Suppressor of cytokine signaling 4 (SOCS4): moderator of ovarian primordial follicle activation.
Mammalian ovarian primordial follicle activation and regulation is considered as one of the most important stages of folliculogenesis and as such requires exquisite control. Selection of quiescent follicles to enter the growing pool determines the rate of supply of maturing follicles over the female reproductive lifespan. To coordinate this process a range of positive and negative input signals contribute to determine follicle fate. This study demonstrates that the cytokine Leukemia Inhibitory Factor (LIF) activates the Janus Kinase 1/Signal Transducers and Activators of Transcription 3 (JAK1/STAT3) signaling pathway in pre-granulosa cells and positively regulates primordial follicle activation. Negative regulation of the JAK/STAT pathway is controlled by the suppressor of cytokine signaling 4 (SOCS4) protein, which target members of negative feedback loops, Cardiotrophin like Cytokine (CLC), Poly (rC) Binding Protein 1 (PCBP1), and Cytosolic Malate Dehydrogenase (MDH1) to suppress follicle growth and development.


Tetrodotoxin, saxitoxin, chiriquitoxin: new perspectives on ionic channels.
Chiriquitoxin is a new, natural analog of tetrodotoxin, differing only in having the -CH2OH on C-6 replaced with an unidentified group of 104 mass units. On isolated frog sartorius muscle fibers, chiriquitoxin is equipotent with tetrodotoxin in blocking the Na+ channel, as shown by their identical dose-response relations on the maximum rate of rise of the action potential. Chiriquitoxin additionally interferes with some K+ channels, as shown by a slowed repolarization of the action potential, a reduced steady-state membrane conductance in current-clamped fibers, and a reduced K+ current in point-voltage-clamped fibers. The effects of chiriquitoxin on the Na+ and K+ channels are apparently exerted by the same molecule because high concentration of tetrodotoxin can either prevent or reverse the effects of chiriquitoxin on the K+ channel. Therefore, the receptor for tetrodotoxin-chiriquitoxin is probably not located inside the Na+ channel, but is on the outside surface of the membrane close to the orifice of the Na+ channel. The results also suggest that the Na+ and K+ channels are probably not randomly distributed throughout the membrane, but occur in clusters with some definite spatial relation to each other. From the structure of tetrodotoxin and a presumed structure of chiriquitoxin, the Na+ and K+ channels are estimated to be separated from each other by not less than 5 nor much more than 15A. The receptor for saxitoxin may be different, but partially overlapping with that for tetrodotoxin-chiriquitoxin.


[Orthotopic uterus transplantation. Sheep model experiment, Cali (Colombia)].
It has been recommended that professionals who are planning to perform uterine transplantation should first carry out animal experiments. This paper describes the procedure for uterine transplant in sheep, as well as short and medium-term results. Experimental surgery study in sheep subjected to uterine explantation and transplant. Four 40-50 kg sheep received uteri transplantation (orthotopic) from four live donors. End-to-side vascular anastomosis was used, the vagina was sutured on one plane and the uterus was fixed to the pelvic wall. Complications and 180-day evolution are described. Transplant surgery was accomplished in the 4 sheep. Surgical time in the first procedure was 240 minutes, while the last procedure lasted 185 minutes. Warm ischemia time was reduced from 42 to 22 minutes. One sheep died on the seventh postoperative day due to an intraoperative complication unrelated to the vascular anastomosis. A second sheep developed local vaginal infection treated with metronidazole and evolved satisfactorily. No transplant rejection had occurred in the remaining 3 sheep after 6 months. The ovine model allowed surgical training in experimental uterine transplant surgery. For the authors, it offered an opportunity to gain knowledge and make progress towards future uterus transplantation in women with uterine factor infertility in Colombia.


Reducing Unplanned Intubations in the Neonatal Intensive Care Unit After Children's Surgery: A Quality Improvement Project.
Unplanned intubation following children's surgery is associated with increased postoperative mortality. In response to being a National Surgical Quality Improvement Program - Pediatric (NSQIP-P) high outlier for postoperative unplanned intubation, we aimed to reduce postoperative unplanned intubation events by 25% in one year. A multidisciplinary team of stakeholders was assembled in 2018. Most unplanned intubation events occurred in the neonatal intensive care unit (NICU). Based on apparent causes of unplanned intubations identified in case reviews, an extubation readiness checklist and a postoperative pain management guideline emphasizing non-opioid analgesics were implemented for NICU patients in September 2019. Postoperative unplanned intubation events were tracked prospectively and evaluated using quality improvement statistical process control methods. Unplanned intubations in the NICU decreased from 0.27 to 0.07 events per patient in the post-intervention group (September 2019-June 2022, n = 145) compared to the pre-intervention group (January 2016-August 2019, n = 200), representing a 76% reduction. Postoperative opioid administration decreased significantly, while acetaminophen usage increased significantly over time. Balancing measures of postoperative pneumonia rate (1.5% vs 0.0%, p = 0.267) and median hospital length of stay [40 (IQR 51) days vs 27 (IQR 60), p = 0.124] were not different between cohorts. The 30-day mortality rate for postoperative patients in the NICU significantly declined [6.5% (n = 13) vs 0.7% (n = 1), p < 0.001]. Postoperative unplanned intubation rates for NICU patients decreased following a quality improvement effort focused on opioid stewardship and extubation readiness. Prospective Quality Improvement. Level III.


Awe in nature heals: Evidence from military veterans, at-risk youth, and college students.
The power of nature to both heal and inspire awe has been noted by many great thinkers. However, no study has examined how the impact of nature on well-being and stress-related symptoms is explained by experiences of awe. In the present investigation, we examine this process in studies of extraordinary and everyday nature experiences. In Study 1, awe experienced by military veterans and youth from underserved communities while whitewater rafting, above and beyond all the other positive emotions measured, predicted changes in well-being and stress-related symptoms one week later. In Study 2, the nature experiences that undergraduate students had during their everyday lives led to more awe, which mediated the effect of nature experience on improvements in well-being. We discuss how accounting for people's emotional experiences during outdoors activities can increase our understanding of how nature impacts people's well-being. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Auditory information is beneficial for adults with Down syndrome in a continuous bimanual task.
Much recent research using discrete unimanual tasks has indicated that individuals with Down syndrome (DS) have more difficulty performing verbal-motor tasks as compared to visual-motor tasks (see Perceptual-Motor Behavior in Down Syndrome, Human Kinetics, Champaign, IL, 2000, p. 305 for a review). In continuous tasks, however, individuals with DS perform better when movement is guided by auditory information compared to visual information (Downs Syndr.: Res. Prac. 4 (1996) 25; J. Sport Exercise Psy. 22 (2000) S90). The aim of the present study was to investigate if there are any differences for adults with DS between visual, auditory and verbal guidance in a continuous bimanual task. Ten adults with DS, 10 adults without DS and 10 typically developing children drew lines bimanually towards the body (down) and away from the body (up) following three different guidance conditions: visual (flashing line), auditory (high tone, low tone), and verbal ("up", "down"). All participants produced mostly in-phase movements and were close to the 1000 ms target time for all guidance conditions. The adults with DS, however, displayed greater variability in their movement time, movement amplitude and bimanual coordination than adults without DS. For all groups, the left hand was slower and more variable in producing the lateral movements than the right hand. The results regarding guidance information suggest that auditory information is beneficial for repetitive bimanual tasks for adults with DS. Possible mechanisms that cause these results will be discussed.


Attention deficit hyperactivity disorder: concordance of the adolescent version of the Composite International Diagnostic Interview Version 3.0 (CIDI) with the K-SADS in the US National Comorbidity Survey Replication Adolescent (NCS-A) supplement.
This paper evaluates the internal consistency reliability and concurrent validity of the assessment of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) attention deficit hyperactivity disorder (ADHD) in the adolescent version of the World Health Organization (WHO) Composite International Diagnostic Interview Version 3.0 (CIDI). The CIDI is a lay-administered diagnostic interview that was carried out in conjunction with the US National Comorbidity Survey Adolescent Supplement, a US nationally representative survey of 10,148 adolescents and their parents. Internal consistency reliability was evaluated using factor and item response theory analyses. Concurrent validity was evaluated against diagnoses based on blinded clinician-administered interviews. Inattention and hyperactivity-impulsivity items loaded on separate but correlated factors, with hyperactivity and impulsivity items forming a single factor in parent reports but separate factors in youth reports. We were able to differentiate hyperactivity and impulsivity factors for parents as well by eliminating a subset who endorsed zero ADHD items from the factor analysis. Although concurrent validity was relatively weak, decomposition showed that this was due to low validity of adolescent reports. A modified CIDI diagnosis based exclusively on parent reports generated a diagnosis that had good concordance with clinical diagnoses [area under the curve (AUC) = 0.78]. Implications for assessing ADHD using the CIDI and the effect of different informants on measurement are discussed.


