Seasonality, biology and threats to Sicalis luteola (Sparrman, 1789) (Aves, Thraupidae) in northeastern Brazil.
Sicalis luteola occurs from Mexico to South America. In the Northeastern Brazilian region its biology, population dynamics and threats are poorly known. The subspecies S. luteola luteiventris apparently migrates northward during austral winter. The specific aims of this work were: 1) to verify the seasonality of the species; 2) to analyze information on molting and breeding, and 3) to check the main threats to this bird in northeastern Brazil. The highest number of records were in March, April, and May (51.12%) and the lowest in November and December (3%).We found a greater population peak in April in the states of Rio Grande do Norte and Ceará, and in April and May in Pernambuco. In Paraíba there was not an apparent seasonal variation in frequency. We captured 66 individuals, all adults, being 38 males and 28 females. 30% of the captured birds showed contour feathers molt, mainly on the head. A total of 23 individuals had brood patch, all being females. Six nests were found and four contained two to three eggs. We found that the main threat is the illegal trade. Our findings may support conservation plans for this bird in the region.


Identification of the feline humoral immune response to Bartonella henselae infection by protein microarray.
Bartonella henselae is the zoonotic agent of cat scratch disease and causes potentially fatal infections in immunocompromised patients. Understanding the complex interactions between the host's immune system and bacterial pathogens is central to the field of infectious diseases and to the development of effective diagnostics and vaccines. We report the development of a microarray comprised of proteins expressed from 96% (1433/1493) of the predicted ORFs encoded by the genome of the zoonotic pathogen Bartonella henselae. The array was probed with a collection of 62 uninfected, 62 infected, and 8 "specific-pathogen free" naïve cat sera, to profile the antibody repertoire elicited during natural Bartonella henselae infection. We found that 7.3% of the B. henselae proteins on the microarray were seroreactive and that seroreactivity was not evenly distributed between predicted protein function or subcellular localization. Membrane proteins were significantly most likely to be seroreactive, although only 23% of the membrane proteins were reactive. Conversely, we found that proteins involved in amino acid transport and metabolism were significantly underrepresented and did not contain any seroreactive antigens. Of all seroreactive antigens, 52 were differentially reactive with sera from infected cats, and 53 were equally reactive with sera from infected and uninfected cats. Thirteen of the seroreactive antigens were found to be differentially seroreactive between B. henselae type I and type II. Based on these results, we developed a classifier algorithm that was capable of accurately discerning 93% of the infected animals using the microarray platform. The seroreactivity and diagnostic potential of these antigens was then validated on an immunostrip platform, which correctly identified 98% of the infected cats. Our protein microarray platform provides a high-throughput, comprehensive analysis of the feline humoral immune response to natural infection with the alpha-proteobacterium B. henselae at an antigen-specific, sera-specific, and genome-wide level. Furthermore, these results provide novel insight and utility in diagnostics, vaccine development, and understanding of host-pathogen interaction.


Host characteristics do not affect community structure of ectoparasites on the fishing bat Noctilio leporinus (L., 1758) (Mammalia: Chiroptera).
Patterns of parasite abundance and prevalence are thought to be influenced by several host characteristics such as size, sex, developmental stage, and seasonality. We examined two obligatory ectoparasites of the bat Noctilio leporinus (L.) (Chiroptera, Noctilionidae) to test whether prevalence and abundance of Noctiliostrebla aitkeni Wenzel and Paradyschiria fusca Speiser (Diptera, Streblidae) are influenced by the host characteristics. During this survey, 2110 flies were collected. The total abundance was 1150 N. aitkeni and 950 P. fusca. The prevalence of both species was shown to be superior to 75% and neither host size, sex, reproductive stage nor season influenced significantly the variation of the observed values. N. aitkeni were more abundant than P. fusca in all seasons except winter. Both flies showed a significant seasonal variation in terms of abundance but host biological characteristics (host size, sex, and reproductive stage) did not play a significant role as structuring factors of the batflies component community.


[Interaction of silicone oil with various intraocular lenses. A light and scanning electron microscopy study].
Silicone oil is increasingly used as an intravitreal tamponade in severe forms of vitreoretinal disorders, also in pseudophakic eyes. In some patients silicone oil was observed to be adherent to the intraocular implant. To investigate the interaction of silicone oil with IOL-materials and the influence of lipoproteins of the serum on this interaction we used the following in vitro experimental set-up: Sterile IOLs of different IOL-materials (e.g. PMMA, silicone, hydrogel) and surface-modifications (e.g. Pharmacia 809P and 809C, Soflex LI41U, Alcon AcrySof M60BM, Allergan SI-30NB, SI-40NB, Chiron adatomed 90D, C10 and C31UB, MemoryLens U940A, Corneal ISHEMA 66, Storz H60M) were stored in vitro together with silicone oil (1000 centistokes) with and without a fresh serum solution at 37 degrees Celsius. This combination was rotated slowly and mixed thoroughly three times a day. After 3 and 6 months and a standardized special preparation in an ultrasound bath and air treatment, the IOLs were examined by light microscopy followed by scanning electron microscopy. Silicone oil strongly adhered to holes and to the IOL surface especially in silicone and PMMA IOLs. Highly hydrophylic IOLs-like the heparin-surface-modified and hydrogel IOL-cleared from silicone oil relatively early. This effect was more pronounced in the group with lipid-/serum solution than without. In some silicone IOLs silicone oil was strongly adherent to the lens and it was nearly impossible to wash off the oil even when using an alcoholic solution. One silicone IOL lost its haptics in the serum-oil-IOL-mixture, another lost small particles from the IOL surface. Silicone oil is more adherent to hydrophobic IOLs than to hydrophylic IOLs. Lipoproteins of the serum play an important role in facilitating an effect of silicone oil on IOL materials. We recommend highly hydrophylic especially surface-modified IOLs for lens implantation following vitreoretinal silicone oil surgery. Implantation of silicone IOLs in vitreoretinal high risk eyes should be avoided.


Targeting the histone demethylase LSD1 prevents cardiomyopathy in a mouse model of laminopathy.
LMNA mutations in patients are responsible for a dilated cardiomyopathy. Molecular mechanisms underlying the origin and development of the pathology are unknown. Herein, using mouse pluripotent embryonic stem cells (ESCs) and a mouse model both harboring the p.H222P Lmna mutation, we found early defects in cardiac differentiation of mutated ESCs and dilatation of mutated embryonic hearts at E13.5, pointing to a developmental origin of the disease. Using mouse ESCs, we demonstrated that cardiac differentiation of LmnaH222P/+ was impaired at the mesodermal stage. Expression of Mesp1, a mesodermal cardiogenic gene involved in epithelial-to-mesenchymal transition of epiblast cells, as well as Snai1 and Twist expression, was decreased in LmnaH222P/+ cells compared with WT cells in the course of differentiation. In turn, cardiomyocyte differentiation was impaired. ChIP assay of H3K4me1 in differentiating cells revealed a specific decrease of this histone mark on regulatory regions of Mesp1 and Twist in LmnaH222P/+ cells. Downregulation or inhibition of LSD1 that specifically demethylated H3K4me1 rescued the epigenetic landscape of mesodermal LmnaH222P/+ cells and in turn contraction of cardiomyocytes. Inhibition of LSD1 in pregnant mice or neonatal mice prevented cardiomyopathy in E13.5 LmnaH222P/H222P offspring and adults, respectively. Thus, LSD1 appeared to be a therapeutic target to prevent or cure dilated cardiomyopathy associated with a laminopathy.


Update on the guideline of guidelines: non-muscle-invasive bladder cancer.
Non-muscle-invasive bladder cancer (NMIBC) is the most common form of bladder cancer, with frequent recurrences and risk of progression. Risk-stratified treatment and surveillance protocols are often used to guide management. In 2017, BJUI reviewed guidelines on NMIBC from four major organizations: the American Urological Association/Society of Urological Oncology, the European Association of Urology, the National Comprehensive Cancer Network, and the National Institute for Health and Care Excellence. The present update will review major changes in the guidelines and broadly summarize new recommendations for treatment of NMIBC in an era of bacillus Calmette-Guérin shortage and immense novel therapy development.


Response of agronomic and forest species to elevated atmospheric carbon dioxide.
The effects of atmospheric carbon dioxide on corn, soybeans, loblolly pine, and sweetgum were studied in the field during a growing season. The plants were exposed to a range of concentrations of carbon dioxide day and night in open-topped, flow-through chambers. At a mean daytime carbon dioxide concentration of 910 parts per million, increases in total biomass ranged from 157 to 186 percent of the control values. Seed yield and wood volume increased and there were changes in plant anatomy and form. Net photosynthesis increased with increasing carbon dioxide concentration in soybeans and sweetgum, but was unaffected in corn. Water use efficiency also increased in corn, soybeans, and sweetgum.


Kv12-encoded K+ channels drive the day-night switch in the repetitive firing rates of SCN neurons.
Considerable evidence suggests that day-night rhythms in the functional expression of subthreshold potassium (K+) channels regulate daily oscillations in the spontaneous firing rates of neurons in the suprachiasmatic nucleus (SCN), the master circadian pacemaker in mammals. The K+ conductance(s) driving these daily rhythms in the repetitive firing rates of SCN neurons, however, have not been identified. To test the hypothesis that subthreshold Kv12.1/Kv12.2-encoded K+ channels play a role, we obtained current-clamp recordings from SCN neurons in slices prepared from adult mice harboring targeted disruptions in the Kcnh8 (Kv12.1-/-) or Kcnh3 (Kv12.2-/-) locus. We found that mean nighttime repetitive firing rates were higher in Kv12.1-/- and Kv12.2-/- than in wild type (WT), SCN neurons. In marked contrast, mean daytime repetitive firing rates were similar in Kv12.1-/-, Kv12.2-/-, and WT SCN neurons, and the day-night difference in mean repetitive firing rates, a hallmark feature of WT SCN neurons, was eliminated in Kv12.1-/- and Kv12.2-/- SCN neurons. Similar results were obtained with in vivo shRNA-mediated acute knockdown of Kv12.1 or Kv12.2 in adult SCN neurons. Voltage-clamp experiments revealed that Kv12-encoded current densities in WT SCN neurons are higher at night than during the day. In addition, the pharmacological block of Kv12-encoded currents increased the mean repetitive firing rate of nighttime, but not daytime, in WT SCN neurons. Dynamic clamp-mediated subtraction of modeled Kv12-encoded currents also selectively increased the mean repetitive firing rates of nighttime WT SCN neurons. Despite the elimination of the nighttime decrease in the mean repetitive firing rates of SCN neurons, however, locomotor (wheel-running) activity remained rhythmic in Kv12.1-/-, Kv12.2-/-, and Kv12.1-targeted shRNA-expressing, and Kv12.2-targeted shRNA-expressing animals.


