temperature modifies the acute effect of particulate air pollution on mortality in Jiang'an district of Wuhan].
To analyze the temperature modification effect on acute mortality due to particulate air pollution. Daily non-accidental mortality, cardiovascular mortality, and respiratory mortality data were obtained from Jiang'an District Center for Disease Control and Prevention. Daily meteorological data on mean temperature and relative humidity were collected from China Meteorological Data Sharing Service System. The daily concentration of particulate matter was collected from Wuhan Environmental Monitoring center. By using the stratified time-series models, we analyzed effects of particulate air pollution on mortality under different temperature zone from 2002 to 2010, meanwhile comparing the difference of age, gender and educational level, in Wuhan city of China. High temperature (daily average temperature > 33.4 ℃) obviously enhanced the effect of PM10 on mortality. With 10 μg/m(3) increase in PM10 concentrations, non-accidental, cardiovascular, and respiratory mortality increased 2.95% (95%CI: 1.68%-4.24%), 3.58% (95%CI: 1.72%-5.49%), and 5.07% (95%CI: 2.03%-9.51%) respectively. However, low temperature (daily average temperature <-0.21 ℃) enhanced PM10 effect on respiratory mortality with 3.31% (95% CI: 0.07%-6.64%) increase. At high temperature, PM10 had significantly stronger effect on non-accidental mortality of female aged over 65 and people with high educational level groups. With an increase of 10 μg/m(3), daily non-accidental mortality increased 4.27% (95% CI:2.45%-6.12%), 3.38% (95% CI:1.93%-4.86%) and 3.47% (95% CI:1.79%-5.18%), respectively. Whereas people with low educational level were more susceptible to low temperature. A 10 μg/m(3) increase in PM10 was associated with 2.11% (95% CI: 0.20%-4.04%) for non-accidental mortality. Temperature factor can modify the association between the PM10 level and cause-specific mortality. Moreover, the differences were apparent after considering the age, gender and education groups.


Using ordinal partition transition networks to analyze ECG data.
Electrocardiogram (ECG) data from patients with a variety of heart conditions are studied using ordinal pattern partition networks. The ordinal pattern partition networks are formed from the ECG time series by symbolizing the data into ordinal patterns. The ordinal patterns form the nodes of the network and edges are defined through the time ordering of the ordinal patterns in the symbolized time series. A network measure, called the mean degree, is computed from each time series-generated network. In addition, the entropy and number of non-occurring ordinal patterns (NFP) is computed for each series. The distribution of mean degrees, entropies, and NFPs for each heart condition studied is compared. A statistically significant difference between healthy patients and several groups of unhealthy patients with varying heart conditions is found for the distributions of the mean degrees, unlike for any of the distributions of the entropies or NFPs.


Experimental demonstration of information to energy conversion in a quantum system at the Landauer limit.
Landauer's principle sets fundamental thermodynamical constraints for classical and quantum information processing, thus affecting not only various branches of physics, but also of computer science and engineering. Despite its importance, this principle was only recently experimentally considered for classical systems. Here we employ a nuclear magnetic resonance set-up to experimentally address the information to energy conversion in a quantum system. Specifically, we consider a three nuclear spins [Formula: see text] (qubits) molecule-the system, the reservoir and the ancilla-to measure the heat dissipated during the implementation of a global system-reservoir unitary interaction that changes the information content of the system. By employing an interferometric technique, we were able to reconstruct the heat distribution associated with the unitary interaction. Then, through quantum state tomography, we measured the relative change in the entropy of the system. In this way, we were able to verify that an operation that changes the information content of the system must necessarily generate heat in the reservoir, exactly as predicted by Landauer's principle. The scheme presented here allows for the detailed study of irreversible entropy production in quantum information processors.


[Case of obsessive-compulsive disorder associated with neuroleptics-induced deficit syndrome (NIDS): successfully treated by discontinuation of neuroleptics followed by SSRI].
A 59-year-old man, who was being trieated for schizophrenia, exhibited a concurrence of obsessive compulsive (OC) symptoms and neuroleptics-induced deficit syndrome (NIDS). His symptoms were remarkably improved by the discontinuation of neuroleptics followed by the introduction of fluvoxamine. He was originally a prudent, suspicious and unsociable person, the character of which corresponds to a schizotypal personality disorder. From his early twenties OC-symptoms appeared along the theme of cleanliness, health, and ethics. After the first half of his forties OC-symptoms worsened with the emergence of a depressive state. He consulted a psychiatric unit at the age of 49 for the first time and was diagnosed as having schizophrenia of a negative symptoms-dominant type associated with obsessive-compulsive disorder. He was started on haloperidol but the condition did not improved at all so that the dose was gradually increased. When he finally moved to our hospital at the age of 57, serious NIDS such as slow thinking, difficulty in concentration, decrease in emotional reaction, and dysphoria was recognized, in addition to parkinsonism. In order to improve the NIDS, we gradually decreased the dose and reduced the variety of neuroleptics and substituted them for risperidone alone. During these periods, no emergence of psychotic symptoms or worsening of OC-symptoms was realized. Accordingly he was admitted to our hospital and started on fluvoxamine, and the NIDS and OC-symptoms were markedly improved. In conclusion the use of neuroleptics specifically for OC-symptoms should be done very carefully in consideration of the possibility of provoking NIDS.


Inverse scattering for rotationally scanned optical coherence tomography.
Optical coherence tomography of luminal structures, such as for intravascular or gastrointestinal imaging, is performed by using a fiber-optic catheter as a beam-delivery probe. The interrogating beam is scanned angularly by rotating the fiber around a fixed central axis. Because the beam is focused only at a fixed distance from the center of the fiber, only scatterers near this distance are resolved. We present a solution of the inverse scattering problem that provides an estimate of the susceptibility of the sample for an angularly scanned Gaussian beam focused at a fixed distance from the origin. This solution provides quantitatively meaningful reconstructions while also extending the volume of the sample that is resolvable by the instrument.


Purification of a major serum protein of rainbow trout (Salmo gairdneri) homologous to the third component of mammalian complement.
The present paper describes the purification and characterization of a major serum protein of the rainbow trout (Salmo gairdneri) required for complement-related functions (target cell lysis and opsonization). This protein, termed C3-1, was identified as the third component (C3) of rainbow trout complement. It is homologous to component C3 of human and other mammalian complements based on its structural and functional characteristics. Rainbow trout C3-1 is a beta-globulin of Mr = 190,000 composed of two polypeptide chains (Mr = 128,000 alpha-chain and Mr = 74,000 beta-chain) linked by disulfide bonds. The chain structure of C3-1 is, therefore, very similar to those of the third and fifth components of mammalian complement. C3-1 retains, on its alpha-chain, a unique hidden thiol site that can be exposed upon attachment of methylamine in the same way as human C3 and C4. The amino acid composition and NH2-terminal sequence of C3-1 show significant homology to mammalian C3 and to cobra venom factor (cobra C3).


