Molecular analysis of Anaplasma phagocytophilum isolated from patients with febrile diseases of unknown etiology in China.
Although anaplasmosis cases have been nationally identified in China, no human isolates of A. phagocytophilum have been obtained, which limits the analysis of any molecular and genetic contributions to patients' severe clinical manifestations and the study of the bacteria's pathogeneses in China. Given this situation, a joint project was conducted in 2009-2010. A total of 421 febrile cases of unknown etiology were collected and the patients' blood samples were collected for laboratory diagnoses including serologic diagnosis based on the four-fold rise in the anti- A. phagocytophilum IgG titer by indirect micro-immunofluorescence assay (IFA), positive PCR assay and confirmation of A. phagocytophilum DNA and positive culture of A. phagocytophilum and confirmed by amplification and sequencing of the 16S rRNA and ank A genes of the A. phagocytophilum isolates. A total of 570 ticks were collected from the patients' domestic animals (456) and from wild fields (114) for culturing and amplifying and sequencing the 16S rRNA gene of A. phagocytophilum. Phylogenetic analyses were performed on the 16S rRNA and ank A gene sequences of the isolates and the ticks tested in the study. A total of 46 (10.9%) confirmed and 16 (3.8%) probable cases were diagnosed and severe clinical features and higher mortality rates were observed in these Chinese patients. Five isolates were obtained and the 16S rRNA genes of the 5 isolates were conserved but variety for ank A genes. Two human isolates and 1 tick isolate from Shandong Peninsula, where all patients exhibited severe clinical manifestations, were grouped as one clan based on the phylogenetic analyses, while 2 other human isolates were clustered in a second clan. 43.5% of H. longicornis were infected with A. phagocytophilum.The present study is the first to obtain clinical isolates of A. phagocytophilum in China. The diversity of the ank A genes of Chinese isolates will help us to further discern the relationship between the variations in the ank A genes and the severity of the disease's clinical manifestations in China.


Cognitive function in Coffin-Lowry syndrome.
Coffin-Lowry syndrome (CLS) is an X-linked disorder associated with mental retardation, distinctive facies and hands, hypotonia, and skeletal abnormalities. The syndrome results from mutations in the RSK2 gene located in Xp22.2. Although the syndrome has been elucidated clinically, few, if any, studies have focused on the cognitive deficits of the affected males or carrier females. The subjects of the present study were selected from two African-American families who have the same missense mutation (C340T) in RSK2. The subjects included six affected males, seven carrier females, three normal males and three non-carrier (normal) females. Normal family members served as contrast/comparison cohorts to control for socio-economic, sociocultural and genetic variables which would impinge on intellectual abilities. Analysis of cognitive function, as measured by the Stanford-Binet Intelligence Scale, 4th edn, demonstrated a distinct hierarchy of abilities from normal to carrier to affected patients. The mean composite IQs of the cohorts were 90.8, 65.0 and 43.2 for normal, carrier and affected individuals, respectively. These findings lend support to the clinical concept of negative intellectual effects in carriers of certain X-linked mental retardation conditions. X-inactivation studies showed that carrier females had mild to significant skewing. Normal females in the family did not demonstrate skewing. The correlation coefficient between IQ and X-inactivation status among carriers was not significant.


Malignant atrophic papulosis (Kohlmeier-Degos disease) in childhood.
Malignant atrophic papulosis (Kohlmeier-Degos disease) is reported for the first time with pathologic verification of central nervous system involvement in a child. The disease began in infancy with rare recurring skin lesions; the child died at the age of 7, after progressive neurologic deterioration. Diagnosis was suspected clinically and confirmed by biopsy of a typical skin lesion. Recognition of this disorder by its dermatologic manifestations may obviate invasive diagnostic procedures.


OncoLink: a multimedia oncology information resource on the Internet.
This paper describes OncoLink, the first multimedia World-Wide-Web (WWW) and gopher server focusing on cancer information for both the health care professional and the patient. OncoLink provides an internetworked hypertext and multimedia resource linking people, computers and information together in an easy to use fashion. Our objective in developing OncoLink is to provide comprehensive and timely information about many aspects of oncology for both patients and healthcare providers. Specifically, OncoLink's purposes are: (1) the rapid dissemination of information relevant to treatment of cancer and concomitant problems; (2) education of health care personnel (at all levels) in the field; (3) education of patients and families of patients who have cancer; (4) posting of clinical trials and eligibility criteria; (5) the rapid collection and dissemination of quality, peer-reviewed information pertinent to oncology in general and specific subspecialties; (6) provide a well-organized, frequently updated hypertext system to access other quality cancer information resources on the Internet. OncoLink attempts to provide one-stop shopping for the patient, healthcare provider, researcher or Internet browser searching for cancer-related information. Since its inception on March 7, 1994, OncoLink has averaged more than 36,000 accesses per month from around the world. While also accessible by text-based gopher servers, preliminary observations infer increased use of multimedia and hypertext documents over traditional text-only resources. From the large following of users, it is clear that electronic dissemination of high quality, peer-reviewed cancer information is very popular. We conclude OncoLink is both useful and has wide interest in the international community.(ABSTRACT TRUNCATED AT 250 WORDS)


Research protocol: a realist synthesis of cross-border patient mobility from low-income and middle-income countries.
People are increasingly mobile for numerous reasons, including healthcare. Patient mobility has vast implications for individuals, communities and whole populations and yet, to date, research on patient mobility has been quite limited. Only a small body of evidence exists on patient mobility between low-income and middle-income countries, instead having focused primarily on cross-border movement between high-income and low-income countries. In this paper, we present a protocol for examining this under-studied phenomenon. We propose to examine patient mobility between low-income and middle-income countries using a realist synthesis approach. Specifically, we aim to document why patients from low-income and middle-income countries cross international borders for healthcare, by identifying the mechanisms through which patients decide to cross-borders, and the contextual characteristics of domestic health markets that influence this choice. An underlying theory was established, based on the lead author's experience and a brief literature review, which will provide the basis to analyse search results in a subsequent paper. Search results will be obtained from databases (Ovid Medline, EMBASE, Scopus, EconLit, Web of Science) and the grey literature. An expert committee will be enlisted, prior to screening results, to review search results to ensure comprehensiveness. Based on this preliminary theory, we propose that, in some low-income and middle-income country markets, the interaction between demand-side and supply-side determinants results in market imperfections that, in turn, lead to patient movement across borders. The study does not involve primary research and, therefore, does not require formal ethical approval; we do, however, follow the relevant standards of utility, usefulness, feasibility, propriety, accuracy and accountability. The standards of realist and meta-narrative evidence synthesis (RAMESES) will be adhered to in reporting the findings of the review. Once completed, the findings of the resulting manuscript will be published in a peer-reviewed journal. This protocol has been registered with PROSPERO, registration number CRD42014014391.


Feeling better about doing worse: social comparisons within romantic relationships.
The authors examined the role of closeness between self and partner in determining the impact of social comparisons within intimate relationships. To the extent that one's partner is a central aspect of one's identity, one may be able to restore one's positive self-regard following an upward comparison with the partner by turning to the relationship as a self-affirmational resource. Studies 1 and 2 examined reactions to imagined comparisons; Studies 3 and 4 examined reactions to actual comparison feedback. Across studies, closeness moderated the impact of upward comparisons with the partner; that is, higher closeness participants responded to a more successful partner by focusing on their relationship-related strengths. However, closeness did not moderate the impact of downward comparisons with the partner.


Looking to the future of nasal drug delivery - an interview with Per Gisle Djupesland.
Per G Djupesland, MD, PhD speaks to Hannah Makin, Commissioning Editor: Dr Djupesland is the inventor of OptiNose®'s patented, bi-directional nasal drug-delivery technology and is a Co-Founder of OptiNose AS. Dr. Djupesland is a lead inventor on all 38 OptiNose patent families/patent applications, and serves as Chief Scientific Officer of OptiNose AS, with primary responsibility for device discovery and early development efforts. These early development efforts include identifying new product opportunities that use bi-directional technology, advancing the design of devices using the bi-directional technology to treat a variety of medical conditions and conducting Phase I and IIa trials with new 'nose-to-brain' applications for the technology. Dr Djupesland is an otolaryngologist (ENT) with a specialization in rhinology and more than 25 years of clinical experience. Among other positions prior to OptiNose, he served as a Clinical Research Fellow at the Hospital for Sick Children and Toronto General in Toronto, Canada, primarily studying the role of nitric oxide in the upper airways. Dr Djupesland has authored more than 60 peer reviewed articles in international medical journals and has lectured at numerous international scientific conferences. He earned medical and doctorate degrees in the field of nasal physiology and aerodynamics from the University of Oslo.


Outcomes of prevention of mother to child transmission of the human immunodeficiency virus-1 in rural Kenya--a cohort study.
Success in prevention of mother-to-child transmission (PMTCT) raises the prospect of eliminating pediatric HIV infection. To achieve global elimination, however, strategies are needed to strengthen PMTCT interventions. This study aimed to determine PMTCT outcomes and identify challenges facing its successful implementation in a rural setting in Kenya. A retrospective cohort design was used. Routine demographic and clinical data for infants and mothers enrolling for PMTCT care at a rural hospital in Kenya were analysed. Cox and logistic regression were used to determine factors associated with retention and vertical transmission respectively. Between 2006 and 2012, 1338 infants were enrolled and followed up for PMTCT care with earlier age of enrollment and improved retention observed over time. Mother to child transmission of HIV declined from 19.4 % in 2006 to 8.9 % in 2012 (non-parametric test for trend p = 0.024). From 2009 to 2012, enrolling for care after 6 months of age, adjusted Odds Ratio [aOR]: 23.3 [95 % confidence interval (CI): 8.3-65.4], presence of malnutrition ([aOR]: 2.3 [95 % CI: 1.1-5.2]) and lack of maternal use of highly active antiretroviral therapy (HAART) (aOR: 6.5 [95 % CI: 1.4-29.4]) was associated with increased risk of HIV infection. Infant's older age at enrollment, malnutrition and maternal HAART status, were also associated with drop out from care. Infants who were not actively followed up were more likely to drop out from care (adjusted Hazard Ratio: 6.6 [95 % CI: 2.9-14.6]). We report a temporal increase in the proportion of infants enrolling for PMTCT care before 3 months of age, improved retention in PMTCT and a significant reduction in the proportion of infants enrolled who became HIV-infected, emphasizing the benefits of PMTCT. A simple set of risk factors at enrollment can identify mother-infant pairs most at risk of infection or drop out for targeted intervention.