The role of metastasectomy in advanced renal cell carcinoma.
Introduction: So far, clinical experiences have proved metastasectomy as the only approach in the setting of metastatic renal cell carcinoma that may achieve the 'no evidence of disease' status, with an associated improvement in survival. Areas covered: This review aims to summarize the body of knowledge on therapeutic approaches to mRCC, with a specific insight on the role of metastasectomy and on which underlying factors could be good predictors to select patients who may benefit from surgery. In detail, we managed to identify as potential selection criteria: the number of lesions and their site, the DFI, patients' performance status and, most of all, the completeness of resection. Expert opinion: The definition of the optimal treatment strategy of mRCC patients is still an unmet clinical need. The decision-making process about treatment strategy should consider specific tumor's and patient's characteristics, as well as the integration of the available therapeutic approaches with the aim to reach the best clinical outcome. We consider multidisciplinary management mandatory in order to tailor the treatment approach according to the patient and disease features. The experience of clinicians may be considered crucial in order to select the best candidates for a multimodal approach.


The distribution of cell-penetrating peptides on polymeric nanoparticles prepared using microfluidics and elucidated with small angle X-ray scattering.
The distribution of three cell-penetrating peptides (CPPs) with different architectures (short, long linear and branched) on poly(lactic-co-glycolic) acid (PLGA) nanoparticles depends on the conjugation approach. Here, we explore the utilization of a zero-length crosslinking reaction for the covalent attachment of CPPs to PLGA nanoparticles and the translation of the reaction into a microfluidic platform. A microfluidic device with a staggered herringbone mixer was used for the formulation of CPP-tagged PLGA nanoparticles. CPP-tagged PLGA nanoparticles were labeled with gold nanoparticles (AuNPs) and transmission electron microscopy (TEM) and small angle X-ray scattering (SAXS) were used to elucidate the distribution of CPPs. The SAXS scattering profiles for the CPP-tagged PLGA nanoparticles prepared with the in situ microfluidics conjugation approach indicated a distribution of the Au-labeled CPPs throughout the PLGA nanoparticles. For the post-microfluidics conjugation approach, the SAXS scattering profiles did not show the feature of the Au-labeled CPPs distributed throughout the PLGA nanoparticles and an arrangement of the Au-labeled CPP on the surface was support by TEM micrographs. The distribution of the CPPs was highly dependent on the conjugation approach and was not influenced by the architecture of the CPPs. The results provided insight for the rational design of CPP-tagged PLGA nanoparticles using microfluidics.


Modeling of simultaneous exchange of colloids and sorbing contaminants between streams and streambeds.
Contaminant transport in streams can be significantly modified by both stream-subsurface exchange and the presence of colloidal particles, but the interaction of these effects is notwell understood. Exchange with the hyporheic zone exposes contaminants to surface-chemical reactions with streambed sediments, while colloidal particles have a large reactive surface area that allows them to carry pollutants that would otherwise be transported primarily as dissolved species. A new theoretical model is developed to predict the role of colloids in mediating advective contaminant exchange between streams and streambeds. Bedform-induced pumping theory is applied to model physical transport, and colloid filtration and reversible contaminant sorption are used to calculate the local distributions of colloids and contaminants within the streambed. Residence time functions of both colloids and contaminants in the bed are then used to link contaminant concentrations in the pore water and streamwater. Model simulations indicate that, under conditions of low colloid filtration and strong contaminant sorption to colloids, contaminants are mobilized by colloids and there is less retention of contaminants in the streambed. This is the case of "colloid-facilitated contaminant transport" commonly considered in groundwater transport. On the other hand, when colloid filtration is high and contaminants still sorb strongly to colloids, contaminant mobility decreases and there is greater contaminant retention in the streambed. We term this case "colloid-impeded contaminant transport". Thus, we find that a variety of contaminanttransport behavior can occur depending on the concentration and mobility of suspended particles in the system and the relative affinity of contaminants for colloids and other solid phases.


Azoospermia Type Does Not Affect Intracytoplasmic Sperm Injection Results When Microdissection Testicular Sperm Extraction Is Performed.
To investigate the effect of azoospermia type on fertilization and clinical pregnancy rates when microdissection testicular sperm extraction (TESE) is performed for sperm retrieval in nonobstructive azoospermia (NOA). STUDY DESIGN: Patients who underwent microdissection TESE for NOA and conventional TESE for obstructive azoospermia (OA) were included in the study. Intracytoplasmic sperm injection (ICSI) results were compared between groups. The mean ages in the 2 groups were similar. FSH and LH levels in the NOA group were significantly higher than those of the OA group. Between groups there was no statistically significant difference in testosterone levels. The sperm retrieval rate was 58.56% in NOA. Fertilization and clinical pregnancy rates were similar for patients with NOA and OA. In patients with NOA, microdissection TESE accurately determines active spermatogenesis areas via the high identification power of the operative microscope. From these areas surgeons can collect healthier spermatozoa, which can result in better ICSI outcomes, the results of which are similar to those with OA.


Cerebral responses to infant-directed speech and the effect of talker familiarity.
A number of behavioral studies suggest that infant-directed speech (IDS) plays a more important role in facilitating both: a) speech perception, and b) adult-infant social interactions than does adult-directed speech (ADS), and hence that IDS contributes to subsequent social and language development. However neural substrates that may underlie these IDS functions have not been examined. The present study examined cerebral hemodynamic responses to IDS in 48 infants (4-13 months of age) using near-infrared spectroscopy (NIRS). Japanese sentences uttered by the infants' own mothers and by unfamiliar mothers were used to record activations in temporal and frontal area separately. Increased activations were observed predominantly in infants' left and right temporal areas when they listened to IDS rather than to ADS when both involved voices of their own and unfamiliar mothers. In contrast, significantly greater activations were observed in the frontal area when infants listened to IDS produced by their own mothers, not when IDS arose from unfamiliar mothers. Furthermore, the present results indicate that responses to IDS do vary as a function of the infant's age and the talker familiarity. These findings suggest a differential function for frontal and temporal areas in processing infant-directed speech by the different speakers.


X-ray diffraction studies of 180 degrees ferroelectric domains in PbTiO3/SrTiO3 superlattices under an applied electric field.
The dielectric response of PbTiO(3)/SrTiO(3) superlattices is studied using electrical and structural measurements. While the dielectric response of paraelectric superlattices is well accounted for by the lattice contribution, superlattices with ferroelectric compositions exhibit an enhanced permittivity. X-ray diffraction allowed the presence of ordered nanodomains in ferroelectric superlattices to be established and their displacement under an applied bias to be directly probed, demonstrating that the enhanced permittivity in these artificial materials is due to domain wall motion.


Ultrasound evaluation and correlates of fatty liver disease: a population study in a Mediterranean area.
The aim of this study was to evaluate the distribution of fatty liver-nonalcoholic (NAFL) and alcoholic (AFL)-and its association with metabolic syndrome and its components in a population sample from a Mediterranean area. A sample of 2974 subjects (1679 males, 1295 females, age range 30-89 years) was randomly drawn from the population of a town in southern Italy. The survey visit included a validated semiquantitative food frequency questionnaire, anthropometric measurements, a blood sample taken in the morning after overnight fasting, as well as abdominal ultrasound examination to evaluate liver fat with a standardized scoring system. The 2001 National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) definition of the metabolic syndrome was adopted. In this Mediterranean population, where alcohol intake is mostly as wine with meals, NAFL is present in 36.8% of men and 25.7% of women and AFL in 13.8% of men and 5.5% of women. NAFL and AFL are associated with metabolic syndrome and its characteristics, body mass index (BMI), and visceral and subcutaneous fat (in AFL subjects, only in women) measured by ultrasound. Stratifying by BMI and controlling for confounders (age, height, smoking habit, and alcohol consumption), in overweight and obese subjects, liver and visceral fat are associated with the metabolic syndrome both in men and women and subcutaneous fat only in women. In normal weight subjects, only liver fat in men is associated with the metabolic syndrome. Fatty liver is highly prevalent in this Mediterranean population and is associated with metabolic syndrome in overweight and obese men and women as well as in men with normal BMI.


Inhibition behaviours of some phenolic acids on rat kidney aldose reductase enzyme: an in vitro study.
Aldose reductase (AR) inhibitors have vital importance in the treatment and prevention of diabetic complications. In this study, rat kidney AR was purified 19.34-fold with a yield of 3.49% and a specific activity of 0.88 U/mg using DE-52 Cellulose anion exchange chromatography, gel filtration chromatography and 2'5' ADP Sepharose-4B affinity chromatography, respectively. After purification, the in vitro inhibition effects of some phenolic acids (tannic acid, chlorogenic acid, sinapic acid, protocatechuic acid, 4-hydroxybenzoic acid, p-coumaric acid, ferulic acid, vanillic acid, syringic acid, α-resorcylic acid, 3-hydroxybenzoic acid and gallic acid) were investigated on purified enzyme. We determined IC50, Ki values and inhibition types of these phenolic acids. As a result, tannic and chlorogenic acid had a strong inhibition effect. On the other hand, gallic acid had a weak inhibition effect. In this study, all phenolic acids except for chlorogenic acid and p-coumaric acid showed non-competitive inhibition effects on rat kidney AR.


