Benign prostatic hyperplasia: an update on minimally invasive therapy including Aquablation.
Lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) is a common condition affecting older men. New interventional treatments have emerged and evolved over the years, each with their own distinct efficacy and safety profiles. While some have fallen out of favor, new options continue to be explored. We provide a review and update on minimally invasive treatment modalities for BPH, including prostatic artery embolization (PAE), Aquablation, convective water vapor thermal therapy (Rezum), and prostatic urethral lift (Urolift). While current urologic guidelines recommend against PAE outside of the context of clinical trials, Aquablation, Rezum, and Urolift have demonstrated excellent efficacy and durability in relieving LUTS in the BPH patient. When compared to the gold standard, transurethral resection of the prostate (TURP), these novel therapies yield equivalent or superior objective outcomes, with the additional benefit of significantly reduced sexual side effects. Additionally, Rezum and Urolift may be performed as outpatient procedures under local anesthesia, allowing for decreased hospitalizations, operative times, catheterization duration, and financial burden on the health care system. Aquablation, Rezum and Urolift are minimally invasive surgical treatment options capable of providing rapid, significant, and durable relief of LUTS secondary to BPH. Each technique demonstrates comparable efficacy to TURP with the added advantages of preserving sexual function, decreasing patient morbidity, and limiting healthcare costs.


Pediatric osteosarcoma: therapeutic strategies, results, and prognostic factors derived from a 10-year experience.
Ninety-eight pediatric patients were treated with three separate protocols (Treatment and investigation of Osteosarcoma [TIOS] I, II, and III) and 47 developed recurrent disease (metastases and/or local recurrence). Actuarial overall disease-free survival (hereafter designated survival) was 43%. Over 90% of the patients were treated initially with preoperative intraarterial cisplatin (CDP). Postoperative chemotherapeutic regimens comprised high-dose methotrexate with leucovorin rescue (MTX-CF), Adriamycin [( ADR] doxorubicin; Adria Laboratories, Columbus, OH), and cyclophosphamide. Primary definitive treatment comprised amputation or limb salvage (TIOS I and TIOS III). Patients treated with preoperative CDP and surgery (TIOS I and III) had a 62% survival. Patients in TIOS II refused surgical extirpation; they were treated exclusively with chemotherapy and had a 23% survival. Survival in patients treated with amputation was 55% and limb salvage 58%. Prognostic factors considered significant in relation to development of pulmonary metastases comprised tumor burden (P = .04) and the percentage of tumor necrosis induced by preoperative chemotherapy (P = .01). Histopathologic subtype was marginally significant: chondroblastic was more favorable as opposed to osteoblastic (P = .05). These findings are compared with results and prognostic factors published in the literature.


The use of gold nanoparticles to enhance radiotherapy in mice.
Mice bearing subcutaneous EMT-6 mammary carcinomas received a single intravenous injection of 1.9 nm diameter gold particles (up to 2.7 g Au/kg body weight), which elevated concentrations of gold to 7 mg Au/g in tumours. Tumour-to-normal-tissue gold concentration ratios remained approximately 8:1 during several minutes of 250 kVp x-ray therapy. One-year survival was 86% versus 20% with x-rays alone and 0% with gold alone. The increase in tumours safely ablated was dependent on the amount of gold injected. The gold nanoparticles were apparently non-toxic to mice and were largely cleared from the body through the kidneys. This novel use of small gold nanoparticles permitted achievement of the high metal content in tumours necessary for significant high-Z radioenhancement.


Fertility in undescended testes.
Since 1956 many children with undescended testes have been treated at the Red Cross War Memorial Children's Hospital in Cape Town, and in this article the conesequent degree of fertility achieved by orchidopexy, the method of treatment, is appraised. In 567 children the condition was unilateral, and in 202 it was bilateral. Assessment of potential fertility in 76 unilateral and in 29 bilateral cases was mainly by semen analysis; the average age of the youths at the time of the examination was 19 years, and parenthood was therefore regarded as an unsuitable criterion for assessment. Four hundred and ninety-two youths had their condition reviewed, and the condition of 587 testes was assessed. The anatomical state of the testes was ascertained to help in the assessment, but also, and of greater importance, to obtain evidence of the usefulness of orchidopexy for cosmetic or psychological benefit. Biopsy of the affected testes, carried out in some, proved to be nor more informative than the anatomical appraisal, with regard to spermatogenesis. Two useful facts emerged from the study. About 10% of bilateral undescended testes are capable of normal spermatogenesis after orchidopexy, and 65% are sterile, while the fertility of persons with unilateral undescended testis is impaired, 28% having little hope of paternity, and 4% no hope at all.


Investigating the feasibility and acceptability of a cognitive behavioural suicide prevention therapy for people in acute psychiatric wards (the 'INSITE' trial): study protocol for a randomised controlled trial.
Suicide is a major cause of preventable death, and suicidal behaviour is prevalent in acute psychiatric wards. People admitted to acute psychiatric wards often experience repeated episodes of suicidal behaviour, causing great distress and heavy use of NHS services. There is little research investigating effective psychological treatments for suicidal patients in inpatient settings although previous research has found support for psychological therapies which specifically target suicidal behaviour. This paper describes the protocol of a single blind RCT to investigate the acceptability and feasibility of a cognitive behavioural intervention targeting suicidality (CBSP) for suicidal people in acute psychiatric wards. A single blind RCT comparing treatment as usual (TAU) to TAU plus Cognitive Behavioural Suicide Prevention (CBSP) therapy (TAU + CBSP). Sixty participants (aged 18-65 years) who are suicidal, or have been within the past 3 months, will be recruited from NHS trusts in the North West of England. Our primary objective is to determine whether CBSP is feasible, acceptable and efficacious when compared to patients who receive TAU alone. Secondary aims are the impact of CBSP on suicidal thinking, behaviours, functioning, quality of life, service use and psychological factors associated with suicide. Assessments take place at baseline, 6 weeks and 6 months (end of treatment). The analysis will report on the feasibility and acceptability of CBSP. Qualitative data from staff and service users will inform feasibility and acceptability data. Psychiatric inpatients are a high-risk group and the use of psychological therapies in these settings is rare and requires evaluation. This study is essential to investigate the unique contextual challenges involved in delivering psychological therapy to suicidal inpatients and to identify any necessary modifications required within inpatient settings. The findings will inform a larger, definitive trial. 15 March 2012, PB-PG-1111-26026, NIHR ISRCTN17890126 .


Susceptibility of Legionella pneumophila grown extracellularly and in human monocytes to indole-3-propionic acid.
Indole-3-propionic acid (IPA), a phytohormone derivative, is a potent inhibitor of growth of Legionella pneumophila cultivated extracellularly in a chemically defined hypotonic medium and intracellularly in human monocytes. The inhibitory activity turns into bactericidal activity with increasing concentrations. The susceptibility of the microorganism to IPA was more evident in "fast-growing" cultures (under conditions of vigorous shaking) than in static cultures growing under an atmosphere of 5% CO2-95% air, which resulted in a decreased growth rate. The MIC, after incubation with the drug for 48 h and as determined by counting of the CFU, was 1.58 microM for fast-growing cultures and 2.64 microM for those grown under static conditions. The MBCs were 5.28 and 26.43 microM, respectively. Tryptophan (Trp) at 150 microM prevented the inhibition caused by 2.64 microM IPA, increased the MIC about 3-fold, and increased the MBC by 10-fold. The effect of Trp was less remarkable in "slow-growing" cultures. The susceptibility of L. pneumophila proliferating in human monocytes was markedly lower than that when it was cultivated extracellularly in the chemically defined hypotonic medium. The MIC after incubation for 48 h was 5.28 microM, and a decrease in viable count was achieved with 105.70 microM. The lower susceptibility was apparently due (at least partially) to the presence of Trp (24.50 microM) in the RPMI 1640 medium that was used for the monocyte cultures. The effect of IPA was time dependent, and prolonged exposure enhanced the bactericidal activity and turned the inhibitory dose into a bactericidal dose. The present data demonstrate that IPA is a potent anti-L. pneumophila factor, although it has a markedly lower activity against bacteria growing intracellularly compared with its activity against extracellularly proliferating microorganisms.


Trends in the management of splenic trauma.
During the 20-year period ending December 1987, 179 consecutive splenic trauma patients were treated at a single institution. Procedures included splenectomy in 121 (67%) patients, splenectomy with autotransplantation in 7 (4%), splenorrhaphy in 23 (13%), laparotomy alone in 7 (4%), and nonoperative management in 21 (12%). Before 1976, all patients were treated by splenectomy. Since 1980, 18 (22%) were treated nonoperatively, 26 (33%) by splenic salvage techniques, and 36 (45%) by splenectomy. We conclude that nonoperative therapy and splenic salvage techniques are being employed with increasing frequency. Selective application of splenorrhaphy for injuries with a realistic expectation of success has resulted in no late procedures for hemorrhage. In the presence of severe splenic or associated injuries, splenectomy remains the procedure of choice.


Prevalence of sleep problems and habits among children in Saudi Arabia: A cross-sectional study.
To investigate children's sleep problems, habits, and lifestyle changes. A cross-sectional study was carried out in Riyadh, Saudi Arabia, over a period of 2 months, from August through September 2022, with parents of children aged 2-14 years after reviewing the literature and formulating a validated Google questionnaire containing 30 questions related to sleep habits, problems, and disorders. In total, 585 questionnaires were included in the analysis. The sample comprised 345 (59%) males and 240 (41%) females. The mean age of patients was 7 (range: 2-14) years. Bed-time resistance was the most prevalent sleep problem (70.3%), followed by sleep-onset delay (58.1%), difficulty waking up in the morning on weekdays (41.3%), weekends (38%), and interrupted sleep (31%). An alarmingly high prevalence of hyperactivity (41.8%) and aggressive behaviour (42.2%) was noted. Co-sleeping with parents was reported in 41% of children. Night terror was reported in 20.6% and 26.5% in nightmares. Statistically significant associations were noted between screen time, snoring, and witnessed apnoea with sleep problems. Sleep problems are common among children in Saudi Arabia. The study sheds some light on sleep habits and practices in this age group in Saudi Arabia, such as the high prevalence of bed-time resistance and sleep-onset delay, hyperactivity, and sleep-affecting culprits such as screen time, snoring, and witnessed apnoea.