Attitudes of Italian women concerning suppression of menstruation with oral contraceptives.
Perceptions of menstruation vary according to culture and religion. This study addresses attitudes of Italian women towards changes in menstrual frequency induced by oral contraceptives (OCs) administered in an extended regimen. Three-hundred-and-fifty healthy women of reproductive age were enrolled in three test areas in Italy. Participants completed a standardized questionnaire. One-hundred-and-ten men, aged 21-54 years, accompanying their partners to the gynaecological consultation were also given a questionnaire to get to know their opinion about the extended use of OCs by their partner. Only 32% of Italian women prefer to bleed monthly. The preferred frequencies in all age groups were 3-monthly (23.7%) or never (26%). Of the OC-users, 57.2% preferred to bleed less than once a month: 26% wished to bleed every 3 months, and 21.2% once a year. Among men, 58.1% considered an extended OC regimen to be acceptable. About 60% of Italian women with spontaneous or OC-driven cycles prefer to bleed less than monthly. This fact should be kept in mind by physicians when prescribing OCs.


[A retrospective analysis of 124 patients with multiple myeloma who received up-front autologous hematopoietic cell transplantation following triplet induction therapy].
The IFM/DFCI group reported that VRD induction followed by up-front autologous peripheral blood stem cell transplantation (ASCT) and maintenance therapy led to median PFS of 50 months, which established up-front ASCT as the standard of care even in the era of novel agents. We conducted a retrospective analysis on outcomes of patients who received triplet induction therapy followed by up-front ASCT at our institution. A total of 124 patients received ASCT between November 2016 and December 2021 at Japanese Red Cross Medical Center. Patient characteristics, treatment response before and after ASCT, and PFS and OS were retrospectively analyzed. VRD-based induction therapy was used for 94%. Among 118 evaluable patients, 116 (98%) received either consolidation and/or maintenance therapy. Best responses were ≥CR 77% and ≥VGPR 94%, respectively. Sixty-eight out of 104 patients achieved MRD-negativity by multiparameter FCM (<10-5). Five-year estimated PFS and OS were 54.7% and 80.2%, respectively. Age ≥65, high-risk cytogenetic abnormalities, and <VGPR before ASCT were identified as worse prognostic factors for PFS. Patients who achieved MRD negativity had significantly PFS (p=0.0048, 4-yr PFS 86.4% vs. 49.8%). The negative impact on PFS in the high-risk group can be overcome by achieving MRD-negativity. Prospective research is warranted to evaluate the effectiveness of consolidation therapy.


The dimensioning of nursing staff according to nursing coordinators: concept, aim and use.
This study aimed to conceptualize the dimensioning of nursing staff, as it is understood by professionals who realize this task, and also to reveal their aim and use of estimation of nursing human resources. It is a descriptive and exploratory study with a qualitative approach analyzed through Content analysis. The definition obtained corresponds to those found in literature and, as to its aim, it serves to preview the number of professionals; to guarantee the operation of the nursing work; to attend clients' expectations regarding their needs; to provide personnel and to guarantee their allocation in the work scale. As to the use of this definition in personnel management, it provides a justification to increase staff through new contracts.


Sex-specific differences in hyperoxic lung injury in mice: implications for acute and chronic lung disease in humans.
Sex-specific differences in pulmonary morbidity in humans are well documented. Hyperoxia contributes to lung injury in experimental animals and humans. The mechanisms responsible for sex differences in the susceptibility towards hyperoxic lung injury remain largely unknown. In this investigation, we tested the hypothesis that mice will display sex-specific differences in hyperoxic lung injury. Eight week-old male and female mice (C57BL/6J) were exposed to 72 h of hyperoxia (FiO2>0.95). After exposure to hyperoxia, lung injury, levels of 8-iso-prostaglandin F2 alpha (8-iso-PGF 2α) (LC-MS/MS), apoptosis (TUNEL) and inflammatory markers (suspension bead array) were determined. Cytochrome P450 (CYP)1A expression in the lung was assessed using immunohistochemistry and western blotting. After exposure to hyperoxia, males showed greater lung injury, neutrophil infiltration and apoptosis, compared to air-breathing controls than females. Pulmonary 8-iso-PGF 2α levels were higher in males than females after hyperoxia exposure. Sexually dimorphic increases in levels of IL-6 (F>M) and VEGF (M>F) in the lungs were also observed. CYP1A1 expression in the lung was higher in female mice compared to males under hyperoxic conditions. Overall, our results support the hypothesis that male mice are more susceptible than females to hyperoxic lung injury and that differences in inflammatory and oxidative stress markers contribute to these sex-specific dimorphic effects. In conclusion, this paper describes the establishment of an animal model that shows sex differences in hyperoxic lung injury in a temporal manner and thus has important implications for lung diseases mediated by hyperoxia in humans.


Red edge excitation shift spectroscopy is highly sensitive to tryptophan composition.
Red edge excitation shift (REES) spectroscopy relies on the unique emission profiles of fluorophore-solvent interactions to profile protein molecular dynamics. Recently, we reported the use of REES to compare the stability of 32 polymorphic IgG antibodies natively containing tryptophan reporter fluorophores. Here, we expand on this work to investigate the sensitivity of REES to variations in tryptophan content using a subset of IgG3 antibodies containing arginine to tryptophan polymorphisms. Structural analysis revealed that the additional tryptophan residues were situated in highly solvated environments. Subsequently, REES showed clear differences in fluorescence emission profiles when compared with the unmutated variants, thereby limiting direct comparison of their structural dynamics. These findings highlight the exquisite sensitivity of REES to minor variations in protein structure and tryptophan composition.


Trends in Violence Victimization and Suicide Risk by Sexual Identity Among High School Students - Youth Risk Behavior Survey, United States, 2015-2019.
Lesbian, gay, and bisexual (LGB) youths continue to experience more violence victimization and suicide risk than heterosexual youths; however, few studies have examined whether the proportion of LGB youths affected by these outcomes has varied over time, and no studies have assessed such trends in a nationally representative sample. This report analyzes national trends in violence victimization and suicide risk among high school students by self-reported sexual identity (LGB or heterosexual) and evaluates differences in these trends among LGB students by sex (male or female) and race/ethnicity (non-Hispanic black, non-Hispanic white, or Hispanic). Data for this analysis were derived from the 2015, 2017, and 2019 cycles of CDC's Youth Risk Behavior Survey (YRBS), a cross-sectional, school-based survey conducted biennially since 1991. Logistic regression models assessed linear trends in prevalence of violence victimization and indicators of suicide risk among LGB and heterosexual students during 2015-2019; in subsequent models, sex-stratified (controlling for race/ethnicity and grade) and race/ethnicity-stratified (controlling for sex and grade) linear trends were examined for students self-identifying as LGB during 2015-2019. Results demonstrated that LGB students experienced more violence victimization and reported more suicide risk behaviors than heterosexual youths. Among LGB youths, differences in the proportion reporting violence victimization and suicide risk by sex and race/ethnicity were found. Across analyses, very few linear trends in these outcomes were observed among LGB students. Results highlight the continued need for comprehensive intervention strategies within schools and communities with the express goal of reducing violence victimization and preventing suicide risk behaviors among LGB students.


Stimulatory effect of arginine on acetylglutamate synthesis in isolated mitochondria of mouse and rat liver.
N-Acetyl-L-glutamate synthetase (EC 220.127.116.11) catalyses the synthesis of N-acetyl-L-glutamate, an allosteric activator of carbamoyl-phosphate synthetase I in the liver of ureotelic animals, and the first enzyme is activated specifically by arginine. We have proposed that arginine can stimulate acetylglutamine synthetase in vivo and thereby increase the mitochondrial content of acetylglutamate. The effects of arginine on acetylglutamate synthesis in isolated mitochondria were investigated in detail in the present work. When rat liver mitochondria were isolated and incubated with [14C]glutamate and unlabelled acetate as substrates, acetyl[14C]glutamate synthesis in the mitochondria was more extensive in the presence than in the absence of L-arginine. There was no significant difference between the specific radioactivities of intramitochondrial [14C]glutamate in the presence and absence of arginine. When rat liver mitochondria were incubated with [14C]acetate and unlabelled glutamate as substrates, arginine also stimulated acetyl[14C]glutamate synthesis in the isolated mitochondria. L-Lysine or L-homoarginine, which does not activate acetylglutamate synthetase, had no effect on acetylglutamate synthesis, in the isolated mitochondria. The arginine concentration giving half-maximal synthesis of acetylglutamate in isolated mitochondria was about 50 microM, which is in the range of physiological concentrations of arginine in the liver. As we previously reported [Kawamoto, Ishida, Mori & Tatibana (1982) Eur. J. Biochem. 123, 637-641], the sensitivity of acetylglutamate synthetase to arginine activation undergoes marked changes after food ingestion. The extent of arginine activation of acetylglutamate synthesis in isolated mitochondria correlated well with the sensitivity of acetylglutamate synthetase extracted from the mitochondria to arginine activation. These data lend further support to the idea that arginine itself activates the mitochondrial synthesis of acetylglutamate.