ARMS2 A69S polymorphism is associated with the number of ranibizumab injections needed for exudative age-related macular degeneration in a pro re nata regimen during 4 years of follow-up.
To investigate whether single-nucleotide polymorphisms (SNPs) known to be strongly associated with the development of age-related macular degeneration (AMD) have an influence on recurrence rate of choroidal neovascularization (CNV) activity during 4-year ranibizumab treatment for exudative AMD. This prospective study included 103 treatment-naïve patients (103 eyes) that received initially a loading dose of 3 monthly ranibizumab injections and thereafter, were treated according to an as-needed regimen for a 4-year follow-up period. Baseline values, visual outcome, and recurrence rate were examined. CFH Y402H and ARMS2 A69S polymorphisms were determined and their association with lesion recurrence and visual outcome was analyzed using a one-way analysis of variance (ANOVA) with post hoc comparison tested by Fisher's LSD method. Multivariate linear regression analysis was then used to identify factors associated with recurrence rate. The cumulative total mean number of ranibizumab injections at the end of each year of the follow-up was 5.3 ± 1.8, 9.2 ± 2.9, 12.6 ± 4.6, and 15.7 ± 6.1. There was great inter-patient variability. Nineteen eyes (18.5%) did not experience recurrence during the first year, and five (4.8%) still displayed inactive CNV after 4 years of follow-up. No significant association was found between the number of injections and mean best corrected visual acuity (BCVA) change or final BCVA at the end of the study period. Genotypes had no influence on baseline characteristics or visual outcome but a significant association was found between the A69S polymorphism and the number of injections needed by the patients. Homozygous for the T risk allele required more retreatments over the 48-month follow-up. The ARMS2 A69S polymorphism was associated with CNV recurrence rate in our patient cohort. Prediction of a greater risk of recurrence could help to design more appropriate follow-up treatment strategies for patients with neovascular AMD.


A Bayesian hierarchical approach to multirater correlated ROC analysis.
In a common ROC study design, several readers are asked to rate diagnostics of the same cases processed under different modalities. We describe a Bayesian hierarchical model that facilitates the analysis of this study design by explicitly modelling the three sources of variation inherent to it. In so doing, we achieve substantial reductions in the posterior uncertainty associated with estimates of the differences in areas under the estimated ROC curves and corresponding reductions in the mean squared error (MSE) of these estimates. Based on simulation studies, both the widths of coverage intervals and MSE of estimates of differences in the area under the curves appear to be reduced by a factor that often exceeds five. Thus, our methodology has important implications for increasing the power of analyses based on ROC data collected from an available study population.


Arctiin induces an UVB protective effect in human dermal fibroblast cells through microRNA expression changes.
Ultraviolet (UV) radiation induces severe alterations in the molecular and cellular components of normal human dermal fibroblast (NHDF) cells by disrupting many intracellular transduction cascades. Although UV responses have been well documented at the genome and proteome levels, UV protective effects have not been elucidated at these levels. The aim of the present study was to demonstrate that arctiin, a phytochemical isolated from the plant Arctium lappa, induced a protective effect against UVB radiation by changing microRNA (miRNA) expression profiles. Using flow cytometry, and water-soluble tetrazolium salt (WST-1)-based cell viability, wound healing, and DNA repair assays we showed that pretreatment with arctiin prior to UVB irradiation reduced UVB-induced apoptosis, cell migration defects, and DNA damage in NHDF cells. It was also found that arctiin‑induced UVB protection is associated with altered miRNA expression profiles. Bioinformatic analysis revealed that the deregulated miRNAs were functionally involved in mitogen-activated protein kinase (MAPK) signaling and cancer signaling pathways. The results suggest that arctiin acts as a UVB protective agent by altering specific miRNA expression in NHDF cells.


Herpesviruses and polyomaviruses in renal transplantation.
Viral infections remain a significant cause of morbidity and mortality among transplant patients despite recent advances in early detection and treatment. Herpesviruses and polyomaviruses are the most relevant viruses post-transplant as they establish latency in immunocompetent individuals and frequently reactivate in the immunosuppressed transplant recipient. Although we have made significant strides in the early diagnosis and treatment of viral infections in renal transplant recipients over the past five years, many questions remain. Optimization of screening and prophylactic/preemptive protocols, as well as standardization of viral diagnostic testing are still needed. Understanding how viruses modify the host's immune responses, and conversely how variations between hosts' ability to mount an immune response against viruses are important areas of research that might allow for more individualization of immunosuppressive regimens. Other exciting areas of ongoing study include the associations between various HLA loci/mismatches and viral replication/infection, the mechanisms by which certain viruses (i.e., Epstein-Barr virus, human herpes virus 8) are oncogenic, and the development of new therapeutic strategies such as adoptive transfer of antigen-specific T cells to restore immunity and control viral infections.


Prescribing Cascades with Recommendations to Prevent or Reverse Them: A Systematic Review.
To reduce prescribing cascades occurring in clinical practice, healthcare providers require information on the prescribing cascades they can recognize and prevent. This systematic review aims to provide an overview of prescribing cascades, including dose-dependency information and recommendations that healthcare providers can use to prevent or reverse them. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was followed. Relevant literature was identified through searches in OVID MEDLINE, OVID Embase, OVID CINAHL, and Cochrane. Additionally, Web of Science and Scopus were consulted to analyze reference lists and citations. Publications in English were included if they analyzed the occurrence of prescribing cascades. Prescribing cascades were included if at least one study demonstrated a significant association and were excluded when the adverse drug reaction could not be confirmed in the Summary of Product Characteristics. Two reviewers independently extracted and grouped similar prescribing cascades. Descriptive summaries were provided regarding dose-dependency analyses and recommendations to prevent or reverse these prescribing cascades. A total of 95 publications were included, resulting in 115 prescribing cascades with confirmed adverse drug reactions for which at least one significant association was found. For 52 of these prescribing cascades, information regarding dose dependency or recommendations to prevent or reverse prescribing cascades was found. Dose dependency was analyzed and confirmed for 12 prescribing cascades. For example, antipsychotics that may cause extrapyramidal syndrome followed by anti-parkinson drugs. Recommendations focused on dosage lowering, discontinuing medication, and medication switching. Explicit recommendations regarding alternative options were given for three prescribing cascades. One example was switching to ondansetron or granisetron when extrapyramidal syndrome is experienced using metoclopramide. In total, 115 prescribing cascades were identified and an overview of 52 of them was generated for which recommendations to prevent or reverse them were provided. Nonetheless, information regarding alternative options for managing prescribing cascades was scarce.


Transcutaneous O2 and CO2 monitoring of neurosurgical patients: detection of air embolism.
Transcutaneous oxygen tension (PtcO2) and transcutaneous carbon dioxide tension (PtcCO2) were monitored in 60 patients undergoing neurosurgical procedures. Twenty-six patients were in the sitting position and underwent routine monitoring for air embolism. Seventeen episodes of air embolism were diagnosed by precordial Doppler ultrasound or transesophageal echocardiography, and the PtcO2 decreased early during the course of each episode. The mean PtcO2 decrease was 48 +/- 35 mmHg. During ten episodes the end-tidal carbon dioxide tension (PETCO2) decreased but only after the PtcO2 had already begun to decrease. PtcCO2 increased during air embolism but PETCO2 changes preceded the change in PtcCO2 by 1-2 min. Transcutaneous values during air embolism were verified with simultaneous arterial blood gas values during six air embolism episodes. A strong positive correlation was found between transcutaneous and arterial oxygen and carbon dioxide tensions. Correcting the PtcCO2 by the patient's baseline PtcCO2/PaCO2 ratio, PtcCO2 monitoring correctly reflected hypocarbia, normocarbia, and hypercarbia in 92% of the cases. PtcO2 monitoring was useful in detecting venous air embolism and may respond sooner than PETCO2. PtcCO2 monitoring was not useful as an early detector of air embolism.


Structured reporting in radiology enables epidemiological analysis through data mining: urolithiasis as a use case.
To investigate the epidemiology and distribution of disease characteristics of urolithiasis by data mining structured radiology reports. The content of structured radiology reports of 2028 urolithiasis CTs was extracted from the department's structured reporting (SR) platform. The investigated cohort represented the full spectrum of a tertiary care center, including mostly symptomatic outpatients as well as inpatients. The prevalences of urolithiasis in general and of nephro- and ureterolithasis were calculated. The distributions of age, sex, calculus size, density and location, and the number of ureteral and renal calculi were calculated. For ureterolithiasis, the impact of calculus characteristics on the degree of possible obstructive uropathy was calculated. The prevalence of urolithiasis in the investigated cohort was 72%. Of those patients, 25% had nephrolithiasis, 40% ureterolithiasis, and 35% combined nephro- and ureterolithiasis. The sex distribution was 2.3:1 (M:F). The median patient age was 50 years (IQR 36-62). The median number of calculi per patient was 1. The median size of calculi was 4 mm, and the median density was 734 HU. Of the patients who suffered from ureterolithiasis, 81% showed obstructive uropathy, with 2nd-degree uropathy being the most common. Calculus characteristics showed no impact on the degree of obstructive uropathy. SR-based data mining is a simple method by which to obtain epidemiologic data and distributions of disease characteristics, for the investigated cohort of urolithiasis patients. The added information can be useful for multiple purposes, such as clinical quality assurance, radiation protection, and scientific or economic investigations. To benefit from these, the consistent use of SR is mandatory. However, in clinical routine SR usage can be elaborate and requires radiologists to adapt.


Photodegradation Study of Sertindole by UHPLC-ESI-Q-TOF and Influence of Some Metal Oxide Excipients on the Degradation Process.
The evaluation of the influence of the excipients present in the pharmaceutical formulations on the drug stability is an important part of quality control of medicines. One of the most commonly applied group of excipients are pigments, such as titanium dioxide or various forms of iron oxides, which are well-known photocatalytic agents. Therefore, the photostability of an atypical antipsychotic drug sertindole and the influence of pigments commonly used in the pharmaceutical formulations (FeOOH, Fe2O3, and TiO2) on this process were studied. The quantitative and qualitative analysis of the process was performed with the use of ultra high pressure liquid chromatography with diode array detection (UHPLC-DAD) system coupled with a high resolution hybrid electrospray ionization quadrupole time-of-flight (ESI-Q-TOF) mass spectrometer. Sertindole turned out to be a highly photolabile molecule. Overall 18 transformation products were found, mainly formed as a consequence of dechlorination, hydroxylation, and dehydrogenation. In all the experiments, except the TiO2-mediated photocatalysis, the product of chlorine substitution with a hydroxyl group was the major product. The presence of Fe2O3 and TiO2 accelerated the degradation process, while FeOOH served as its inhibitor. The experiments conducted with the use of the pharmaceutical formulations confirmed the catalytic activity of the used excipients. The exploration of the obtained phototransformation profiles with the use of principal component analysis (PCA) revealed that the presence of both iron oxides could influence the qualitative and quantitative aspect of the studied processes. In silico assessment of the properties showed that the transformation products are generally less toxic to rodents, possess lower hERG blocking potential, but could be more mutagenic than the parent molecule.