The long-term results of Charnley low-friction arthroplasty in young patients who have congenital dislocation, degenerative osteoarthrosis, or rheumatoid arthritis.
We present the long-term results of 226 Charnley low-friction arthroplasties that were performed with use of cement in 161 patients between 1966 and 1978. Forty-four patients (sixty hips) had congenital dislocation of the hip, fifty-four patients (sixty-six hips) had degenerative osteoarthrosis, and sixty-three patients (100 hips) had rheumatoid arthritis. There were 114 female patients and forty-seven male patients. The average age of the patients at the time of the operation was 31.7 years (range, seventeen to thirty-nine years). Sixty-five patients (40 per cent) had a bilateral hip replacement. Thirty-eight patients (24 per cent; fifty-five hips), twenty-seven of whom had juvenile-onset chronic rheumatoid arthritis, died during the follow-up period. The average duration of follow-up for the entire series until the time of death, revision of both components, or the latest evaluation was 236 months (19.7 years; range, twenty-four to 361 months). Survivorship analysis was performed with the Kaplan-Meier method. At twenty-five years, the survival of the femoral component (with 95 per cent confidence intervals) was 89 per cent (80 to 98 per cent) in the patients who had congenital dislocation of the hip, 85 per cent (77 to 93 per cent) in the patients who had rheumatoid arthritis, and 74 per cent (61 to 87 per cent) in the patients who had degenerative osteoarthrosis. The rate of survival of the acetabular component was lower: at twenty-five years, it was 58 per cent (42 to 74 per cent) in the patients who had congenital dislocation, 79 per cent (70 to 88 per cent) in the patients who had rheumatoid arthritis, and 59 per cent (41 to 77 per cent) in the patients who had degenerative osteoarthrosis. The forty-four patients (sixty hips) who had congenital dislocation had the highest rates of aseptic loosening (twenty-two hips; 37 per cent), migration (seventeen hips; 28 per cent), and revision (twenty-two hips; 37 per cent) of the acetabular component. The fifty-four patients (sixty-six hips) who had degenerative osteoarthrosis had the highest rates of aseptic loosening (seventeen hips; 26 per cent) and revision (eighteen hips; 27 per cent) of the femoral component as well as the highest rate of femoral endosteal lysis (thirteen hips; 20 per cent). The sixty-three patients (100 hips) who had rheumatoid arthritis had the lowest prevalences of loosening and revision of the acetabular component but the highest rates of trochanteric non-union (fifteen hips; 15 per cent) and mortality (twenty-seven patients; 43 per cent). The average rate of wear of the acetabular component for the entire series was 0.11 millimeter per year; the average rate for the revised components (0.19 millimeter per year) was higher than that for the surviving components (0.09 millimeter per year). This was a consistent finding in each of the three diagnostic groups, and an increased annual rate of wear was found to be significantly associated with increased rates of migration and revision of the acetabular component (p < 0.01 for both). The femoral component proved to be durable: the twenty-five-year rate of survival for the entire series was 81 per cent (95 per cent confidence interval, 76 to 87 per cent). The major factors that limited the longevity of the cemented total hip implants in the present study were wear, loosening, and revision of the acetabular component, for which the twenty-five-year probability of survival was 68 per cent (95 per cent confidence interval, 61 to 75 per cent).


C35 is overexpressed in colorectal cancer and is associated tumor invasion and metastasis.
The aim of this study was to investigate the expression of C35, an oncogene previously found in breast and prostate cancers, and its clinicopathological significance in colorectal cancer (CRC). Qualitative and quantitative detection of C35 mRNA expression was performed using reverse transcription-PCR (RT-PCR) and real-time PCR. C35 protein expression was determined using immunohistochemistry. C35 mRNA was detected in none of 10 normal colorectal tissue samples, 55 of 65 (84.6%) CRC tissue samples, and 43 of 55 (78.2%) adjacent non-cancerous tissue samples. In addition, the level of C35 mRNA in CRC tissue samples was markedly higher than that in tumor adjacent non-cancerous tissue samples. C35 protein expression was detected in 58 of 80 (72.5%) CRC tissue samples and was closely associated with tumor serosal invasion, lymphnode metastasis, and an advanced Dukes stage. These results suggest that C35 might serve as a biomarker or therapeutic target for management of CRC.


Effects of bisphenol-A and other endocrine disruptors compared with abnormalities of schizophrenia: an endocrine-disruption theory of schizophrenia.
In recent years, numerous substances have been identified as so-called "endocrine disruptors" because exposure to them results in disruption of normal endocrine function with possible adverse health outcomes. The pathologic and behavioral abnormalities attributed to exposure to endocrine disruptors like bisphenol-A (BPA) have been studied in animals. Mental conditions ranging from cognitive impairment to autism have been linked to BPA exposure by more than one investigation. Concurrent with these developments in BPA research, schizophrenia research has continued to find evidence of possible endocrine or neuroendocrine involvement in the disease. Sufficient information now exists for a comparison of the neurotoxicological and behavioral pathology associated with exposure to BPA and other endocrine disruptors to the abnormalities observed in schizophrenia. This review summarizes these findings and proposes a theory of endocrine disruption, like that observed from BPA exposure, as a pathway of schizophrenia pathogenesis. The review shows similarities exist between the effects of exposure to BPA and other related chemicals with schizophrenia. These similarities can be observed in 11 broad categories of abnormality: physical development, brain anatomy, cellular anatomy, hormone function, neurotransmitters and receptors, proteins and factors, processes and substances, immunology, sexual development, social behaviors or physiological responses, and other behaviors. Some of these similarities are sexually dimorphic and support theories that sexual dimorphisms may be important to schizophrenia pathogenesis. Research recommendations for further elaboration of the theory are proposed.


The resident's view of residency training in Canada.
In the view of residents in their last year of specialty training, the Fellowship is now becoming the operative standard for obtaining hospital privileges in urban centres and they felt that this implied that the two standards, the Certificate and the Fellowship of the Royal College, were not achieving the purpose for which they were designed. Although 80% of the residents intended to write the Fellowship, few viewed a year in a basic science department or in research as of intrinsic value in terms of their future practice.The examinations of the Royal College were the subject of criticism, most residents feeling that the examinations did not test the knowledge and ability gained in training. Most expressed a desire for ongoing evaluation during the training period.Service responsibilities were generally regarded as too heavy.Despite the criticism of both training and examination, most residents felt that their training had provided them with the experience and background they needed to practise as specialists.


Predictors of cancer worry in unaffected women from high risk breast cancer families: risk perception is not the primary issue.
Some women at increased familial risk of breast cancer experience elevated levels of cancer-specific worry, which can possibly act as a barrier to screening, and may be a significant factor in decisions regarding risk-reducing surgery. The aim of this study was to comprehensively examine predictors of cancer-specific worry in high risk women and to test a model which proposes that perceived breast cancer risk mediates the impact of other factors on worry. 1,437 unaffected women from high risk breast cancer families completed questionnaires and interviews. Path analysis was used to test the model of potential predictors of cancer worry, including familial, personal and psychological variables, mediated via perceived cancer risk. Levels of cancer-specific worry were generally low despite an average perceived risk of 50.3%. The goodness-of-fit of the proposed model was poor, explaining only 9% of the variance for perceived risk and 10% of the variance for cancer specific worry. An alternative model of a direct relationship between all of the predictor variables and cancer worry, explained 24% of the variation in cancer worry. General anxiety, perceived risk, the stressful impact of recent cancer related events, a relative risk greater than 10, being closer in age to the youngest breast cancer diagnosis in family, and knowledge of personal mutation status, all independently contributed to cancer worry. Addressing general affective responses, experiences of recent cancer related events, in addition to education about personal risk, should be considered in counselling women with elevated cancer worry. Risk perception appears to act independently of other factors in its formulation and impact on cancer worry. Further research on the way in which women come to perceive their risk is indicated.


A real-life multicentre clinical practice study to evaluate the efficacy and safety of intravesical chondroitin sulphate for the treatment of interstitial cystitis.
To report a multicentre, community based open-label study designed to assess the efficacy and safety of intravesical sodium chondroitin sulphate in the treatment of patients with the clinical diagnosis of interstitial cystitis (IC). Chondroitin sulphate is a naturally occurring glycosaminoglycan (GAG) in the bladder mucus layer and changes in this GAG have been implicated in the pathogenesis of IC, and small single-centre studies have suggested that intravesical chondroitin sulphate may have efficacy in IC. Patients with IC were treated with sodium chondroitin sulphate (Uracyst, Stellar Pharmaceuticals Inc., London ON, Canada) solution 2.0% via urinary catheter weekly for 6 weeks and then monthly for 16 weeks for a total of 10 treatments. The primary efficacy endpoint was the percentage of responders to treatment as indicated by a marked or moderate improvement on a seven-point patient Global Response Assessment (GRA) scale at week 10 (4 weeks after the initial six treatments) compared with baseline. A major secondary efficacy endpoint (durability) was the percentage of responders on the GRA scale after 10 treatments. Additional secondary efficacy objectives were differences from baseline in Patient Symptom/Problem Index scores over the course of the treatment compared with baseline. In all, 47% of the 53 enrolled patients with long standing moderately severe IC (mean [SD, range] diagnosis of IC 3.0 [3.4, 0.1-16] years; duration of symptoms 9.2 [9.2, 1-39] years; baseline symptom score 14.2 [3.2]) were responders at week 10. At 24 weeks, 60% were responders. There was a statistically and clinically significant decrease in the mean (SD) symptom and bother scores from baseline at 10 weeks and 24 weeks, at 9.0 (4.3) and 8.1 (5.0), respectively (P < 0.001). There were no significant safety issues during the study. This multicentre community based real-life clinical practice study suggests that intravesical chondroitin sulphate may have an important role in the treatment of IC and validates the rationale for a randomized placebo-controlled trial.


Clinicopathological aspects of small pancreatic cancer.
Small pancreatic cancers, intractable diseases, offer the possibility of cure. Can this be true? Through the National Pancreatic Cancer Registry, the Japan Pancreas Society (JPS) has collected 822 cases of invasive cancer with tumors <2 cm in diameter (TS1 pancreatic cancer). Papillary adenocarcinoma and the well-differentiated type of tubular adenocarcinoma are more frequent in TS1 pancreatic cancer than the larger tumors, suggesting that further genetic and phenotypic changes occur during their progression. Patients with TS1 pancreatic cancer presented with abdominal pain, jaundice, and exacerbation of diabetes, while 17.3% of them had no symptoms. Further imaging diagnosis should be employed to detect TS1 pancreatic cancer, but conventional US and ERCP play an important role in the diagnostic process. In this study, of 822 patients with TS1 pancreatic cancer, only 216 patients (26.3%) had T1 tumors because of invasion to adjacent tissue. There were 306 patients (37.2%) with lymph node metastasis, of whom 63 (7.7%) had N3 metastasis that is counted as a distant metastasis. As a result, only 136 patients (16.5%) had stage I disease with a median survival time of 78.2 months and a 5-year survival rate of 58.1%. Small pancreatic cancer does not necessarily mean early pancreatic cancer, and surgery alone is not sufficient to cure this disease.