Unraveling gut microbiota in Parkinson's disease and atypical parkinsonism.
Although several studies have suggested that abnormalities in gut microbiota may play a critical role in the pathogenesis of PD, data are still extremely heterogeneous. 16S gene ribosomal RNA sequencing was performed on fecal samples of 350 individuals, subdivided into idiopathic PD (n = 193, of whom 39 were drug naïve) stratified by disease duration, PSP (n = 22), MSA (n = 22), and healthy controls (HC; n = 113). Several confounders were taken into account, including dietary habits. Despite the fact that unadjusted comparison of PD and HC showed several differences in relative taxa abundances, the significant results were greatly reduced after adjusting for confounders. Although most of these differences were associated with disease duration, lower abundance in Lachnospiraceae was the only difference between de novo PD and HC (remaining lower across almost all PD duration strata). Decreased Lachnospiraceae and increased Lactobacillaceae and Christensenellaceae were associated with a worse clinical profile, including higher frequencies of cognitive impairment, gait disturbances, and postural instability. When compared with HC, MSA and PSP patients shared the changes in PD, with a few exceptions: in MSA, Lachnospiraceae were not lower, and Prevotellaceae were reduced; in PSP, Lactobacillaceae were similar, and Streptococcaceae were reduced. Gut microbiota may be an environmental modulator of the pathogenesis of PD and contribute to the interindividual variability of clinical features. Data are influenced by PD duration and several confounders that need to be taken into account in future studies. Prospective studies in de novo PD patients are needed to elucidate the net effect of dysbiosis on the progression of the disease. © 2018 International Parkinson and Movement Disorder Society.


Associations between the Chronotypes and Eating Habits of Hong Kong School-Aged Children.
Later chronotypes have been found to be associated with unhealthy diets in adolescents and adults, but no study has been conducted in children. The aim of this study was to investigate the associations between the chronotypes and dietary patterns of school-aged children. Children aged 7-11 and their parents were recruited from five mainstream schools in Hong Kong. The parents were told to complete questionnaires on the children's circadian preferences, food frequency, and dietary behaviors. All of the questionnaires were distributed and collected by schoolteachers. No gender differences in chronotype were observed (all p > 0.05). The evening-type was associated with significantly greater odds of viewing television (TV) during meals (adjusted odds ratios (OR) = 5.62 in boys and 5.39 in girls). Evening-oriented boys were prone to skipping breakfast (adjusted OR = 14.78), whereas evening-oriented girls were at risk of consuming fast food (adjusted OR = 7.74). There are indications of some gender differences in chronotype-related eating patterns. Sleep duration and screen time significantly mediated the associations between later chronotypes and unhealthy eating habits. Individualized dietary recommendations in accordance with circadian preferences may be effective at promoting healthy and nutritious diets for school-aged children.


The Course of Mycosis Fungoides under Cytokine Pathway Blockers: A Multicentre Analysis of Real-life Clinical Data.
Literature regarding the effect of biologics on the course of mycosis fungoides (MF) is scarce. This multicentre study analysed retrospective data on 19 patients with MF, who were treated with biologics; 12 for inflammatory conditions coexisting with MF, and 7 for MF misdiagnosed as an inflammatory skin disease. Eight patients were treated with anti-tumour necrosis factor-α-monotherapy; 6 had early-stage MF, in 3 patients MF preceded and in 3 MF was diagnosed after initiation of biologics, with no stage-progression or with stable disease, respectively (median treatment time concurrent with MF 57 months). Two patients had advanced stage MF: IIB, treated for 15 months with no stage-progression, and IVA1, treated for 8 months, died of disease 10 months later. The other 11/19 patients received anti-interleukin-17A and/or anti-interleukin-12/23 or anti-interleukin-23 (with/without anti-tumour necrosis factor-α/anti-interleukin-4/13), with stage-progression in 8 patients after a median of 8 months' treatment. Although, in general, biologics should be avoided in patients with MF, these results indicate that anti-tumour necrosis factor-α-monotherapy might not aggravate the disease course in early-stage patients. Interleukin-17A, interleukin-12/23 and interleukin-23 pathway-blockers may prompt progression of MF.


Two Distinct Categories of Focal Deletions in Cancer Genomes.
One of the key questions about genomic alterations in cancer is whether they are functional in the sense of contributing to the selective advantage of tumor cells. The frequency with which an alteration occurs might reflect its ability to increase cancer cell growth, or alternatively, enhanced instability of a locus may increase the frequency with which it is found to be aberrant in tumors, regardless of oncogenic impact. Here we've addressed this on a genome-wide scale for cancer-associated focal deletions, which are known to pinpoint both tumor suppressor genes (tumor suppressors) and unstable loci. Based on DNA copy number analysis of over one-thousand human cancers representing ten different tumor types, we observed five loci with focal deletion frequencies above 5%, including the A2BP1 gene at 16p13.3 and the MACROD2 gene at 20p12.1. However, neither RNA expression nor functional studies support a tumor suppressor role for either gene. Further analyses suggest instead that these are sites of increased genomic instability and that they resemble common fragile sites (CFS). Genome-wide analysis revealed properties of CFS-like recurrent deletions that distinguish them from deletions affecting tumor suppressor genes, including their isolation at specific loci away from other genomic deletion sites, a considerably smaller deletion size, and dispersal throughout the affected locus rather than assembly at a common site of overlap. Additionally, CFS-like deletions have less impact on gene expression and are enriched in cell lines compared to primary tumors. We show that loci affected by CFS-like deletions are often distinct from known common fragile sites. Indeed, we find that each tumor tissue type has its own spectrum of CFS-like deletions, and that colon cancers have many more CFS-like deletions than other tumor types. We present simple rules that can pinpoint focal deletions that are not CFS-like and more likely to affect functional tumor suppressors.


Competition between Chlorellae in chimeric infections of Hydra viridis: the evolution of a stable symbiosis.
Aposymbiotic polyps of Hydra viridis were infected with one or two of the following strains of Chlorella: the native strain obtained from green H, viridis, and the originally non-symbiotic strains Fs and 211/8p cultured in vitro. Larvae of Artemia served as infecting vectors. Chimeric infections were obtained with two different Chlorella strains cohabiting in the same cells and polyps. In time, the chimeric infections disappeared and mixed populations of Hydra were formed with different strains of Chlorella in different polyps. We suggest that the Chlorella/Hydra symbiosis was initiated originally by an infection of preadapted hydra by preadapted chlorellae. Through intracellular interalgal competition and competition between dissimilar infected cells and polyps, the present-day stable symbiosis has evolved.


Screening and Characterization of Allosteric Small Molecules Targeting Bruton's Tyrosine Kinase.
Bruton's Tyrosine Kinase (BTK) is a nonreceptor tyrosine kinase that belongs to the TEC family. Mutations in the BTK gene cause X-linked agammaglobulinemia (XLA) leading to an arrest in B-cell development. BTK is also a drug target for B-cell lymphomas that rely on an intact B-cell receptor signaling cascade for survival. All FDA approved drugs for BTK target the ATP binding site of the catalytic kinase domain, leading to potential adverse events due to off-target inhibition. In addition, acquired resistance mutations occur in a subset of patients, rendering available BTK inhibitors ineffective. Therefore, allosteric sites on BTK should be explored for drug development to target BTK more specifically and in combination with active site inhibitors. Virtual screening against nonactive site pockets and in vitro experiments resulted in a series of small molecules that bind to BTK outside of the active site. We characterized these compounds using biochemical and biophysical techniques and narrowed our focus to compound "C2". C2 activates full-length BTK and smaller multidomain BTK fragments but not the isolated kinase domain, consistent with an allosteric mode of action. Kinetic experiments reveal a C2-mediated decrease in Km and an increase in kcat leading to an overall increase in the catalytic efficiency of BTK. C2 is also capable of activating the BTK XLA mutants. These proof-of-principle data reveal that BTK can be targeted allosterically with small molecules, providing an alternative to active site BTK inhibitors.