"It All Makes Us Feel Together": Young People's Experiences of Virtual Group Music-Making During the COVID-19 Pandemic.
We know little about the psychological experiences of children and young people who have participated in virtual group music-making during the Coronavirus disease (COVID-19) pandemic. Adopting a mixed-methods design, we worked across three music education hubs in the UK, with a total 13 virtual music groups. These included a range of mainstream ensembles, inclusive ensembles targeting young people with special educational needs and/or disabilities, and inclusive music production spaces, targeting young people from lower socio-economic backgrounds. Reported progress in intra- and inter-personal psychological outcomes was investigated using quantitative and qualitative staff session reports, which were collected since before the pandemic (n1 for in-person sessions = 87, n2 for virtual sessions = 68), and surveys distributed to tutors, young people, and their parents during the first and second United Kingdom (UK) national lockdowns (n3 for qualitative responses = 240, n4 for quantitative responses = 96). Satisfaction of three basic psychological needs of self-determination theory and their relation to joint music-making in virtual spaces was also observed in real time by the researchers performing quantitative checklist observations on 16 separate occasions. Findings indicated that virtual music groups represented a meaningful psychological resource for the participating children and young people, especially considering the lack of opportunities offered by their schools and other extra-curricular activities. Through their participation with virtual group music-making activities, young people used music as a tool for self-expression and emotion management, restored lost musical identities and confidence, and preserved treasured social connections. Virtual alternatives to group music-making appear to indirectly nurture the sense of belongingness, mediated by supportive staff behaviors, but their direct connection, which has been widely reported for in-person group music-making experiences, has not been observed in virtual music groups.


A modified microcomplement fixation test for antigen or antibody determination in soluble immune complexes, using gel filtration.
A Modified Microcomplement Fixation Test (MMFT), useful for detecting and quantifying soluble immune complexes (ICs) and their components in chromatographic separations, is described. This method is based on the addition of excess specific antibody to the ICs against any of their components in order to increase the ICs' anticomplementarity. The concentration of ICs is expressed as the sample dilution which fixes 50% of the added Complement. The MMFT was applied to profiles of ICs obtained in vivo and in vitro. MMFT allows great sensitivity, good reproductibility and the detection of noncomplement fixing ICs without any interference of free antigen (Ag) or free antibody (Ab).


Chromatographic enantioseparation by poly(biphenylylacetylene) derivatives with memory of both axial chirality and macromolecular helicity.
Novel poly(biphenylylacetylene) derivatives bearing two acetyloxy groups at the 2- and 2'-positions and an alkoxycarbonyl group at the 4'-position of the biphenyl pendants (poly-Ac's) were synthesized by the polymerization of the corresponding biphenylylacetylenes using a rhodium catalyst. The obtained stereoregular (cis-transoidal) poly-Ac's folded into a predominantly one-handed helical conformation accompanied by a preferred-handed axially twisted conformation of the biphenyl pendants through noncovalent interactions with a chiral alcohol and both the induced main-chain helicity and the pendant axial chirality were maintained, that is, memorized, after complete removal of the chiral alcohol. The stability of the helicity memory of the poly-Ac's in a solution was lower than that of the analogous poly(biphenylylacetylene)s bearing two methoxymethoxy groups at the 2- and 2'-positions of the biphenyl pendants (poly-MOM's). In the solid state, however, the helicity memory of the poly-Ac's was much more stable and showed a better chiral recognition ability toward several racemates than that of the previously reported poly-MOM when used as a chiral stationary phase for high-performance liquid chromatography. In particular, the poly-Ac-based CSP with a helicity memory efficiently separated racemic benzoin derivatives into enantiomers.


Dynamic modelling predicts lactate and IL-1β as interventional targets in metabolic-inflammation-clock regulatory loop in glioma.
In an attempt to understand the role of dysregulated circadian rhythm in glioma, our recent findings highlighted the existence of a feed-forward loop between tumour metabolite lactate, pro-inflammatory cytokine IL-1β and circadian CLOCK. To further elucidate the implication of this complex interplay, we developed a mathematical model that quantitatively describes this lactate dehydrogenase A (LDHA)-IL-1β-CLOCK/BMAL1 circuit and predicts potential therapeutic targets. The model was calibrated on quantitative western blotting data in two glioma cell lines in response to either lactate inhibition or IL-1β stimulation. The calibrated model described the experimental data well and most of the parameters were identifiable, thus the model was predictive. Sensitivity analysis identified IL-1β and LDHA as potential intervention points. Mathematical models described here can be useful to understand the complex interrelationship between metabolism, inflammation and circadian rhythm, and in designing effective therapeutic strategies. Our findings underscore the importance of including the circadian clock when developing pharmacological approaches that target aberrant tumour metabolism and inflammation. Insight box The complex interplay of metabolism-inflammation-circadian rhythm in tumours is not well understood. Our recent findings provided evidence of a feed-forward loop between tumour metabolite lactate, pro-inflammatory cytokine IL-1β and circadian CLOCK/BMAL1 in glioma. To elucidate the implication of this complex interplay, we developed a mathematical model that quantitatively describes this LDHA-IL-1β-CLOCK/BMAL1 circuit and integrates experimental data to predict potential therapeutic targets. The study employed a multi-start optimization strategy and profile likelihood estimations for parameter estimation and assessing identifiability. The simulations are in reasonable agreement with the experimental data. Sensitivity analysis found LDHA and IL-1β as potential therapeutic points. Mathematical models described here can provide insights to understand the complex interrelationship between metabolism, inflammation and circadian rhythm, and in identifying effective therapeutic targets.


Effects of prices, civil and criminal sanctions, and law enforcement on alcohol-related mortality.
Alcohol use has been linked to several causes of death. This study provides an empirical analysis of the effects of various public policies on mortality rates by state and year for the years 1982-88. Causes of death analyzed are: alcohol primary cause; traffic accident; homicides; suicides; falls, fires and other accidents; and contributory cause deaths (cancers of the alimentary tract). We find that increasing the price of alcohol decreases mortality rates for some of the causes, but not for primary cause deaths. Higher excise taxes on cigarettes reduce contributory cause mortality. Dram shop laws have negative and statistically significant effects not only on mortality rates from traffic accidents, but for several of the other causes. There is a need for further analysis to determine how these reductions are achieved. We find no evidence that imposing mandatory minimum jail terms, fines or license revocation for a DUI conviction affects alcohol-related mortality. However, increased police protection decreases mortality rates for several categories, especially homicides and traffic accidents. We find that imposing the death penalty reduces homicide rates. Reductions in alcohol-related mortality may be achieved by implementing a mix of public policies. No single policy is a panacea.


Evaluation of selected properties of gluten-free instant gruels processed under various extrusion-cook- ing conditions.
For consumers suffering with gluten intolerance, the only way to manage the condition is to avoid foods which are high in gluten. Instant gruels, processed from gluten-free corn and rice by extrusion cooking, could be used as a ready meal both for children and for adults on a gluten-free diet. The aim of the study was to evaluate the effects of various processing conditions on selected characteristics of corn-rice instant gruels. Corn-rice mixtures (75:25 and 50:50) were processed at 12, 14, 16 and 18% of initial moisture content, using an extruder with screw speeds of 80, 100 and 120 rpm. Bulk density, water absorption and solubility, gel formation, color and sensory characteristics were assessed, under various pro- cessing conditions and with various corn:rice ratios. The composition of the raw materials, initial moisture content and screw speed applied during processing affected the characteristics of the corn-rice extruded instant gruels. Increasing the amount of rice in the recipe from 25 to 50% resulted in decreased bulk density, water solubility, volumetric gel formation ability and b* value. Increasing the initial moisture content increased the bulk density, L*, a* and b* intensity, and gel formation index values of extrudates made with a 75:25 corn-rice recipe. Increased rpm increased extrudate solubility and water absorption, if the initial moisture content was higher than 14%. The highest scores for overall acceptability were found for milk suspensions of 75:25 and 50:50 corn-rice instant gruels processed at 12 and 14% of initial moisture content, at 120 rpm. Corn-rice instant gruels can be successfully produced by extrusion-cooking. Variable param- eters, like the initial moisture content of raw materials or screw speed during processing significantly affected the properties of the products. An understanding of the effects of processing conditions on some qualities of extruded instant gruels allows more desirable products to be created. Moreover, the various components can be used for extruded products for consumers on gluten-free diets. Functional additives incorporated in the recipe to improve the nutritional value of the extrudates, which will be investigated in our upcoming research.


A new technique of experimental heterotopic cardiac transplantation.
Heterotopic cardiac transplantation is a useful method for studying allograft rejection. In this study a new technique of cardiac transplantation was carried out, which involved retroperitoneal anastomoses of the donor ascending aorta and main pulmonary artery with the recipient abdominal aorta and inferior vena cava respectively. The procedure was simple and effective and was accomplished with minimal operative mortality and postoperative morbidity. The method allows better access to the allograft for repeated open myocardial biopsies, obviating the limitations of transvenous fluoroscopically directed endomyocardial biopsy. This technique of retroperitoneal heterotopic cardiac transplantation has important advantages compared with similar procedures performed in the neck, abdomen, or thorax.


Localization of sound presented via a spatial audio display during visually induced vection in pitch, roll, and yaw.
There is growing interest in the potential application of 3D audio displays to impart spatial information to aircraft pilots. As the aviation environment is dynamic, the effect on sound localization of the visual and vestibular stimulation resulting from motion during flight needs to be assessed. In this study, we investigated whether sound localization is affected by visual cues to self-motion. Participants localized bursts of broadband acoustic noise presented from the frontal hemifield under conditions of yaw, pitch, and roll vection (around the z-, y-, and x-axis, respectively) induced by wide-field visual motion of a projected sinusoidal grating. Lateral and elevation components of localization errors were measured. Average signed lateral and elevation errors were less than 1.6 degrees for all vection conditions. The effects of vection condition on lateral and elevation errors were not statistically significant. Also, the interactions between vection condition and sound-source location for these errors were not significant. The magnitudes of the 95% confidence intervals for the differences in lateral and elevation errors between the no-vection condition and each of the other vection conditions did not exceed 3 degrees. In the presence of visual cues to yawing, pitching, or rolling self-motion, the perception of auditory space is generally consistent with the available head-centered auditory cues to sound-source location. These results support the application of 3D audio displays in dynamic visual environments such as that experienced during flight.