The evolution of extreme cooperation via shared dysphoric experiences.
Willingness to lay down one's life for a group of non-kin, well documented historically and ethnographically, represents an evolutionary puzzle. Building on research in social psychology, we develop a mathematical model showing how conditioning cooperation on previous shared experience can allow individually costly pro-group behavior to evolve. The model generates a series of predictions that we then test empirically in a range of special sample populations (including military veterans, college fraternity/sorority members, football fans, martial arts practitioners, and twins). Our empirical results show that sharing painful experiences produces "identity fusion" - a visceral sense of oneness - which in turn can motivate self-sacrifice, including willingness to fight and die for the group. Practically, our account of how shared dysphoric experiences produce identity fusion helps us better understand such pressing social issues as suicide terrorism, holy wars, sectarian violence, gang-related violence, and other forms of intergroup conflict.


Effects of Bacillus anthracis hydrophobicity and induction of host cell death on sample collection from environmental surfaces.
The objective of this study is to determine whether DNA signature recovery of Bacillus anthracis strains from different environmental substrates correlates with pathogen cell surface hydrophobicity and induction of host cell death. We compared recovery of DNA signatures from a panel of B. anthracis strains collected from two environmental substrates, non-porous surfaces and soil, using real-time qPCR. We further assessed both cell surface hydrophobicity of the B. anthracis strains by contact angle measurements and host cell viability in response to B. anthracis infection in a mouse macrophage cell model system. Our studies demonstrated correlation between reduced B. anthracis sample recovery from environmental substrates and increased cell surface hydrophobicity. Surprisingly, the most hydrophilic strain, K4596, which exhibited the highest level of recovery from the environmental surfaces, induced the highest level of host cell cytotoxicity compared to more hydrophobic B. anthracis strains in the panel. Our results suggest that cell surface hydrophobicity may play a leading role in mediating pathogen adherence to environmental surfaces. These findings can contribute to the optimization of pathogen detection efforts by understanding how bacterial parameters such as hydrophobicity and induction of host cell death affect bacterial adherence to environmental surfaces.


Nutritional support in sickle cell anemia: theoretical considerations.
Despite the clinical diversity of sickle cell anemia (HbSS) this autosomal recessive disorder, often characterized by a 6- to 20-fold increase in destruction rates of the red blood cells (RBC) without a corresponding increase in synthesis, is essentially a chronic hypermetabolic condition. The stress of HbSS produces caloric inefficiency and a marked increase in resting metabolic rate. Nitrogen metabolism is set at a higher than normal dietary intake, and data are still incomplete regarding the possibility that this genetic disorder may have special amino acid requirements. The physiologic needs for most vitamins and essential mineral elements are increased because of the elevated dietary requirements for energy and nitrogen. Many of these micronutrients, especially α-tocopherol, ascorbic acid, retinol, zinc, and selenium, are free radical scavengers, and thus play crucial roles in retarding premature aging of RBCs caused by peroxidation of the membrane. Evaluation of the dietary requirements of the HbSS victim must also take into account the variable, often age-related, increase in nutrient losses after functional impairment in organs, such as the kidneys, which are usually elicited by repeated vaso-occlusive insults.


[New insight into medication adherence in chronic skin diseases].
In everyday medical practice, often even carefully designed treatment plan does not bring the expected results. In such cases, it often tums out that the reason of it is lack of patient compliance to doctor's recommendations (non-adherence). This problem affects up to 50% of patients, it may be the result of many factors, such as their socioeconomic status, knowledge, motivation for treatment, and the availability and quality of medical care. The relationship between doctor and patient, the nature of disease, drug prices and the possibility of adverse side effects are also significant. Lack of involvement of patients in the treatment process is particularly evident in chronic diseases that require prolonged and regular treatment. Interpersonal skills of the clinician and a possibility to establish a good relationship between doctor and patient have strong influence on adherence. In the Internet age, patients often gain on their own information about their disease, which can both positively and negatively affect the healing process. For this reason, one of the factors that increase the compliance is a proper education of patients. In addition, the doctor may use several other useful methods to enhance the therapeutic effect. Patient's preference when selecting medicinal preparations, simplifying treatment regimens and accurate information given to patients regarding the use of drugs also have a significant impact in such cases.


Effect of intermittent induced aeration on nitrogen removal and denitrifying-bacterial community structure in Cork and gravel vertical flow pilot-scale treatment wetlands.
In this work, we have evaluated the impact of intermittent induced aeration in total nitrogen (TN), ammonia (NH4-N) and nitrate-nitrogen (NO3-N) removal in four pilot-scale vertical flow constructed wetlands (VFCW) (two aerated two non-aerated) using cork by-product or gravel as the filter material and planted with Phragmites australis. Both aerated and non-aerated systems achieved high COD and BOD5 elimination rates (≥ 90%) at the end of the 5-month test period. However, the aerated systems presented maximal COD and BOD5 removal from the third month of operation onwards since air supply favored the oxidative bioprocesses occurring within the wetlands. Cork and gravel aerated VFCW also proved to be more efficient (p < 0.05) in NO3-N removal than the non-aerated systems and this upgraded performance was correlated with a significant higher relative abundance of the nirS gene. The aerated systems also showed a slightly improved NH4-N removal. Noticeably, cork VFCW showed higher TN removal mean values (∼35%) than gravel wetlands (27-28%) regardless aeration. Moreover, cork VFCW showed higher relative abundance of the nosZ gene. Our results demonstrated a better nitrogen elimination for the aerated cork pilot-scale VFCW, and this behavior was correlated with a higher abundance of both nirS and nosZ, two of the key functional genes involved in nitrogen metabolism.


Recent advances in rheumatoid arthritis.
Management of rheumatoid arthritis (RA) has radically changed over the last decade. Diagnostic methods have improved with availability of highly specific tests such as antibody to cyclic citrullinated peptide (specificity approximately 96%), and introduction of advanced imaging modalities such as ultrasound and magnetic resonance imaging to facilitate earlier diagnosis. The current aim of management is to achieve remission and prevent joint damage. In order to achieve this goal, inflammation is suppressed as much as possible during the early phase of the disease before onset of joint damage. Aggressive treatments with combinations of disease modifying anti-rheumatic drugs are commenced earlier in the course of disease, and tight control maintained with regular objective monitoring of disease activity. Early use of anti-TNFalpha (tumour necrosis factor alpha) therapy in combination with methotrexate helps to achieve better clinical and radiographic outcomes, which can be maintained for up to 5 years after withdrawal of anti-TNFalpha therapy. Apart from anti-TNFalpha, several other biological treatments are now available, including those that target CD20 on B cells (rituximab), cytokines such as IL1 (anakinra) and IL6 (tocilizumab), and molecules that cause interaction between antigen presenting cells and T cells (abatacept). There is better awareness and understanding of RA associated complications such as cardiovascular disease and osteoporosis. Use of non-steroidal anti-inflammatory drugs is on the decline in light of recent concerns about cardiovascular safety. Evidence is emerging in support of statins and bisphosphonates for improving RA disease activity and preventing erosions, respectively. In the coming years, further improvements in therapeutic strategies are likely with the pace at which research is currently progressing.


Microfilaremia and peak expiratory flow rate, Philippines.
We studied the peak expiratory flow rate in residents of two villages in the Philippines; one with a high prevalence, one with an intermediate prevalence of microfilaremia. We also determined the presence and level of microfilaremia in the individuals by examining thick films of 40 cmm of peripheral blood taken at night. We have found that the slope of the peak expiratory flow with age is steeper in the village with a high prevalence of microfilaremia and that it is also steeper in individuals from the high prevalence village with microfilaremia as compared with those without parasitemia. We conclude that there is a relationship between the presence of microfilariae and airflow obstruction.