Hypoxia-inducible factor 1α predicts recurrence in high-grade soft tissue sarcoma of extremities and trunk wall.
Sarcomas are of mesenchymal origin and typically show abundant tumour stroma and presence of necrosis. In search for novel biomarkers for personalised therapy, we determined the prognostic impact of stromal markers, hypoxia and neovascularity in high-grade soft tissue leiomyosarcoma and pleomorphic undifferentiated sarcoma. We evaluated CD163, colony-stimulating factor (CSF)-1, CD16 and hypoxia-inducible factor 1 (HIF-1)α using immunohistochemical staining and assessed microvessel density using CD31 in 73 high-grade leiomyosarcomas and undifferentiated pleomorphic sarcomas of the extremities and the trunk wall. The results were correlated to metastasis-free and overall survival. Expression of HIF-1α was associated with the presence of necrosis and independently predicted shorter metastasis-free survival (HR 3.2, CI 1.4 to 7.0, p=0.004), whereas neither expression of the stromal markers CD163, CD16 and CSF-1 nor microvessel density was prognostically relevant in this series. There is increasing evidence for the prognostic role of hypoxia in high-grade soft tissue sarcoma, and these data suggest that HIF-1α expression represents a candidate prognostic biomarker for clinical application in high-grade leiomyosarcoma and undifferentiated pleomorphic sarcoma.


Provider perspectives on equity in use of mobile health autism screening tools.
Families may find information about autism online, and health care and education providers may use online tools to screen for autism. However, we do not know if online autism screening tools are easily used by families and providers. We interviewed primary care and educational providers, asking them to review results from online tools that screen for autism. Providers had concerns about how usable and accessible these tools are for diverse families and suggested changes to make tools easier to use.


Cardiac and pericardial calcifications on chest radiographs.
Many types of cardiac and pericardial calcifications identified on chest radiographs can be recognized and distinguished based on characteristic locations and appearances. The purpose of this review is to emphasize the importance of detecting cardiac and pericardial calcifications on chest radiographs, and to illustrate and describe the various types of calcifications that may be encountered and how they may be differentiated from one another. Each type of cardiac and pericardial calcification is discussed, its location and appearance described, and its significance explained. Recognizing and understanding these calcifications is important as they are often encountered in daily practice and play an important role in patient care.


[Clinical effect of radiotherapy in the treatment of non-Hodgkin's lymphoma in children].
The results of combined treatment were analysed retrospectively in 85 children with nonlymphoblastic non-Hodgkin's lymphomas (NHL) of I-II-III stages (Ann Arbor). The importance of involved-field radiation therapy (IFRT) combined with ACOP, MEV, COP chemotherapy was assessed. All patients experienced high grade nonlymphoblastic subtypes of NHL as follows: follicular center cells, undifferentiated, immunoblastic (Lukes-Collins classification). Adjuvant IFRT resulted in significantly increased rate of 5-year overall and disease-free survival and diminished relapse frequency.


Crystallographic structures of Discosoma red fluorescent protein with immature and mature chromophores: linking peptide bond trans-cis isomerization and acylimine formation in chromophore maturation.
The mature self-synthesizing p-hydroxybenzylideneimidazolinone-like fluorophores of Discosoma red fluorescent protein (DsRed) and Aequorea victoria green fluorescent protein (GFP) are extensively studied as powerful biological markers. Yet, the spontaneous formation of these fluorophores by cyclization, oxidation, and dehydration reactions of tripeptides within their protein environment remains incompletely understood. The mature DsRed fluorophore (Gln 66, Tyr 67, and Gly 68) differs from the GFP fluorophore by an acylimine that results in Gln 66 Calpha planar geometry and by a Phe 65-Gln 66 cis peptide bond. DsRed green-to-red maturation includes a green-fluorescing immature chromophore and requires a chromophore peptide bond trans-cis isomerization that is slow and incomplete. To clarify the unique structural chemistry for the individual immature "green" and mature "red" chromophores of DsRed, we report here the determination and analysis of crystal structures for the wild-type protein (1.4 A resolution), the entirely green DsRed K70M mutant protein (1.9 A resolution), and the DsRed designed mutant Q66M (1.9 A resolution), which shows increased red chromophore relative to the wild-type DsRed. Whereas the mature, red-fluorescing chromophore has the expected cis peptide bond and a sp(2)-hybridized Gln 66 Calpha with planar geometry, the crystal structure of the immature green-fluorescing chromophore of DsRed, presented here for the first time, reveals a trans peptide bond and a sp(3)-hybridized Gln 66 Calpha with tetrahedral geometry. These results characterize a GFP-like immature green DsRed chromophore structure, reveal distinct mature and immature chromophore environments, and furthermore provide evidence for the coupling of acylimine formation with trans-cis isomerization.


Self-healing cyclic peptide hydrogels.
Hydrogels are soft materials of great interest in different areas such as chemistry, biology, and therapy. Gels made by the self-assembly of small molecules are known as supramolecular gels. The modulation of their properties by monomer molecular design is still difficult to predict due to the potential impact of subtle structural modifications in the self-assembly process. Herein, we introduce the design principles of a new family of self-assembling cyclic octapeptides of alternating chirality that can be used as scaffolds for the development of self-healing hydrogelator libraries with tunable properties. The strategy was used in the preparation of an amphiphilic cyclic peptide monomer bearing an alkoxyamine connector, which allowed the insertion of different aromatic aldehyde pendants to modulate the hydrophobic/hydrophilic balance and fine-tune the properties of the resulting gel. The resulting amphiphiles were able to form self-healable hydrogels with viscoelastic properties (loss tangent, storage modulus), which were strongly dependent on the nature and number of aromatic moieties anchored to the hydrophilic peptide. Structural studies by SEM, STEM and AFM indicated that the structure of the hydrogels was based on a dense network of peptide nanotubes. Excellent agreement was established between the peptide primary structure, nanotube length distributions and viscoelastic behaviour.


Chlamydia specific IgG and IgA antibodies in women with obstructive infertility as determined by immunoblotting and immunoperoxidase assays.
The prevalence rate of IgG and IgA antibodies to Chlamydia was analyzed in 50 women with laparoscopy-verified tubal infertility and in 50 age-matched control women by single serovar (L2) inclusion immunoperoxidase assay (IPA) and by immunoblotting technique (IB). Women with tubal infertility had significantly (p less than 0.001) elevated IPA Chlamydia IgG antibody titer greater than or equal to 128 and greater than or equal to 256 than controls (64% vs 16%. Odds ratios = 9.3 and 50% vs 10%, Odds ratio = 9 respectively). The prevalence rate of IPA IgA antibody titer (greater than or equal to 16) to Chlamydia was also significantly higher (p less than 0.001) in women with tubal infertility than controls (48% vs 8%, Odds ratio = 10.6). Antibodies to at least 19 chlamydial structural polypeptides ranging in molecular weight from 30 kD to 204 kD, were detected by the IB technique in the IPA seropositive sera. Antibodies to 57-60 kD were detectable in almost all the IPA IgG and IgA seropositive sera. The prevalence rate of IgG antibody to 57 kD-60 kD was significantly higher in women with obstructive infertility than healthy woman (84% vs. 56% p less than 0.01; Odds ratio = 3.8). More significantly, higher differences to 57-60 kD polypeptide were found in the case of IgA between the infertile women and controls (52% vs. 10%, p less than 0.001; Odds ratio = 9.7). The significance of IPA and IB technique for screening of infertile women is discussed.


The Effect of Topical Anaesthesia on the Cortisol Responses of Calves Undergoing Dehorning.
Dehorning causes pain and distress to cattle, and there is a need to provide effective and practical analgesia to improve animal welfare. We conducted an experiment to determine the effect of a modified post-operative topical wound management formulation containing two local anaesthetics (TA) on the plasma cortisol concentration (PCC) of scoop-dehorned calves. Two months old Holstein-Friesian heifer calves (n = 30) were randomly allocated to sham dehorning control (CON), scoop dehorning (D), or scoop dehorning with immediate post-operative application of the TA (DTA). Blood samples were obtained via jugular venepuncture prior to sham or actual dehorning, and 40 min, 1.5, 4 and 24 h later. PCC changed significantly over time (p < 0.01). There was a trend for lower PCC in DTA calves compared to D calves (p = 0.09), with the PCC area under the curve lowest in CON calves as compared to D and DTA calves (p = 0.02). Cortisol concentrations were similar between D and DTA at all time points. The TA did not reduce cortisol concentrations up to 24 h following treatment and the cortisol response likely reflects the pain induced by the procedure, the effect of handling and restraint, and haemorrhaging which limited adherence of the TA actives. A multimodal analgesic approach, as assessed through multiple pain indicators, should be the focus of future work.