Structure and function of the Toscana virus cap-snatching endonuclease.
Toscana virus (TOSV) is an arthropod-borne human pathogen responsible for seasonal outbreaks of fever and meningoencephalitis in the Mediterranean basin. TOSV is a segmented negative-strand RNA virus (sNSV) that belongs to the genus phlebovirus (family Phenuiviridae, order Bunyavirales), encompassing other important human pathogens such as Rift Valley fever virus (RVFV). Here, we carried out a structural and functional characterization of the TOSV cap-snatching endonuclease, an N terminal domain of the viral polymerase (L protein) that provides capped 3'OH primers for transcription. We report TOSV endonuclease crystal structures in the apo form, in complex with a di-ketoacid inhibitor (DPBA) and in an intermediate state of inhibitor release, showing details on substrate binding and active site dynamics. The structure reveals substantial folding rearrangements absent in previously reported cap-snatching endonucleases. These include the relocation of the N terminus and the appearance of new structural motifs important for transcription and replication. The enzyme shows high activity rates comparable to other His+ cap-snatching endonucleases. Moreover, the activity is dependent on conserved residues involved in metal ion and substrate binding. Altogether, these results bring new light on the structure and function of cap-snatching endonucleases and pave the way for the development of specific and broad-spectrum antivirals.


Contrasting population genetic structure among freshwater-resident and anadromous lampreys: the role of demographic history, differential dispersal and anthropogenic barriers to movement.
The tendency of many species to abandon migration remains a poorly understood aspect of evolutionary biology that may play an important role in promoting species radiation by both allopatric and sympatric mechanisms. Anadromy inherently offers an opportunity for the colonization of freshwater environments, and the shift from an anadromous to a wholly freshwater life history has occurred in many families of fishes. Freshwater-resident forms have arisen repeatedly among lampreys (within the Petromyzontidae and Mordaciidae), and there has been much debate as to whether anadromous lampreys, and their derived freshwater-resident analogues, constitute distinct species or are divergent ecotypes of polymorphic species. Samples of 543 European river lamprey Lampetra fluviatilis (mostly from anadromous populations) and freshwater European brook lamprey Lampetra planeri from across 18 sites, primarily in the British Isles, were investigated for 13 polymorphic microsatellite DNA loci, and 108 samples from six of these sites were sequenced for 829 bp of mitochondrial DNA (mtDNA). We found contrasting patterns of population structure for mtDNA and microsatellite DNA markers, such that low diversity and little structure were seen for all populations for mtDNA (consistent with a recent founder expansion event), while fine-scale structuring was evident for nuclear markers. Strong differentiation for microsatellite DNA loci was seen among freshwater-resident L. planeri populations and between L. fluviatilis and L. planeri in most cases, but little structure was evident among anadromous L. fluviatilis populations. We conclude that postglacial colonization founded multiple freshwater-resident populations with strong habitat fidelity and limited dispersal tendencies that became highly differentiated, a pattern that was likely intensified by anthropogenic barriers.


Acute appendicitis in complete situs inversus.
An acute appendicitis was diagnosed in a 29-year-old patient with situs in inversus totalis. Appendectomy was carried out. The incidence, etiology and the diagnosis of complete situs inversus as well as the diagnosis and pitfalls of acute appendicitis in this rare congenital abnormally are described.


Human Milk Oligosaccharide Profiles and the Secretor and Lewis Gene Status of Indonesian Lactating Mothers.
Human milk oligosaccharides (HMOs) may be genetically determined based on the secretor and Lewis status of the mother. This study aims to determine the HMO profile and the secretor and Lewis gene status of Indonesian lactating mothers. Baseline data of 120 mother-infant pairs between 0-4 months post-partum obtained from a prospective longitudinal study was used. The concentrations of 2'-fucosyllactose (2'FL), lacto-N-fucopentaose I (LNFP I), lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT), 3'-sialyllactose (3'SL), and 6'-sialyllactose (6'SL) were measured. Genetic analysis was performed for mothers using targeted next-generation sequencing and Sanger sequencing. Wild-type AA with the rs1047781 (A385T) polymorphism was categorized as secretor positive, while heterozygous mutant AT was classified as a weak secretor. The presence of rs28362459 (T59G) heterozygous mutant AC and rs3745635 (G508A) heterozygous mutant CT genes indicated a Lewis negative status, and the absence of these genes indicated a positive status. Subsequently, breast milk was classified into various groups, namely Group 1: Secretor+Lewis+ (Se+Le+), Group 2: Secretor-Lewis+ (Se-Le+), Group 3: Secretor+Lewis- (Se+Le-), and Group 4: Secretor-Lewis- (Se-Le-). Data were analyzed using the Mann-Whitney and Kruskal-Wallis rank tests, and a p-value of 0.05 indicated statistical significance. A total of 58.3% and 41.7% of the samples had positive and weak secretor statuses, respectively. The proportion of those in Group 1 was 85%, while 15% were Group 3. The results showed that only 2'FL significantly differed according to the secretor status (p-value=0.018). All Indonesian lactating mothers in this study were secretor positive, and most of them had a Lewis-positive status.


Tapered and inhomogeneous dielectric light concentrators.
A detailed analysis of tapered and inhomogeneous dielectric light collectors was worked out for both illumination and solar energy applications. In particular, tapered dielectric guides have been investigated both theoretically and experimentally together with their capability to collect and transmit high fluxes of light energy. Furthermore, GRIN rods are considered as matching devices, to improve the collecting performance of tapered guides.


Live colonocytes in newborn stool: surrogates for evaluation of gut physiology and disease pathogenesis.
Studies of gastrointestinal pathophysiology are not feasible by biopsies in human neonates. We examined the utility of live colonocytes in stool in studying cellular markers during early neonatal life. Expression of IgA, IgG, cluster of differentiation-45 cells (CD45), and toll-like receptors-2 and 4 (TLR2 and TLR4) were analyzed by flow cytometry. Colonocyte RNA extracts were used in quantitative real-time PCR (qRT-PCR) to examine the expression of cytokeratin-19, ribosomal protein-24, and tight-junction (Tj) protein zonula occludens-1 (ZO-1). Colonocyte yield varied between 5 × 10⁴ to 2 × 10⁶ cells/g of stool. Meconium samples yielded a highly enriched population of viable cells. Although low, all samples showed CD45-positive cells during the initial weeks of life. Starting as early as d 2, IgA expression was observed in 69% of the cells. Low to moderate expression of IgG was observed with a linear increase as the infants grew. There was an almost total lack of TLR2 staining; however, >55% of the colonocytes showed TLR4 expression. Although high levels of IgA in gut cells may serve as a natural protectant during neonatal period, increased TLR4 may provide a niche for lipopolysaccharide (LPS)-mediated epithelial damage. Use of stool colonocytes can be a valuable noninvasive approach for studying gut pathophysiology in the neonatal period.


Innate immunity in the adult mammalian heart: for whom the cell tolls.
Recent studies suggest that the heart possesses an intrinsic system that is intended to delimit tissue injury, as well as orchestrate homoeostatic responses within the heart. The extant literature suggests that this intrinsic stress response is mediated, at least in part, by a family of pattern recognition receptors that belong to the innate immune system, including CD14, the soluble pattern recognition receptor for lipopolysaccharide, and Toll like receptors-2, 3, 4, and 6. Although this intrinsic stress response system provides a short-term adaptive response to tissue injury, the beneficial effects of this phylogenetically ancient system may be lost if myocardial expression of these molecules either becomes sustained and/or excessive, in which case the salutary effects of activation of these pathways may be contravened by the known deleterious effects of inflammatory signaling. Herein we present new information with regard to activation of innate immune gene expression in the failing human heart. Taken together, these new observations provide provisional evidence that the innate immune system is activated in human heart failure, raising the interesting possibility that this pathway may represent a target for the development of novel heart failure therapeutics.


Activated NKT Cells Can Condition Different Splenic Dendritic Cell Subsets To Respond More Effectively to TLR Engagement and Enhance Cross-Priming.
The function of dendritic cells (DCs) can be modulated through multiple signals, including recognition of pathogen-associated molecular patterns, as well as signals provided by rapidly activated leukocytes in the local environment, such as innate-like T cells. In this article, we addressed the possibility that the roles of different murine DC subsets in cross-priming CD8(+) T cells can change with the nature and timing of activatory stimuli. We show that CD8α(+) DCs play a critical role in cross-priming CD8(+) T cell responses to circulating proteins that enter the spleen in close temporal association with ligands for TLRs and/or compounds that activate NKT cells. However, if NKT cells are activated first, then CD8α(-) DCs become conditioned to respond more vigorously to TLR ligation, and if triggered directly, these cells can also contribute to priming of CD8(+) T cell responses. In fact, the initial activation of NKT cells can condition multiple DC subsets to respond more effectively to TLR ligation, with plasmacytoid DCs making more IFN-α and both CD8α(+) and CD8α(-) DCs manufacturing more IL-12. These results suggest that different DC subsets can contribute to T cell priming if provided appropriately phased activatory stimuli, an observation that could be factored into the design of more effective vaccines.


A Spectroscopic Approach to Unravel the Local Conformations of a G-Quadruplex Using CD-Active Fluorescent Base Analogues.
The formation of a stable G-quadruplex (GQ) can inhibit the increased telomerase activity that is common in most cancers. The global structure and the thermal stability of the GQs are usually evaluated by spectroscopic methods and thermal denaturation properties. However, most biochemical processes involving GQs might require local conformational changes at the guanine tetrad (G4) level. These local conformational changes of individual G4 layers during protein and drug interactions have not yet been explored in detail. In this study, we monitored the local conformations of individual G4 layers in GQs using 6-methylisoxanthopterine (6MI) chromophores, which are circular dichroism (CD)-active fluorescent base analogues of guanine, as local conformational probes. A synthetic, tetramolecular, parallel GQ with site-specifically positioned 6MI monomers or dimers was used as the experimental construct. Analytical ultracentrifugation studies and gel electrophoretic studies showed that properly positioned 6MI monomers and dimers could form stable GQs with CD-active fluorescent G4 layers. The local conformation of individual fluorescent G4 layers in the GQ structure was then tracked by monitoring the absorbance, fluorescence intensity, thermal melting, fluorescence quenching, and CD changes of the incorporated probes. Overall, these studies showed that site-specifically incorporated fluorescent base analogues could be used as probes to monitor the local conformational changes of individual G4 layers of a GQ structure. This method can be applied to explore the details of small molecule-GQ interaction at the level of the individual G4 layers, which may prove to be useful in designing drugs to treat GQ-related genetic disorders, cancer, and aging.