Mechanism of Initiation, Association, and Formation of Amyloid Fibrils Modeled with the N-Terminal Peptide Fragment, IKYLEFIS, of Myoglobin G-Helix.
Some peptides and proteins undergo self-aggregation under certain conditions, leading to amyloid fibrils formation, which is related to many disease conditions. It is important to understand such amyloid fibrils formation to provide mechanistic detail that governs the process. A predominantly α-helical myoglobin has been reported recently to readily form amyloid fibrils at a higher temperature, similar to its G-helix segment. Here, we have investigated the mechanism of amyloid fibrils formation by performing multiple long molecular dynamics simulations (27 μs) on the N-terminal segment of the G-helix of myoglobin. These simulations resulted in the formation of a single-layered tetrameric β-sheet with mixed parallel and antiparallel β-strands and this is the most common event irrespective of many different starting structures. Formation of the single-layered tetrameric β-sheet takes place following three distinctive pathways. The process of fibril initiation is dependent on temperature. Further, this study provides mechanistic insights into the formation of multilayered fibrilar structure, which could be applicable to a wider variety of peptides or proteins to understand the amyloidogenesis.


An engineered tetra-valent antibody fully activates the Tie2 receptor with comparable potency to its natural ligand angiopoietin-1.
Activation of the tyrosine kinase with Ig and epidermal growth factor homology domain 2 (Tie2) receptor by angiopoietin-1 (Ang1) is critical for vascular stabilization: it promotes survival signal transduction via auto-phosphorylation and reduces vascular permeability by strengthening tight junctions between endothelial cells. Thus, Tie2/Ang1 signaling is a promising therapeutic target for vascular diseases. However, in vivo use of existing Tie2 signaling modulators, such as recombinant Ang1, is restricted by limitations in manufacturability and stability. Here, we present a novel engineered tetra-valent agonistic antibody, ASP4021, which can specifically and fully activate the Tie2 receptor in an equivalent manner to Ang1. ASP4021 induced Tie2 self-phosphorylation and inhibited apoptosis in a human primary endothelial cell line. Additionally, single administration of ASP4021 significantly suppressed mustard-oil-induced vascular permeability in rats. ASP4021 may thus be a potential therapeutic candidate for diseases associated with vascular weakness such as diabetic retinopathy, diabetic macular edema and critical limb ischemia.


Sustainable changes are needed to reduce preventable sepsis deaths.
Sepsis is a leading cause of mortality in children and adults worldwide. About 44,000 people die from sepsis in the UK each year and the cost to the NHS is estimated to be £2.5 billion. Sepsis is common but still poorly recognised, and delays to treatment are frequent. This situation has prompted many organisations to study how they respond to patients who may have signs or symptoms of sepsis.


Chronic Tender Ulcers on the Calf and Both Forearms.
An elderly woman presented with a 3-month history of nonhealing, tender ulcers involving the right calf and both forearms. She denied any history of similar lesions or trauma. Two trials of oral antibiotics had led to no improvement. Her medical history was significant for rheumatoid arthritis treated with methotrexate, hydroxychloroquine, and prednisone. A review of clinical manifestations was otherwise negative for disease. Physical examination of the patient's right calf revealed two punched-out ulcers with central necrotic black eschars, underlying retiform purpuric pattern, and mild fibrinopurulent drainage (Figure 1). Similar lesions were present on her forearms (Figures 2 and 3). No other remarkable skin changes were noted. The differential diagnosis included polyarteritis nodosa, cutaneous necrosis secondary to antiphospholipid syndrome, cryoglobulinemic vasculitis, and an atypical presentation of pyoderma gangernosum.


Issues of representation and limited capacity in the visuospatial sketchpad.
This article is about a visual short-term store called the visuospatial sketchpad (VSSP), which is tested by immediate ordered recall. Several claims are made: first, even for categorizable stimuli such as digits and letters, the representation in VSSP is uncategorized and unparsed. Second, the representation in VSSP is parsed and categorized just prior to recall in a process called recovery. The probability of recovering an item depends upon the fidelity of that item's representation. Third, VSSP has a fixed amount of representational medium which is allocated proportionally to the items in the presentation. When too many items are presented for recall, not all of the items are represented with sufficient fidelity to be recovered, producing the phenomenon of limited capacity.


[The construction and primary screening of a phage display library of HCV C and E1 genes evolved with an artificial pattern].
To construct and screen a primarily phage display library of HCV C and E1 genes evolved with an artificial pattern. Two genes of about 1 kb with different genotypes were evolved by DNA shuffling. The re-assembled HCV C and E1 genes were cloned into a phage vector. After being rescued with helper phage M13KO7, a phage display library was constructed. Then the library was screened with anti-C and E1 McAb. Double-antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA) was carried out on twenty individual phage clones selected randomly to detect their binding and reactive activity with high-titer HCV-positive sera. Normal sera were used as controls. The phage display library of HCV C and E1 genes which evolved with an artificial pattern was constructed. Their capacity amounted to 1.64 x 10(6), and 86 percent of the clones contained C and E1 genes. After four rounds of panning, the phage library was specifically enriched. Twelve positive clones were successfully screened. The capacity and diversity of the constructed library are enough for screening. The results demonstrate the superiority of the specific binding and reactive activity and affinity of the 12 phage clones from the HCV positive sera.


Thrombomodulin allosterically modulates the activity of the anticoagulant thrombin.
Exosite 1 of thrombin consists of a cluster of basic residues (Arg-35, Lys-36, Arg-67, Lys-70, Arg-73, Arg-75, and Arg-77 in chymotrypsinogen numbering) that play key roles in the function of thrombin. Structural data suggest that the side chain of Arg-35 projects toward the active site pocket of thrombin, but all other residues are poised to interact with thrombomodulin (TM). To study the role of these residues in TM-mediated protein C (PC) activation by thrombin, a charge reversal mutagenesis approach was used to replace these residues with a Glu in separate constructs. The catalytic properties of the mutants toward PC were analyzed in both the absence and presence of TM and Ca2+. It was discovered that, with the exception of the Arg-67 and Lys-70 mutants, all other mutants activated PC with similar maximum rate constants in the presence of a saturating concentration of TM and Ca2+, although their affinity for interaction with TM was markedly impaired. The catalytic properties of the Arg-35 mutant were changed so that PC activation by the mutant no longer required Ca2+ in the presence of TM, but, instead, it was accelerated by EDTA. Moreover, the activity of this mutant toward PC was improved approximately 25-fold independent of TM. These results suggest that Arg-35 is responsible for the Ca2+ dependence of PC activation by the thrombin-TM complex and that a function for TM in the activation complex is the allosteric alleviation of the inhibitory interaction of Arg-35 with the substrate.