A Revised Genome Assembly of the Region 5' to Canine SOX9 Includes the RevSex Orthologous Region.
The SOX gene family includes many genes that play a determinant role in several developmental pathways. The SOX9 gene has been identified as a major factor in testis development in mammals after it is activated by the SRY gene. However, duplication of the gene itself in some mammalian species, or of a well-delimited upstream 'RevSex' region in humans, has been shown to result in testis development in the absence of the SRY gene. In the current study, we present an accurate analysis of the genomic organization of the SOX9 locus in dogs by both in silico and FISH approaches. Contrary to what is observed in the current dog genome assembly, we found that the genomic organization is quite similar to that reported in humans and other mammalian species, including the position of the RevSex region in respect to SOX9. The analysis of the conserved sequences within this region in 7 mammalian species facilitated the highlighting of a consensus sequence for SRY binding. This new information could help in the identification of evolutionarily conserved elements relevant for SOX9 gene regulation, and could provide valid targets for mutation analysis in XY DSD patients.


Cardiovascular toxicity of abacavir: a clinical controversy in need of a pharmacological explanation.
: There is a long-lasting controversy surrounding an association between abacavir (ABC) and an increased risk of cardiovascular disease in HIV-positive patients. Although differing in their specifics, a number of published cohort studies and clinical trials support such an association, usually relating it to recent exposure to the drug, independently of traditional predisposing factors. However, other clinical trials have failed to reveal such a relation and have pointed to methodological differences to explain discrepancies. Significantly, the controversy has been fueled by the lack of a credible mechanism of action to justify the putative detrimental actions of ABC. There is a myriad of contradictory clinical indicators which are not clearly compatible with known profiles of either vascular physiopathology or pharmacological interference. However, basic research has recently hinted at altered homeostatic mechanisms, though this requires clinical validation. In particular, recurrent evidence - both clinical and experimental - relates ABC with vascular inflammation, a leading contributor to the atherosclerotic plaque and thrombosis. ABC's chemical structure is very close to that of endogenous purines (ATP, ADP and AMP), major paracrine signaling molecules capable of triggering prothrombotic and proinflammatory vascular programs. Other proposed mechanisms are a competitive inhibition of guanylyl cyclase in platelets and a subsequent decrease in cyclic guanosine monophosphate (cGMP). The present review aims to shed light on this complex subject by summarizing and critically evaluating all the available clinical data regarding a relationship between ABC and cardiovascular disease, and to put forward potential pharmacological explanations compatible with both the clinical scenario and experimental findings.


[Selected pages of history of vascular surgery in Russia (contribution of Russian surgeons to world vascular surgery)].
The article describes the most significant for Russian surgery personalities, facts, and events of the last 180years. An emphasis is placed upon those works, discoveries or operations made by Russians for the first timein the world's practice. To such we refer N.J. Pirogov's topographical anatomy of vessels (1837), N. V. Ekk's portocaval anastomosis (1877), A.A. Yanovsky's lateral arterial suture (1889), S.S. Bryukhonenko's artificial circulation unit (1923-1924), Yu. Yu. Voronoy's renal replantation onto femoral vessels (1933), V.P. Demikhov'stransplantation of vital organs (1946-1959), V.I. Kolesov's mammary-coronary anastomosis (1964),F.A. Serbinenko's endovascular neurosurgery ( 1979), E. I. Chasov's intracoronary thrombolysis by E.I. Chazov( 1974), endovascular prosthetic repair of the thoracic aorta by N.L. Volodos ( 1985) and a series of other facts.


The surrogate matrix methodology: A reference implementation for low-cost assembly in isogeometric analysis.
A reference implementation of a new method in isogeometric analysis (IGA) is presented. It delivers low-cost variable-scale approximations (surrogates) of the matrices which IGA conventionally requires to be computed by element-scale quadrature. To generate surrogate matrices, quadrature must only be performed on a fraction of the elements in the computational domain. In this way, quadrature determines only a subset of the entries in the final matrix. The remaining matrix entries are computed by a simple B-spline interpolation procedure. We present the modifications and extensions required for a reference implementation in the open-source IGA software library GeoPDEs. The exposition is fashioned to help facilitate similar modifications in other contemporary software libraries.•The surrogate matrix methodology is implemented in GeoPDEs.•Poisson's problem is considered.•The matrix assembly time is significantly reduced at negligible cost to solution accuracy.


Biosynthesis of (-)-5-Hydroxy-equol and 5-Hydroxy-dehydroequol from Soy Isoflavone, Genistein Using Microbial Whole Cell Bioconversion.
Equols are isoflavandiols formed by reduction of soy isoflavones such as daidzein and genistein by gut microorganisms. These phytoestrogens are of interest for their various biological effects. We report biosynthesis from genistein to (-)-5-hydroxy-equol in recombinant E. coli expressing three reductases (daidzein reductase DZNR, dihidrodaidzein reductase DHDR, tetrahydrodaidzein reductase THDR) and a racemase (dihydrodaidzein racemase, DDRC) originating from the gut bacterium, Slackia isoflavoniconvertens. The biosynthesized 5-hydroxy-equol proved as an optically negative enantiomer, nonetheless it displayed an inverse circular dichroism spectrum to (S)-equol. Compartmentalized expression of DZNR and DDRC in one E. coli strain and DHDR and THDR in another increased the yield to 230 mg/L and the productivity to 38 mg/L/h. If the last reductase was missing, the intermediate spontaneously dehydrated to 5-hydroxy-dehydroequol in up to 99 mg/L yield. This novel isoflavene, previously not known to be synthesized in nature, was also detected in this biotransformation system. Although (S)-equol favors binding to human estrogen receptor (hER) β over hERα, (-)-5-hydroxy-equol showed the opposite preference. This study provides elucidation of the biosynthetic route of (-)-5-hydroxy-equol and measurement of its potent antagonistic character as a phytoestrogen for the first time.


Nonproteinogenic D-amino acids at millimolar concentrations are a toxin for anaerobic microorganisms relevant to early Earth and other anoxic planets.
The delivery of extraterrestrial organics to early Earth provided a potentially important source of carbon and energy for microbial life. Optically active organic compounds of extraterrestrial origin exist in racemic form, yet life on Earth has almost exclusively selected for L- over D-enantiomers of amino acids. Although D-enantiomers of proteinogenic amino acids are known to inhibit aerobic microorganisms, the role of concentrated nonproteinogenic meteoritic D-amino acids on anaerobic metabolisms relevant to early Earth and other anoxic planets such as Mars is unknown. Here, we test the inhibitory effect of D-enantiomers of two nonproteinogenic amino acids common to carbonaceous chondrites, norvaline and α-aminobutyric acid, on microbial iron reduction. Three pure strains (Geobacter bemidjiensis, Geobacter metallireducens, Geopsychrobacter electrodiphilus) and an iron-reducing enrichment culture were grown in the presence of 10 mM D-enantiomers of both amino acids. Further tests were conducted to assess the inhibitory effect of these D-amino acids at 1 and 0.1 mM. The presence of 10 mM D-norvaline and D-α-aminobutyric acid inhibited microbial iron reduction by all pure strains and the enrichment. G. bemidjiensis was not inhibited by either amino acid at 0.1 mM, but D-α-aminobutyric acid still inhibited at 1 mM. Calculations using published meteorite accumulation rates to the martian surface indicate D-α-aminobutyric acid may have reached inhibitory concentrations in little over 1000 years during peak infall. These data show that, on a young anoxic planet, the use of one enantiomer over another may render the nonbiological enantiomer an environmental toxin. Processes that generate racemic amino acids in the environment, such as meteoritic infall or impact synthesis, would have been toxic processes and could have been a selection pressure for the evolution of early racemases.


Chest Radiographs and CT Findings during Healthcare Workers' Tuberculosis Screening Using Interferon-Gamma Release Assay: Retrospective Observational Study.
To investigate the incidence of tuberculosis (TB) in healthcare workers (HCWs) with positive interferon-gamma release assay (IGRA) results based on chest X-ray (CXR) and CT findings and determine the role of imaging in the diagnosis of TB. Among 1976 hospital personnel screened for TB using IGRA, IGRA-positive subjects were retrospectively investigated. Clustered nodular and/or linear streaky opacities in the upper lung zone were considered positive on CXR. The CT findings were classified as active, indeterminate, inactive, or normal. The active or indeterminate class was considered CT-positive. IGRA was positive in 255 subjects (12.9%). CXR and CT were performed in 249 (99.2%) and 113 subjects (45.0%), respectively. CXR- and CT-positive findings were found in 7 of 249 (2.8%) and 9 of 113 (8.0%) patients, respectively. Among the nine CT-positive subjects, active and indeterminate TB findings were found in 6 (5.3%) and 3 (2.7%) patients, respectively. Microbiological tests, including acid-fast bacilli staining, culture, and polymerase chain reaction for TB, were negative in all nine CT-positive subjects. Empirical anti-TB medications were administered to 9 CT-positive subjects, and 3 of these nine subjects were CXR-negative for pulmonary TB. CT helped diagnose asymptomatic TB in IGRA-positive HCWs.