A critical discussion of the use of antiseptics in acute traumatic wounds.
Approximately 10 million patients with traumatic wounds are treated in US emergency departments annually. The practice of wound cleansing or antiseptic management has a dichotomous history anchored in tradition and science. The merits of antiseptic fluid irrigation of traumatic wounds have received little scientific study. The purpose of this article is to critically evaluate the potential harm to patient outcome by the use of antiseptics on acute wounds. First, animal and cell culture data that describe the effects of topical antiseptics on wound healing are offered. Second, human case studies are presented to illustrate the potential harm of the indiscriminate use of antiseptics. Finally, data from previously published reviews are presented and evaluated for clinically based evidence to justify the current practice of antiseptic use in acute traumatic wounds.


A Janus-Faced Bacterium: Host-Beneficial and -Detrimental Roles of Cutibacterium acnes.
The bacterial species Cutibacterium acnes (formerly known as Propionibacterium acnes) is tightly associated with humans. It is the dominant bacterium in sebaceous regions of the human skin, where it preferentially colonizes the pilosebaceous unit. Multiple strains of C. acnes that belong to phylogenetically distinct types can co-exist. In this review we summarize and discuss the current knowledge of C. acnes regarding bacterial properties and traits that allow host colonization and play major roles in host-bacterium interactions and also regarding the host responses that C. acnes can trigger. These responses can have beneficial or detrimental consequences for the host. In the first part of the review, we highlight and critically review disease associations of C. acnes, in particular acne vulgaris, implant-associated infections and native infections. Here, we also analyse the current evidence for a direct or indirect role of a C. acnes-related dysbiosis in disease development or progression, i.e., reduced C. acnes strain diversity and/or the predominance of a certain phylotype. In the second part of the review, we highlight historical and recent findings demonstrating beneficial aspects of colonization by C. acnes such as colonization resistance, immune system interactions, and oxidant protection, and discuss the molecular mechanisms behind these effects. This new insight led to efforts in skin microbiota manipulation, such as the use of C. acnes strains as probiotic options to treat skin disorders.


Revealing signaling pathway deregulation by using gene expression signatures and regulatory motif analysis.
Gene expression signatures consisting of tens to hundreds of genes have been found to be informative for different biological states. Recently, many computational methods have been proposed for biological interpretation of such signatures. However, there is a lack of methods for identifying cell signaling pathways whose deregulation results in an observed expression signature. We present a strategy for identifying such signaling pathways and evaluate the strategy using six human and mouse gene expression signatures.


Evaluation of physical and mechanical properties of porous poly (ethylene glycol)-co-(L-lactic acid) hydrogels during degradation.
Porous hydrogels of poly(ethylene glycol) (PEG) have been shown to facilitate vascularized tissue formation. However, PEG hydrogels exhibit limited degradation under physiological conditions which hinders their ultimate applicability for tissue engineering therapies. Introduction of poly(L-lactic acid) (PLLA) chains into the PEG backbone results in copolymers that exhibit degradation via hydrolysis that can be controlled, in part, by the copolymer conditions. In this study, porous, PEG-PLLA hydrogels were generated by solvent casting/particulate leaching and photopolymerization. The influence of polymer conditions on hydrogel architecture, degradation and mechanical properties was investigated. Autofluorescence exhibited by the hydrogels allowed for three-dimensional, non-destructive monitoring of hydrogel structure under fully swelled conditions. The initial pore size depended on particulate size but not polymer concentration, while degradation time was dependent on polymer concentration. Compressive modulus was a function of polymer concentration and decreased as the hydrogels degraded. Interestingly, pore size did not vary during degradation contrary to what has been observed in other polymer systems. These results provide a technique for generating porous, degradable PEG-PLLA hydrogels and insight into how the degradation, structure, and mechanical properties depend on synthesis conditions.


Pregnancy outcome after ultrasound diagnosis of fetal intra-abdominal umbilical vein varix.
Fetal intra-abdominal umbilical vein (FIUV) varix is a focal dilatation of the intra-abdominal portion of the umbilical vein, which has been reported to be associated with intrauterine death and other anomalies. Our aim was to examine our experience with this diagnosis at a single tertiary-care center and to correlate it with clinical outcome. This was a retrospective case series study. Our ultrasound database was searched for all cases with a diagnosis of FIUV varix identified at our facility between 1997 and 2007. We reviewed all ultrasound examinations, maternal antenatal records, delivery records and newborns' medical records. We identified 52 cases of FIUV among a population of approximately 68,000. Three cases of trisomy 21 were identified, all of which were accompanied by other anomalies. There was intrauterine death of one fetus with trisomy 21 at 35 weeks of gestation. We did not find an association between FIUV varix and other obstetric complications. The outcome of pregnancies with FIUV varix is generally favorable. The finding of a FIUV varix should prompt the search for other anomalies, especially markers of aneuploidy.


Reaction time performance in upper airway resistance syndrome versus obstructive sleep apnea syndrome.
Patients with obstructive sleep apnea syndrome (OSAS) are known to have an increased risk for motor vehicle crashes. They suffer from sleep-related respiratory abnormality causing repetitive arousal leading to daytime sleepiness. In turn, it has been demonstrated that sleepiness can impair human psychomotor performance causing slowing of reaction times (RTs). Patients with OSAS present with RTs comparable to young adults under the influence of blood alcohol concentrations above the legally permitted level to drive a motor vehicle. Vigilance related risk levels in patients with upper airway resistance syndrome (UARS) and potential deficits in psychomotor performance are unknown. We designed a study to compare psychomotor performance in UARS and compared it to patients with OSAS. Forty-seven UARS patients were matched by gender and age with 47 OSAS patients. All subjects completed a standardized vigilant attention task utilizing reaction time before undergoing polygraphic sleep studies. Patients with UARS presented worse psychomotor performance on most test metrics than patients with OSAS. Our study results may suggest that patients with UARS may also present an increased risk for motor vehicle crashes as previously demonstrated in OSAS patients.


Postnatal changes in critical cardiac output and oxygen transport in conscious lambs.
We lowered cardiac output progressively in a controlled, stepwise fashion in conscious, unsedated lambs to determine the critical cardiac output or systemic oxygen delivery (the level at which oxygen consumption decreased abruptly). With the use of incremental inflation of a balloon-tipped catheter placed in the right atrium to lower cardiac output, we examined the response of oxygen consumption, systemic oxygen transport, fractional oxygen extraction, arterial lactate, and blood pressure. We studied lambs at 2 (n = 5), 4 (n = 5), and 8 wk (n = 6) of age and found that the 4-wk-old lambs reached critical values of cardiac output and systemic oxygen transport with the smallest proportional decreases from base-line values. Therefore, the 4-wk-old lambs were the least tolerant of acute decreases in cardiac output. We also found that fractional oxygen extraction was able to increase even after critical systemic oxygen transport was achieved. Furthermore, we found at every age that lactic acid accumulation began when the critical level of cardiac output was reached.


Multiple ventricular premature beats in five adolescents.
Multiple, short runs of repetitive ventricular premature beats are present in 5 adolescents. These premature beats are continually present, uniform, long and variably coupled and occasionally fuse with sinus beats. This pattern is constant over several years and is associated with generally healthy individuals and otherwise normal hearts. Four of the subjects are completely asymptomatic without syncope or palpitations. The 5th case was asymptomatic for 2 yr until she died suddenly during sleep. Autopsy revealed a pathology of the specialized conduction system in the region of the AV junction. The distinctive pattern and characteristics of this arrhythmia suggest a congenital etiology and a mechanism different from other forms of ventricular ectopia. The single incident of sudden death indicates that this disorder is not benign.


Immunological studies of ribonuclease C from human urine.
Antiserum to human urinary RNase C [ribonuclease (pancreatic), EC 18.104.22.168], developed in rabbits, was used to characterize this enzyme through studies of inhibition of RNase C-catalyzed poly(C) hydrolysis and of competition in a RIA. By either assay, the antiserum failed to cross react with human urinary RNase U (EC 3.1.27.-) or bovine pancreatic RNase A (EC 22.214.171.124). RNase C is immunologically identical to the poly(C)-active RNase in various human sera, including samples obtained from normal individuals, patients with pancreatic carcinoma, pancreatitis, or other malignant and nonmalignant diseases. This conclusion is based on the finding of superimposable antibody dose-inhibition curves for poly(C) hydrolysis and parallel competition RIA curves for RNase C and the various sera. There was a positive correlation (r = 0.73; p less than 0.001) between concentrations of RNase C as determined by poly(C) hydrolysis and competition RIA in serum samples from 102 patients. Therefore, the latter technique provides al alternative method for measuring RNase C in sera.


Periostin expression and epithelial-mesenchymal transition in cancer: a review and an update.
Periostin, also called osteoblast-specific factor 2, is a secreted cell adhesion protein, which shares a homology with the insect cell adhesion molecule fasciclin I. It has been shown to be an important regulator of bone and tooth formation and maintenance, and of cardiac development and healing. Recent studies revealed that periostin plays an important role in tumor development and is upregulated in a wide variety of cancers such as colon, pancreatic, ovarian, breast, head and neck, thyroid, and gastric cancer as well as in neuroblastoma. Periostin binding to the integrins activates the Akt/PKB- and FAK-mediated signaling pathways which lead to increased cell survival, angiogenesis, invasion, metastasis, and importantly, epithelial-mesenchymal transition of carcinoma cells. In this review we summarize recent clinicopathological studies that have investigated periostin expression in lung, kidney, prostate, liver cancer, and malignant pleural mesothelioma and discuss the role of periostin isoforms in tumorigenesis and their potential as targets for stroma-targeted anticancer therapy.