The pathogenesis of cauliflower ear. An experimental study in rabbits.
Appreciating an imcomplete understanding of the pathogenesis of cauliflower ear, an experimental study was designed to demonstrate the pathophysiology of this deformity. The investigation was conducted in 2-month-old rabbits. In one ear a collection of blood was placed under the raised perichondrium which was then sutured back in place and the skin closed. In the other ear an equal amount of blood was deposited between the intact perichondrium and skin. In the first study new cartilage developed under the perichondrium, but in the ear in which the blood was left above the surface of the perichondrium-covered cartilage, complete resorption of the clot occurred. The cauliflower ear was thus shown to be generating cartilage, arising from a layer of raised perichondrium which was further stimulated by a sero-sanguinous medium. The subperichondrial hematoma was extensively invaded by chondroblasts within 2 weeks, and over a period of 4 weeks the new tissue gradually changed into more mature cartilage. It was a consistent finding that the separated perichondrium retracted, thus causing the original cartilage to rise and buckle over the hamatoma, similar to the picture observed in the human pathology.


Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to insulin sensitivity in mice and in humans.
Insulin resistance is frequently associated with hypertension and type 2 diabetes. The cytochrome P450 (CYP) arachidonic acid epoxygenases (CYP2C, CYP2J) and their epoxyeicosatrienoic acid (EET) products lower blood pressure and may also improve glucose homeostasis. However, the direct contribution of endogenous EET production on insulin sensitivity has not been previously investigated. In this study, we tested the hypothesis that endogenous CYP2C-derived EETs alter insulin sensitivity by analysing mice lacking CYP2C44, a major EET producing enzyme, and by testing the association of plasma EETs with insulin sensitivity in humans. We assessed insulin sensitivity in wild-type (WT) and Cyp2c44 -/- mice using hyperinsulinaemic-euglycaemic clamps and isolated skeletal muscle. Insulin secretory function was assessed using hyperglycaemic clamps and isolated islets. Vascular function was tested in isolated perfused mesenteric vessels. Insulin sensitivity and secretion were assessed in humans using frequently sampled intravenous glucose tolerance tests and plasma EETs were measured by mass spectrometry. Cyp2c44 -/- mice showed decreased glucose tolerance (639 ± 39.5 vs 808 ± 37.7 mmol/l × min for glucose tolerance tests, p = 0.004) and insulin sensitivity compared with WT controls (hyperinsulinaemic clamp glucose infusion rate average during terminal 30 min 0.22 ± 0.02 vs 0.33 ± 0.01 mmol kg-1 min-1 in WT and Cyp2c44 -/- mice respectively, p = 0.003). Although glucose uptake was diminished in Cyp2c44 -/- mice in vivo (gastrocnemius Rg 16.4 ± 2.0 vs 6.2 ± 1.7 μmol 100 g-1 min-1, p < 0.01) insulin-stimulated glucose uptake was unchanged ex vivo in isolated skeletal muscle. Capillary density was similar but vascular KATP-induced relaxation was impaired in isolated Cyp2c44 -/- vessels (maximal response 39.3 ± 6.5% of control, p < 0.001), suggesting that impaired vascular reactivity produces impaired insulin sensitivity in vivo. Similarly, plasma EETs positively correlated with insulin sensitivity in human participants. CYP2C-derived EETs contribute to insulin sensitivity in mice and in humans. Interventions to increase circulating EETs in humans could provide a novel approach to improve insulin sensitivity and treat hypertension.


Localization of substance P-like immunoreactivity in the anterior eye segment of squirrels: an immunohistochemical analysis.
Localization of substance P (SP)-like immunoreactivity in the anterior eye segment of the squirrel was examined immunohistochemically. The present study demonstrates a dense network of SP-positive fibers in the ciliary body, particularly in the muscle layers, and several SP-positive fibers in the iris, in addition to scattered SP-positive fibers in the cornea. These facts strongly suggest that SP has an important role in the physiologic functions of the anterior eye segment.


Report from the extended HLA-DPA1 ~ promoter ~ HLA-DPB1 haplotype of the 18th international HLA and immunogenetics workshop.
The primary goal of the HLA-DPA1 ~ promoter ~ HLA-DPB1 haplotype component of the 18th IHIWS was to characterise the extended haplotypes within the HLA-DP region and survey the extent of genetic diversity in this region across human populations. In this report, we analysed single-nucleotide polymorphisms (SNPs) in 255 subjects from 6 different cohorts. The results from the HLA-DP haplotype component have validated findings from the initial pilot study. SNPs in this region were inherited in strong linkage, particularly HLA-DPA1, SNP-linked promoter haplotypes and motifs in exon 2 of HLA-DPB1. We reported 17 SNP-linked haplotypes in the promoter region. Together with HLA-DPA1 and HLA-DPB1 alleles, they formed 74 distinct extended HLA-DP haplotypes in 438 sequences. We also observed the presence of region-specific alleles and promoter haplotypes. Our approach involved phasing extended SNPs including promoter SNPs, HLA-DPA1 and HLA-DPB1 alleles, in a 22 kb region, GRCh38/hg38 (chr6:33,064,111-33,086,679), followed by clustering of these SNPs as one extended haplotype. This hierarchical clustering revealed four major clades, suggesting that haplotypes within each clade may have diverged from a common ancestral haplotype and undergone similar evolutionary processes. The correlation between HLA-DPA1 and the promoter region raises questions about the role of HLA-DPA1 antigen in the heterodimer. This finding requires validation on a larger sample size specifically designed for anthropological analysis. Nevertheless, the results from this study highlight the clinical potential of selecting better-matched donors for patients awaiting haematopoietic stem cell transplants from genetically overlapping groups that share common ancestral haplotypes.


Super-achromatic optical coherence tomography capsule for ultrahigh-resolution imaging of esophagus.
Endoscopic optical coherence tomography (OCT) is a noninvasive technology allowing for imaging of tissue microanatomies of luminal organs in real time. Conventional endoscopic OCT operates at 1300 nm wavelength region with a suboptimal axial resolution limited to 8-20 μm. In this paper, we present the first ultrahigh-resolution tethered OCT capsule operating at 800 nm and offering about 3- to 4-fold improvement of axial resolution (plus enhanced imaging contrast). The capsule uses diffractive optics to manage chromatic aberration over a full ~200 nm spectral bandwidth centering around 830 nm, enabling to achieve super-achromaticity and an axial resolution of ~2.6 μm in air. The performance of the OCT capsule is demonstrated by volumetric imaging of swine esophagus ex vivo and sheep esophagus in vivo, where fine anatomic structures including the sub-epithelial layers are clearly identified. The ultrahigh resolution and excellent imaging contrast at 800 nm of the tethered capsule suggest the potential of the technology as an enabling tool for surveillance of early esophageal diseases on awake patients without the need for sedation.


Atomistic simulations of mixed-lipid bilayers in gel and fluid phases.
The slow rate of diffusive mixing poses a challenge for molecular dynamics (MD) simulation studies of mixed-lipid bilayers. A mixed Monte Carlo-molecular dynamics (MC-MD) approach, which uses mutation moves to swap lipid types throughout the system within the semi-grand canonical ensemble, is here applied to a comparison of binary mixtures in the gel and liquid crystalline phases. The two lipid components modeled, distearoylphosphatidylcholine (DSPC) and dimyristoylphosphatidylcholine (DMPC), differ by four carbons in the lengths of their acyl tails and are investigated here at full hydration at a temperature (313 K) between their transition temperatures, where coexistence between a DSPC-rich gel phase and a DMPC-rich liquid crystalline phase is expected. An analysis of DSPC-DMPC mixtures in the gel phase indicates strong deviation from ideality in the thermodynamics of mixing, accompanied by a tendency of the shorter-tailed component DMPC to associate laterally and for DMPC headgroups to be displaced toward the bilayer midplane. The liquid crystal phase mixtures, in contrast, show more mild deviation from thermodynamically ideal mixing with no apparent tendency for similar lipids to cluster laterally and no difference in headgroup normal distribution profiles.