MRI evidence for preserved regulation of intracranial pressure in patients with cerebral arteriovenous malformations.
The purpose of this study was to investigate intracranial pressure and associated hemo- and hydrodynamic parameters in patients with cerebral arteriovenous malformations AVMs. Thirty consecutive patients with arteriovenous malformations (median age 38.7 years, 27/30 previously treated with radiosurgery) and 30 age- and gender-matched healthy controls were investigated on a 3.0T MR scanner. Nidus volume was quantified on dynamic MR angiography. Total arterial cerebral blood flow (tCBF), venous outflow as well as aqueductal and craniospinal stroke volumes were obtained using velocity-encoded cine-phase contrast MRI. Intracranial volume change during the cardiac cycle was calculated and intracranial pressure (ICP) was derived from systolic intracranial volume change (ICVC) and pulse pressure gradient. TCBF was significantly higher in AVM patients as compared to healthy controls (median 799 vs. 692 mL/min, p=0.007). There was a trend for venous flow to be increased in both the ipsilateral internal jugular vein (IJV, 282 vs. 225 mL/min, p=0.16), and in the contralateral IJV (322 vs. 285 mL/min, p=0.09), but not in secondary veins. There was no significant difference in median ICP between AVM patients and control subjects (6.9 vs. 8.6 mmHg, p=0.30) and ICP did not correlate with nidus volume in AVM patients (ρ=-0.06, p=0.74). There was a significant positive correlation between tCBF and craniospinal CSF stroke volume (ρ=0.69, p=0.02). The elevated cerebral blood flow in patients with AVMs is drained through an increased flow in IJVs but not secondary veins. ICP is maintained within ranges of normal and does not correlate with nidus volume.


Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I.
The calcineurin inhibitors ciclosporin (cyclosporine) and tacrolimus are immunosuppressant drugs used for the prevention of organ rejection following transplantation. Both agents are metabolic substrates for cytochrome P450 (CYP) 3A enzymes--in particular, CYP3A4 and CYP3A5--and are transported out of cells via P-glycoprotein (ABCB1). Several single nucleotide polymorphisms (SNPs) have been identified in the genes encoding for CYP3A4, CYP3A5 and P-glycoprotein, including CYP3A4 -392A>G (rs2740574), CYP3A5 6986A>G (rs776746), ABCB1 3435C>T (rs1045642), ABCB1 1236C>T (rs1128503) and ABCB1 2677G>T/A (rs2032582). The aim of this review is to provide the clinician with an extensive overview of the recent literature on the known effects of these SNPs on the pharmacokinetics of ciclosporin and tacrolimus in solid-organ transplant recipients. Literature searches were performed, and all relevant primary research articles were critiqued and summarized. Influence of the CYP3A4 -392A>G SNP on the pharmacokinetics of either ciclosporin or tacrolimus appears limited. Variability in CYP3A4 expression due to environmental factors is likely to be more important than patient genotype. Influence of the CYP3A5 6986A>G SNP on the pharmacokinetics of ciclosporin is also uncertain and likely to be small. CYP3A4 may play a more dominant role than CYP3A5 in the metabolism of ciclosporin. The CYP3A5 6986A>G SNP has a well established influence on the pharmacokinetics of tacrolimus. Several studies in kidney, heart and liver transplant recipients have reported an approximate halving of tacrolimus dose-adjusted trough concentrations and doubling of tacrolimus dose requirements in heterozygous or homozygous carriers of a CYP3A5*1 wild-type allele compared with homozygous carriers of a CYP3A5*3 variant allele. Carriers of a CYP3A5*1 allele take a longer time to reach target blood tacrolimus concentrations. Influence of ABCB1 3435C>T, 1236C>T and 2677G>T/A SNPs on the pharmacokinetics of ciclosporin and tacrolimus remains uncertain, with inconsistent results. Genetic linkage between the three variant genotypes suggests that the pharmacokinetic effects are complex and not related to any one ABCB1 SNP. It is likely that these polymorphisms exert a small but combined effect, which is additive to the effects of the CYP3A5 6986A>G SNP. In liver transplant patients, recipient and donor liver genotypes may act together in determining overall drug disposition, hence the importance of assessing both. Studies with low patient numbers may account for many inconsistent results to date. Meta-analyses of the current data should help resolve some discrepancies. The majority of studies have only evaluated the effects of individual SNPs; however, multiple polymorphisms may interact to produce a combined effect. Further haplotype analyses are likely to be useful. It is not yet clear whether pharmacogenetic profiling of calcineurin inhibitors will be a useful clinical tool for personalizing immunosuppressant therapy.


Genome-Wide Identification and Comprehensive Analysis of the FtsH Gene Family in Soybean (Glycine max).
The filamentation temperature-sensitive H (FtsH) gene family is critical in regulating plant chloroplast development and photosynthesis. It plays a vital role in plant growth, development, and stress response. Although FtsH genes have been identified in a wide range of plants, there is no detailed study of the FtsH gene family in soybean (Glycine max). Here, we identified 34 GmFtsH genes, which could be categorized into eight groups, and GmFtsH genes in the same group had similar structures and conserved protein motifs. We also performed intraspecific and interspecific collinearity analysis and found that the GmFtsH family has large-scale gene duplication and is more closely related to Arabidopsis thaliana. Cis-acting elements analysis in the promoter region of the GmFtsH genes revealed that most genes contain developmental and stress response elements. Expression patterns based on transcriptome data and real-time reverse transcription quantitative PCR (qRT-PCR) showed that most of the GmFtsH genes were expressed at the highest levels in leaves. Then, GO enrichment analysis indicated that GmFtsH genes might function as a protein hydrolase. In addition, the GmFtsH13 protein was confirmed to be localized in chloroplasts by a transient expression experiment in tobacco. Taken together, the results of this study lay the foundation for the functional determination of GmFtsH genes and help researchers further understand the regulatory network in soybean leaf development.


Role of steroid dose in hypertension early after liver transplantation with tacrolimus (FK506) and cyclosporine.
Transplant immunosuppression using either cyclosporine (CsA) or tacrolimus (FK506) leads to renal vasoconstriction and nephrotoxicity. Despite producing similar effects within the kidney and blood vessels, clinical hypertension occurs less frequently with tacrolimus during the first year after transplantation, compared with CsA. To examine the role of steroid dose in early posttransplant hypertension, we measured blood pressure and kidney function in liver transplant recipients treated with tacrolimus and either high-dose (TAC-HI-P, n = 19) or low-dose (TAC-LO-P,n = 20) prednisone, compared with CsA-treated recipients (n = 29) receiving prednisone doses similar to the TAC-HI-P group. At 1 month, hypertension occurred more often with CsA (72%) than with TAC-HI-P (42%, P < 0.05) or TAC-LO-P (30%, P < 0.05). By 4 months after transplantation, hypertension developed in nearly twice as many TAC-HI-P (63%) as TAC-LO-P patients (32%, P < 0.05), with no difference between TAC-HI-P and CsA (86%, NS). Daily prednisone dose at 1 month closely paralleled cumulative steroid dose in the first month in the TAC-HI-P and TAC-LO-P groups. Fourteen of 19 TAC-HI-P patients (74%) required bolus steroids for treatment of rejection within the first month, compared with 3/20 (15%) TAC-LO-P and 10/29 (34%) CsA recipients. Glomerular filtration rate fell from pretransplant levels at 1 month and 4 months to the same degree in CsA, TAC-HI-P, and TAC-LO-P patients. These results demonstrate a central role for steroid dose in the rate of onset of hypertension early after liver transplantation using tacrolimus immunosuppression. Both daily dose and cumulative dosage, including bolus treatment for rejection, may impact on the development of hypertension. Since prevalence rates rise to levels comparable to CsA by 24 months regardless of steroid dose, hypertension after liver transplant may be mediated by different mechanisms at different stages of the posttransplant course.


Improvement of Flap Necrosis in a Rat Random Skin Flap Model by In Vivo Electroporation-Mediated HGF Gene Transfer.
Despite great understanding of underlying mechanisms for flap necrosis and advances in surgical techniques, flap necrosis remains a critical issue. In the present study, the authors investigated the efficacy of electroporation-mediated hepatocyte growth factor (HGF) gene delivery to random dorsal skin flaps (McFarlane) to accelerate wound healing and reduce flap necrosis. Fifteen male Wistar rats (290 to 320 g) were divided randomly into three groups. Group a, the control group (n = 5), underwent surgery and received no gene transfer. Group b received electroporation-mediated HGF gene delivery 24 hours after surgery as a treatment. Group c received electroporation-mediated HGF gene delivery 24 hours before surgery as prophylaxis (n = 5). Planimetry, laser Doppler imaging, and immunohistochemistry were used to assess the efficacy of HGF gene therapy among the groups. Electroporation-mediated HGF gene delivery significantly decreased flap necrosis percentage compared with the control group in prophylactic and treatment groups (p = 0.0317 and p = 0.0079, respectively) and significantly increased cutaneous perfusion compared with the control group (p = 0.0317 and p = 0.0159, respectively). Moreover, Spearman rank correlation showed a significant negative correlation between flap necrosis percentage and laser index (p = 0.0213 and r = -0.5964, respectively). Furthermore, significantly higher mean CD31 vessel density was detected in treatment and prophylactic groups (p = 0.0079 and p = 0.0159, respectively). In addition, quantitative image analysis revealed significantly higher HGF protein expression in groups b and c (p = 0.0079 and p = 0.0079, respectively). These findings suggested in vivo electroporation-mediated HGF gene delivery enhanced viability and vascularity of the ischemic skin flap.


Unique and concise system translation matrices for evaluating optical aberration variations.
New unique and concise translation matrices are derived for evaluating the aberration variations of conceptual and real lenses when the paraxial marginal and chief ray paths are arbitrarily changed. They are helpful in investigating the general behaviors of lenses and optimizing the balanced aberrations of lens components in prime and zoom lenses. These new matrices, with a dimension of 9×9 for monochromatic aberrations and a dimension of 4×4 for chromatic aberrations, are derived based on our earlier algorithms of which four cases with distinct translation factors and matrices are required according to the relationships of the original and new positions of the object and pupil; otherwise, division-by-zero errors or insufficient numerical accuracy will be encountered. As a comparison, the new matrices have several advantages. First, by introducing four meaningful equivalent optical invariants, multiplying the old matrices, and simplifying the new matrices, they have concise expressions to significantly reduce the calculation time. Second, they are unique and always accurate to apply for all kinds of object and pupil positions without suffering any mathematical problems, i.e., four separated algorithms are no longer necessary. Third, due to the unique property, the component contributions of original aberrations to new aberrations can be directly evaluated and analyzed.