The effects of glutamine on intestinal epithelial cell proliferation in parenterally fed rats.
Several papers have indicated that glutamine is a preferred fuel for the enterocyte and that it can increase intestinal epithelial cell proliferation. To investigate the effects of glutamine on intestinal epithelial cell proliferation in the parenterally fed rat. Five groups of six rats were fed parenterally; a group of orally fed rats was also studied. Crypt cell proliferation was studied after six days using native mitoses in microdissected crypts and bromodeoxyuridine labelling. No effect of treatment was seen on intestinal weight; however, the weights of the small intestine, caecum, and colon were all significantly heavier in the orally fed group than in the total parenteral nutrition groups (p<0.001). There was no effect of any of the glutamine treatments on mitotic activity in the small intestine. In the colon there was a small increase in native mitoses with glutamine (p=0.03). There was also an indication of increased proliferative activity in the first fifth of the small intestine and colon with glutamine. Little effect of glutamine on bromodeoxyuridine labelling in either site was observed, but there was a small but significant reduction in growth fraction of the colon of the glutamine treated group. The labelling distribution curve from sections and the mitotic distribution curve obtained from crypt squashes showed a good correlation. Glutamine has a small, but significant effect on mitotic activity but only in the colon. Modest effects on the distribution of labelled cells were also seen.


A variant of fibroblast growth factor receptor 2 (Fgfr2) regulates left-right asymmetry in zebrafish.
Many organs in vertebrates are left-right asymmetrical located. For example, liver is at the right side and stomach is at the left side in human. Fibroblast growth factor (Fgf) signaling is important for left-right asymmetry. To investigate the roles of Fgfr2 signaling in zebrafish left-right asymmetry, we used splicing blocking morpholinos to specifically block the splicing of fgfr2b and fgfr2c variants, respectively. We found that the relative position of the liver and the pancreas were disrupted in fgfr2c morphants. Furthermore, the left-right asymmetry of the heart became random. Expression pattern of the laterality controlling genes, spaw and pitx2c, also became random in the morphants. Furthermore, lefty1 was not expressed in the posterior notochord, indicating that the molecular midline barrier had been disrupted. It was also not expressed in the brain diencephalon. Kupffer's vesicle (KV) size became smaller in fgfr2c morphants. Furthermore, KV cilia were shorter in fgfr2c morphants. We conclude that the fgfr2c isoform plays an important role in the left-right asymmetry during zebrafish development.


Methods of measuring physical fitness.
Clinical pharmacology is in need of standarized test-methods for guaranteeing objective controls of therapeutic efficacy. In the field of cardiology, test methods had been created for electrocardiographic and special cardiologic examinations by Kaltenbach, Korkmann et al. For objectivating the therapeutic success in hypertension and orthostatic tolerancy, some regimens had been made and published in their journal, according to the test methods of Kirchhoff. This report is to discuss the criteria which show an assessment for the range and the limit of efficacy of functional circles and circular systems determining the efficiency.


A split-mouth study on microbiological profile in clinical healthy teeth and implants related to key inflammatory mediators.
This split-mouth study investigated the correlation of the qualitative and quantitative bacterial composition in dental plaque around clinically healthy periodontal and peri-implant subgingival sites with the levels of selected pro- and anti-inflammatory cytokines and the inflammatory infiltrate in the soft tissue surrounding a healthy dental implant and natural tooth in the same patient. Nine patients, all in good health and non-smokers, were studied. All of the patients were highly motivated in terms of oral hygiene and had healthy natural teeth and at least one healthy implant. After three sessions of professional oral care, clinical parameters were recorded. A sample of subgingival plaque was harvested with a sterile curette from the buccal side of the selected implants and teeth. The plaque samples were cultured to quantify the total microbiota and the number of obligate and facultative bacterial strains. Simultaneously, from the lingual/palatal aspect of the same implants and teeth the keratinized periodontal and peri-implant soft tissues were biopsied for cytokine expression and histomorphometric analysis. The tissue biopsies were halved: the real-time reverse transcriptase-polymerase chain reaction (PCR) was performed to detect active TNF-alpha, IL-1beta, IL-8, and TGF-beta2 and distribution, composition, quantification of inflammation were assessed in parallel. The patients harbored no periodontopathogens and the microbiological composition of the plaque taken from implant sites did not differ from that harvested from teeth. No significant differences were seen between implants and teeth for both proand anti-inflammatory cytokines. Even the histological examination showed no significant epithelial changes, although slight perivascular lymphocytic infiltration was seen in some biopsies.


Internally excited acoustic resonator for photoacoustic trace detection.
The quantum-cascade laser can be used as an infrared source for a small portable photoacoustic trace gas detector. The device that we describe uses a quantum-cascade laser without collimating optics mounted inside an acoustic resonator. The laser is positioned in the center of a longitudinal resonator at a pressure antinode and emits radiation along the length of the resonator exciting an axially symmetric longitudinal acoustic mode of an open-ended cylindrical resonator. Experiments are reported with an 8-microm, quasi-cw-modulated, room-temperature laser used to detect N2O.


SERI Surgical Scaffold as an Adjunct to Conventional Brachioplasty.
Although the popularity of longitudinal brachioplasty has grown tremendously in recent years, dealing with the unpredictable scar remains a challenge for the surgeon and the patient. The scar often heals slowly and widens over time, perpetuated by the effects of gravity, body movements, and the thin nature of the superficial fascial system (SFS) of the arm. Scar widening may correlate with recurrence of the soft-tissue deformity as the repaired underlying SFS stretches. Therefore, techniques that support and stabilize the SFS are highly desirable for addressing the problematic scar. In the present case, the author used a silk-derived surgical scaffold (SERI) as an adjunct to conventional brachioplasty. SERI provided the requisite support for the patient's SFS, resulting in a faster maturation process and a better-quality scar. This stands in stark contrast to the majority of longitudinal brachioplasty results reported in the medical literature.


A model for the evolution of paralog families in genomes.
We introduce and analyse a simple probabilistic model of genome evolution. It is based on three fundamental evolutionary events: gene loss, duplication and accumulated change. This is motivated by previous works which consisted in fitting the available genomic data into, what is called paralog distributions. This formalism is described by a system of infinite number of linear equations. We show that this system generates a semigroup of linear operators on the space l (1). We prove that size distribution of paralogous gene families in a genome converges to the equilibrium as time goes to infinity. Moreover we show that when probabilities of gene removal and duplication are close to each other, then the resulting distribution is close to logarithmic distribution. Some empirical results for yeast genomes are presented.


Multidisciplinary treatment for a patient with traumatically intruded permanent canine and premolar.
When selecting treatment for traumatically intruded teeth, various factors should be evaluated including the degree of intrusion, pulp vitality, patient's age and maturity of the tooth. Treatment options consist of surgical repositioning, orthodontic extrusion and spontaneous re-eruption. This study describes a case of a 22-year-old male with traumatically intruded maxillary canine and first premolar that was treated comprehensively by an orthodontist, endodontist and prosthodontist two months after injury.


Umbilical cord blood stem cell transplantation: current status and future prospects (1992).
Human umbilical cord and placental blood provide a rich source of hematopoietic stem cells. On the basis of this finding, umbilical cord blood stem cells (CBSCs) have been used to reconstitute hematopoiesis in children with malignant and nonmalignant diseases after treatment with myeloablative doses of chemoradiotherapy. Early results have been sufficiently encouraging to (1) embark on large-scale banking of cord blood for purposes of future autologous and allogeneic stem cell transplantation, (2) warrant studies of in vitro CBSC expansion, (3) initiate investigations of retroviral-mediated gene transfer into CBSCs for future gene therapy trials, and (4) justify the development of CBSC study groups in both Europe and the United States. This review briefly summarizes what is known about CBSCs in transplantation as well as potential future directions for this unique source of hematopoietic stem cells.


Most head injury related motorcycle crash deaths are related to poor riding practices.
To report the characteristics of head injury related motorcycle crash deaths. Motorcycle crash deaths with head injury (Abbreviated Injury Severity score > or = 2) between 1 January 1998 and 31 December 1999 were identified from the Western Australia State Coronial Database. Demographics, incident and death locations, type of incident and role of unsafe riding behaviour were examined. There were 39 deaths analysed (35 motorcycle riders and four pillion passengers). The median age was 29 years (range 9-64 years), with 22 deaths (56.4%) in the range 15-29 years and 92.3% of those killed being male. Twenty-one motorcycle crashes were single-vehicle crashes (53.8%). There were 25 deaths at scene (64.1%). Ethanol was implicated in 12 cases (30.8%) and other drugs were implicated in 11 cases (28.2%). Speeding was implicated in 12 cases (30.8%) and a lack of appropriate safety equipment was implicated in five cases (12.8%). One or more of the unsafe practices above was identified in 23 cases (59%). Overall, there was no difference in the rate of unsafe practices in single-vehicle incidents compared with incidents involving another vehicle (P = 0.342). Ethanol was associated with 10 single motorcycle incidents (47.6%) compared with two (11.1%) involving another vehicle (P = 0.018). Unsafe practices were involved in 76% of at-scene deaths, compared with 28.6% in those surviving to hospital (P = 0.007). A large proportion of head injury related motorcycle crash deaths are related to the unsafe behaviour of motorcyclists. A preventative campaign focusing on young male motorcycle riders and unsafe driving behaviour may reduce this death toll.