Epidemiology of Hepatitis C virus infection among incarcerated populations in North Dakota.
This retrospective cohort study was conducted to determine the prevalence of HCV infections among individuals incarcerated in a state prison system and identify potential contributing factors to HCV infection. North Dakota Department of Corrections and Rehabilitation (NDDOCR) data from 2009 to 2018 was used and period prevalence was calculated for this 10-year time period. The period prevalence of HCV infection was (15.13% (95% CI 14.39-15.90) with a marginally significant (p-value: 0.0542) increasing linear trend in annual prevalence over this period. Multivariate logistic regression analysis was used to identify risk factors associated with HCV infection. The main significant independent risk factors for HCV infection in this incarcerated population were age >40 years [OR: 1.78 (1.37-2.32)]; sex [OR: 1.21 (1.03-1.43)]; race/ethnicity [OR: 1.97 (1.69-2.29)]; history of intravenous drug use (IVDU) [OR: 7.36 (6.41-8.44)]; history of needle or syringe sharing [OR: 7.57 (6.62-8.67)]; and alcohol use [OR: 0.87 (0.77-0.99)]. Study limitations include uncollected information on sexual history, frequency or duration of injection drug use and blood transfusion history of the incarcerated population. Considering the high prevalence of HCV infection and its associated risk factors, it is important to implement prevention programs such as syringe/needle exchanges and counsel with imprisoned IVD users.


The clinical challenges of homologous recombination proficiency in ovarian cancer: from intrinsic resistance to new treatment opportunities.
Ovarian cancer is the most lethal gynecologic cancer. Optimal cytoreductive surgery followed by platinum-based chemotherapy with or without bevacizumab is the conventional therapeutic strategy. Since 2016, the pharmacological treatment of epithelial ovarian cancer has significantly changed following the introduction of the poly (ADP-ribose) polymerase inhibitors (PARPi). BRCA1/2 mutations and homologous recombination deficiency (HRD) have been established as predictive biomarkers of the benefit from platinum-based chemotherapy and PARPi. While in the absence of HRD (the so-called homologous recombination proficiency, HRp), patients derive minimal benefit from PARPi, the use of the antiangiogenic agent bevacizumab in first line did not result in different efficacy according to the presence of homologous recombination repair (HRR) genes mutations. No clinical trials have currently compared PARPi and bevacizumab as maintenance therapy in the HRp population. Different strategies are under investigation to overcome primary and acquired resistance to PARPi and to increase the sensitivity of HRp tumors to these agents. These tumors are characterized by frequent amplifications of Cyclin E and MYC, resulting in high replication stress. Different agents targeting DNA replication stress, such as ATR, WEE1 and CHK1 inhibitors, are currently being explored in preclinical models and clinical trials and have shown promising preliminary signs of activity. In this review, we will summarize the available evidence on the activity of PARPi in HRp tumors and the ongoing research to develop new treatment options in this hard-to-treat population.


Steven (Steve) Walfish (1953-2016).
Presents an obituary for Steven (Steve) Walfish, who passed away in Atlanta, Georgia, on April 27, 2016. Walfish was a passionate clinical scholar and educator for independent practitioners. Well respected for his evaluations and consultations (presurgical weight loss, substance abuse, psychiatric issues), he became the go-to person for referrals for evidence-based practice with adults and couples. His untimely death to cancer deeply saddened the innumerable clients whose lives he touched and his diverse professional collaborators. (PsycINFO Database Record


Involvement of ack-pta operon products in alpha-ketobutyrate metabolism by Salmonella typhimurium.
The herbicide sulfometuron methyl inhibits acetolactate synthase II of Salmonella typhimurium, resulting in toxic accumulation of alpha-ketobutyrate. Four mutants, containing Tn10 insertions in the acetate kinase (ack) or phosphotransacetylase (pta) genes, were found among a collection of mutants hypersensitive to sulfometuron methyl. The genetic map location of these four Tn10 insertions at 46 min was identical to that of ack and pta point mutants. The insertion and point mutants shared the following phenotypes: resistance to fluoroacetate, sensitivity to alizarin yellow, inability to utilize inositol as a sole carbon source, and hypersensitivity to sulfometuron methyl. Three of the four Tn10 insertion mutants were deficient in phosphotransacetylase but not in acetate kinase activities, indicating insertion of Tn10 in the pta gene. The fourth mutant contained an insertion in the ack gene and was deficient in both acetate kinase and phosphotransacetylase activities. This polarity is consistent with cotranscription of ack and pta. All ack and pta mutants tested were defective in alpha-ketobutyrate turnover. Acetate kinase and phosphotransacetylase are proposed to be part of a pathway for alpha-ketobutyrate metabolism. Propionyl-CoA, an intermediate of that pathway, and propionate, the product of the pathway, accumulated upon inhibition of acetolactate synthase.


Salvage of an avascular thumb by arteriovenous flow reversal and a microvascular "kite" flap: case report.
This case report describes the salvage of an avascular thumb by retrograde venous arterialization. The thumb survived with a 30 percent tissue loss at the radial aspect. Soft-tissue reconstruction and contour correction were achieved with a new microvascular free flap--the free "kite" flap--from the contralateral index finger. Aesthetic and functional results were excellent, and the patient returned to his original occupation. It can be concluded that retrograde arterialization can provide successful salvage in replantation and revascularization under favorable circumstances.


EWS-FLI1 impairs aryl hydrocarbon receptor activation by blocking tryptophan breakdown via the kynurenine pathway.
Ewing sarcoma (ES) is an aggressive pediatric tumor driven by the fusion protein EWS-FLI1. We report that EWS-FLI1 suppresses TDO2-mediated tryptophan (TRP) breakdown in ES cells. Gene expression and metabolite analyses reveal an EWS-FLI1-dependent regulation of TRP metabolism. TRP consumption increased in the absence of EWS-FLI1, resulting in kynurenine and kynurenic acid accumulation, both aryl hydrocarbon receptor (AHR) ligands. Activated AHR binds to the promoter region of target genes. We demonstrate that EWS-FLI1 knockdown results in AHR nuclear translocation and activation. Our data suggest that EWS-FLI1 suppresses autocrine AHR signaling by inhibiting TDO2-catalyzed TRP breakdown.