Sustainable chronic disease management in remote Australia.
The Sharing Health Care Initiative (SHCI) demonstration project, which aimed to improve management of chronic diseases, was implemented in four small remote communities in the Katherine region which are serviced by the Katherine West Health Board, a remote Aboriginal-community-controlled health organisation in the Northern Territory. We reviewed the project proposal, final report, evaluation reports and transitional funding proposal, and supplemented these with in-depth interviews with key individuals. We determined factors critical to the sustainability of the SHCI project in relation to context, community engagement, systems flexibility and adaptability, the availability and effect of information systems, and the human nature of health care and policy. The project had a significant impact on community awareness of chronic disease and an improvement in clinic processes. We found that a number of interrelated factors promoted sustainability, including: An implementation strategy sufficiently flexible to take account of local conditions; A high level of community engagement; Appropriate timeframes, timing and congruence between national policy and local readiness to implement a chronic disease project; Effective communication between participating organisations; Project champions (key individuals) in participating organisations; Effective use of monitoring and evaluation data; and Adequate and ongoing funding. The absence of a number of these factors, such as poor communication, inhibited sustainability. Other factors could both promote and inhibit. For example, the impact of key individuals was important, but could be idiosyncratic and have negative effects.


Epigenetic Regulation of Antibody Responses by the Histone H2A Deubiquitinase MYSM1.
B cell-mediated antibody response plays critical roles in protective immunity, as well as in the pathogenesis of allergic and autoimmune diseases. Epigenetic histone and DNA modifications regulate gene transcription and immunity; however, so far, little is known about the role of epigenetic regulation in antibody responses. In this study, we found that mice deficient in the histone H2A deubiquitinase MYSM1, despite their severe defect in B cell development, exhibit an enhanced antibody response against both T cell-dependent and independent antigens. We revealed that MYSM1 intrinsically represses plasma cell differentiation and antibody production. Mechanistic studies demonstrated that MYSM1 is a transcriptional activator of Pax5, the repressors of plasma cell differentiation, by facilitating key transcriptional factor recruitment and coordinating histone modifications at the Pax5 loci. Hence, this study uncovers a critical role for MYSM1 in epigenetically repressing plasma cell differentiation and antibody production, in addition to its opposing, active role in B cell development. Importantly, this study further provides a new target and strategy to modulate antibody production and responses with profound therapeutic implications.


Multifunctionalized iron oxide nanoparticles for selective drug delivery to CD44-positive cancer cells.
Nanomedicine nowadays offers novel solutions in cancer therapy and diagnosis by introducing multimodal treatments and imaging tools in one single formulation. Nanoparticles acting as nanocarriers change the solubility, biodistribution and efficiency of therapeutic molecules, reducing their side effects. In order to successfully apply these novel therapeutic approaches, efforts are focused on the biological functionalization of the nanoparticles to improve the selectivity towards cancer cells. In this work, we present the synthesis and characterization of novel multifunctionalized iron oxide magnetic nanoparticles (MNPs) with antiCD44 antibody and gemcitabine derivatives, and their application for the selective treatment of CD44-positive cancer cells. The lymphocyte homing receptor CD44 is overexpressed in a large variety of cancer cells, but also in cancer stem cells (CSCs) and circulating tumor cells (CTCs). Therefore, targeting CD44-overexpressing cells is a challenging and promising anticancer strategy. Firstly, we demonstrate the targeting of antiCD44 functionalized MNPs to different CD44-positive cancer cell lines using a CD44-negative non-tumorigenic cell line as a control, and verify the specificity by ultrastructural characterization and downregulation of CD44 expression. Finally, we show the selective drug delivery potential of the MNPs by the killing of CD44-positive cancer cells using a CD44-negative non-tumorigenic cell line as a control. In conclusion, the proposed multifunctionalized MNPs represent an excellent biocompatible nanoplatform for selective CD44-positive cancer therapy in vitro.


Resveratrol has protective effects against airway remodeling and airway hyperreactivity in a murine model of allergic airways disease.
New therapies for asthma which can address three main interrelated features of the disease, airway inflammation, airway remodeling and airway hyperreactivity, are urgently required. Resveratrol, a well known red wine polyphenol has received much attention due to its potential anti-aging properties. This compound is an agonist of silent information regulator two histone deacetylases and has many effects that are relevant to key aspects of the pathophysiology of asthma including inflammation, cell proliferation and fibrosis. Therefore, resveratrol may offer a novel asthma therapy that simultaneously inhibits airway inflammation, and airway remodeling which are the main contributors to airway hyperreactivity and irreversible lung function loss. We evaluated the effects of systemic resveratrol treatment in a murine model of chronic allergic airways disease which displays most of the clinicopathological features of severe human asthma. Wild-type Balb/c mice with allergic airways disease were treated with 12.5 mg/kg resveratrol or vehicle control. Airway inflammation was assessed by bronchoalveolar lavage fluid cell counts and histological examination of lung tissue sections. Further, remodeling was assessed by morphometric analysis and lung function was assessed by invasive plethysmography measurement of airway resistance and dynamic compliance. Mice treated with resveratrol exhibited reduced tissue inflammation as compared to vehicle treated mice (p<0.05). Additionally, resveratrol treatment resulted in reduced subepithelial collagen deposition as compared to vehicle treated mice (p<0.05) and attenuated airway hyperreactivity (p<0.05). These novel findings demonstrate that treatment with resveratrol can reduce structural airway remodeling changes and hyperreactivity. This has important implications for the development of new therapeutic approaches to asthma.


Serotonergic, noradrenergic and dopaminergic markers are related to cognitive function in adults with 22q11 deletion syndrome.
Patients with 22q11 deletion syndrome (22q11DS) have a high prevalence of psychiatric disorders and intellectual disability. At present the neurobiology underlying psychopathology in 22q11DS is still not understood. In the present study, we analyzed urinary serotonergic, dopaminergic and noradrenergic markers in 67 adults with 22q11DS. Levels of serotonin and the catecholamine metabolite homovanillic acid were significantly lower in the 22q11DS subjects compared to healthy controls. Within the 22q11DS group, levels of dopamine, homovanillic acid, norepinephrine, vanillyl mandelic acid and serotonin positively correlated with Full Scale Intelligence Quotient scores. Our results suggest that cognitive deficits in 22q11DS are associated with abnormal function of several neurotransmitters.


Limited Cross-Protection against Infectious Bronchitis Provided by Recombinant Infectious Bronchitis Viruses Expressing Heterologous Spike Glycoproteins.
Gammacoronavirus infectious bronchitis virus (IBV) causes an economically important respiratory disease of poultry. Protective immunity is associated with the major structural protein, spike (S) glycoprotein, which induces neutralising antibodies and defines the serotype. Cross-protective immunity between serotypes is limited and can be difficult to predict. In this study, the ability of two recombinant IBV vaccine candidates, BeauR-M41(S) and BeauR-4/91(S), to induce cross-protection against a third serotype, QX, was assessed. Both rIBVs are genetically based on the Beaudette genome with only the S gene derived from either M41 or 4/91, two unrelated serotypes. The use of these rIBVs allowed for the assessment of the potential of M41 and 4/91 S glycoproteins to induce cross-protective immunity against a heterologous QX challenge. The impact of the order of vaccination was also assessed. Homologous primary and secondary vaccination with BeauR-M41(S) or BeauR-4/91(S) resulted in a significant reduction of infectious QX load in the trachea at four days post-challenge, whereas heterologous primary and secondary vaccination with BeauR-M41(S) and BeauR-4/91(S) reduced viral RNA load in the conjunctiva-associated lymphoid tissue (CALT). Both homologous and heterologous vaccination regimes reduced clinical signs and birds recovered more rapidly as compared with an unvaccinated/challenge control group. Despite both rIBV BeauR-M41(S) and BeauR-4/91(S) displaying limited replication in vivo, serum titres in these vaccinated groups were higher as compared with the unvaccinated/challenge control group. This suggests that vaccination with rIBV primed the birds for a boosted humoral response to heterologous QX challenge. Collectively, vaccination with the rIBV elicited limited protection against challenge, with failure to protect against tracheal ciliostasis, clinical manifestations, and viral replication. The use of a less attenuated recombinant vector that replicates throughout the respiratory tract could be required to elicit a stronger and prolonged protective immune response.


Borderline Personality Disorder in the Emergency Department: Good Psychiatric Management.
Patients with borderline personality disorder (BPD) are high utilizers of psychiatric emergency services and present unique challenges in that setting. Frequently advised to visit an emergency department (ED) if safety is in question, their experiences once there often do not have beneficial effects. Issues specific to patients with BPD in the ED include volatile interactions with staff, repeat visits, concerns about safety (and liability), and disposition. Emergency department staff attitudes toward these patients are frequently negative when compared to patients with other diagnoses, and can detrimentally affect outcomes and perpetuate stigma regarding BPD. These attitudes are often due to lack of education and training about how to understand, approach, and treat the patient with BPD. The limited literature regarding the treatment of BPD in the ED offers few guidelines. This article presents an approach based on Good Psychiatric Management that can reduce negative reactions by ED staff and make ED visits more effective and less harmful. Relevant principles include psychoeducation, the reinforcement of the connection between symptoms and interpersonal stressors, and employment of an active, authentic therapeutic stance. Training ED staff in these principles could lead to attitudinal changes, reduced stigma, and potentially improved outcomes.


Litigation in arthroscopic surgery: a 20-year analysis of legal actions in France.
The main objective of this study was to identify the epidemiological characteristics of litigation following arthroscopic procedures, performed in private practice and public hospitals in France. The secondary objective was to establish a risk profile for medical malpractice lawsuits after arthroscopic surgery. All court decisions related to arthroscopic surgery between 1994 and 2020 were collected and reviewed cases from the two main French legal databases (Legifrance and Doctrine). Data were retrospectively collected and included: gender, joint and defendant's specialty involved, reason behind the lawsuit, initial indication and the type of arthroscopic procedure performed. The final verdicts as well as the indemnity awarded to the plaintiff (if any) were recorded. One-hundred eighty cases met the inclusion criteria of the study and were analyzed: 58 cases were before administrative courts and 122 were before civil courts. An orthopaedic surgeon was involved alone or in solidum in 45.6% of cases (82/180), followed by anesthesiologists in 5.6% (10/180). The private surgery center or public hospital were implicated in 63.9% (115/180) of cases. The 2 most common joints involved in litigation following arthroscopic surgery were the knee (82.2%, n = 148) and the shoulder (11.1%, n = 20). The main reasons behind the lawsuit were related to postoperative infection in 78/180 cases and to a musculoskeletal complication in 45/180 cases (25%). A failure to inform was also reported in 34/180 cases (18.9%). Of the 180 cases, 122 cases (67.8%) resulted in a verdict for the plaintiff. The average indemnity award for the plaintiff was 77.984 euros [2.282-1.117.667]. A verdict for the plaintiff was significantly associated with postoperative infection or a wrong-side surgery, while technical error and musculoskeletal complications were more significantly likely to result in a verdict in favor of the defendant (p = 0.003). This study evaluated and mapped lawsuits following after arthroscopic surgery in France over a period of more than 20 years. The main joint involved in lawsuits was knee. The main causes of lawsuits following arthroscopic surgery were related to postoperative infection, musculoskeletal complications and failure to inform. Level IV.