Social isolation, cognitive reserve, and cognition in healthy older people.
There is evidence to suggest that social isolation is associated with poor cognitive health, although findings are contradictory. One reason for inconsistency in reported findings may be a lack of consideration of underlying mechanisms that could influence this relationship. Cognitive reserve is a theoretical concept that may account for the role of social isolation and its association with cognitive outcomes in later life. Therefore, we aimed to examine the relationship between social isolation and cognition in later life, and to consider the role of cognitive reserve in this relationship. Baseline and two year follow-up data from the Cognitive Function and Ageing Study-Wales (CFAS-Wales) were analysed. Social isolation was assessed using the Lubben Social Network Scale-6 (LSNS-6), cognitive function was assessed using the Cambridge Cognitive Examination (CAMCOG), and cognitive reserve was assessed using a proxy measure of education, occupational complexity, and cognitive activity. Linear regression modelling was used to assess the relationship between social isolation and cognition. To assess the role of cognitive reserve in this relationship, moderation analysis was used to test for interaction effects. After controlling for age, gender, education, and physically limiting health conditions, social isolation was associated with cognitive function at baseline and two year follow-up. Cognitive reserve moderated this association longitudinally. Findings suggest that maintaining a socially active lifestyle in later life may enhance cognitive reserve and benefit cognitive function. This has important implications for interventions that may target social isolation to improve cognitive function.


Effectiveness of adherence to a renal health program in a health network in Peru.
OBJECTIVE To evaluate the effectiveness of adherence to a multidisciplinary renal health program in reducing mortality and progression to hemodialysis. METHODS We used a database that included patient monitoring (2013-2017), dialysis admissions and all cause of mortality in Peru. Adherence to the program was established by meeting minimum visits during the first year of monitoring. The outcome of interest was hemodialysis admissions or all cause-mortality. Kaplan-Meier curves, Log-Rank test and competing survival analysis methods were used to estimate the differential risk between adherent and non-adherent patients. RESULTS A total of 20,354 participants was evaluated; 54.1% were male, 72.1 years old in average, 2.2 years average follow-up, and 15,279 (75.1%) belonged to the early stages (1 to 3a) of Chronic Kidney Disease. Adherence decreased the risk of renal replacement therapy in 41.0% (HR = 0.59, 95%CI 0.41-0.85) in the low-risk group and mortality in the high-risk group was 31.0% (HR = 0.69, 95%CI 0.57-0.83). CONCLUSIONS The multidisciplinary care strategy with standardized assessments by stage is effective in reducing admission to .0when the patient is identified in early stages and in reducing mortality in advanced stages.


Derivation and Clinical Validation of a Redox-Driven Prognostic Signature for Colorectal Cancer.
Colorectal cancer (CRC), a seriously threat that endangers public health, has a striking tendency to relapse and metastasize. Redox-related signaling pathways have recently been extensively studied in cancers. However, the study and potential role of redox in CRC remain unelucidated. We developed and validated a risk model for prognosis and recurrence prediction in CRC patients via identifying gene signatures driven by redox-related signaling pathways. The redox-driven prognostic signature (RDPS) was demonstrated to be an independent risk factor for patient survival (including OS and RFS) in four public cohorts and one clinical in-house cohort. Additionally, there was an intimate association between the risk score and tumor immune infiltration, with higher risk score accompanied with less immune cell infiltration. In this study, we used redox-related factors as an entry point, which may provide a broader perspective for prognosis prediction in CRC and have the potential to provide more promising evidence for immunotherapy.


Analytical Considerations in Nanoscale Flow Cytometry of Extracellular Vesicles to Achieve Data Linearity.
Platelet microparticles (PMPs) and their abundance in the blood are a prognostic biomarker in thrombotic disorders and cancer. Nanoscale flow cytometry (nFC) is ideal for high-throughput analysis of PMPs but these clinical assays have not been developed previously. This article demonstrates that nFC is a suitable technology to enumerate PMPs present in plasma samples in a clinical setting. nFC was performed using the Apogee A50-Micro instrument. Instrument settings and acquisition parameters were developed with the use of fluorescent beads and plasma samples. Sample preparation and handling was also optimized. nFC allows for linear detection of particles between approximately 200 and 1,000 nm based on calibration beads and was dependent on dilution factor and flow rate. Linearity in event analysis as samples became more diluted was lost when events approximately 100 nm were gated while linearity was maintained despite dilution of sample in events larger than 200 nm in diameter. Higher flow rates lead to an under-estimation of events analysed per microlitre of analyte and this was more pronounced when plasma samples were not diluted more than 1/20×. nFC offers multi-parametric analysis of PMPs when optimal calibration of acquisition and sample processing settings is performed. Analysis of plasmas from metastatic prostate cancer patients and leukaemia patients revealed that PMP levels were larger than 100 nm and were equally abundant in patients that responded to or failed androgen deprivation therapy or between patients representing different stages of leukaemia.


SURVEY OF GERIATRIC ELEPHANT MEDICAL CARE, NUTRITION, HUSBANDRY, AND WELFARE.
Improvements in husbandry, veterinary care, and nutrition have led to increased longevity of animals in human care, including elephants. The goal of this study was to collect and synthesize information pertaining to geriatric elephant medicine, management, husbandry, and nutrition. An electronic survey was created and distributed to American Association of Zoo Veterinarians members through an online link. A total of 61 responses were received from veterinarians, nutritionists, and elephant managers with data encompassing 314 elephants, of which 142 were geriatric (over 40 years old) and 51 were on their final set of molars. Following the initial survey, willing respondents were contacted for follow-up interviews. Osteoarthritis, foot disease, and colic were the most commonly reported diseases, and flunixin meglumine and phenylbutazone were the analgesics most often used. Respondents described diseases treated, husbandry changes specific for older animals, welfare assessments and quality of life monitoring, nutritional modifications for dental attrition, a variety of integrative medicine modalities, and unique cases. It is the hope that the information identified in this study can be used to improve treatment, management practices, and overall welfare for geriatric elephants.


CHEK2 is a potential prognostic biomarker associated with immune infiltration in clear cell renal cell carcinoma.
Checkpoint kinase 2 (CHEK2) plays a crucial role in responding to DNA damage and is linked to diverse cancer types. However, its significance in the prediction of prognosis and impacts on the immune status of clear cell renal cell carcinoma (ccRCC) remains unclear. This study aimed to identify the role of CHEK2 in prognosis and immune microenvironment of ccRCC. We analyzed transcriptome and clinicopathological data from the cancer genome atlas (TCGA) database and conducted functional enrichment analysis to explore molecular mechanisms. The relationship between CHEK2 and immune infiltration was evaluated, and drug sensitivity analysis was performed using the CellMiner database. The results showed that CHEK2 was an independent predictor of ccRCC prognosis and was closely associated with immune-related processes. Additionally, high expression of CHEK2 was linked to resistance to certain targeted drugs. These findings suggest that CHEK2 could serve as a biomarker for ccRCC, providing insights into tumor immune microenvironment alterations and immunotherapeutic response. Further investigation is needed to fully understand the potential of CHEK2 as a prognostic predictor and therapeutic target for ccRCC.


Binding affinities of commonly employed sensitizers of viral inactivation.
Methylene blue (MB), riboflavin (RB) and psoralen sensitizers (4' aminomethyl-4,5',8-trimethylpsoralen [AMT] and derivatives) are under study as sensitizers of viral inactivation of blood products such as plasma proteins, platelets and red cells, all of which lack genomic nucleic acid. To predict where these sensitizers accumulate in viruses and in cells, their relative affinities for calf thymus DNA, neutral and negatively charged phospholipids and albumin were determined by dialysis. MB has a strong affinity for nucleic acid and negatively charged phospholipid, but little affinity for albumin or neutral phospholipid. RB has modest affinity for nucleic acid and little affinity for albumin or either phospholipid. AMT has substantial affinity for nucleic acid, neutral and negatively charged phospholipids and albumin. Neither AMT nor RB binds to poly G, although MB has some affinity for this polymer. Evidence of association of RB with guanosine monophosphate, adenosine monophosphate and tryptophan methylester hydrochloride in PBS buffer in the presence and absence of formamide was obtained from nonlinear Stern-Volmer plots and shifts in the ground state absorption spectrum of RB.