Upregulation of COX-2 and PGE2 Induced by TNF-α Mediated Through TNFR1/MitoROS/PKCα/P38 MAPK, JNK1/2/FoxO1 Cascade in Human Cardiac Fibroblasts.
Tumor necrosis factor-α (TNF-α) has been shown to exert as a pathogenic factor in cardiac fibrosis and heart failure which were associated with the up-regulation of cyclooxygenase (COX)-2/prostaglandin E2 (PGE2) axis. However, whether TNF-α-induced COX-2/PGE2 upregulation mediated through ROS-dependent cascade remains elusive in human cardiac fibroblasts (HCFs). This study aims to address the underlying mechanisms of TNF-α-induced COX-2/PGE2 expression. Here, we used TNF receptor neutralizing antibody (TNFR nAb), pharmacologic inhibitors, and siRNAs to dissect the involvement of signaling components examined by Western blot and ELISA in TNF-α-mediated responses in HCFs. MitoSOX Red was used to measure mitoROS generation. Isolation of subcellular fractions was performed to determine membrane translocation of PKCα. Promoter luciferase assay and chromatin immunoprecipitation (ChIP) assay were used to determine the role of transcription factor. We found that TNF-α time- and concentration-dependently upregulated COX-2 protein and mRNA expression as well as PGE2 synthesis which was attenuated by TNFR1 nAb, the inhibitor of mitochondrial ROS scavenger (MitoTEMPO), protein kinase C [(PKC)α, Gö6976], p38 MAPK [p38 inhibitor VIII, (p38i VIII)], JNK1/2 (SP600125), or forkhead box protein O1 [(FoxO1), AS1842856], and transfection with their respective siRNAs in HCFs. TNF-α-stimulated PKCα phosphorylation was inhibited by TNFR1 nAb, MitoTEMPO, or Gö6976. TNF-α stimulated phosphorylation of p38 MAPK and JNK1/2 was attenuated by TNFR1 nAb, MitoTEMPO, Gö6976, and their inhibitors p38i VIII and SP600125. Moreover, TNF-α-triggered FoxO1 phosphorylation was abolished by AS1842856, TNFR1 nAb, and its upstream inhibitors MitoTEMPO, Gö6976, p38i VIII, and SP600125. Phosphorylation of FoxO1 could enhance its interaction with the COX-2 promoter element revealed by ChIP assay, which was attenuated by AS1842856. Our results suggested that TNF-α-induced COX-2/PGE2 upregulation is mediated through TNFR1-dependent MitoROS/PKCα/p38 MAPK and JNK1/2 cascade to activate FoxO1 binding with the COX-2 promoter in HCFs.


Pushrim kinetics during advanced wheelchair skills in manual wheelchair users with spinal cord injury.
To assess the peak force during wheelchair propulsion of individuals with spinal cord injury propelling over obstacles from the Wheelchair Skills Test. Twenty-three individuals with spinal cord injury (SCI) who are full-time manual wheelchair users were included in this prospective study. A SmartWheel (Three Rivers Holdings, LLC) was used to analyze each push while subjects negotiated standardized obstacles used in the Wheelchair Skills Test, including tile, carpet, soft surface, 5° and 10° ramps, 2 cm, 5 cm, and 15 cm curbs. When the peak forces of the advanced skills were compared to level 10 m tile/10 m carpet, there was a statistically significant increase in all peak forces (P value ranged from .0001 to .0268). It is well documented that a large number of individuals with SCI develop upper limb pain. One of the recommendations to preserve the upper limb is to minimize force during repetitive tasks. Advanced wheelchair skills require an increase in force to accomplish. The increase in forces ranged from 18% to 130% over that required for level 10 m tile/10 m carpet.


Endocrine dysfunction in chronic renal failure.
The kidney has a central role in producing and metabolizing a variety of hormones. In addition, chronic renal failure results in alterations in the internal milieu that affects the synthesis and secretory rate of hormones as well as causing alterations of hormone effects on target tissue. Our review highlights the alterations in endocrine function that develop in patients with uremia. Special emphasis is placed on the diagnostic and therapeutic quandaries posed by these alterations in endocrine function.


Deconstructing green fluorescent protein.
Green fluorescent protein (GFP) has been reassembled from two pieces, a large fragment 214 amino acids in length that is produced recombinantly (GFP 1-10) and a short synthetic peptide corresponding to the 11th stave of the beta-barrel that is 16 amino acids long (synthetic GFP 11), following a system developed by Waldo and co-workers (Cabantous, S.; et al. Nat. Biotechnol. 2005, 23, 102-7) as an in vivo probe for protein association and folding. We demonstrate that the reassembled protein has identical absorption and excited-state proton transfer dynamics as a whole protein of the identical sequence. We show that the reassembled protein can be taken apart and the peptide replaced with a different synthetic peptide designed to perturb the chromophore absorption. Thus, this semisynthetic reassembly process offers a general route for studying the assembly of the beta-barrel as well as the introduction of unnatural amino acids.


Review of the impact of water quality on reliable laboratory testing and correlation with purification techniques.
In recent years, many rapid and automated instruments with highly complex testing methodologies have been introduced to our laboratories, almost all of which require the use of water. Many investigators have discussed the impact of water quality on the accuracy and reliability of clinical laboratory testing and technologies. Evaluation of water quality and specifications according to international standards and guidelines has helped laboratories to judge water quality before using the water in question as part of testing. In the past few years, dramatic introduction of different water purification technologies has shown significant improvements in laboratory testing accuracy. In this review, we delve into the intricate factors that influence water quality.


How to measure community tolerance levels for noise.
Relationships between noise exposure and transportation noise induced annoyance have been studied extensively for several decades. The annoyance due to aircraft noise exposure is in the present paper assumed to be influenced by the day-night yearly average sound level (DNL). It has long been recognized that the annoyance also depends on non-DNL factors, but this is complicated-resulting in a variety of different modeling strategies. Motivated by this, the community tolerance level (CTL) was introduced in 2011 for a loudness-based psychometric function. It is a single parameter that accounts for the aggregate influence of other factors. This paper suggests and investigates different methods for the measurement of the CTL. The methods are illustrated on data found in the literature, on recent surveys around two Norwegian airports, and on simulated data. The results from the presented methods differ significantly. An elementary method is shown to give a measurement of the CTL with smaller uncertainty, and is recommended as a replacement for the originally suggested least-squares method. Methods for evaluating the measurement uncertainty are also presented.


The use of nonsteroidal anti-inflammatory drugs in critically ill horses.
To review the physiology of the cyclooxygenase (COX) enzymes with reference to the beneficial effects of nonsteroidal anti-inflammatory drugs (NSAIDs) related to their analgesic and antiendotoxic properties as well as the mechanisms responsible for adverse gastrointestinal, renal, and coagulation effects. Human and veterinary peer reviewed literature NSAIDs are frequently administered to critically ill horses for their analgesic and anti-inflammatory effects. However, NSAIDs have significant side effects principally on the gastrointestinal mucosa and kidneys. These side effects may be exacerbated in critically ill horses if they have gastrointestinal damage or are volume depleted This review provides important information for equine veterinarians and criticalists on the advantages and disadvantages of using traditional NSAIDs and newer equine COX-2 selective NSAIDs for the management of different conditions in critically ill horses.


The effectiveness of exercise therapy for ankylosing spondylitis: a review.
Exercise therapy is an important component of current standard therapy for patients with ankylosing spondylitis. The purpose of this review is to provide important guidelines when prescribing exercises by reviewing articles evaluating the effectives and usefulness of exercise therapy in patients with ankylosing spondylosis.


Human T-lymphotropic virus 2 (HTLV-2) prevalence of blood donors in the state of Pará, Brazil.
The present study had the objective to describe the molecular prevalence and epidemiological aspects of the human T-lymphotropic virus 2 (HTLV-2) infection in the blood donor population of the Pará state. The present study is a descriptive, retrospective, and cross-sectional review of epidemiological, serological, and molecular data on inapt blood donors in the State Center for Hematology and Hemotherapy from January 2015 to December 2021. The data were digitalized to create a database using the Statistical Package for Social Sciences program. The prevalence of HTLV-2 was calculated based on the total number of donations during the study period. Descriptive frequency was used to analyze the qualitative data. A total of 665,568 blood donations were made. Out of these, 1884 (0.2%) samples presented serological detection to HTLV and further were evaluated using molecular confirmatory tests. Out of these, 36 samples were positive for HTLV-2 using qPCR Taqman assay based on pol gene region (0.005%). The HTLV-2 was found to be more prevalent in women (63.9%); aged between 39 and 59 years (55.6%); residents of the metropolitan region of Belém (80.6%); with self-declared race as brown (80.6%); individuals who had completed high school (58.6%); and first-time donors (58.3%) CONCLUSION: The present study identified the presence of HTLV-2 (1 HTLV-2 case/20,000 donations; 0.005%) in the specific population of blood donors in Pará state. These findings can contribute to the existing literature on the subject both for specific population groups under study and for understanding the prevalence of HTLV-2 in the general population.


SEQUENTIAL TESTING OF MEASUREMENT ERRORS IN INTER-RATER RELIABILITY STUDIES.
Inter-rater reliability is usually assessed by means of the intraclass correlation coefficient. Using two-way analysis of variance to model raters and subjects as random effects, we derive group sequential testing procedures for the design and analysis of reliability studies in which multiple raters evaluate multiple subjects. Compared with the conventional fixed sample procedures, the group sequential test has smaller average sample number. The performance of the proposed technique is examined using simulation studies and critical values are tabulated for a range of two-stage design parameters. The methods are exemplified using data from the Physician Reliability Study for diagnosis of endometriosis.


How does melatonin control seasonal reproductive cycles?
The pineal gland is essential for the perception of photoperiod change in many species. Information about photoperiod length is conveyed through pineal secretion of the methoxyindole melatonin. Melatonin, suitably administered in physiological quantities is equipotent with artificial photoperiod in the induction of photoperiodic responses. Most experimental work suggests that it is the duration of high night time melatonin secretion (positively correlated with the length of the natural or artificial dark phase) which conveys the photoperiodic signal. Continuous release implants induce short day effects in ewes, entirely comparable to daily feeding of melatonin or short photoperiod. A minimum duration of secretion rather than a specific duration is therefore probably critical to short day effects. There appears to be a seasonal variation in sensitivity to short day melatonin effects (induction of early oestrus) which can be shifted to an earlier time of year following one oestrus advance the previous year. Short duration melatonin is read as a long day even secreted with 22 hour periodicity, suggesting a lack of circadian variation in sensitivity to melatonin.