Effect of water restriction during growth and adulthood on kidney morphology of bobwhite quail.
We raised bobwhite quail (Colinus virginianus) either with unrestricted water (HYD birds) or with restricted water (DEH birds). DEH quail grew more slowly and reached lower adult body mass. Despite this, kidney mass was not different in the two groups. The number of nephrons per kidney, heterogeneity of glomerular sizes, number of medullary cones per kidney, and lengths of medullary cones (equivalent to the lengths of the longest loops of Henle) did not differ between HYD and DEH quail. However, the mass of an individual medullary cone was greater in the DEH birds; this included both hypertrophy and hyperplasia of the epithelia in thick ascending limbs of Henle and hypertrophy without hyperplasia in the collecting ducts. We found no differences among groups in the sizes of tubule cross sections from cortical nephron segments (proximal tubules). Water restriction of HYD birds for 5 days as adults stimulated tubule hypertrophy but not to the same extent as the chronic regimen and with no evidence for hyperplasia. DEH quail given unrestricted water as adults maintained elevated drinking rates for the full week water was available; this rehydration had no effect on sizes of tubule epithelia.


Epidermal growth factor receptors and cyclooxygenase-2 in the pathogenesis of non-small cell lung cancer: potential targets for chemoprevention and systemic therapy.
The epidermal growth factor receptor (EGFR) is part of a family of plasma membrane receptor tyrosine kinases that control many important cellular functions, from growth and proliferation to cell death. Cyclooxygenase (COX)-2 is an enzyme which catalyses the conversion of arachidonic acid to prostagladins and thromboxane. It is induced by various inflammatory stimuli, including the pro-inflammatory cytokines, Interleukin (IL)-1beta, Tumour Necrosis Factor (TNF)-alpha and IL-2. Both EGFR and COX-2 are over-expressed in non-small cell lung cancer (NSCLC) and have been implicated in the early stages of tumourigenesis. This paper considers their roles in the development and progression of lung cancer, their potential interactions, and reviews the recent progress in cancer therapies that are directed toward these targets. An increasing body of evidence suggests that selective inhibitors of both EGFR and COX-2 are potential therapeutic agents for the treatment of NSCLC, in the adjuvant, metastatic and chemopreventative settings.


Age-related changes in thyroid function: a longitudinal study of a community-based cohort.
In cross-sectional studies, serum TSH concentrations increase with age. This has not been examined longitudinally, and it is uncertain whether the TSH increase reflects healthy aging or occult thyroid failure. We measured serum TSH, free T(4), thyroid peroxidase, and thyroglobulin antibodies in 1100 participants in the 1981 and 1994 Busselton Health Surveys and derived a reference group of 908 individuals without thyroid disease or thyroid antibodies. We examined changes in thyroid function longitudinally and, in 781 participants, explored associations with the CAPZB polymorphism rs10917469. At 13 yr follow-up, mean serum TSH increased from 1.49 to 1.81 mU/liter, a change in mean TSH (ΔTSH) of 0.32 mU/liter [95% confidence interval (CI) 0.27, 0.38, P < 0.001], whereas mean free T(4) concentration was unchanged (16.6 vs. 16.6 pmol/liter, P = 0.7). The TSH increase was most marked in the elderly, such that gender-adjusted ΔTSH increased by 0.08 mU/liter (95% CI 0.04, 0.11) for each decade of baseline age. People with higher baseline TSH values had proportionally smaller increases in TSH, with each additional 1.0 mU/liter of baseline TSH associated with a 0.13 mU/liter decrease (age and gender adjusted) in ΔTSH (95% CI 0.09, 0.16). The ΔTSH did not differ significantly by CAPZB genotype. Aging is associated with increased serum TSH concentrations, with no change in free T(4) concentrations. The largest TSH increase is in people with the lowest TSH at baseline. This suggests that the TSH increase arises from age-related alteration in the TSH set point or reduced TSH bioactivity rather than occult thyroid disease.


Structure-function associations of successful associative encoding.
Functional magnetic resonance imaging (MRI) studies have demonstrated a critical role of hippocampus and inferior frontal gyrus (IFG) in associative memory. Similarly, evidence from structural MRI studies suggests a relationship between gray-matter volume in these regions and associative memory. However, how brain volume and activity relate to each other during associative-memory formation remains unclear. Here, we used joint independent component analysis (jICA) to examine how gray-matter volume and brain activity would be associated during associative encoding, especially in medial-temporal lobe (MTL) and IFG. T1-weighted images were collected from 27 young adults, and functional MRI was employed during intentional encoding of object pairs. A subsequent recognition task tested participants' memory performance. Unimodal analyses using voxel-based morphometry revealed that participants with better associative memory showed larger gray-matter volume in left anterior hippocampus. Results from the jICA revealed one component that comprised a covariance pattern between gray-matter volume in anterior and posterior MTL and encoding-related activity in IFG. Our findings suggest that gray matter within the MTL modulates distally distinct parts of the associative encoding circuit, and extend previous studies that demonstrated MTL-IFG functional connectivity during associative memory tasks.


[The frequency of recurrences and metastases of bladder cancer following a radical course of radiotherapy].
The authors compare the incidence of bladder carcinoma recurrences and dissemination after long-distance gamma-beam therapy, carried out according to a traditional method, and in an accelerated hyperfractionation mode combined with metronidazole therapy. The recurrences were most frequently detected at the site of the primary tumor (62-67% of cases) in 6 to 18 months after the treatment. They come to a conclusion that accelerated hyperfractionation and local metronidazole radio-modification were conducive to a reduction of the incidence of recurrences from 45 to 28% as against the traditional split radiotherapy course in the classical fractionation mode.


Interactions between Muscle and Bone-Where Physics Meets Biology.
Muscle and bone interact via physical forces and secreted osteokines and myokines. Physical forces are generated through gravity, locomotion, exercise, and external devices. Cells sense mechanical strain via adhesion molecules and translate it into biochemical responses, modulating the basic mechanisms of cellular biology such as lineage commitment, tissue formation, and maturation. This may result in the initiation of bone formation, muscle hypertrophy, and the enhanced production of extracellular matrix constituents, adhesion molecules, and cytoskeletal elements. Bone and muscle mass, resistance to strain, and the stiffness of matrix, cells, and tissues are enhanced, influencing fracture resistance and muscle power. This propagates a dynamic and continuous reciprocity of physicochemical interaction. Secreted growth and differentiation factors are important effectors of mutual interaction. The acute effects of exercise induce the secretion of exosomes with cargo molecules that are capable of mediating the endocrine effects between muscle, bone, and the organism. Long-term changes induce adaptations of the respective tissue secretome that maintain adequate homeostatic conditions. Lessons from unloading, microgravity, and disuse teach us that gratuitous tissue is removed or reorganized while immobility and inflammation trigger muscle and bone marrow fatty infiltration and propagate degenerative diseases such as sarcopenia and osteoporosis. Ongoing research will certainly find new therapeutic targets for prevention and treatment.


Characterization in vitro and in vivo of progressively adriamycin-resistant B16-BL6 mouse melanoma cells.
Adriamycin (ADR)-resistant sublines of B16-BL6 mouse melanoma selected by exposure to increasing concentrations of ADR were characterized in vitro for growth properties and in vivo for tumorigenicity and pulmonary metastases. The progressively resistant sublines adapted to grow in the presence of 0.025, 0.05, 0.1, and 0.25 microgram/ml ADR in monolayer culture were found to be 5-, 10-, 20-, and 40-fold ADR-resistant, respectively, compared to the parental sensitive cells, using a soft-agar colony assay and continuous ADR treatment for 7 days. The doubling time in monolayer culture of the parent sensitive and progressively ADR-resistant sublines of B16-BL6 melanoma cells was approximately 16-18 h. Although the colony-forming efficiency in soft agar of parental sensitive cells was only 0.5-4%, the 5-, 10-, 20-, and 40-fold ADR-resistant sublines had colony-forming efficiencies of 15, 20, 30, and 77%, respectively. Tumorigenicity in C57BL/6 mice of progressively ADR-resistant sublines was similar to parental sensitive cells following s.c. and i.p. implantation of 10(5)-10(6) tumor cells. Experimental pulmonary metastases were significantly lower in ADR-resistant sublines with progressive resistance. Additionally, unlike the parental sensitive and 5-fold ADR-resistant B16-BL6 cells, the 10-, 20-, and 40-fold ADR-resistant sublines were spontaneously nonmetastatic. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunochemical detection of P-glycoprotein revealed the presence of a Mr 170,000 plasma membrane glycoprotein in the 40-fold ADR-resistant subline and its counterpart maintained for 1 year in ADR-free medium. Results from this study suggest that progressively ADR-resistant B16-BL6 mouse melanoma cells selected in vitro demonstrate a marked increase in colony formation in soft agar and a decrease in the ability to produce pulmonary metastases, without alterations in tumorigenicity.