A meta-analysis of the clinical efficacy of Tanreqing injection combined with antibiotics vs antibiotics alone for treating pulmonary infection secondary to intracerebral hemorrhage.
Pulmonary infection is the most common complication to develop after intracerebral hemorrhage (ICH). Antibiotics have certain limitations when used to treat pulmonary infection, while Tanreqing injection (TRQI) is extensively used to treat pulmonary infection as an adjuvant to antibiotics. The aim of this meta-analysis was to investigate the clinical efficacy of TRQI for the treatment of lung infection secondary to ICH. Randomized controlled trials (RCTs) assessing the combination of TRQI and antibiotics compared to antibiotics alone for pulmonary infection after ICH were comprehensively searched for in 7 electronic databases from their establishment to August 2020. Two independent researchers conducted the literature retrieval, screening, and data extraction. The assessment tool of Cochrane risk of bias and Review Manager 5.3 software were applied to assess the methodological quality and analyze the data, respectively. Seventeen RCTs involving 1122 patients with pulmonary infection after ICH were included. Compared to antibiotics alone, the combination treatment enhanced the clinical effective rate, shortened the hospital stay, reduced the white blood cell, procalcitonin, and C-reactive protein levels, ameliorated the times to the resolution of fever, cough, and lung rales, and increased the oxygenation index. The evidence indicated that TRQI combined with antibiotics caused no adverse reactions. Our study showed that the combination of TRQI and antibiotics was effective for treating pulmonary infection after ICH. However, high-quality multicenter RCTs are needed to further verify the clinical efficacy of TRQI due to the publication bias and the low methodological quality of the included RCTs.


New technique using temporary balloon occlusion for transcatheter closure of patent ductus arteriosus with Gianturco coils.
We describe our early experience with a new technique involving temporary balloon occlusion for transcatheter closure of patent ductus arteriosus (PDA) using single or multiple Gianturco coils. Coil occlusion was attempted in 21 patients of median age 3 (range 1-11) years, and angiographic PDA diameter 3.0 mm +/- 0.87 mm. The inflated balloon of a pulmonary wedge pressure catheter over a transductal wire was used to mechanically hold the first extruded loop of the coil at the pulmonary end of the duct. If a residual shunt persisted after the delivery of the first coil, additional coils were delivered with or without the balloon support. One to nine coils (median 2) of different sizes varying between 3-12 mm diameter and 4-15 cm length were used. Immediate angiographic occlusion rate was 47.6%. However color Doppler (CD) at 24 hours and at 6 weeks revealed complete closure in 66.6% and 80.9%, respectively. Blood transfusion was required in 2 (9.5%) patients. Three out of 56 coils (5.4%) embolized during deployment. The use of balloon occlusion is effective and safe in the treatment of ducti up to 4.7 mm. Residual shunts lend to occlude with time.


Sodium salicylate protects against rotenone-induced parkinsonism in rats.
Complex I deficiency culminating in oxidative stress is proposed as one of the upstream mechanisms of nigral neuronal death in Parkinson's disease. We investigated whether sodium salicylate, an active metabolite of aspirin, could afford protection against rotenone-induced oxidative stress, neuronal degeneration, and behavioral dysfunction in rats, because it has the potential to accept a molecule each of hydroxyl radical (•OH) at the third or fifth position of its benzyl ring. Rotenone caused dose-dependent increase in •OH in isolated mitochondria from the cerebral cortex and time- (24-48 h) and dose-dependent (0.1-100 µM) increase in the substantia nigra and the striatum, ipsilateral to the side of rotenone infusion. Administration of sodium salicylate at 12-h intervals for 4 days showed dose-dependent (50-100 mg/kg, i.p) reductions in the levels of •OH in the nigra on the fifth day. These animals showed significant attenuation in rotenone-induced loss in striatal dopamine levels, number of nigral dopaminergic neurons, reduced and oxidized glutathione levels, and complex I activity loss, but superoxide dismutase activity was increased further. Amphetamine- or apomorphine-induced ipsilateral rotations in rotenone-treated rats were significantly reduced in rats treated with sodium salicylate. Our results indicate a direct role of •OH in mediating nigral neuronal death by rotenone and confirm the neuroprotective potential of salicylate in a rodent model of parkinsonism.


Bilingualism augments memory advantage of accent congruency in word recognition.
Potential differences in word and speaker recognition, among monolinguals versus bilinguals, were investigated. Participants heard English words spoken by a male or female with a native Canadian English accent or a Chinese accent at study. Then, participants performed an old/new word recognition test with new words and half of the study words. Last, participants performed a same/different voice recognition test with the other half of the study words. Voice congruency varied so that each trial represented a same-talker, same-accent/different-gender, different-accent/same-gender, or different-accent/different-gender condition. Results indicated a word recognition benefit of accent congruency for participants fluent in the primary language of the talker. This finding suggests that familiarity with accent provides a benefit in verbal memory. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Pemphigus vulgaris: a rare cause of dysphagia.
Pemphigus vulgaris is a rare autoimmune blistering disease of the skin and mucous membranes. The case reported presented unusually with dyspepsia that was not responsive to protein pump inhibitor (PPI) therapy. This progressed to severe dysphagia and odynophagia. An esophagogastroduodenoscopy showed extensive ulceration of the esophagus, and direct immunofluorescence of an esophageal biopsy showed bright intercellular staining with C3 and IgG, confirming the diagnosis of pemphigus vulgaris. Immunological remission was achieved after a number of courses of pulsed intravenous methylprednisolone and cyclophosphamide. The patient has remained in remission for 5 years, but has required regular dilation of esophageal strictures for symptom relief. During this period, a chronic lymphocytosis was incidentally noted on routine blood tests, and chronic lymphocytic leukaemia was diagnosed. It is essential to investigate PPI-resistant symptoms, dysphagia and odynophagia, as they may indicate a serious underlying cause.


Evidence of direct thermal action upon the vestibular receptors in the caloric test. A re-interpretation of the data of Coats and Smith.
Although Bárány's convection theory has gained wide acceptance, there is strong evidence that the caloric response may include a component resulting from direct thermal stimulation of the vestibular end organs. It is argued on theoretical grounds that important new information could be obtained from a precise determination of the neutral head positions at which caloric irrigation fails to elicit a response. Although experimental studies using a bracketing procedure proved unsuccessful for this purpose, a re-examination of the extensive studies of Coats and Smith revealed that this information was already available. Reinterpreted in this way, their data clearly indicate that the hot and cold components resulting from direct thermal action equate to 42% and 34% respectively of the responses obtained in the planes of maximum reactivity. This is of sufficient magnitude to account for the anomalous findings in Spacelab I. Because of non-linearity in the relationship between neural discharge evoked by caloric irrigation and nystagmus magnitude, this component may be significantly less in the conventional caloric position. For this and other reasons there would seem to be no good reason to re-evaluate the clinical reliability of the caloric test.


[Minor head injuries. Prognostic factors in the evaluation of patients].
In order to identify signs to be used in the decision whether or not to admit patients after minor head injuries (MHI), the records of 713 females and 1163 males were reviewed. Skull X-ray was not obtained routinely, all patients were able to talk and walk when they reached medical contact. Nine patients developed an intracranial complication, three had an operation and one died. The risk of developing an ICC was 16.7% when the patient was agitated, 3.4% in the presence of impaired consciousness and 2.1% when positive neurological signs were observed at the time of examination. Based on the medical history, amnesia for more than five minutes and vomiting were associated with a risk of 3.3% and 1.2% respectively. The risk increased considerably in the presence of two of the above mentioned signs and was 60% if the patient was agitated and had amnesia for more than five minutes. Consequently, we recommend that all patients with one or more of the above symptoms or alcohol intoxication after a MHI should be admitted for observation. This policy may hold the possibility of considerable economic savings.