AZP2006, a new promising treatment for Alzheimer's and related diseases.
Progranulin (PGRN) is a protein with multiple functions including the regulation of neuroinflammation, neuronal survival, neurite and synapsis growth. Although the mechanisms of action of PGRN are currently unknown, its potential therapeutic application in treating neurodegenerative diseases is huge. Thus, strategies to increase PGRN levels in patients could provide an effective treatment. In the present study, we investigated the effects of AZP2006, a lysotropic molecule now in phase 2a clinical trial in Progressive Supranuclear Palsy patients, for its ability to increase PGRN level and promote neuroprotection. We showed for the first time the in vitro and in vivo neuroprotective effects of AZP2006 in neurons injured with Aβ1-42 and in two different pathological animal models of Alzheimer's disease (AD) and aging. Thus, the chronic treatment with AZP2006 was shown to reduce the loss of central synapses and neurons but also to dramatically decrease the massive neuroinflammation associated with the animal pathology. A deeper investigation showed that the beneficial effects of AZP2006 were associated with PGRN production. Also, AZP2006 binds to PSAP (the cofactor of PGRN) and inhibits TLR9 receptors normally responsible for proinflammation when activated. Altogether, these results showed the high potential of AZP2006 as a new putative treatment for AD and related diseases.


[Expression of goat follicle-stimulating hormone analogous gene in Pichia pastoris].
In order to obtain the long-acting FSH preparation, the single strand long-acting analogous gene FSHbeta-CTP-alpha was successfully constructed by the C-terminal peptide(CTP) of carboxyl-terminal region of human chorionic gonadotropin with the goat FSHalpha-subunit and beta-subunit genes, then it was inserted into pPIC9K vector. The recombinant plasmid pPIC9K FSHbeta-CTP-alpha was transformed into Pichia pastoris GS115 by electroporation. The multi-copy inserts His+Mut+ were gained by the screening of phenotype and hyper-resistance to G418. After methanol induction, the supernatant was analysised by SDS-Polyacrylamide Gen Electrophoresis and Western blot. The results show that the transformants of FSHbeta-CTP-alpha could express the objective protein successfully and the molecular weight is about 29 kD. The concentration of supernatant was detected by Radio-immunoassay and the average expression of multi-inserts is 91.849 mIU/mL and the low-inserts is 37.419 mIU/mL. The expression of multi-inserts is higher than the low-inserts significantly. This research lay the foundation for studying the structure of FSH and the production of long-acting FSH preparation.


Effect of atorvastatin on hematologic parameters in patients with hypercholesterolemia.
Hematologic parameters such as mean platelet volume (MPV), red cell distribution width (RDW), and neutrophil to lymphocyte (N/L) ratio are associated with increased cardiovascular risk. We investigated the effect of atorvastatin on hematologic parameters in patients with hypercholesterolemia. A total of 79 patients with hypercholesterolemia and 47 normocholesterolemic healthy participants were included. Patients with hypercholesterolemia received 10 to 80 mg/d atorvastatin during a 24-week period. Hematologic parameters were measured at baseline and after 6 months. Atorvastatin treatment produced a significant decrease in MPV levels (9.3 ± 1.3 vs 9.1 ± 1.2 fL, P = .008) and platelet count (259 ± 61 vs 248 ± 51 10(9)/L, P = .005). The N/L ratio decreased significantly after atorvastatin treatment from 2.9 ± 1.2 to 2.6 ± 1.1, (P = .014). The RDW and platelet distribution width levels were not different among the study groups, before and after treatment. Atorvastatin may beneficially reduce MPV levels and N/L ratio. This antiplatelet and anti-inflammatory effect of atorvastatin treatment could play a role in reducing cardiovascular risk.


Interposition arthroplasty in post-traumatic temporomandibular joint ankylosis: A retrospective study.
Temporomandibular joint ankylosis which is most frequently caused by trauma, presents with restriction in mouth opening in early stages and if children are the victim and not treated early, it presents with growth retardation of the involved mandibular side. Various methods are available for surgical correction. We have reviewed our experience with the efficacy of different interpositional materials in post-traumatic cases in our set up with special reference to temporal fascia over last three years. Twenty seven patients with history of trauma, mostly fall from height, have been studied. They were evaluated clinically and by computed tomography (CT) scan, orthopantogram and x- ray lateral oblique view. The most common age group was 10-15 years with mean 12.5 years and male to female ratio 1:2. Preoperative mouth opening (inter incisor distance) was 1-2 mm in 17 cases and 2-4 mm in 10 cases. We have used temporalis fascia in nine, costochondral graft in seven, silastic sheets in five and T-plates in six cases. Post-operatively, adequate mouth opening of 30-50 mm was observed in six months follow-up and more than 50 mm at one year follow up in 21 cases out of which nine cases have interpositional material as temporalis fascia alone. The postoperative period was uneventful in all cases and none required re-operation for recurrences. We conclude that interpositional arthroplasty, especially with pedicled temporal fascia, is the best method to prevent recurrences and establish good mouth opening and full range of jaw movements.


Spectroscopic Techniques using Synchrotron Radiation and Free-Electron and Conventional Lasers.
Considerable progress in the investigation of the electronic and vibrational properties of atoms, molecules, materials, surfaces and interfaces has been achieved by combining different photon sources of complementary characteristics. In this paper some experimental results obtained recently at LURE by using two synchronized sources, such as the IR free-electron laser (FEL) CLIO, the VUV storage ring FEL, synchrotron radiation and table lasers, are presented. Using CLIO synchronized with a YAG laser allows the investigation of the vibrational properties of adsorbed species by the non-linear optical technique of visible-IR sum (difference) frequency generation, as shown for the adsorption of hydrogen on platinum in the electrochemical environment. The second result reported here relates to the study of the intersubband stimulated emission in GaAs/GaAlAs quantum wells by pump-probe experiments using the two-colour configuration of CLIO. The combination of a mode-locked Ar(+) laser and synchrotron radiation has been used for investigations in a pump-probe arrangement of the ionization of Xe atoms via the resonant state Xe* 5p(5)5d [3/2](1). The final example is a time-resolved core-level spectroscopy study of photoexcited Si(111) 2 x 1 surfaces by using a combination of the naturally synchronized UV storage ring laser and synchrotron radiation.


Picroside Ⅱ inhibits hypoxia/reoxygenation-induced cardiomyocyte apoptosis by ameliorating mitochondrial function through a mechanism involving a decrease in reactive oxygen species production.
Reactive oxygen species (ROS)‑induced mitochondrial dysfunction plays an important role in cardiomyocyte apoptosis during myocardial ischemia/reperfusion (I/R) injury. Picroside Ⅱ, isolated from Picrorhiza scrophulariiflora Pennell (Scrophulariaceae), has been reported to protect cardiomyocytes from hypoxia/reoxygenation (H/R)‑induced apoptosis, but the exact mechanism is not fully clear. The aim of the present study was to explore the protective effects of picroside Ⅱ on H/R‑induced cardiomyocyte apoptosis and the underlying mechanism. In the H9c2 rat cardiomyocyte cell line, picroside Ⅱ (100 µg/ml) was added for 48 h prior to H/R. The results showed that picroside Ⅱ markedly inhibited H/R‑induced cardiomyocyte apoptosis. In addition, picroside Ⅱ was also able to decrease the opening degree of mitochondrial permeability transition pore (mPTP), increase the mitochondrial membrane potential, inhibit cytochrome c release from mitochondria to cytosol and downregulate caspase‑3 expression and activity concomitantly with the decreased ROS production. These results suggested that picroside Ⅱ inhibited H/R‑induced cardiomyocyte apoptosis by ameliorating mitochondrial function through a mechanism involving a decrease in ROS production.


[Fine needle aspiration cytology of thyroid nodules: a cytopathologic study of 2 043 cases].
To evaluate the clinical value of thyroid fine needle aspiration cytology(FNAC) and the Bethesda system for reporting thyroid cytopathology(TBSRTC). FNAC was performed for 2 043 cases and cytopathological data were retrospectively analyzed. Cytopathological diagnoses according to TBSRTC were classified as non-diagnostic, benign, atypia of undetermined significance/follicular lesion of undetermined significance(AUS/FLUS), follicular neoplasm/suspicious for follicular neoplasm(FN/SFN), suspicious for malignancy(SM) and malignancy. The results of 234 FNAC samples in which surgery was performed were compared with the histological diagnoses. Of the 2 043 FNAC samples, 15.7%(320/2 043)were non-diagnostic, 51.2%(1 047/2 043)were benign, 16.6%(339/2 043) were AUS/FLUS, 2.3%(46/2 043)were FN/SFN, 8.6%(176/2 043)were SM and 5.6%(115/2 043)were malignant. In 234 cases, there was follow-up histology. Rates of malignancy were as follows: non-diagnostic, 18.2%(2/11); benign(2.2%, 1/45); AUS/FLUS(25.6%, 10/29); FN/SFN(12.1%, 10/39); SM(91.8%, 56/61); malignant(100.0%, 45/45). The sensitivity, specificity, false positive rate, false negative rate and overall accuracy of FNAC in the diagnosis of thyroid nodules was 87.1%(101/116), 95.3%(102/107), 4.7%(5/107), 12.9%(15/116), 91.0%(203/223). FNAC is a reliable diagnostic method for evaluation of thyroid disease. TBSRTC is a accurate and effective reporting system for cytopathological diagnoses, so it is worthy of being widely popularized in clinical application.


Fm1-43 reveals membrane recycling in adult inner hair cells of the mammalian cochlea.
Neural transmission of complex sounds demands fast and sustained rates of synaptic release from the primary cochlear receptors, the inner hair cells (IHCs). The cells therefore require efficient membrane recycling. Using two-photon imaging of the membrane marker FM1-43 in the intact sensory epithelium within the cochlear bone of the adult guinea pig, we show that IHCs possess fast calcium-dependent membrane uptake at their apical pole. FM1-43 did not permeate through the stereocilial mechanotransducer channel because uptake kinetics were neither changed by the blockers dihydrostreptomycin and d-tubocurarine nor by treatment of the apical membrane with BAPTA, known to disrupt mechanotransduction. Moreover, the fluid phase marker Lucifer Yellow produced a similar labeling pattern to FM1-43, consistent with FM1-43 uptake via endocytosis. We estimate the membrane retrieval rate at approximately 0.5% of the surface area of the cell per second. Labeled membrane was rapidly transported to the base of IHCs by kinesin-dependent trafficking and accumulated in structures that resembled synaptic release sites. Using confocal imaging of FM1-43 in excised strips of the organ of Corti, we show that the time constants of fluorescence decay at the basolateral pole of IHCs and apical endocytosis were increased after depolarization of IHCs with 40 mm potassium, a stimulus that triggers calcium influx and increases synaptic release. Blocking calcium channels with either cadmium or nimodipine during depolarization abolished the rate increase of apical endocytosis. We suggest that IHCs use fast calcium-dependent apical endocytosis for activity-associated replenishment of synaptic membrane.