Burn plasma mediates cardiac myocyte apoptosis via endotoxin.
Thermal trauma is associated with cardiac myocyte apoptosis in vivo. To determine whether cardiac myocyte apoptosis could be secondary to burn-induced cytokines or inflammatory mediators, we investigated the effects of tumor necrosis factor-alpha (TNF-alpha) and burn plasma on a murine cardiac myocyte cell line and primary culture myocytes. HL-1 cells were exposed to plasma isolated from burned or sham rats. Burn, but not sham plasma, induced significant increases in caspase-3 activity and DNA fragmentation. Similar results were obtained in primary culture rat myocytes. A dose-dependent increase in caspase-3 activity was observed when HL-1 cells were incubated with increasing concentrations of TNF-alpha. Even though TNF-alpha increased apoptosis, enzyme-linked immunosorbent assay detected no TNF-alpha in burn plasma. Burn plasma also failed to induce TNF-alpha mRNA, eliminating an autocrine mechanism of TNF-alpha secretion and binding. Also, treatment of burn plasma containing rhuTNFR:Fc failed to inhibit apoptosis. To examine the possibility that endotoxin within burn plasma might account for the apoptotic effect, burn plasma was preincubated with rBPI(21). Caspase-3 activity was reduced to control levels. These data indicate that burn plasma induces apoptosis in cardiac myocytes via an endotoxin-dependent mechanism and suggest that systemic inhibition of endotoxin may provide a therapeutic approach for treatment of burn-associated cardiac dysfunction.


Non-specific bronchial hyper-responsiveness in children with allergic rhinitis: relationship with the atopic status.
An increased prevalence of bronchial hyper-responsiveness (BHR) has been demonstrated in children from a general population, and in non-asthmatic adults with allergic rhinitis. Thus, also children with allergic rhinitis are expected to be at higher risk of BHR. We evaluated the prevalence of BHR in a sample of non-asthmatic children with allergic rhinitis by means of the methacholine (Mch) bronchial challenge, and by monitorizing the airway patency using the daily peak expiratory flow variability (PEFv). Fifty-one children (ranged 6-15 years of age) with allergic rhinitis, ascertained by skin prick test to inhalant allergens, underwent a 14-day peak expiratory flow monitoring, and a Mch bronchial provocation challenge. Thirty healthy children matched for age, and sex served as control group. Thirty-one children in the rhinitis group (61%), and six (20%) in the control group were Mch+ (Mch provocative dose causing a 20% fall of forced expiratory volume in 1 s respect to baseline <2250 microg, equivalent to 11.50 micromol). In rhinitic children the PEFv did not significantly differ between Mch+ and Mch- subjects, but the total serum immunoglobulin E (IgE) were higher among Mch+. The persistent form of rhinitis was significantly associated to Mch positivity. Non-asthmatic children with allergic rhinitis displayed a high prevalence of BHR. The BHR was significantly associated with persistent rhinitis and with higher total IgE levels. Nevertheless, the spontaneous changes in airway patency, as expressed by PEFv, were within normal limits both in Mch+ and Mch- children.


Hepatic steatosis associated with microsporidiosis in teleost fishes from Marajó Island, Brazil.
A total of 40 specimens of the teleost fish Gobioides grahamae Palmer & Wheeler, 1955 were obtained from the municipality of Salvaterra on Marajó Island in the Brazilian state of Pará. Their livers were removed and processed for light microscopy. Overall, 90% of the specimens presented some degree of steatosis of the liver, which was invariably associated with the presence of Microsporidium sp. The present study confirms the occurrence of steatosis in G. grahamae associated with parasitic infections by Microsporidium. The findings indicate that the condition of otherwise healthy fishes in their natural environment may be affected negatively by parasites.


Estimation of Study Time Reduction Using Surrogate End Points Rather Than Overall Survival in Oncology Clinical Trials.
Surrogate end points in oncology trade the advantage of reducing the time needed to conduct clinical trials for the disadvantage of greater uncertainty regarding the treatment effect on patient-centered end points, such as overall survival (OS) and quality of life. To quantify the amount of time saved through the acceptance of surrogate end points, including response rate (RR) and progression-free survival (PFS). This retrospective study of US Food and Drug Administration (FDA) oncology approvals and their drug registration trials based on actual publication analyzed the original and updated clinical trials data that led to FDA-approved drug indications in oncology from 2006 to 2017 by using existing publications, conference abstracts, and package inserts from the FDA. Data related to cancer type, line of therapy (first-line, second-line, and third- or later-line treatment of advanced or metastatic disease), FDA approval type, end point basis for approval (RR, PFS, or OS/quality of life), sample size, accrual rate, and drug RR were extracted by March 23, 2018. All data were analyzed by July 13, 2018. The main outcome was the study duration needed to complete the primary end point analysis used for each drug indication approval. This was estimated from reported enrollment dates, analysis cutoff dates, time to response, median duration of response, median PFS, and median OS. In total, 188 distinct indications among 107 cancer drugs were identified. The RR was more often used for FDA approval in subsequent lines of therapy (17 of 71 drug indications [24%] in first-line therapy vs 34 of 77 drug indications [44%] in second-line therapy vs 19 of 24 drug indications [79%] in third- or later-line therapy, P < .001). Study duration for PFS (median, 31 [range, 10-104] months) was similar to that for OS (median, 33 [range, 12-117] months; P = .31), whereas study duration for RR (median, 25 [range, 11-54] months) was shorter than that for OS (P = .001). In multivariate analysis, compared with using OS, use of PFS as the end point was associated with study durations that were shorter by a mean of 11 months (95% CI, 5-17 months), and the use of RR as the end point was associated with study durations that were shorter by a mean of 19 months (95% CI, 13-25 months). From the findings of this study, an estimated 11 months appeared to be needed (ie, approximately 12% longer in the drug development cycle) to assess the OS benefit of a cancer drug. This study's findings suggest that this must be weighed against the downside of increased uncertainty of clinical benefit arising from using surrogate end points.


Effects of nickel treatment on H3K4 trimethylation and gene expression.
Occupational exposure to nickel compounds has been associated with lung and nasal cancers. We have previously shown that exposure of the human lung adenocarcinoma A549 cells to NiCl(2) for 24 hr significantly increased global levels of trimethylated H3K4 (H3K4me3), a transcriptional activating mark that maps to the promoters of transcribed genes. To further understand the potential epigenetic mechanism(s) underlying nickel carcinogenesis, we performed genome-wide mapping of H3K4me3 by chromatin immunoprecipitation and direct genome sequencing (ChIP-seq) and correlated with transcriptome genome-wide mapping of RNA transcripts by massive parallel sequencing of cDNA (RNA-seq). The effect of NiCl(2) treatment on H3K4me3 peaks within 5,000 bp of transcription start sites (TSSs) on a set of genes highly induced by nickel in both A549 cells and human peripheral blood mononuclear cells were analyzed. Nickel exposure increased the level of H3K4 trimethylation in both the promoters and coding regions of several genes including CA9 and NDRG1 that were increased in expression in A549 cells. We have also compared the extent of the H3K4 trimethylation in the absence and presence of formaldehyde crosslinking and observed that crosslinking of chromatin was required to observe H3K4 trimethylation in the coding regions immediately downstream of TSSs of some nickel-induced genes including ADM and IGFBP3. This is the first genome-wide mapping of trimethylated H3K4 in the promoter and coding regions of genes induced after exposure to NiCl(2). This study may provide insights into the epigenetic mechanism(s) underlying the carcinogenicity of nickel compounds.


Data ambiguity and clinical decision making: A qualitative case study of the use of predictive information technologies in a personalized cancer clinical trial.
Personalized medicine aims to tailor the treatment to the specific characteristics of the individual patient. In the process, physicians engage with multiple sources of data and information to decide on a personalized treatment. This article draws on a qualitative case study of a clinical trial testing a method for matching treatments for advanced cancer patients. Specialists in the trial used data and information processed by a specifically developed drug-efficacy predictive algorithm and other information artifacts to make personalized clinical decisions. While using high-resolution data in the trial was expected to provide a more accurate basis for action, sociomaterial engagements of oncologists with data and its representation by artifacts paradoxically hindered personalized clinical decisions. I contend that the engagement between human discretion, ambiguous data, and malleable artifacts in this non-standardized trial produced moments of contradiction within entanglement. Sociomaterial approaches should acknowledge such conflicts in further analyses of medical practice transitions.


Invasion success depends on invader body size in a size-structured mixed predation-competition community.
1. The size of an individual is an important determinant of its trophic position and the type of interactions it engages in with other heterospecific and conspecific individuals. Consequently an individual's ecological role in a community changes with its body size over ontogeny, leading to that trophic interactions between individuals are a size-dependent and ontogenetically variable mixture of competition and predation. 2. Because differently sized individuals thus experience different biotic environments, invasion success may be determined by the body size of the invaders. Invasion outcome may also depend on the productivity of the system as productivity influences the biotic environment. 3. In a laboratory experiment with two poeciliid fishes the body size of the invading individuals and the daily amount of food supplied were manipulated. 4. Large invaders established persistent populations and drove the resident population to extinction in 10 out of 12 cases, while small invaders failed in 10 out of 12 trials. Stable coexistence was virtually absent. Invasion outcome was independent of productivity. 5. Further analyses suggest that small invaders experienced a competitive recruitment bottleneck imposed on them by the resident population. In contrast, large invaders preyed on the juveniles of the resident population. This predation allowed the large invaders to establish successfully by decreasing the resident population densities and thus breaking the bottleneck. 6. The results strongly suggest that the size distribution of invaders affects their ability to invade, an implication so far neglected in life-history omnivory systems. The findings are further in agreement with predictions of life-history omnivory theory, that size-structured interactions demote coexistence along a productivity gradient.


A Human Proteome Array Approach to Identifying Key Host Proteins Targeted by Toxoplasma Kinase ROP18.
Toxoplasma kinase ROP18 is a key molecule responsible for the virulence of Toxoplasma gondii; however, the mechanisms by which ROP18 exerts parasite virulence via interaction with host proteins remain limited to a small number of identified substrates. To identify a broader array of ROP18 substrates, we successfully purified bioactive mature ROP18 and used it to probe a human proteome array. Sixty eight new putative host targets were identified. Functional annotation analysis suggested that these proteins have a variety of functions, including metabolic process, kinase activity and phosphorylation, cell growth, apoptosis and cell death, and immunity, indicating a pleiotropic role of ROP18 kinase. Among these proteins, four candidates, p53, p38, UBE2N, and Smad1, were further validated. We demonstrated that ROP18 targets p53, p38, UBE2N, and Smad1 for degradation. Importantly, we demonstrated that ROP18 phosphorylates Smad1 Ser-187 to trigger its proteasome-dependent degradation. Further functional characterization of the substrates of ROP18 may enhance understanding of the pathogenesis of Toxoplasma infection and provide new therapeutic targets. Similar strategies could be used to identify novel host targets for other microbial kinases functioning at the pathogen-host interface.