Divergent methylation of CRISPR repeats and cas genes in a subtype I-D CRISPR-Cas-system.
The presence and activity of CRISPR-Cas defense systems is a hallmark of many prokaryotic microorganisms. Here, the distribution of sequences related to the highly iterated palindrome 1 (HIP1) element and the DNA methylation of CGATCG motifs embedded within HIP1 as a vital part of the CRISPR1 repeat sequence was analyzed in the cyanobacterium Synechocystis sp. PCC 6803. Previously suggested functions of HIP1 include organization of chromosomal structure, DNA recombination or gene regulation, all of which could be relevant in CRISPR-Cas functionality. The CRISPR1 repeat-spacer array contains more than 50 CGATCG elements that are double-methylated (5mCG6mATCG) by the enzymes M.Ssp6803I and M.Ssp6803III. Hence, more than 200 possible methylation events cluster over a stretch of 3600 bp of double-stranded DNA. Bisulfite sequencing showed that these motifs were highly methylated at the m5CGATCG positions whereas specific motifs within the CRISPR1 cas genes were hypomethylated suggesting a lowered accessibility for the DNA methylase to these regions. Assays for conjugation and CRISPR1-mediated DNA interference revealed a 50% drop in conjugation efficiency in the mutant lacking the 5mC methylation of CGATCG motifs, while the highly efficient DNA interference activity was not affected by the lack of m5CGATCG DNA-methylation, nor was the capability to differentiate between self and non-self targets based on the protospacer adjacent motifs (PAMs) GTA and GTC versus the non-PAM AGC. A third DNA methylation mediated by M.Ssp6803II modifies the first cytosine in the motif GGCC yielding GGm4CC. We found a remarkable absence of GGCC motifs and hence the corresponding methylation over an 11 kb stretch encompassing all the cas genes involved in interference and crRNA maturation but not adaptation of the CRISPR1 system. The lack of GGCC tetranucleotides along the CRISPR1 interference and maturation genes supports the reported hybrid character of subtype I-D CRISPR-Cas systems. We report tight and very high 5mC methylation of the CRISPR1 repeat sequences. Nevertheless, cells lacking the 5mC methylation activity were unaffected in their CRISPR1-mediated interference response but the efficiency of conjugation was reduced by 50%. These results point to an unknown role of m5CGATCG DNA-methylation marks in conjugation and DNA transformation.


β-sheet-like formation during the mechanical unfolding of prion protein.
Single molecule experiments and simulations have been widely used to characterize the unfolding and folding pathways of different proteins. However, with few exceptions, these tools have not been applied to study prion protein, PrP(C), whose misfolded form PrP(Sc) can induce a group of fatal neurodegenerative diseases. Here, we apply novel atomistic modeling based on potential energy surface exploration to study the constant force unfolding of human PrP at time scales inaccessible with standard molecular dynamics. We demonstrate for forces around 100 pN, prion forms a stable, three-stranded β-sheet-like intermediate configuration containing residues 155-214 with a lifetime exceeding hundreds of nanoseconds. A mutant without the disulfide bridge shows lower stability during the unfolding process but still forms the three-stranded structure. The simulations thus not only show the atomistic details of the mechanically induced structural conversion from the native α-helical structure to the β-rich-like form but also lend support to the structural theory that there is a core of the recombinant PrP amyloid, a misfolded form reported to induce transmissible disease, mapping to C-terminal residues ≈160-220.


Analysis of PKC-ζ protein levels in normal and malignant breast tissue subtypes.
It is estimated that breast cancer will be the second leading cause of cancer-associated mortality in women in 2018. Previous research has demonstrated that the atypical protein kinase C-ζ (PKC-ζ) is a component of numerous dysregulated pathways in breast cancer, including cellular proliferation, survival, and cell cycle upregulation. The present study investigated the PKC-ζ protein in breast tissue to evaluate its potential as a biomarker for breast cancer invasion, and demonstrated that an overexpression of PKC-ζ protein can be indicative of carcinogenesis. The present study analyzed the expression of PKC-ζ in individuals with no tumor complications and malignant female human breast tissue samples (lobular carcinoma in situ, invasive lobular carcinoma, ductal carcinoma in situ and invasive ductal carcinoma) with the use of western blot analysis, immunohistochemistry and statistical analysis (83 samples). The present study also evaluated the invasive behavior of MDA-MB-231 breast cancer cells following the knockdown of PKC-ζ with a Transwell invasion assay and an immunofluorescent probe for filamentous actin (F-actin) organization. The data demonstrated that PKC-ζ expression was identified to be higher in invading tissues when compared with non-invading tissues. The results also suggest that PKC-ζ is more abundant in ductal tissues when compared with lobular tissues. In addition, the protein studies also suggest that PKC-ζ is a component for invasive behavior through the Ras-related C3 botulinum toxin substrate 1 (Rac1) and Ras homolog gene family member A (RhoA) pathway, and PKC-ζ is required for the F-actin reorganization in invasive cells. Therefore, PKC-ζ should be considered to be a biomarker in the development of breast cancer as well as an indicator of invading tumor cells.


E-5-(2-bromovinyl)-2'-deoxyuridine vs. interferon in the systemic treatment of infection with herpes simplex virus of athymic nude mice.
The effects of systemic administration of E-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and interferon (IFN)--mouse IFN type I (MuIFN-alpha plus -beta), mouse IFN type II (MuIFN-gamma), and polyriboinosinic-polyribocytidylic acid (an IFN inducer)--on the development of herpetic skin lesions and associated mortality were studied in athymic nude (nu/nu) mice inoculated intracutaneously with herpes simplex virus (HSV) type 1 (strain KOS). BVDU was given intraperitoneally or orally at dosages of up to 5 mg per mouse per day; IFN and polyriboinosinic-polyribocytidylic acid were given intraperitoneally at dosages of up to 10(6) units per mouse per day and 100 microgram per mouse per day, respectively. Under conditions in which BVDU effectively suppressed the progression of the disease, IFN and polyriboinosinic-polyribocytidylic acid failed to suppress the disease. Thus, BVDU was superior to IFN in the treatment of HSV infection in immunologically compromised mice.


How to assess ventriculoarterial coupling in sepsis.
We will highlight the role of ventriculoarterial coupling in the pathophysiology of sepsis and how to assess it. Most septic patients show a ventriculoarterial uncoupling at the time of diagnosis with arterial elastance (Ea) greater than left ventricle (LV) end-systolic elastance (Ees), often despite arterial hypotension. Ventriculoarterial coupling levels predict the cardiovascular response to resuscitation in this heterogeneously responding population. Ventriculoarterial coupling is quantified as the ratio of Ea to Ees. The efficiency of the cardiovascular function is optimal when Ea/Ees is near one. When the hydraulic load of the arterial system is excessive either from increased vasomotor tone, decreased LV contractility or both, Ea/Ees becomes greater than 1 (i.e. ventriculoarterial decoupling), and cardiac efficiency decreases leading to heart failure, loss of volume responsiveness, and if sustained, increased mortality. Noninvasive echocardiographic techniques when linked with arterial pressure monitoring allow for the bedside estimates of both Ea and Ees. Studies using this approach have documented the key role ventriculoarterial coupling has defining initial cardiovascular state, response to therapy and outcome from critical illness. Sequential monitoring of ventriculoarterial coupling at the bedside offers a unique opportunity to assess relevant cardiovascular determinants in septic patients requiring resuscitation.