The role of AFAP1-AS1 in mitotic catastrophe and metastasis of triple-negative breast cancer cells by activating the PLK1 signaling pathway.
Triple-negative breast cancer (TNBC) is characterized by fast growth, high metastasis, high invasion, and a lack of therapeutic targets. Mitosis and metastasis of TNBC cells are two important biological behaviors in TNBC malignant progression. It is well known that the long noncoding RNA AFAP1-AS1 plays a crucial role in various tumors, but whether AFAP1-AS1 is involved in the mitosis of TNBC cells remains unknown. In this study, we investigated the functional mechanism of AFAP1-AS1 in targeting Polo-like Kinase 1 (PLK1) activation and participating in mitosis of TNBC cells. We detected the expression of AFAP1-AS1 in the TNBC patient cohort and primary cells by in situ hybridization (ISH), northern blot, fluorescent in situ hybridization (FISH) and cell nucleus/cytoplasm RNA fraction isolation. High AFAP1-AS1 expression was negatively correlated with overall survival (OS), disease-free survival (DFS), metastasis-free survival (MFS) and recurrence-free survival (RFS) in TNBC patients. We explored the function of AFAP1-AS1 by transwell, apoptosis, immunofluorescence (IF) and patient-derived xenograft (PDX) models in vitro and in vivo. We found that AFAP1-AS1 promoted TNBC primary cell survival by inhibiting mitotic catastrophe and increased TNBC primary cell growth, migration and invasion. Mechanistically, AFAP1-AS1 activated phosphorylation of the mitosis-associated kinase PLK1 protein. Elevated levels of AFAP1-AS1 in TNBC primary cells increased PLK1 pathway downstream gene expression, such as CDC25C, CDK1, BUB1 and TTK. More importantly, AFAP1-AS1 increased lung metastases in a mouse metastasis model. Taken together, AFAP1-AS1 functions as an oncogene that activates the PLK1 signaling pathway. AFAP1-AS1 could be used as a potential prognostic marker and therapeutic target for TNBC.


Polychlorinated dibenzofurans as a causal agent of fetal Yusho.
Polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and dioxin-like polychlorinated biphenyls (dioxin-like PCBs) are highly-toxic environmental pollutants that are still ubiquitous. About 40 years ago, a mass food poisoning, termed "Yusho", occurred in western Japan, and the causal agent of Yusho was thought to be PCDFs. The preserved umbilical cords of babies who were born to mothers with Yusho 2-5 years after the outbreak of Yusho and diagnosed with fetal Yusho were recently obtained, and the concentrations of PCDDs, PCDFs, dioxin-like PCBs and polychlorinated biphenyls (PCBs) in these preserved umbilical cords were determined. Among babies with fetal Yusho, the pollutant concentrations in umbilical cords were compared between "black babies", a term that describes the dermatologic abnormality that is classically seen in fetal Yusho, and "non-black babies". There was almost no difference in the concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) toxic equivalents (TEQ) concentrations of PCDDs, PCDFs and dioxin-like PCBs found in these two groups of babies. Therefore, the Yusho infants with the dark brown skin pigmentation seemed to have a hypersensitive genetic predisposition to the production of melanin pigment in the skin after the exposure to these toxic compounds. The concentrations of PCDDs, PCDFs, dioxin-like PCBs and PCBs in the preserved umbilical cords of infants diagnosed with fetal Yusho and of healthy babies were also determined and compared. PCDDs, dioxin-like PCBs and PCBs were detected in both groups. PCDFs, however, were found at high concentration only in the babies with fetal Yusho. In 2,3,7,8-TCDD TEQ concentrations, 90% of the total TEQ concentrations were attributable to PCDFs after taking into account the baseline concentrations found in healthy babies. This evidence shows that fetal Yusho is caused by PCDF intoxication.


Prioritizing treatment outcomes: How people with acne vulgaris decide if their treatment is working.
To collect information about how people with acne make day-to-day decisions concerning the effectiveness of their treatment. Between May and August 2013, an optional question was embedded in the James Lind Alliance Acne Priority Setting Partnership's online survey to collect treatment uncertainties. The question asked people with acne to "Tell us in your own words how you decide if your treatment has been effective." A total of 742 respondents specified at least one outcome or means of assessing change (outcome measure). Fewer spots were the most commonly cited outcome, identified by 272 respondents (36.7%). Other frequently mentioned outcomes were in descending order: less redness (19.4%), reduction in spot size (12.1%), and less pain/discomfort (11.4%). Signs were much more commonly used than symptoms and surrogate outcomes such as changes in aspects of life quality were infrequently mentioned. Visual inspection of the skin was the most widely adopted outcome measure (16.3%). Although the most frequently used methods map well onto the outcome measures adopted in the majority of acne trials, namely physician-assessed changes in lesion counts and global acne severity, people with acne often take into account several factors that cannot be assessed by a third party at a single point in time. The minimal use of changes in psychosocial wellbeing and mood may reflect that these are regarded as secondary consequences of improvements in appearance. The robustness of these findings now requires independent evaluation. If confirmed, they could form the basis of a new patient-reported outcome measure.


Hyperbaric oxygen therapy for the treatment of perianal fistulas in Crohn's disease (HOT-TOPIC): study protocol of a prospective interventional cohort study with one-year follow-up.
Perianal fistulizing Crohn's disease (pCD) has a significant impact on patients' health and quality of life. Current treatment options have a relatively low success rate and a high recurrence risk. Positive effects of hyperbaric oxygen (HBO2) therapy have been indicated in animal studies as well as in small case series. This is a non-randomized, controlled pilot study. A total of 20 patients with pCD who have been refractory to standard therapy for at least six months will be included. Patients with a seton and stable treatment regimen will be included. Patients with anal strictures, rectovaginal fistulas, stoma or deep ulceration of the rectum will be excluded. Patients who are eligible but refuse HBO2 will be asked to serve as controls. Patients in the HBO2 group will be treated with 40 sessions of HBO2 therapy at 243-253 kPa, with the seton being removed after 30 sessions. Co-primary endpoints are changes in the perianal disease activity index and MRI-scores. Secondary outcomes are fistula drainage assessment, laboratory findings and patient-reported outcomes. Assessment will be done at baseline, 16 weeks, 34 weeks and 60 weeks after finishing HBO2. The aim of this study is to investigate the feasibility and therapeutic effect of HBO2 on pCD. The one-year follow-up should provide information on the effect durability. A comparison between patients treated with HBO2 and patients who continue to receive standard care will be made. The risk of bias will be limited by using clearly defined inclusion and exclusion criteria, baseline characteristics and consecutive recruitment of patients through an outpatient fistula clinic. The HOT-TOPIC trial has been approved by the local Medical Ethical Committee of the Academic Medical Centre in Amsterdam, the Netherlands. The trial has been registered at the Netherlands Trial Register (www.trialregister.nl), registration number: NTR 6676. Protocol version: August 2017, version 3.0.


A 50-kDa fragment from the NH2-terminus of the heavy subunit of Clostridium botulinum type A neurotoxin forms channels in lipid vesicles.
1. A 50-kDa fragment representing the NH2-terminus of the heavy subunit of botulinum type A neurotoxin was found, at low pH, to evoke the release of K+ from lipid vesicles loaded with potassium phosphate. Similar K+ release was also observed with the intact neurotoxin, its heavy chain and a fragment consisting of the light subunit linked the 50-kDa NH2-terminal heavy chain fragment. The light subunit alone, however, was inactive. 2. In addition to K+, the channels formed in lipid bilayers by botulinum neurotoxin type A or the NH2-terminal heavy chain fragment were found to be large enough to permit the release of NAD (Mr 665). 3. The optimum pH for the release of K+ was found to be 4.5. Above this value K+ release rapidly decreased and was undetectable above pH 6.0. 4. The binding of radiolabelled botulinum toxin to a variety of phospholipids was assessed. High levels of toxin binding were only observed to lipid vesicles with an overall negative charge; much weaker binding occurred to lipid vesicles composed of electrically neutral phospholipids. 5. A positive correlation between the efficiency of toxin-binding and the efficiency of K+ release from lipid vesicles was not observed. Whereas lipid vesicles containing the lipids cardiolipin or dicetyl phosphate bound the highest levels of neurotoxin, the toxin-evoked release of K+ was low compared to vesicles containing either phosphatidyl glycerol, phosphatidyl serine or phosphatidyl inositol. 6. The implications of these observations to the mechanism by which the toxin molecule is translocated into the nerve ending are discussed.