Morphometric network differences in ageing versus Alzheimer's disease dementia.
Age being the main risk factor for Alzheimer's disease, it is particularly challenging to disentangle structural changes related to normal brain ageing from those specific to Alzheimer's disease. Most studies aiming to make this distinction focused on older adults only and on a priori anatomical regions. Drawing on a large, multi-cohort dataset ranging from young adults (n = 468; age range 18-35 years), to older adults with intact cognition (n = 431; age range 55-90 years) and with Alzheimer's disease (n = 50 with late mild cognitive impairment and 71 with Alzheimer's dementia, age range 56-88 years), we investigated grey matter organization and volume differences in ageing and Alzheimer's disease. Using independent component analysis on all participants' structural MRI, we first derived morphometric networks and extracted grey matter volume in each network. We also derived a measure of whole-brain grey matter pattern organization by correlating grey matter volume in all networks across all participants from the same cohort. We used logistic regressions and receiver operating characteristic analyses to evaluate how well grey matter volume in each network and whole-brain pattern could discriminate between ageing and Alzheimer's disease. Because increased heterogeneity is often reported as one of the main features characterizing brain ageing, we also evaluated interindividual heterogeneity within morphometric networks and across the whole-brain organization in ageing and Alzheimer's disease. Finally, to investigate the clinical validity of the different grey matter features, we evaluated whether grey matter volume or whole-brain pattern was related to clinical progression in cognitively normal older adults. Ageing and Alzheimer's disease contributed additive effects on grey matter volume in nearly all networks, except frontal lobe networks, where differences in grey matter were more specific to ageing. While no networks specifically discriminated Alzheimer's disease from ageing, heterogeneity in grey matter volumes across morphometric networks and in the whole-brain grey matter pattern characterized individuals with cognitive impairments. Preservation of the whole-brain grey matter pattern was also related to lower risk of developing cognitive impairment, more so than grey matter volume. These results suggest both ageing and Alzheimer's disease involve widespread atrophy, but that the clinical expression of Alzheimer's disease is uniquely associated with disruption of morphometric organization.


The unfolded protein response impacts melanoma progression by enhancing FGF expression and can be antagonized by a chemical chaperone.
The mechanisms hallmarking melanoma progression are insufficiently understood. Here we studied the impact of the unfolded protein response (UPR) - a signalling cascade playing ambiguous roles in carcinogenesis - in melanoma malignancy. We identified isogenic patient-derived melanoma cell lines harboring BRAFV600E-mutations as a model system to study the role of intrinsic UPR in melanoma progression. We show that the activity of the three effector pathways of the UPR (ATF6, PERK and IRE1) was increased in metastatic compared to non-metastatic cells. Increased UPR-activity was associated with increased flexibility to cope with ER stress. The activity of the ATF6- and the PERK-, but not the IRE-pathway, correlated with poor survival in melanoma patients. Using whole-genome expression analysis, we show that the UPR is an inducer of FGF1 and FGF2 expression and cell migration. Antagonization of the UPR using the chemical chaperone 4-phenylbutyric acid (4-PBA) reduced FGF expression and inhibited cell migration and viability. Consistently, FGF expression positively correlated with the activity of ATF6 and PERK in human melanomas. We conclude that chronic UPR stimulates the FGF/FGF-receptor signalling axis and promotes melanoma progression. Hence, the development of potent chemical chaperones to antagonize the UPR might be a therapeutic approach to target melanoma.


Unexpected admissions following a day case surgery.
A day case surgery is an important part of the practice of surgery and is very popular with expanding applications. The aim of this study is to investigate the reasons for unexpected admission after a day case surgery. All the procedures were carried out at a general hospital, over a 12-month period. All data of the cases admitted for a day case surgery were obtained from the day surgery unit and the admitting wards. There were 5182 surgical procedures performed, 1081 as a day case (21%). Twenty three (2%) patients had to be admitted after planned for a day case surgery. Fourteen due to hemorrhage in different locations, 2 due to anesthetic reasons, 2 for social reasons and 5 for other different complications. There were 5 unexpected admissions (10%) out of total number of 50, for infants aged 3 months or less. A day case surgery is a safe and effective way of delivering surgical care with an accepted complication and unexpected admission rate.


Dependence of the interaction mechanisms between L-serine and O-phospho-L-serine with calcium hydroxyapatite and copper modified hydroxyapatite in relation with the acidity of aqueous medium.
Motivated by the role of copper ions in biological processes the aim of this study was to elucidate the impact of copper ions bound to hydroxyapatite on L-serine (L-Ser) and O-phospho-L-serine (O-Ph-L-Ser) adsorption at different acidity of aqueous solutions. The adsorption phenomenon was studied by FTIR, UV, and AA spectroscopy, XRD and thermal analysis methods together with the evolved gases analysis taking into consideration the ionic state of the amino acids as well as the apatite surface state, which are tightly correlated with the solution pH. In acidic solution, the main process involves apatite dissolution releasing calcium and copper ions. At pH > 5 the complexation of amino acids with Ca2+ or Cu2+ ions is more important leading also to the release of cations. The ability of copper ions to form water soluble complexes with L-Ser and O-Ph-L-Ser leads to an important loss of these ions, while calcium release is very low at this pH. Therefore, the use of copper ions substituting calcium in the apatite structure to enhance the ability of amino acids adsorption on the apatite surface seems problematic even at pH > 5.


Impact of an intensive HIV prevention programme for female sex workers on HIV prevalence among antenatal clinic attenders in Karnataka state, south India: an ecological analysis.
To examine the impact of an intensive HIV preventive intervention (IPI) among female sex workers (FSW) on community HIV transmission, as represented by HIV prevalence among young antenatal clinic (ANC) attenders in Karnataka state, south India. The IPI was initiated in 18 of the 27 districts in Karnataka in 2003, and was generally at scale by mid-2005, covering over 80% of the urban FSW population. We examined trends over time in HIV prevalence from annual HIV surveillance conducted among ANC attenders in Karnataka under the age of 25 years from 2003 to 2007, comparing the IPI with the other districts. Overall, HIV prevalence among ANC attenders under 25 years of age declined from 1.40% to 0.77%. In a multivariate model, the decline in HIV prevalence in the IPI districts compared to the other districts was statistically significant (P = 0.01), with an adjusted annual odds ratio of 0.88 (95% CI 0.79-0.97). The decline in standardized HIV prevalence in the IPI districts over the period was 56%, compared to 5% in the non-IPI districts. Although this analysis is limited by lack of precise comparative data on intervention coverage and intensity, it supports the notion that scaled-up, intensive, targeted HIV preventive interventions among high-risk groups can have a measurable and relatively rapid impact on HIV transmission in the general population, particularly young sexually active populations as represented by ANC attenders. Such focused intervention programmes should be rapidly taken to scale in all HIV epidemics, and especially in concentrated epidemics such as in India.


Serum endostatin correlates with progression and prognosis of non-small cell lung cancer.
The relationship between non-small cell lung cancer and platelet counts, serum levels of vascular endothelial growth factor (VEGF) and endostatin, is unclear. Platelet counts and serum VEGF and endostatin levels were measured preoperatively in 99 patients with non-small cell lung cancer, and the relationship between these factors and clinicopathological features, including prognosis, was examined. Mean serum VEGF level was slightly higher in patients than in healthy subjects (P=0.23). Mean serum endostatin level was 42.4+/-40.4 ng/ml in patients compared to 16.3+/-10.3 ng/ml in healthy subjects (P=0.0003). Serum endostatin levels were significantly higher in patients with involvement greater than T2 or stage IB, compared to other patients. Platelet count and serum endostatin level greater than the median were associated with poor prognosis. Our results suggested that platelet count and serum endostatin level may be useful markers for non-small cell lung cancer.


A phylogenetic analysis of the British flora sheds light on the evolutionary and ecological factors driving plant invasions.
Darwin's naturalization hypothesis predicts that invasive species should perform better in their novel range in the absence of close relatives in the native flora due to reduced competition. Evidence from recent taxonomic and phylogenetic-based studies, however, is equivocal. We test Darwin's naturalization hypothesis at two different spatial scales using a fossil-dated molecular phylogenetic tree of the British native and alien flora (ca. 1600 species) and extensive, fine-scale survey data from the 1998 Countryside Survey. At both landscape and local scales, invasive species were neither significantly more nor less related to the native flora than their non-invasive alien counterparts. Species invasiveness was instead correlated with higher nitrogen and moisture preference, but not other life history traits such as life-form and height. We argue that invasive species spread in Britain is hence more likely determined by changes in land use and other anthropogenic factors, rather than evolutionary history. Synthesis. The transition from non-invasive to invasive is not related to phylogenetic distinctiveness to the native community, but instead to their environmental preferences. Therefore, combating biological invasions in the Britain and other industrialized countries need entirely different strategies than in more natural environments.