Mass spectrometry quantitation of immunosuppressive drugs in clinical specimens using online solid-phase extraction and accurate-mass full scan-single ion monitoring.
Therapeutic drug monitoring (TDM) of immunosuppressants is essential for optimal care of transplant patients. Immunoassays and liquid chromatography-mass spectrometry (LC-MS) are the most commonly used methods for TDM. However, immunoassays can suffer from interference from heterophile antibodies and structurally similar drugs and metabolites. Additionally, nominal-mass LC-MS assays can be difficult to optimize and are limited in the number of detectable compounds. The aim of this study was to implement a mass spectrometry-based test for immunosuppressant TDM using online solid-phase extraction (SPE) and accurate-mass full scan-single ion monitoring (FS-SIM) data acquisition mode. LC-MS analysis was performed on a TLX-2 multi-channel HPLC with a Q-Exactive Plus mass spectrometer. TurboFlow online SPE was used for sample clean up. The accurate-mass MS was set to positive electrospray ionization mode with FS-SIM for quantitation of tacrolimus, sirolimus, everolimus, and cyclosporine A. MS2 fragmentation pattern was used for compound confirmation. The method was validated in terms of precision, analytical bias, limit of quantitation, linearity, carryover, sample stability, and interference. Quantitation of tacrolimus, sirolimus, everolimus, and cyclosporine A correlated well with results from an independent reference laboratory (r = 0.926-0.984). Accurate-mass FS-SIM can be successfully utilized for immunosuppressant TDM with good correlation with results generated by standard methods. TurboFlow online SPE allows for a simple "protein crash and shoot" sample preparation protocol. Compared to traditional MRM, analyte quantitation by FS-SIM facilitates a streamlined assay optimization process.


Remission in nonradiographic axial spondyloarthritis treated with anti-tumor necrosis factor-α drugs: an Italian multicenter study.
To investigate the possibility of achieving partial remission (PR) in patients with nonradiographic axial spondyloarthritis (nr-axSpA) versus ankylosing spondylitis (AS) treated with anti-tumor necrosis factor (TNF)-α antagonists, such as adalimumab (ADA), etanercept (ETN), and infliximab (IFX), in a real clinical practice setting. The Assessment of SpondyloArthritis international Society (ASAS) 20, ASAS40, and Ankylosing Spondylitis Disease Activity Score were also calculated. A retrospective study was conducted in patients with axSpA treated with ADA, ETN, and IFX from 2000 to 2013. All patients fulfilled the ASAS or the modified New York criteria. PR was reached when the score was < 20 mm (on a visual analog scale of 0-100 mm) in each of these domains: (1) patient global assessment, (2) pain, (3) function, and (4) inflammation. A total of 321 patients with axSpA were treated. Among them, 62 were nr-axSpA while the remaining 259 were AS. Log-rank test to compare survival curves showed that the probability of obtaining PR in nr-axSpA and AS during treatment with anti-TNF-α was not significantly different. At 12 weeks of exposure to the first anti-TNF-α drug, PR was achieved in 7 patients with nr-axSpA (11.3%) and in 68 patients with AS (26.2%). Our results, obtained from clinical practice, showed that PR is an achievable target of anti-TNF-α treatment in nr-axSpA. The PR rate, as a reliable indicator of sustained effectiveness, is similar in nr-axSpA and in AS.


Drug use evaluation of statins at Siriraj Hospital, 2008.
Statins are commonly used for lipid reduction. There is no significant difference in the efficiency of each type of statins. The study of statins' efficacy shows that only generic simvastatin is cost-effective in coronary heart disease prevention. To determine the use and appropriateness of usage of statins in out-patients attending Siriraj Hospital in 2008. Medical records of all patients in Siriraj Hospital who received statins from January 1st to December 31st, 2008 were reviewed. The appropriateness of statins used was analyzed in 247 medical records based on number of risks and 10-year risk. There were 105,950 patients who received statins with total value of 308 million baht in 2008. The major usages of statins were simvastatin (65%), atorvastatin (12%) and rosuvastatin (6%). However, the costs of statins were 9%, 42%, and 20% for simvastatin, atorvastatin and rosuvastatin, respectively. Analysis of 247 medical records of the patients who received statins showed that statins were appropriately used in 19.4% of cases. Inappropriate use of statins was due to not starting drugs treatment with simvastatin, or shifting from simvastatin to other statins inappropriately. Inappropriate use of statins at Siriraj Hospital is very common. Interventions for promoting more appropriate use of statins should be implemented.


Cognitive Versus Hemorrhagic Onset in Cerebral Amyloid Angiopathy: Neuroimaging Features.
Intracerebral hemorrhage and cognitive decline are typical clinical presentations of cerebral amyloid angiopathy (CAA). To determine whether magnetic resonance imaging (MRI) features differ between CAA with hemorrhagic versus cognitive onset. In this retrospective study, sixty-one patients with CAA were classified by onset presentation of the disease: hemorrhage (n = 31) or cognitive decline (n = 30). The two groups were compared for MRI markers of small vessel disease, namely cerebral microbleeds (CMBs), cortical superficial siderosis, white matter hyperintensities (WMHs), enlarged perivascular spaces, cortical microinfarcts, and visual rating scales for cortical atrophy. In the patients with cognitive onset, further exploratory analyses investigated MRI markers according to cerebrospinal fluid (CSF) and neuropsychological profiles. Patients with cognitive onset showed a higher prevalence of CMBs (p < 0.001), particularly in temporal (p = 0.015) and insular (p = 0.002) lobes, and a higher prevalence of WMHs (p = 0.012). Within the cognitive onset group, 12 out of 16 (75%) patients had an Alzheimer's disease (AD) CSF profile but did not differ in MRI markers from those without AD pathology. Patients with cognitive onset displayed a multidomain profile in 16 out of 23 (70%) cases; patients with this profile showed increased WMHs and CMBs in parietal lobes compared with the amnestic group (p = 0.002) and dysexecutive group (p = 0.032), respectively. Higher burdens of WMHs and CMBs, especially in temporal and insular lobes, are associated with the cognitive onset of CAA. MRI markers could help to shed light on the clinical heterogeneity of the CAA spectrum and its underlying mechanisms.


Heat transport through a two-level system embedded between two harmonic resonators.
We investigate heat transport through an assembly consisting of a two-level system coupled between two harmonic oscillators, which is described by the quantum Rabi model, as a prototype of nanoscale heat devices using controllable multi-level systems. Using the noninteracting-blip approximation, we find that the linear thermal conductance shows a characteristic temperature dependence with a two-peak structure. We also show that heat transport is sensitive to model parameters for weak system-bath coupling and strong hybridization between the two-level system and the harmonic oscillators. This property characteristic of the multi-level system is advantageous for applications such as a heat transistor, and can be examined in superconducting circuits.