[Endothelin-1 in the mechanisms of the nephrotoxic action of x-ray contrast media].
The authors study mechanisms of nephrotoxic action of high-osmolar radiopaque substance (RPS) and the role of endothelin-1, hormonal endothelial factor, in these mechanisms in patients with different variants of chronic glomerulonephritis. Endothelin-1 is a potent endogenic vasoconstrictor participating in regulation of intrarenal hemodynamics and renal function the synthesis of which id related to Ca metabolism. Mechanisms of nephrotoxic action of RPS involve disturbances of Ca metabolism (hypercalcemia), high concentration of blood endothelin-1 which directly correlated with baseline creatinine in the serum and deterioration of renal function after RPS introduction. Ca ions antagonists (corinfar) contribute to prevention of changes in endothelin-1 synthesis relevant renal dysfunction induced by RPS.


One-year outcome after percutaneous coronary intervention in nonagenarians: Insights from the J-PCI OUTCOME registry.
Nonagenarian patients who undergo percutaneous coronary intervention (PCI) are increasing, and a few previous studies have reported their long-term outcomes. However, differences in their long-term outcomes between generations remain unclear. This study aimed to investigate 1-year all-cause and cardiovascular (CV) mortality, and major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, and stroke) of nonagenarian patients who underwent PCI compared with the other elder patients, using a nationwide registration system. The patient-level data registered between January 2017 and December 2017 was extracted from the J-PCI OUTCOME Registry endorsed by the Japanese Association of Cardiovascular Intervention and Therapeutics (CVIT). The one-year all-cause and cardiovascular (CV) mortality, MACE, and major bleeding events were identified. Out of 40,722 patients over 60 years of age, 880 (2.1%) were nonagenarians. For nonagenarians, the 1-year mortality rate was substantial (13.5%). The MACE and CV death rates were also high (8.1%, and 6.8%, respectively) for nonagenarians, and these event rates were approximately 1.5 times higher in nonagenarians than octogenarians. Multivariate regression analysis showed that presentation with cardiogenic shock [hazard ratio (HR) 2.32; 95 confidence intervals (CI): 1.22-4.41], or cardiac arrest (HR 2.91; 90% CI: 1.28-6.62), and use of oral anticoagulants (HR 2.10; 90% CI: 1.07-4.12) were the predictors of 1-year MACE. Even in the contemporary era, nonagenarians who have undergone PCI still face a considerably increased risk for adverse cardiovascular events that reduces long-term survival. In addition to having poorer lesion characteristics, adverse events, including death, MACEs, and major bleeding, occurred 1.5 times more frequently in nonagenarians than in octogenarians.


Involvement of activating NK cell receptors and their modulation in pathogen immunity.
Natural Killer (NK) cells are endowed with cell-structure-sensing receptors providing inhibitory protection from self-destruction (inhibitory NK receptors, iNKRs, including killer inhibitory receptors and other molecules) and rapid triggering potential leading to functional cell activation by Toll-like receptors (TLRs), cytokine receptors, and activating NK cell receptors including natural cytotoxicity receptors (NCRs, i.e., NKp46, NKp46, and NKp44). NCR and NKG2D recognize ligands on infected cells which may be endogenous or may directly bind to some structures derived from invading pathogens. In this paper, we address the known direct or indirect interactions between activating receptors and pathogens and their expression during chronic HIV and HCV infections.


5-Methyl-3-phenyl-isoxazole-4-carb-oxy-lic acid.
In the title compound, C11H9NO3, the phenyl and isoxazole rings form a dihedral angle of 56.64 (8)°. The carb-oxy group is almost in the same plane as the isoxazole ring with a C-C-C-O torsion angle of -3.3 (2)°. In the crystal, pairs of O-H⋯O hydrogen bonds link the mol-ecules into head-to-head dimers. C-H⋯N hydrogen bonds and π-π stacking inter-actions between phenyl rings [centroid-centroid distance = 3.9614 (17)Å] link the dimers into a three-dimensional network.


[Procedure for using adrenomimetic preparations in heart surgery].
On the basis of experience in the use of adrenomimetics in the treatment of acute circulatory disorder in 112 patients who underwent operation on an open heart under extracorporeal circulation, the authors find that these agents are often the only effective measure in the control of low cardiac output that is not caused by hypovolemia. An increase in the cardiac output caused by adrenomimetic with a potent vasoconstrictive effect relieves the peripheral spasm because of the prevalence of their cardiostimulating effect. The doses of the adrenomimetics should be minimum at the beginning of treatment, and then should be doubled subsequently till the necessary effect is produced. It is advisable to combine them with agents which reduce myocardial excitability. Adrenomimetics should not be used as substitutes for measures which cause an effect on the ethiopathogenetic links of circulatory disorders: hypovolemia, hypoxemia, side-effects of anesthesiological agents, vagal hyper-reactions, disorders of the electrolyte balance, etc.


GENERALIST: A latent space based generative model for protein sequence families.
Generative models of protein sequence families are an important tool in the repertoire of protein scientists and engineers alike. However, state-of-the-art generative approaches face inference, accuracy, and overfitting- related obstacles when modeling moderately sized to large proteins and/or protein families with low sequence coverage. Here, we present a simple to learn, tunable, and accurate generative model, GENERALIST: GENERAtive nonLInear tenSor-factorizaTion for protein sequences. GENERALIST accurately captures several high order summary statistics of amino acid covariation. GENERALIST also predicts conservative local optimal sequences which are likely to fold in stable 3D structure. Importantly, unlike current methods, the density of sequences in GENERALIST-modeled sequence ensembles closely resembles the corresponding natural ensembles. Finally, GENERALIST embeds protein sequences in an informative latent space. GENERALIST will be an important tool to study protein sequence variability.


Small ribosomal protein RPS0 stimulates translation initiation by mediating 40S-binding of eIF3 via its direct contact with the eIF3a/TIF32 subunit.
The ribosome translates information encoded by mRNAs into proteins in all living cells. In eukaryotes, its small subunit together with a number of eukaryotic initiation factors (eIFs) is responsible for locating the mRNA's translational start to properly decode the genetic message that it carries. This multistep process requires timely and spatially coordinated placement of eIFs on the ribosomal surface. In our long-standing pursuit to map the 40S-binding site of one of the functionally most complex eIFs, yeast multisubunit eIF3, we identified several interactions that placed its major body to the head, beak and shoulder regions of the solvent-exposed side of the 40S subunit. Among them is the interaction between the N-terminal domain (NTD) of the a/TIF32 subunit of eIF3 and the small ribosomal protein RPS0A, residing near the mRNA exit channel. Previously, we demonstrated that the N-terminal truncation of 200 residues in tif32-Δ8 significantly reduced association of eIF3 and other eIFs with 40S ribosomes in vivo and severely impaired translation reinitiation that eIF3 ensures. Here we show that not the first but the next 200 residues of a/TIF32 specifically interact with RPS0A via its extreme C-terminal tail (CTT). Detailed analysis of the RPS0A conditional depletion mutant revealed a marked drop in the polysome to monosome ratio suggesting that the initiation rates of cells grown under non-permissive conditions were significantly impaired. Indeed, amounts of eIF3 and other eIFs associated with 40S subunits in the pre-initiation complexes in the RPS0A-depleted cells were found reduced; consistently, to the similar extent as in the tif32-Δ8 cells. Similar but less pronounced effects were also observed with the viable CTT-less mutant of RPS0A. Together we conclude that the interaction between the flexible RPS0A-CTT and the residues 200-400 of the a/TIF32-NTD significantly stimulates attachment of eIF3 and its associated eIFs to small ribosomal subunits in vivo.


Choosing a medical school: Advice for applicants.
This article was migrated. The article was marked as recommended. Applying for a medical school place is a challenging step that can have long term consequences. Competition is strong, both for applicants to gain a place and for medical schools to recruit the 'best' applicants. Strategies to increase candidate success flourish, but many are unproven. Potential applicants should invest time and effort in exploring which schools and programs might suit best their particular circumstances and interests. Back-up plans should be considered for both success and failure. Not succeeding first time or at a first-choice school may be disappointing, but there are other paths to success in both medical and non-medical careers. Before accepting an offer, make sure that this is the best choice for the best reasons, and then make the best of whatever follows. In the longer term, career success is shaped more by what happens after than during primary medical education.


Aggregation of biologically important peptides and proteins: inhibition or acceleration depending on protein and metal ion concentrations.
The process of aggregation of proteins and peptides is dependent on the concentration of proteins, and the rate of aggregation can be altered by the presence of metal ions, but this dependence is not always a straightforward relationship. In general, aggregation does not occur under normal physiological conditions, yet it can be induced in the presence of certain metal ions. However, the extent of the influence of metal ion interactions on protein aggregation has not yet been fully comprehended. A consensus has thus been difficult to reach because the acceleration/inhibition of the aggregation of proteins in the presence of metal ions depends on several factors such as pH and the concentration of the aggregated proteins involved as well as metal concentration level of metal ions. Metal ions, like Cu2+, Zn2+, Pb2+ etc. may either accelerate or inhibit aggregation simply because the experimental conditions affect the behavior of biomolecules. It is clear that understanding the relationship between metal ion concentration and protein aggregation will prove useful for future scientific applications. This review focuses on the dependence of the aggregation of selected important biomolecules (peptides and proteins) on metal ion concentrations. We review proteins that are prone to aggregation, the result of which can cause serious neurodegenerative disorders. Furthering our understanding of the relationship between metal ion concentration and protein aggregation will prove useful for future scientific applications, such as finding therapies for neurodegenerative diseases.


Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy: a 5-year cohort study.
Although human immunodeficiency virus (HIV)-related morbidity and mortality rates in patients with advanced HIV infection who are treated with combination antiretroviral drugs have declined, significant metabolic adverse effects associated with these regimens have been increasingly recognized. However, since data from patients studied before and after initiation of protease inhibitor (PI) therapy are scant, the true effect of PIs on these metabolic changes remains unknown. To examine temporal trends in serum glucose and lipid levels after initiation of PI therapy, to assess whether changes are independent of virological response and improvement in disease severity, and to determine risk factors associated with the development of hyperglycemia, hyperlipidemia, and lipodystrophy. A 5-year historical cohort analysis in a population of 221 HIV-infected patients observed in the Infectious Diseases Clinic of a tertiary care center from October 1, 1993, through July 31, 1998. Clinical and laboratory data were retrieved from medical records and a computerized database. The main outcome measure was the incidence of hyperglycemia, hypercholesterolemia, hypertriglyceridemia, and lipodystrophy. Adjusted incidence rate ratios (IRRs) were estimated by means of Poisson regression. In addition, mixed regression analyses were performed to examine effects of PIs on serum lipid and glucose levels, modeled as continuous outcomes. The cumulative incidence of new-onset hyperglycemia, hypercholesterolemia, hypertriglyceridemia, and lipodystrophy was 5%, 24%, 19%, and 13%, respectively. Most of these events occurred after initiation of PI therapy. Protease inhibitors were independently associated with hyperglycemia (adjusted IRR, 5.0; 95% confidence interval [CI], 1. 3-19.4), hypercholesterolemia (adjusted IRR, 2.8; 95% CI, 1.5-5.2), hypertriglyceridemia (adjusted IRR, 6.1; 95% CI, 3.1-11.7), and lipodystrophy (adjusted IRR, 5.1; 95% CI, 1.9-13.9). Anabolic steroids and psychotropic medications were also associated with lipodystrophy. Inclusion of potential intermediate variables (eg, virological suppression and increase in body weight) did not reduce the magnitude of the association with PIs. The association between hypertriglyceridemia and ritonavir was stronger than for other PIs (Wald test, P=.02). In contrast, the incidence of hyperglycemia, hypercholesterolemia, and lipodystrophy did not vary significantly across different PIs. Longitudinal mixed models confirmed that serum lipid levels were more substantially affected by antiretroviral therapy, particularly PIs, than serum glucose levels. Similarly, controlling for surrogate markers did not abolish the strong association between PIs and increase in serum lipid levels. We found an independent association between PI use and hyperglycemia, hyperlipidemia, and lipodystrophy that is not explained by the antiviral and therapeutic effect of PIs.


Reproducibility studies and interlaboratory concordance for androgen assays in female plasma.
We conducted studies to determine the magnitude and sources of variability in androgen assay results and to identify laboratories capable of performing such assays for large epidemiological studies. We studied androstanediol (ADIOL), androstanediol glucuronide (ADIOL G), androstenedione (ADION), androsterone glucuronide (ANDRO G), androsterone sulfate (ANDRO S), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA S), dihydrotestosterone (DHT), and testosterone (TESTO). A single sample of plasma was obtained from five postmenopausal women, five premenopausal women in the midfollicular phase of the menstrual cycle, and five women in the midluteal phase, divided into aliquots, and stored at -70 degrees. Four sets of two coded aliquots from each woman were then sent to participating labs for analysis at monthly intervals over 4 months. Using the logarithm of assay measurements, we estimated the components of variance and three measures of reproducibility. The usual coefficient of variation is a function of the components that are under the control of the laboratory. The intraclass correlation between measurements for a given individual is the proportion of the total variability that is associated with individuals. The minimum detectable relative difference is important to evaluate study feasibility. Results suggest that a single sample of ADIOL G, DHEA, DHEA S, and ANDRO G (with two lab replicates per sample) can be used to discriminate reliably among women in a given menstrual phase or menopausal status. The results for DHT, TESTO, ADION, and ANDRO S are more problematic and suggest that the present measurement techniques should be used with care, especially with midluteal phase women. The results for ADIOL suggest that this assay is not yet ready for use in epidemiological studies.


Rates of Primary and Secondary Syphilis Among White and Black Non-Hispanic Men Who Have Sex With Men, United States, 2014.
Men who have sex with men (MSM) in the United States experience an approximately 100-fold greater rate of primary and secondary (P&S) syphilis diagnoses compared with men who have sex with women only. As in the general population, racial/ethnic disparities in P&S syphilis diagnosis rates may exist among MSM, but MSM-specific P&S syphilis rates by race/ethnicity are unavailable. We enhanced a published modeling approach to estimate area-level MSM populations by race/ethnicity and provide the first estimates of P&S syphilis among black and white non-Hispanic MSM. We used data from the American Community Survey (ACS), published findings from the National Health and Nutrition Examination Survey (NHANES), and national syphilis surveillance data to estimate state-level rates of P&S syphilis diagnoses among MSM, overall and for black and white non-Hispanic MSM. We also used variability around ACS and NHANES estimates to calculate 95% confidence intervals for each rate. Among 11,359 cases of P&S syphilis among MSM with known race/ethnicity in 2014, 72.5% were among white (40.3%) or black (32.2%) MSM. The national rate of P&S syphilis diagnosis was 168.4/100,000 for white MSM and 583.9/100,000 for black MSM. Regional rates for black MSM ranged from 602.0/100,000 (South) to 521.5/100,000 (Midwest) and were consistently higher than those for white MSM. Although white MSM accounted for more P&S syphilis diagnoses than black MSM in 2014, when evaluating diagnoses based on rate per 100,000, black MSM had consistently and markedly higher rates than white MSM, with the highest impacted states located in the US South.


A Guide to Facial Trauma Triage and Precautions in the COVID-19 Pandemic.
COVID-19 is an emerging viral illness that has rapidly transmitted throughout the world. Its impact on society and the health care system has compelled hospitals to quickly adapt and innovate as new information about the disease is uncovered. During this pandemic, essential medical and surgical services must be carried out while minimizing the risk of disease transmission to health care workers. There is an elevated risk of COVID-19 viral transmission to health care workers during surgical procedures of the head and neck due to potential aerosolization of viral particles from the oral cavity/naso-oropharynx mucosa. Thus, patients with facial fractures pose unique challenges to the variety of injuries and special considerations, including triaging injuries and protective measures against infection. The proximity to the oral cavity/naso-oropharyngeal mucosa, and potential for aerosolization of secretions containing viral particles during surgical procedures make most patients undergoing operative interventions for facial fractures high risk for COVID-19 transmission. Our proposed algorithm aims to balance patient care with patient/medical personnel protection as well as judicious health care utilization. It stratifies facial trauma procedures by urgency and assigns a recommended level of personal protective equipment, extreme or enhanced, incorporating current best practices and existing data on viral transmission. As this pandemic continues to evolve and more information is obtained, the protocol can be further refined and individualized to each institution.


Would Adults with Autism be less likely to Bury the Survivors? An Eye Movement Study of Anomalous Text Reading.
In a single eye movement experiment we investigated the effects of context on the time course of local and global anomaly processing during reading in adults with Autism Spectrum Disorder (ASD). In one condition short paragraph texts contained anomalous target words. Detection of the anomaly was only possible through evaluation of word meaning in relation to the global context of the whole paragraph (Passage Level Anomalies). In another condition the anomaly could be detected via computation of a local thematic violation within a single sentence embedded in the paragraph (Sentence Level Anomalies). For the sentence level anomalies the ASD group, in contrast with the typically developing (TD) group, showed early detection of the anomaly as indexed by regressive eye movements from the critical target word upon fixation. Conversely, for the passage level anomalies, and in contrast with the ASD group, the TD group showed early detection of the anomaly, with increased regressive eye movements once the critical word had been fixated. The reversal of the pattern of regression path data for the two groups, for the sentence and passage level anomalies, is discussed in relation to cognitive accounts of ASD.


Emerging role of N6-methyladenosine in the homeostasis of glucose metabolism.
N6-methyladenosine (m6A) is the most prevalent post-transcriptional internal RNA modification, which is involved in the regulation of diverse physiological processes. Dynamic and reversible m6A modification has been shown to regulate glucose metabolism, and dysregulation of m6A modification contributes to glucose metabolic disorders in multiple organs and tissues including the pancreas, liver, adipose tissue, skeletal muscle, kidney, blood vessels, and so forth. In this review, the role and molecular mechanism of m6A modification in the regulation of glucose metabolism were summarized, the potential therapeutic strategies that improve glucose metabolism by targeting m6A modifiers were outlined, and feasible directions of future research in this field were discussed as well, providing clues for translational research on combating metabolic diseases based on m6A modification in the future.


The architecture of respiratory complex I.
Complex I is the first enzyme of the respiratory chain and has a central role in cellular energy production, coupling electron transfer between NADH and quinone to proton translocation by an unknown mechanism. Dysfunction of complex I has been implicated in many human neurodegenerative diseases. We have determined the structure of its hydrophilic domain previously. Here, we report the alpha-helical structure of the membrane domain of complex I from Escherichia coli at 3.9 A resolution. The antiporter-like subunits NuoL/M/N each contain 14 conserved transmembrane (TM) helices. Two of them are discontinuous, as in some transporters. Unexpectedly, subunit NuoL also contains a 110-A long amphipathic alpha-helix, spanning almost the entire length of the domain. Furthermore, we have determined the structure of the entire complex I from Thermus thermophilus at 4.5 A resolution. The L-shaped assembly consists of the alpha-helical model for the membrane domain, with 63 TM helices, and the known structure of the hydrophilic domain. The architecture of the complex provides strong clues about the coupling mechanism: the conformational changes at the interface of the two main domains may drive the long amphipathic alpha-helix of NuoL in a piston-like motion, tilting nearby discontinuous TM helices, resulting in proton translocation.