Does Severity of Brain Injury on Magnetic Resonance Imaging Predict Short-Term Outcome in Neonates Who Received Therapeutic Hypothermia?
The National Institute of Child Health and Human Development (NICHD) magnetic resonance imaging (MRI) pattern of brain injury is a known biomarker of childhood outcome following therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy (HIE). However, usefulness of this classification has not been evaluated to predict short-term outcomes. The study aimed to test the hypothesis that infants with NICHD MRI pattern of severe hypoxic-ischemic brain injury will be sicker with more severe asphyxia-induced multiorgan dysfunction resulting in prolonged length of stay (LOS) following therapeutic hypothermia. We also evaluated the role of other risk factors which may prolong LOS. We retrospectively reviewed the medical records of 71 consecutively cooled neonates to examine the ability of MRI patterns of brain injury to predict the LOS. A neuroradiologist masked to outcomes classified the patterns of brain injury on MRI as per NICHD. Pattern 2A (basal ganglia thalamic, internal capsule, or watershed infarction), 2B (2A with cerebral lesions), and 3 (hemispheric devastation) of brain injury was deemed "severe injury." Out of 71 infants, 59 surviving infants had both MRI and LOS data. LOS was higher for infants who had Apgar's score of ≤5 at 10 minutes, severe HIE, seizures, coagulopathy, or needed vasopressors or inhaled nitric oxide, or had persistent feeding difficulty, or remained intubated following cooling. However, median LOS did not differ between the infants with and without MRI pattern of severe injury (15 days, interquartile range [IQR]: 9-28 vs. 12 days, IQR: 10-20; p = 0.4294). On multivariate linear regression analysis, only persistent feeding difficulty (β coefficient = 11, p = 0.001; or LOS = 11 days longer if had feeding difficulty) and ventilator days (β coefficient 1.7, p < 0.001; or LOS increased 1.7 times for each day of ventilator support) but not the severity of brain injury predicted LOS. Unlike neurodevelopmental outcome, LOS is not related to severity of brain injury as defined by the NICHD. · The NICHD pattern of brain injury on MRI predicts neurodevelopmental outcome following hypothermia treatment for neonatal HIE.. · LOS did not differ between the infants with and without MRI patterns of severe injury.. · The severity of brain injury as defined by the NICHD was not predictive of the LOS following therapeutic hypothermia..


[Gerontopsychiatry--psychiatry for the aged].
The multimorbidity is increasing with high age. The number of elderly and especially of the very old is going to increase in the next decades. This leads to a necessity to introduce more profound undergraduate and postgraduate training for those who are likely to work with and care for the elderly. The following article describes in detail the most important psychiatric disturbances in the old age, their etiology--as far as we know it--, clinical picture and treatment possibilities.


The Formation of Neochromosomes during Experimental Evolution in the Yeast Saccharomyces cerevisiae.
Novel, large-scale structural mutations were previously discovered during the cultivation of engineered Saccharomyces cerevisiae strains in which essential tRNA synthetase genes were replaced by their orthologs from the distantly related yeast Yarrowia lipolytica. Among those were internal segmental amplifications forming giant chromosomes as well as complex segmental rearrangements associated with massive amplifications at an unselected short locus. The formation of such novel structures, whose stability is high enough to propagate over multiple generations, involved short repeated sequences dispersed in the genome (as expected), but also novel junctions between unrelated sequences likely triggered by accidental template switching within replication forks. Using the same evolutionary protocol, we now describe yet another type of major structural mutation in the yeast genome, the formation of neochromosomes, with functional centromeres and telomeres, made of extra copies of very long chromosomal segments ligated together in novel arrangements. The novel junctions occurred between short repeated sequences dispersed in the genome. They first resulted in the formation of an instable neochromosome present in a single copy in the diploid cells, followed by its replacement by a shorter, partially palindromic neochromosome present in two copies, whose stability eventually increased the chromosome number of the diploid strains harboring it.


Treatment Outcomes of Stenotrophomonas maltophilia Bacteremia in Critically Ill Children: A Multicenter Experience.
Stenotrophomonas maltophilia is a gram-negative opportunistic bacterium that may cause a myriad of clinical diseases in immunocompromised individuals. We aimed to describe the clinical characteristics, risk factors, mortality, and treatment of S. maltophilia bacteremia in critically ill children, a topic on which data are sparse. A multicenter observational retrospective study in which medical charts of critically ill children with S. maltophilia bacteremia were reviewed between 2012 and 2017. Data were collected from each of the four largest PICUs nationwide, allocated in tertiary medical centers to which children with complex conditions are referred regularly. A total of 68 suitable cases of S. maltophilia bacteremia were retrieved and reviewed. The total occurrence rate of S. maltophilia isolation had increased significantly during the study period (r = 0.65; p = 0.02). The crude mortality was 42%, and the attributed mortality was 18%. Significant risk factors for mortality were a longer length of hospital stay prior to infection (33 d in nonsurvivors vs 28 in survivors; p = 0.03), a nosocomial source of infection (p = 0.02), presentation with septic shock (p < 0.001), and treatment with chemotherapy (p = 0.007) or carbapenem antibiotics (p = 0.05) prior to culture retrieval. On multivariate analysis, septic shock (odds ratio, 14.6; 95% CI, 1.45-147.05; p = 0.023) and being treated with chemotherapy prior to infection (odds ratio, 5.2; 95% CI, 1.59-17.19; p = 0.006)] were associated with mortality. The combination of ciprofloxacin, trimethoprim-sulfamethoxazole, and minocycline resulted in the longest survival time (p < 0.01). The significant attributed mortality associated with S. maltophilia bacteremia in critically ill children calls for an aggressive therapeutic approach. The findings of this investigation favor a combination of trimethoprim-sulfamethoxazole, ciprofloxacin, and minocycline.


On-Chip Spyhole Nanoelectrospray Ionization Mass Spectrometry for Sensitive Biomarker Detection in Small Volumes.
A polyimide microfluidic chip with a microhole emitter (Ø 10-12 μm) created on top of a microchannel by scanning laser ablation has been designed for nanoelectrospray ionization (spyhole-nanoESI) to couple microfluidics with mass spectrometry. The spyhole-nanoESI showed higher sensitivity compared to standard ESI and microESI from the end of the microchannel. The limits of detection (LOD) for peptide with the spyhole-nanoESI MS reached 50 pM, which was 600 times lower than that with standard ESI. The present microchip emitter allows the analysis of small volumes of samples. As an example, a small cell lung cancer biomarker, neuron-specific enolase (NSE), was detected by monitoring the transition of its unique peptide with the spyhole-nanoESI MS/MS. NSE at 0.2 nM could be well identified with a signal to noise ratio (S/N) of 50, and thereby its LOD was estimated to be 12 pM. The potential application of the spyhole-nanoESI MS/MS in cancer diagnosis was further demonstrated with the successful detection of 2 nM NSE from 1 μL of human serum. Before the detection, the serum sample spiked with NSE was first depleted with immune spin column, then desalted by centrifugal filter device, and finally digested by trypsin, without any other complicated preparation steps. The concentration matched the real condition of clinical samples. In addition, the microchips can be disposable to avoid any cross contamination. The present technique provides a highly efficient way to couple microfluidics with MS, which brings additional values to various microfluidics and MS-based analysis. Graphical Abstract .


Neonatal sevoflurane anesthesia induces long-term memory impairment and decreases hippocampal PSD-95 expression without neuronal loss.
Volatile anesthetics are widely used in the clinic, and sevoflurane is the most prevalent volatile anesthetic in pediatric anesthesia. Recent findings question the potential risks of volatile anesthetics on brain development. Evidence suggests that sevoflurane may cause neuronal deficiency. This study investigates the long-term effect of sevoflurane in the developing brain. We anesthetized 7 day-old rats for 4 h with 2.5% sevoflurane. A Morris water maze was used to evaluate hippocampal function 7 weeks after sevoflurane exposure. Nissl staining was performed to analyze neuronal loss. PSD-95 (postsynaptic density protein-95) expression in the hippocampus was measured using a western blot. The exposure to 2.5% sevoflurane caused long-term deficits in hippocampal function and decreased hippocampal PSD-95 expression without neuronal loss. This study demonstrates that P7 rats exposed for 4 h to 2.5% sevoflurane have significant spatial learning and memory impairment 7 weeks after anesthesia. In addition, PSD-95 expression in the hippocampus decreased at P56 without neuronal loss. These data suggest that sevoflurane causes neurotoxicity in the developing brain, which may be attributed to decreased PSD-95 in the hippocampus.


[The baseline assessment of the German National Cohort (NAKO Gesundheitsstudie): participation in the examination modules, quality assurance, and the use of secondary data].
The German National Cohort (NAKO) is an interdisciplinary health study aimed at elucidating causes for common chronic diseases and detecting their preclinical stages. This article provides an overview of design, methods, participation in the examinations, and their quality assurance based on the midterm baseline dataset (MBD) of the recruitment. More than 200,000 women and men aged 20-69 years derived from random samples of the German general population were recruited in 18 study centers (2014-2019). The data collection comprised physical examinations, standardized interviews and questionnaires, and the collection of biomedical samples for all participants (level 1). At least 20% of all participants received additional in-depth examinations (level 2), and 30,000 received whole-body magnet resonance imaging (MRI). Additional information will be collected through secondary data sources such as medical registries, health insurances, and pension funds. This overview is based on the MBD, which included 101,839 participants, of whom 11,371 received an MRI. The mean response proportion was 18%. The participation in the examinations was high with most of the modules performed by over 95%. Among MRI participants, 96% completed all 12 MRI sequences. More than 90% of the participants agreed to the use of complementary secondary and registry data. Individuals selected for the NAKO were willing to participate in all examinations despite the time-consuming program. The NAKO provides a central resource for population-based epidemiologic research and will contribute to developing innovative strategies for prevention, screening and prediction of chronic diseases.


Blockade of type A, but not type B, CCK receptors postpones satiety in rhesus monkeys.
The exogenous administration of the brain/gut peptide cholecystokinin (CCK) inhibits food intake in a variety of species, including subhuman primates and humans. To determine the role of endogenously released CCK in the control of food intake in rhesus monkeys, we examined the ability of the selective type A and type B CCK antagonists devazepide and L-365260 to affect total daily food intake and various meal patterns. Various doses of the antagonists were administered intragastrically 30 min before a daily 4-h feeding period. One-gram food pellets were delivered in response to lever pulls, and intake was computer monitored. Intragastric administration of the type A CCK receptor antagonist devazepide (10-320 micrograms/kg) significantly increased food intake in a dose-related fashion. The threshold for increasing intake was 32 micrograms/kg, and a maximal effect was obtained at a dose of 100 micrograms/kg that increased total 4-h food intake by 47%. The effect of devazepide on food intake was mediated by significant increases in the size and duration of the initial meal, lengthening of the subsequent intermeal interval, and a decrease in the satiety ratio (intermeal interval/1st meal size). In contrast, intragastric administration of the type B CCK receptor antagonist L-365260 (3.2-320 micrograms/kg) did not significantly affect total food intake or any of the meal parameters. These data demonstrate that endogenously released CCK acting through type A CCK receptors plays a role in regulating food intake in rhesus monkeys.