Testosterone for low libido in postmenopausal women?
Use of testosterone in older woman with hypoactive sexual-desire disorder (HSDD) is controversial. One concern about existing testosterone therapies for HSDD is the common recommendation to concomitantly administer estradiol because of the known risks of such therapy in postmenopausal women. This large, year-long, double-blind, placebo-controlled trial of testosterone therapy in postmenopausal women examined the hypothesis that testosterone alone would be efficacious in improving HSDD. The results of this trial confirm the improvement in sexual function for postmenopausal women seen in earlier studies using testosterone in combination with estradiol, implying that estradiol administration may not be essential for the beneficial effects of testosterone. However, this study raised some concerns regarding testosterone therapy on the risk of breast and endometrial cancer, highlighting the need for further long-term trials to better assess the long-term safety of this approach for the treatment of HSDD in women.


Hyperthermia-induced cardiac arrest in monkeys: limited efficacy of standard CPR.
Successful resuscitation from heatstroke cardiopulmonary arrest has been only partially explored and the data covering the post resuscitation pathophysiology leading to secondary arrest is, in most cases, insufficient. Following heatstroke-cardiopulmonary arrest, successful resuscitation may be achieved by standard CPR with surface cooling and administration of glucose. We ponder the sequence of early circulatory responses and the pathophysiological changes following successful resuscitation. We exposed 12 pigtail monkeys to total-body hyperthermia (cerebral T 42 degrees C) until cardiac arrest ensued. Standard external CPR with surface cooling and glucose 5% IV were administered for up to 30 min. Control group A (n = 6) was compared with experimental group B (n = 6), which received additional steroid, glucagon and hypertonic glucose during CPR attempts. No significant differences were found between the outcome of the two groups. The 30-min CPR attempt succeeded in restoration of spontaneous circulation (ROSC) in 8/12 monkeys-5 animals from group A and 3 in group B. The animals in whom resuscitation was unsuccessful had significantly prolonged periods of rectal temperature exceeding 42.5 degrees C (p < 0.05), and significantly higher rectal temperatures at the end of 30 min of CPR and cooling (p < 0.05). All the resuscitated animals later rearrested at 158 +/- 68 (95-228) min after ROSC; pulmonary edema occurred in 6/8 animals. We conclude that experimentally-induced heatstroke can be transiently reversed by standard resuscitative procedures, but is followed by a delayed, irreversible, secondary shock state, which could not be prevented by the treatment we employed. We were, however, able to document in detail the pathophysiologic processes involved in the resuscitation, and the irreversible shock one sees after "successful" CPR.


RALA-mediated delivery of FKBPL nucleic acid therapeutics.
RALA is a novel 30 mer bioinspired amphipathic peptide that is showing promise for gene delivery. Here, we used RALA to deliver the FK506-binding protein like - FKBPL gene (pFKBPL) - a novel member of the immunophilin protein family. FKBPL is a secreted protein, with overexpression shown to inhibit angiogenesis, tumor growth and stemness, through a variety of intra- and extracellular signaling mechanisms. We also elucidated proangiogenic activity and stemness after utilizing RALA to deliver siRNA (siFKBPL). The RALA/pFKBPL and RALA/siFKBPL nanoparticles were characterized in terms of size, charge, stability and toxicity. Overexpression and knockdown of FKBPL was assessed in vitro and in vivo. RALA delivered both pFKBPL and siFKBPL with less cytotoxicity than commercially available counterparts. In vivo, RALA/pFKBPL delivery retarded tumor growth, and prolonged survival with an associated decrease in angiogenesis, while RALA/siFKBPL had no effect on tumor growth rate or survival, but resulted in an increase in angiogenesis and stemness. RALA is an effective delivery system for both FKBPL DNA and RNAi and highlights an alternative therapeutic approach to harnessing FKBPL's antiangiogenic and antistemness activity.


Status of the diagnostics development for the first operation phase of the stellarator Wendelstein 7-X.
An overview of the diagnostics which are essential for the first operational phase of Wendelstein 7-X and the set of diagnostics expected to be ready for operation at this time are presented. The ongoing investigations of how to cope with high levels of stray Electron Cyclotron Resonance Heating (ECRH) radiation in the ultraviolet (UV)/visible/infrared (IR) optical diagnostics are described.


Cadmium sulphide (CdS) nanotechnology: synthesis and applications.
Over the past few years there has been sustained interest in the synthesis, characterization and application of cadmium sulphide (CdS) nanostructures such as nanoparticles, nanowires, nanobelts, nanospheres. The history of CdS, more recent advances in the chemistry and synthesis of CdS nanostructures, and their application as nanoscale devices in diverse technology areas from electronics to targeted drug delivery is described. Although the focus is on CdS, the review provides an excellent overview of the materials, methods, processes and promising solutions that are emerging.


Pilot study compares scores of the Resident Assessment Instrument Minimum Data Set Version 2.0 (MDS 2.0) Pressure Ulcer Risk Scale with the Braden Pressure Ulcer Risk assessment for patients in complex continuing care.
To determine if the Braden Scale for Predicting Pressure Sore Risk (Braden Scale) and the Resident Assessment Instrument Minimum Data Set Version 2.0 (MDS 2.0) Pressure Ulcer Risk Scale (PURS) provide a comparable assessment of the level of risk of developing a pressure ulcer at admission in complex continuing care. Saint-Vincent Hospital, Bruyère Continuing Care, a 336-bed complex continuing care facility that provides restorative, complex, specialized, and supportive care to adults in Ottawa, Ontario, Canada. A retrospective chart review was conducted from February 2012 to April 2012 on 51 patient charts that were chosen based on the completion of an admission Braden Scale assessment within a maximum of 4 weeks from admission and completed admission MDS 2.0. The Braden Scale categorized 63% of patients at risk when using scores between 15 and 23, compared with 33% for the MDS 2.0 PURS scores of 0-2 (low and very low risk). Both scales were comparable in identifying patients in the lower risk categories when data was reviewed using a cutoff point of 18 for the Braden. At the high risk end of the spectrum, the MDS 2.0 PURS categorized more patients, 45%, as high or very high risk, compared with 21% for using the Braden Scale. This preliminary study may provide some evidence that the MDS 2.0 PURS may be an alternative risk assessment tool option that utilizes mandatory collected data, reduces workload duplication, and would generate a Resident Assessment Protocol, when indicated, in complex continuing care.


[Clinical characteristics of methicillin-resistant Staphylococcus aureus in phlegm specimens].
To investigate the clinical characteristics of methicillin-resistant Staphylococcus aureus (MRSA) in phlegm specimens of positive patients, so as to provide evidences for the nosocomial infection control. We retrospectively analyzed the clinical data of 211 hospitalized patients who were MRSA-positive in their phlegm specimens in PUMC Hospital from January 2005 to October 2007. Among the 211 patients, 196 (92.9%) had received antibiotics three months before the detection of MRSA, and 128 (60.7%) had received more than three antibiotics. Over 90% of MRSA were resistant to levofloxacin, erythromycin, clindamycin, and gentamicin, and 73.9% were resistant to rifampicin. Improper use of antibiotics should be avoided. Vancomycin is the first choice for MRSA treatment.


Cardiac Resynchronization Therapy in Inotrope-Dependent Heart Failure Patients: A Systematic Review and Meta-Analysis.
The purpose of this study was to evaluate outcomes after cardiac resynchronization therapy (CRT) in inotrope-dependent patients with heart failure (HF) to ascertain the viability of CRT in these patients. During the last decade, significant numbers of trials have demonstrated the beneficial effect of CRT in the treatment of patients with HF and systolic dysfunction, prolonged QRS complex duration, and New York Heart Association functional class III or IV. However, it is currently undetermined whether CRT may benefit patients who require inotropic support. The authors systematically searched Medline, Embase, Scopus, and the Cochrane Library through March 2017 for studies evaluating outcomes after CRT in inotrope-dependent patients with HF. The study analyzed 8 studies including 151 patients. Most of the patients were in New York Heart Association functional class IV (80.1%), and all had severe systolic HF, with a left ventricular ejection fraction <30% and a significant intraventricular conduction delay in their surface electrocardiogram (QRS complex duration >130 ms). The pooled analysis demonstrated that 93% of the reported patients (95% confidence interval: 86% to 100%) were weaned from inotropic support after CRT, and the overall 12-month survival rate was 69% (95% confidence interval: 56% to 83%). This study suggests that rescue CRT may be considered a viable therapeutic option in inotrope-dependent patients with HF. In these patients, rescue CRT may allow them to be weaned from inotropic therapy, improve their quality of life, and decrease the rate of mortality; furthermore, rescue CRT may serve as a possible bridge to cardiac transplantation or left ventricular assist device therapy.


Sarcomatoid carcinoma of the gallbladder: a case report.
Sarcomatoid carcinoma is a rare type of gallbladder cancer with no specific clinical manifestation. The final diagnosis depends on pathological and immunohistochemical examination. Sarcomatoid carcinoma is characterized by early lymphatic metastasis, rapid progression, a high short-term recurrence rate, and a worse prognosis than adenocarcinoma. This report describes a 60-year-old woman with poorly differentiated adenocarcinoma of the gallbladder. She underwent treatment with chemotherapy and surgery. Palliative surgery was performed for treatment of tumor recurrence in April 2018. Postoperative pathology showed infiltration of poorly differentiated carcinomas, most of which were sarcomatoid. After four cycles of chemotherapy, the disease continued to progress. Anlotinib tablets were given from August 2018 to November 2018 but were then stopped because of gastrointestinal bleeding. The patient died in April 2019. This paper reports the whole process of diagnosis and treatment in this case of gallbladder sarcomatoid carcinoma, thus providing a reference for treatment.


Insulin receptor kinase activation releases a constraint maintaining the receptor on microvilli.
To examine whether the surface redistribution of the insulin receptor from microvilli, where it sits in its unoccupied form, to the nonvillous domain, where it is internalized through clathrin-coated pits, is an active movement or a passive redistribution linked to the release of a restraint maintaining it on microvilli, we have generated a mutated insulin receptor with a truncation of exons 17-22 and tracked it biochemically and morphologically. Biochemical analysis indicates that this mutated receptor is constitutively internalized and recycled even in the absence of ligand. Quantitative electron microscope autoradiography analysis reveals that it does not preferentially associate with microvilli in its unoccupied form but is normally segregated in clathrin-coated pits through the preserved signal sequence(s) of exon 16. We conclude that (a) insulin receptor internalization initiated through receptor kinase activation and autophosphorylation, which free the receptor from constraints maintaining it on microvilli; (b) the signal sequences contained in exon 16 are entirely sufficient to promote clathrin-coated pit-mediated internalization of insulin receptors; (c) these sequences are not uncovered by kinase activation; and (d) the "code" maintaining the unoccupied receptors on microvilli is contained within exons 17-21 of the receptor.