[Laboratory and clinical studies on T-1982 (cefbuperazone) in the field of pediatrics].
T-1982 (cefbuperazone), a new 7 alpha-methoxycephem antibiotic, was fundamentally and clinically studied, and the following results were obtained. The antibacterial activities of T-1982 against clinical isolates of S. aureus, E. coli, K. pneumoniae, S. marcescens, P. mirabilis and P. aeruginosa were determined in comparison with those of CER, CEZ, CMZ and CTT. Against S. aureus, CER and CEZ exhibited excellent activity, whereas T-1982 was less active with the peak MIC of 12.5 micrograms/ml even with the inoculum size of 10(6) cells/ml. The activity of T-1982 was equal to that of CTT and by far superior to that of CER, CEZ and CMZ against E. coli, K. pneumoniae and P. mirabilis, the peak MICs with the inoculum size of 10(6) cells/ml being less than or equal to 0.1-0.2 microgram/ml, less than or equal to 0.1-0.2 microgram/ml and 0.2-0.39 microgram/ml, respectively. Against S. marcescens, T-1982 was superior to CMZ and CTT and 48% of the strains were inhibited by 3.13 micrograms/ml or less, whereas all the strains were resistant to CER and CEZ. The MIC of T-1982 against most strains of P. aeruginosa was more than 100 micrograms/ml. 10 mg/kg or 20 mg/kg of T-1982 was administered by one shot intravenous injection or 1 hour drip infusion to 23 pediatric patients to measure serum levels and urinary recovery. At 30 minutes after one shot injection of 10 mg/kg and 20 mg/kg, the highest serum levels of 22.0-38.8 micrograms/ml and 52.4-80 micrograms/ml were observed, the half-lives being 1.32 hours and 1.76 hours. When given by 1 hour drip infusion, the serum levels attained the peaks of 29.2-42.6 micrograms/ml and 49.0-75.6 micrograms/ml at the end of infusion, the half-lives being 1.24 hours and 1.19 hours. The urinary recovery rates within 6 hours were 74.2-92.5% and 50.2-66.5% by one shot injection and 63.4-84.2% and 53.9-79.0% by drip infusion. T-1982 was administered at a dose of 50 mg/kg by 30 minutes drip infusion to a child with purulent meningitis. The levels of T-1982 in the cerebrospinal fluid at 1 hour after administration were 4.8-6.7 micrograms/ml with the CSF/serum ratios of 4.4-8.4%. A total of 36 pediatric patients (21 cases of respiratory tract infection, 9 cases of urinary tract infection and each 1 case of purulent cervical lymphadenitis, scarlet fever, purulent meningitis, acute colitis, peritonitis and sinusitis) was treated with 40-80 mg/kg/day of T-1982 (252.6 mg/kg/day in purulent meningitis). The response was excellent in 27 patients and good in 7 patients, the efficacy rate being 94.4%. Diarrhea or eruption were observed in each 1 case. No abnormal laboratory findings were noted in any cases.


Proportional hazards models with random effects to examine centre effects in multicentre cancer clinical trials.
In randomized clinical trials comparing treatment effects on diseases such as cancer, a multicentre trial is usually conducted to accrue the required number of patients within a reasonable period of time. The fundamental point of conducting a multicentre trial is that all participating investigators must agree to follow the common study protocol. However, even with every attempt having been made to standardize the methods for diagnosing severity of disease and evaluating response to treatment, for example, they might be applied differently at different centres, and these may vary from comprehensive cancer centres to university hospitals to community hospitals. Therefore, in multicentre trials there is likely to be some degree of variation (heterogeneity) among centres in both the baseline risks and the treatment effects. While we estimate the overall treatment effect using a summary measure such as hazard ratio and usually interpret it as an average treatment effect over the centre, it is necessary to examine the homogeneity of the observed treatment effects across centres, that is, treatment-by-centre interaction. If the data are reasonably consistent with homogeneity of the observed treatment effects across centres, a single summary measure is adequate to describe the trial results and those results will contribute to the scientific generalization, the process of synthesizing knowledge from observations. On the other hand, if heterogeneity of treatment effects is found, we should carefully interpret the trial results and investigate the reason why the variation is seen. In the analyses of multicentre trials, a random effects approach is often used to model the centre effects. In this article, we focus on the proportional hazards models with random effects to examine centre variation in the treatment effects as well as the baseline risks, and review the parameter estimation procedures, frequentist approach-penalized maximum likelihood method--and Bayesian approach--Gibbs sampling method. We also briefly review the models for bivariate responses. We present a few real data examples from the biometrical literature to highlight the issues.


Management advice for patients with reflux-like symptoms: an evidence-based consensus.
Patients with reflux-like symptoms (heartburn and regurgitation) are often not well advised on implementing individualised strategies to help control their symptoms using dietary changes, lifestyle modifications, behavioural changes or fast-acting rescue therapies. One reason for this may be the lack of emphasis in management guidelines owing to 'low-quality' evidence and a paucity of interventional studies. Thus, a panel of 11 gastroenterologists and primary care doctors used the Delphi method to develop consolidated advice for patients based on expert consensus. A steering committee selected topics for literature searches using the PubMed database, and a modified Delphi process including two online meetings and two rounds of voting was conducted to generate consensus statements based on prespecified criteria (67% voting 'strongly agree' or 'agree with minor reservation'). After expert discussion and two rounds of voting, 21 consensus statements were generated, and assigned strength of evidence and Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) rating. Eleven statements achieved the strongest (100%) agreement: five are related to diet and include identification and avoidance of dietary triggers, limiting alcohol, coffee and carbonated beverages, and advising patients troubled by postprandial symptoms not to overeat; the remaining six statements concern advice around smoking cessation, weight loss, raising the head-of-the-bed, avoiding recumbency after meals, stress reduction and alginate use. The aim of developing the consensus statements is that they may serve as a foundation for tools and advice that can routinely help patients with reflux-like symptoms better understand the causes of their symptoms and manage their individual risk factors and triggers.


Hierarchical watermarking for secure image authentication with localization.
Several fragile watermarking schemes presented in the literature are either vulnerable to vector quantization (VQ) counterfeiting attacks or sacrifice localization accuracy to improve security. Using a hierarchical structure, we propose a method that thwarts the VQ attack while sustaining the superior localization properties of blockwise independent watermarking methods. In particular, we propose dividing the image into blocks in a multilevel hierarchy and calculating block signatures in this hierarchy. While signatures of small blocks on the lowest level of the hierarchy ensure superior accuracy of tamper localization, higher level block signatures provide increasing resistance to VQ attacks. At the top level, a signature calculated using the whole image completely thwarts the counterfeiting attack. Moreover, "sliding window" searches through the hierarchy enable the verification of untampered regions after an image has been cropped. We provide experimental results to demonstrate the effectiveness of our method.


Effects of glucocorticoids and interleukin-1 beta on expression and activity of aggrecanases in equine chondrocytes.
To determine effects of interleukin (IL)-1 beta and glucocorticoids on total glycosaminoglycan (GAG) loss and aggrecanase-mediated matrix degradation in equine cartilage. Cartilage from 24 equine cadavers free of sepsis and musculoskeletal disease. Effects of IL-1 beta, IL-1 beta with glucocorticoids (dexamethasone and triamcinolone, 10(-6) and 10(-7)M), and glucocorticoids alone on degradation of equine articular and nasal cartilage explants were assessed by measuring GAG release in media and GAG content in cartilage. Aggrecanase-mediated cleavage within the interglobular domain at Glu373-Ala374 was evaluated via western blot analysis and ELISAs. Steady-state mRNA concentrations of matrix metalloproteinase (MMP)-3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)4, and ADAMTS5 were assessed by use of real-time reverse transcriptase PCR assay (cartilage explants) and northern blot analysis (cell culture). IL-1 beta increased GAG release and aggrecanase activity (11-fold). The MMP-3, MMP-13, and ADAMTS4 mRNA were upregulated with IL-1 beta, whereas ADAMTS5 mRNA was increased (13-fold), but significantly less than ADAMTS4 mRNA (27-fold), suggesting a role for both ADAMTS4 and ADAMTS5 in degradation of cytokine-stimulated cartilage. Despite downregulation of MMP-3 and MMP-13 mRNA, glucocorticoids did not alter GAG degradation. A further increase in aggrecanase activity was detected with ELISAs and western blot analysis, whereas ADAMTS4 mRNA was downregulated and ADAMTS5 mRNA was maintained or upregulated. MMP-3, MMP-13, and ADAMTS4 were regulated differently than ADAMTS5. Glucocorticoids increased aggrecanase activity despite down-regulation of ADAMTS4 mRNA, suggesting a major role of ADAMTS5. Effects of glucocorticoids on aggrecanase activity have important implications in terms of treatment.


Granulocyte colony-stimulating factor enhances interleukin 3-dependent proliferation of multipotential hemopoietic progenitors.
In cultures of spleen cells from normal mice, recombinant human granulocyte colony-stimulating factor (G-CSF) supported the formation of multipotential blast cell colonies. Serial replating of the blast cell colonies in the presence of G-CSF, however, failed to demonstrate any direct effect of G-CSF on murine multipotential progenitors. We therefore examined the effects of G-CSF in combination with murine interleukin 3 on proliferation of murine blast cell colony-forming cells. The time course of total colony formation and multilineage colony formation by spleen cells harvested from mice 4 days after injection of 5-fluorouracil at 150 mg/kg was significantly shortened in cultures containing both factors in contrast with cultures supported by either factor alone. Serial observations of individual multipotential blast cell colonies (mapping) revealed that blast cell colonies emerged at random time intervals in the presence of interleukin 3 or G-CSF. The appearance of blast cell colonies, however, was significantly hastened in cultures containing both factors relative to cultures grown with either factor. In cultures of day-2 post-5-fluorouracil bone marrow cells, G-CSF in concentrations as low as 1 unit/ml revealed synergism with interleukin 3 in supporting the proliferation of multipotential progenitors. This synergistic activity may explain the previous in vivo studies suggesting the effects of G-CSF on apparent multipotential stem cells.


Calprotectin as a Biomarker for Diagnosis and Severity of Acute Noninfectious Anterior Uveitis in Egyptian Patients.
To study the relation between serum calprotectin level and acute noninfectious anterior uveitis in Egyptian patients. An observational prospective study carried out at Menoufia University Hospital during the period from March 2021 till June 2022, after informed consent from all studied patients. This study included 20 eyes of patients with Acute Anterior Uveitis (AAU) and 20 eyes healthy individuals matched sex and age as the control group. Full history taking, ophthalmological examination and serum calprotectin levels were performed for both patients and controls. Serum calprotectin levels were substantially higher in patients' eyes with acute anterior uveitis than in healthy eyes (61.45±7.89 vs 32.50±11.64; 95% CI: 22.58-35.32; P < 0.001). ROC curve analysis showed that the cut-off point of serum calprotectin in severity detection of AAU was ≥58.0, with sensitivity of 95%, specificity of 43% at AUC of 0.986, with reached to significant level (p < 0.001). Serum calprotectin levels were significantly elevated with positive previous uveitis and marked grade indicating a possible role of calprotectin in the pathogenesis of non-infectious AAU. The serum calprotectin cut-off points for severity detection of AAU were 58.0, with sensitivity of 95% and specificity of 43%. Finally, we identified serum calprotectin as a potential biomarker for detection of anterior uveitis severity and patients' morbidity risk. Further investigation with large sample size is needed to assess the relationship between calprotectin and uveitis activity.