Effect of replacing corn with hulled and hulless or low-amylose hulless barley varieties on growth performance and carcass quality of Italian growing-finishing pig.
A study was conducted to evaluate the effect of diets based on hulled or hulless (normal- and low-amylose) barley varieties on growth performance and carcass characteristics in heavy growing-finishing pigs for the production of protected designation of origin (PDO) Italian products. The study was performed with 40 gilts and 40 barrows (Italian Duroc × Italian Large White). Four diets were formulated: 1) corn-based diet (control), 2) control diet with 80% of a normal-amylose hulled barley variety named Cometa (Cometa), 3) control diet with 80% of a normal-amylose hulless barley variety named Astartis (Astartis), and 4) control diet with 80% of a low-amylose hulless barley variety named Alamo (Alamo). The diets were formulated according to 3 growth phases (P1, 40 to 80 kg BW; P2, 80 to 120 kg BW; and P3, 120 to 170 kg BW), with the same Lys:DE ratio (2.60, 2.20, and 1.80, respectively in P1, P2, and P3) according to the NRC requirements for P1 and P2 and according to requirements for high-performing pigs for P3. The diets were analyzed for their in vitro starch digestion potentials (predicted glycemic index, pGI) and for their resistant starch (RS) contents. In P1, P2, and P3, the Alamo diet had the numerically lowest RS contents and greatest pGI values, whereas the control diet had the numerically greatest RS contents and the lowest pGI values. Throughout the study, the pigs fed Cometa and Alamo diets grew faster (P < 0.01) than those fed the control diet, whereas pigs receiving Astartis diet grew in a similar manner to those receiving all the other diets. Pigs fed Cometa and Alamo achieved greater final BW (P < 0.01) compared with those fed the control diet. The pigs receiving the Astartis diet had a mean final BW similar to that of the pigs fed other diets. Throughout the study, the control group had a lower grams per megacalorie DE (P < 0.01) compared with the pigs fed diets with barley, whereas the gain per megacalorie of DE (G/Mcal DE) was greater (P < 0.01) for the pigs fed hulled barley compared with the pig fed hulless barleys. No difference in carcass characteristics was found among treatments (P > 0.05). This study showed that diets based both on hulled and hulless barley might be suitable for the heavy pig breeding intended to the production of Italian PDO products. In addition, hulled or low-amylose hulless barley could be valuable to support maximum pig growth performance without affecting carcass composition.


A Flow Cytometry-Based Phenotypic Screen To Identify Novel Endocytic Factors in Saccharomyces cerevisiae.
Endocytosis is a fundamental process for internalizing material from the plasma membrane, including many transmembrane proteins that are selectively internalized depending on environmental conditions. In most cells, the main route of entry is clathrin-mediated endocytosis (CME), a process that involves the coordinated activity of over 60 proteins; however, there are likely as-yet unidentified proteins involved in cargo selection and/or regulation of endocytosis. We performed a mutagenic screen to identify novel endocytic genes in Saccharomyces cerevisiae expressing the methionine permease Mup1 tagged with pHluorin (pHl), a pH-sensitive GFP variant whose fluorescence is quenched upon delivery to the acidic vacuole lumen. We used fluorescence-activated cell sorting to isolate mutagenized cells with elevated fluorescence, resulting from failure to traffic Mup1-pHl cargo to the vacuole, and further assessed subcellular localization of Mup1-pHl to characterize the endocytic defects in 256 mutants. A subset of mutant strains was classified as having general endocytic defects based on mislocalization of additional cargo proteins. Within this group, we identified mutations in four genes encoding proteins with known roles in endocytosis: the endocytic coat components SLA2, SLA1, and EDE1, and the ARP3 gene, whose product is involved in nucleating actin filaments to form branched networks. All four mutants demonstrated aberrant dynamics of the endocytic machinery at sites of CME; moreover, the arp3R346H mutation showed reduced actin nucleation activity in vitro Finally, whole genome sequencing of two general endocytic mutants identified mutations in conserved genes not previously implicated in endocytosis, KRE33 and IQG1, demonstrating that our screening approach can be used to identify new components involved in endocytosis.


Fabrication of GaN/Diamond Heterointerface and Interfacial Chemical Bonding State for Highly Efficient Device Design.
The direct integration of gallium nitride (GaN) and diamond holds much promise for high-power devices. However, it is a big challenge to grow GaN on diamond due to the large lattice and thermal-expansion coefficient mismatch between GaN and diamond. In this work, the fabrication of a GaN/diamond heterointerface is successfully achieved by a surface activated bonding (SAB) method at room temperature. A small compressive stress exists in the GaN/diamond heterointerface, which is significantly smaller than that of the GaN-on-diamond structure with a transition layer formed by crystal growth. A 5.3 nm-thick intermediate layer composed of amorphous carbon and diamond is formed at the as-bonded heterointerface. Ga and N atoms are distributed in the intermediate layer by diffusion during the bonding process. Both the thickness and the sp2 -bonded carbon ratio of the intermediate layer decrease as the annealing temperature increases, which indicates that the amorphous carbon is directly converted into diamond after annealing. The diamond of the intermediate layer acts as a seed crystal. After annealing at 1000 °C, the thickness of the intermediate layer is decreased to approximately 1.5 nm, where lattice fringes of the diamond (220) plane are observed.


Subcutaneous zygomycosis (phycomycosis).
Decrease of host resistance in subcutaneous zygomycosis appears to be very specific. Potassium iodide causes nonspecific resolution of the eosinophilic granuloma. The disease offers a unique direct human model for the study of host resistance and granuloma resolution.


A Stroke Risk Detection: Improving Hybrid Feature Selection Method.
Stroke is one of the most common diseases that cause mortality. Detecting the risk of stroke for individuals is critical yet challenging because of a large number of risk factors for stroke. This study aimed to address the limitation of ineffective feature selection in existing research on stroke risk detection. We have proposed a new feature selection method called weighting- and ranking-based hybrid feature selection (WRHFS) to select important risk factors for detecting ischemic stroke. WRHFS integrates the strengths of various filter algorithms by following the principle of a wrapper approach. We employed a variety of filter-based feature selection models as the candidate set, including standard deviation, Pearson correlation coefficient, Fisher score, information gain, Relief algorithm, and chi-square test and used sensitivity, specificity, accuracy, and Youden index as performance metrics to evaluate the proposed method. This study chose 792 samples from the electronic records of 13,421 patients in a community hospital. Each sample included 28 features (24 blood test features and 4 demographic features). The results of evaluation showed that the proposed method selected 9 important features out of the original 28 features and significantly outperformed baseline methods. Their cumulative contribution was 0.51. The WRHFS method achieved a sensitivity of 82.7% (329/398), specificity of 80.4% (317/394), classification accuracy of 81.5% (645/792), and Youden index of 0.63 using only the top 9 features. We have also presented a chart for visualizing the risk of having ischemic strokes. This study has proposed, developed, and evaluated a new feature selection method for identifying the most important features for building effective and parsimonious models for stroke risk detection. The findings of this research provide several novel research contributions and practical implications.


Early stage Parkinson's disease patients and normal volunteers: comparative mechanisms of sequence learning.
Early-stage nondemented Parkinson's disease (PD(es)) patients can learn short but not long sequences as well as controls. We have previously shown that to achieve normal performance, PD(es) patients activated the same right-sided cortical regions as controls plus the homologous left sided cortex and bilateral cerebellum. In this study, we evaluated two related hypotheses to explain the behavioral abnormalities and the increased bilateral brain activation observed in the PD(es) group. Hypothesis 1 proposed that PD(es) patients recruit regions from a normal bilateral network specialized for sequence learning that healthy controls would activate if performing difficult tasks. Thus, PD(es) patients can learn short sequences as well as controls. Hypothesis 2 proposed that information processing within the network in the PD(es) group is impaired. Thus, PD(es) patients cannot learn as difficult a sequence as controls. To test hypothesis 1, we increased task difficulty and statistical power in the control group and showed that the control and the PD(es) groups activated the same regions. To test hypothesis 2, we analyzed the equal performance data using two partial least squares (PLS) multivariate analyses. The task-PLS analysis showed that to perform equally with controls, the PD(es) group expressed the normal bilateral network more than the control group. The behavior-PLS analysis showed that the correlation between learning performance and regional activation was significantly different between the groups. We conclude that PD(es) patients have near normal learning if task difficulty is moderate because they can recruit additional regions from a normal bilateral network specialized for sequence learning. However, when a difficult task would normally require bilateral activation, PD(es) patients fail to learn because information processing within the network is impaired. Hum. Brain Mapp. 20:246-258, 2003.


Relationship of coping ways and anxiety with Pregnancy Specific-stress.
To explore whether coping strategies and general anxiety are associated with pregnancy-specific stress (PSS) and how much of variance of PSS is explained with these variables. A cross sectional study was conducted at two teaching hospitals between November 2013 and December 2015. Total 190 pregnant women (60 women at 6-13-weeks of gestation, 60 at 13-26 weeks, and 70 at 27-40 weeks of gestation) completed the study. The participants completed three questionnaires including; Pregnancy experience scale (PES-41), Ways of Coping Questionnaire (WCQ), and State-Trait anxiety inventory (SATI). Pearson coefficients and analysis of regression was done to assess the correlations between variables. Pregnant women who experienced higher mean level of pregnancy specific-stress had significantly higher mean level of occult anxiety, overt anxiety, and total anxiety than women who did not experience PSS. Although there was a positive and significant relationship between intensity of hassles and uplifts and ways of coping, the correlation between PSS and ways of coping was not significant. The results of analysis regression showed that general anxiety during pregnancy predicted 25% of the variance of PSS (F=4.480, β=0.159). Also, ways of coping predicted 38% of the variance in pregnancy Hassles (F=7.033, β=0.194). The ways of coping predicted the variance of pregnancy hassles, but does not evaluate pregnancy specific-stress. To think about PSS in terms of general anxiety may help to clarify past findings and to guide future research and interventions.