Papillary thyroid carcinoma managed at the Mayo Clinic during six decades (1940-1999): temporal trends in initial therapy and long-term outcome in 2444 consecutively treated patients.
It is uncertain whether more extensive primary surgery and increasing use of radioiodine remnant ablation (RRA) for papillary thyroid carcinoma (PTC) have resulted in improved rates of cause-specific mortality (CSM) and tumor recurrence (TR). Details of the initial presentation, therapy, and outcome of 2444 PTC patients consecutively treated during 1940-1999 were recorded in a computerized database. Patients were followed for more than 43,000 patient-years. The 25-year rates for CSM and TR were 5% and 14%, respectively. Temporal trends were analyzed for six decades. During the six decades, the proportion with initial MACIS (distant Metastasis, patient Age, Completeness of resection, local Invasion, and tumor Size) scores <6 were 77%, 82%, 84%, 86%, 85%, and 82%, respectively (p = 0.06). Lobectomy accounted for 70% of initial procedures during 1940-1949 and 22% during 1950-1959; during 1960-1999 bilateral lobar resection (BLR) accounted for 91% of surgeries (p <0.001). RRA after BLR was performed during 1950-1969 in 3% but increased to 18%, 57%, and 46% in successive decades (p <0.001). The 40-year rates for CSM and TR during 1940-1949 were significantly higher (p = 0.002) than during 1950-1999. During the last 50 years the 10-year CSM and TR rates for the 2286 cases did not significantly change with successive decades. Moreover, the 10-year rates for CSM and TR were not significantly improved during the last five decades of the study, either for the 1917 MACIS <6 patients or the 369 MACIS < 6 patients. Increasing use of RRA has not apparently improved the already excellent outcome, achieved before 1970, in low risk (MACIS <6) PTC patients managed by near-total thyroidectomy and conservative nodal excision.


Intraductal tubulopapillary neoplasm accompanied by invasive carcinoma of the pancreas: A case report and review of the literature.
Intraductal tubulopapillary neoplasms (ITPNs) are rare pancreatic neoplasms accounting for ~0.4% of pancreatic tumors. However, their clinicopathological characteristics have not been clearly determined and the number of available clinical studies on this type of tumor is limited at present. Due to the rare incidence of ITPN, diagnosis is often delayed. We herein present a unique case of a 38-year-old man who was diagnosed with ITPN accompanied with invasive carcinoma of the pancreas and underwent total pancreatectomy. The morphological characteristics of ITPN include closely packed tubular glands, without mucin secretion, accompanied with invasion of the loose connective tissue. The immunohistochemical staining suggested that the tumors did not originate from the gastrointestinal tract but rather from the bile duct. In addition, the Ki-67 positive staining rate of tumor cells was <20%. The microsatellite instability analysis demonstrated microsatellite stability, without detected gene mutations of epidermal growth factor receptor, Kirsten rat sarcoma viral oncogene homolog, neuroblastoma RAS viral oncogene homolog or B-Raf proto-oncogene. However, a mutation was identified in exon 9 of the P53 gene, the most frequently mutated gene in human cancer, which suggested the underlying mechanism of ITPN. On the basis of this case, the aim of this study was to summarize and review the relevant reports of ITPNs in recent years, in order to investigate the clinicopathological characteristics and differential diagnosis of ITPN.


Genome-Wide Identification of MADS-Box Genes in Taraxacum kok-saghyz and Taraxacum mongolicum: Evolutionary Mechanisms, Conserved Functions and New Functions Related to Natural Rubber Yield Formation.
MADS-box transcription regulators play important roles in plant growth and development. However, very few MADS-box genes have been isolated in the genus Taraxacum, which consists of more than 3000 species. To explore their functions in the promising natural rubber (NR)-producing plant Taraxacum kok-saghyz (TKS), MADS-box genes were identified in the genome of TKS and the related species Taraxacum mongolicum (TM; non-NR-producing) via genome-wide screening. In total, 66 TkMADSs and 59 TmMADSs were identified in the TKS and TM genomes, respectively. From diploid TKS to triploid TM, the total number of MADS-box genes did not increase, but expansion occurred in specific subfamilies. Between the two genomes, a total of 11 duplications, which promoted the expansion of MADS-box genes, were identified in the two species. TkMADS and TmMADS were highly conserved, and showed good collinearity. Furthermore, most TkMADS genes exhibiting tissue-specific expression patterns, especially genes associated with the ABCDE model, were preferentially expressed in the flowers, suggesting their conserved and dominant functions in flower development in TKS. Moreover, by comparing the transcriptomes of different TKS lines, we identified 25 TkMADSs related to biomass formation and 4 TkMADSs related to NR content, which represented new targets for improving the NR yield of TKS.


Blood pressure-lowering effects of incretin-based diabetes therapies.
Glucagon-like peptide-1 receptor (GLP-1) agonists and dipeptidyl-peptidase-4 (DPP-4) inhibitors are therapies that are used to treat hyperglycemia in patients with type 2 diabetes mellitus. Although both of these medication types primarily lower prandial and fasting blood glucose levels by enhanced GLP-1 receptor signalling, they have distinct mechanisms of action. Whereas DPP-4 inhibitors boost patient levels of endogenously produced GLP-1 (and glucose-dependent insulinotropic peptide) by preventing its metabolism by DPP-4 enzymatic activity, GLP-1 receptor agonists are either synthetic analogues of human GLP-1 or exendin-4 based molecules. They are tailored to resist hydrolysis by DPP-4 activity and to provide longer durability in the circulation compared with native GLP-1. Several roles for incretin-based diabetes therapies beyond the endocrine pancreas and their glycemic-lowering properties have now been described, including attenuation of cardiac myocyte injury and reduction in post-ischemic infarction size after cardiovascular insult. Favourable outcomes have also been observed on systolic blood pressure reduction, postprandial intestinal lipoprotein metabolism, endothelial cell function, modulation of innate immune-mediated inflammation and surrogate markers of renal function. As hypertension is an independent risk factor for premature death in patients with type 2 diabetes, potential favourable extrapancreatic actions, particularly within the heart, blood vessels and kidney, for this drug class are of considerable clinical interest. Herein, we highlight and provide critical appraisal of the clinical data supporting the antihypertensive effects of GLP-1 receptor agonists and DPP-4 inhibitors and link possible mechanisms of action to clinical outcomes reported for this drug class.


The medial pneumothorax.
The intrapleural air of a pneumothorax may largely collect medial to the anterior aspect of the lung in supine infants. The mechanical basis for this phenomenon is presented with supporting experimental evidence. This distribution of intrapleural air poses problems in recognition of the pneumothorax radiographically, in differentiation of the pneumothorax from pneumomediastinum, in estimation of the true volume of intrapleural air, and in the proper placement of drainage tubes. The importance of horizontal-beam lateral radiographs and of careful attention to the position of intrapleural tubes is emphasized, especially in supine, immobile newborns.


Sex-Specific Effects of Respiratory Muscle Endurance Training on Cycling Time Trial Performance in Normoxia and Hypoxia.
Objectives: We tested the hypotheses that respiratory muscle endurance training (RMET) improves endurance cycling performance differently in women and men and more so in hypoxia than in normoxia. Design: A prospective pre-post cross-over study with two testing conditions. Methods: Healthy and active women (seven, 24 ± 4 years, mean ± standard deviation [SD]) and men (seven, 27 ± 5 years) performed incremental cycling to determine maximum oxygen consumption (VO2peak) and power output (Wpeak) and on different days two 10-km cycling time trials (TTs) in normoxia and normobaric hypoxia (FiO2, 0.135, ~3,500 m equivalent), in a balanced randomized order. Next they performed supervised RMET in normoxia (4 weeks, 5 days/week, 30 min/day eucapnic hyperpnea at ~60% predicted maximum voluntary ventilation) followed by identical post-tests. During TTs, heart rate, ear oximetry reading, and Wpeak were recorded. Results: The VO2peak and Wpeak values were unchanged after RMET. The TT was improved by 7 ± 6% (p < 0.001) in normoxia and 16 ± 6% (p < 0.001) in hypoxia. The difference between normoxic and hypoxic TT was smaller after RMET as compared with that before RMET (14% vs. 21%, respectively, p < 0.001). All effects were greater in women (p < 0.001). The RMET did not change the heart rate or ear oximetry reading during TTs. Conclusion: We found a greater effect of RMET on cycling TT performance in women than in men, an effect more pronounced in hypoxia. These findings are congruent with the contention of a more pronounced performance-limiting role of the respiratory system during endurance exercise in hypoxia compared with normoxia and more so in women whose respiratory system is undersized compared with that of men.


Polymorphs and solvates of nicardipine hydrochloride. Selective stabilization of different diastereomeric racemates.
Molecular understanding of the drug nicardipine hydrochloride (NHc) is provided within this study. For this reason, the polymorphism and crystal structures, including stereochemistry, of the known and the new discovered polymorphs of NHc are discussed. Three new crystalline forms of the nicardipine hydrochloride drug have been isolated: (i) a bishydrated phase, (ii) a chloroform solvate and (iii) a toluene hemisolvate. The crystal structures of these new solvated phases and those of the previously known α and β polymorphs have been determined from conventional single-crystal X-ray diffraction analysis (α phase and chloroform solvate) or from high quality powder X-ray diffraction data using direct-space methods (β phase, bishydrate and toluene hemisolvate). The analysis of the crystal structures revealed that nicardipine hydrochloride crystallizes, in all studied phases, as a racemate with the organic moiety adopting different diastereoisomeric configurations (addressed by the presence of two stereocenters, the C1 and N3 atoms) depending on the actual solvent or polymorph. The chirality of the protonated nicardipine molecules is driven, in the solids, by the strong electrostatic interactions between chloride ions and the protonated nitrogen atoms, which result, in the α phase and in the chloroform solvate, in centrosymmetric dimers built by R,R and S,S molecules. At variance, the β polymorph contains R,S and S,R molecules, still arranged in dimers, but possessing a markedly different molecular shape. Interestingly, in the bishydrated and toluene hemisolvate phases, a slightly disordered crystal structure about the positively charged ammonium group is formed, and both diasteroisomeric couples are present (although with different site occupation factors).