Rapid manufacturing of aluminum components.
A manufacturing technique for the production of aluminum components is described. A resin-bonded part is formed by a rapid prototyping technique and then debound and infiltrated by a second aluminum alloy under a nitrogen atmosphere. During thermal processing, the aluminum reacts with the nitrogen and is partially transformed into a rigid aluminum nitride skeleton, which provides the structural rigidity during infiltration. The simplicity and rapidity of this process in comparison to conventional production routes, combined with the ability to fabricate complicated parts of almost any geometry and with high dimensional precision, provide an additional means to manufacture aluminum components.


Parkinson's disease.
Parkinson's disease is a common disabling disease of old age. The diagnosis of idiopathic Parkinson's disease is based on clinical signs and has poor sensitivity, with about 25% of patients confidently diagnosed as having the disease actually having other conditions such as multi-system atrophy and other parkinsonism-plus syndromes. Benign essential tremor and arteriosclerotic pseudo-parkinsonism can easily be confused with Parkinson's disease. The cause of Parkinson's disease remains unknown. Speculative research highlights the role of oxidative stress and free radical mediated damage to dopaminergic cells. Parkinson's disease is the one neurodegenerative disorder in which drugs have been demonstrated to be of value. There is now a wide variety of drugs and formulations available, including anticholinergics, amantidine, L-dopa, dopamine agonists including apomorphine, selegiline and soon to be available catechol-O-methyltransferase inhibitors. Disabling side-effects of treatment, fluctuations, dyskinesias and psychiatric problems require strategic use of the drugs available. There is an increasing potential for neurosurgical intervention.


The cost of fluctuating inbreeding depression.
We present a phenotypic model for the evolution of self-fertilization in an infinite population of annual hermaphrodites for the case in which fitness and inbreeding depression vary among generations (e.g., due to fluctuations in the environment from year to year). Conditions for the evolution of selfing, mixed mating, and outcrossing are derived and are compared with results from numerical calculations that assume a normal distribution of inbreeding depression. In contrast to the situation in which inbreeding depression does not vary, when inbreeding depression fluctuates in a stochastic manner among generations with a mean less than 0.5, selfing is not necessarily selected. Thus, fluctuating inbreeding depression can be viewed as an additional cost of selfing that may stabilize mixed mating systems. These results emphasize the need to take into account fluctuating inbreeding depression in empirical studies aimed at understanding mating system evolution in annuals.


Utility of Bedside Ultrasound in Percutaneous Tracheostomy.
Background: Percutaneous tracheostomy placement is a common procedure performed in the intensive care unit. The use of an anterior neck ultrasound exam is routinely performed preprocedure, allowing for vessel visualization in determining the safety and feasibility of performing the procedure bedside. This prospective observational cohort study was conducted to determine whether vasculature in the anterior neck, seen on bedside ultrasound exam, contributes to bleeding complications during or after percutaneous tracheostomy (PCT) placement. Research Question: Do the vessels identified on preprocedure neck ultrasound affect the risk of bleeding during and after bedside PCT placement? Study Design and Methods: Preprocedural ultrasound was used to identify standard anatomical landmarks and vascular structures in the anterior neck in all patients undergoing bedside PCT placement under bronchoscopic guidance. A blinded survey of our recorded preprocedural images was provided to an expert panel who regularly perform bedside PCTs to determine the influence the images have on their decision to perform the procedure at the bedside. Results: One out of 15 patients (7%) had intra-operative minimal bleeding which was not clinically significant and resolved by gauze compression for 30 s. None of the patients had post-procedural bleeding after tracheostomy placement. Based on the blinded interpretation of neck ultrasound, there was 0.214 inter-operator variability among the expert panelists for decision-making regarding performing bedside PCT. Interpretation: Vessels visualized with anterior neck ultrasound were found to be small venous structures and did not significantly contribute to bleeding risk in patients who underwent PCT placement. The size and location of veins on neck ultrasound may commonly contribute to abandoning bedside PCT. This study suggests that veins measuring 3.9 mm or smaller identified at the site of access do not increase the risk of bleeding in PCT placement.


Effects of a participatory ergonomics team among hospital orderlies.
High rates of work-related injuries are seen among health care workers involved in lifting and transferring patients. We studied the effects of a participatory worker-management ergonomics team among hospital orderlies. This prospective intervention trial examined work injuries and other outcomes before and after the intervention, with other hospital employees used as a concurrent control. All orderlies in a 1,200-bed urban hospital were studied using passively collected data (mean employment during study period 100-110 orderlies); 67 orderlies (preintervention) and 88 orderlies (postintervention) also completed a questionnaire. The intervention was the formation of a participatory ergonomics team with three orderlies, one supervisor, and technical advisors. This team designed and implemented changes in training and work practices. The 2-year postintervention period was marked by decreased risks of work injury (RR = 0.50, 95% CI 0.35-0.72), lost time injury (RR = 0.26, 95% CI 0.14-0.48), and injury with three or more days of time loss (RR = 0.19, 95% CI 0.07-0.53). Total lost days declined from 136.2 to 23.0 annually per 100 full-time worker equivalents (FTE). Annual workers' compensation costs declined from $237/FTE to $139/FTE. The proportion of workers with musculoskeletal symptoms declined and there were statistically significant improvements in job satisfaction, perceived psychosocial stressors, and social support among the orderlies. Substantial improvements in health and safety were seen following implementation of a participatory ergonomics program.


Translating the WHO 25×25 goals into a UK context: the PROMISE modelling study.
Model the impact of targets for obesity, diabetes, raised blood pressure, tobacco use, salt intake, physical inactivity and harmful alcohol use, as outlined in the Global Non-Communicable Disease Action Plan 2013-2020, on mortality and morbidity in the UK population. Dynamic population modelling study. UK population. Not available. Mortality and morbidity (years lived with disability) from non-communicable diseases (NCDs) that are averted or delayed. Probability of achieving a 25% reduction in premature mortality from NCDs by 2025 (current WHO target) and a 33% reduction by 2030 (proposed target). The largest improvements in mortality would be achieved by meeting the obesity target and the largest improvements in morbidity would be achieved by meeting the diabetes target. The UK could achieve the 2025 and 2030 targets for reducing premature mortality with only a little additional preventive effort compared with current practice. Achieving all 7 risk targets could avert a total of 300 000 deaths (95% uncertainty interval 250 000 to 350 000) and 1.3 million years lived with disability (1.2-1.4 million) from NCDs by 2025, with the majority of health gains due to reduced mortality and morbidity from heart disease and stroke, and reduced morbidity from diabetes. Potential reductions in morbidity from depression and in morbidity and mortality from dementia at older ages are also substantial. The global premature mortality targets are a potentially achievable goal for countries such as the UK that can capitalise on many decades of effort in prevention and treatment. High morbidity diseases and diseases in later life are not addressed in the Global NCD Action Plan and targets, but must also be considered a priority for prevention in the UK where the population is ageing and the costs of health and social care are rising.


Gastrointestinal helminths in calves and cows in an organic milk production system.
The main aim of this study was to determine the distribution of populations of gastrointestinal helminths in lactating crossbred cows and calves during the grazing season in an organic milk production system. In addition, the potential importance of the peripartum in relation to the parasite load was examined. Between January 2007 and December 2008, parasitological fecal examinations were performed on cattle belonging to the Integrated Animal Production Program of Embrapa Agrobiology. The cows' parasite load remained low during the study period, and there were no statistical differences (p > 0.05) in comparisons between the seasons. The average egg count showed a positive correlation (0.80) with the peripartum, such that egg elimination per gram (p < 0.05) was higher during the week of labor than during the pre and postpartum periods. Calves showed low parasite loads, with significantly higher egg elimination (p < 0.05) during the winter. The study indicated that infection with gastrointestinal helminths was not a limiting factor for milk production in the organic system. Specifically, it was concluded that the nematode load can be maintained at moderate levels throughout the production system, even in the absence of anthelmintic treatment.


MR elastography of human lung parenchyma: technical development, theoretical modeling and in vivo validation.
To develop a novel MR-based method for visualizing the elastic properties of human lung parenchyma in vivo and to evaluate the ability of this method to resolve differences in parenchymal stiffness at different respiration states in healthy volunteers. A spin-echo MR Elastography (MRE) pulse sequence was developed to provide both high shear wave motion sensitivity and short TE for improved visualization of lung parenchyma. The improved motion sensitivity of this approach was modeled and tested with phantom experiments. In vivo testing was then performed on 10 healthy volunteers at the respiratory states of residual volume (RV) and total lung capacity (TLC). Shear wave propagation was visualized within the lungs of all volunteers and was processed to provide parenchymal shear stiffness maps for all 10 subjects. Density corrected stiffness values at TLC (1.83 ± 0.22 kPa) were higher than those at the RV (1.14 ± 0.14 kPa) with the difference being statistically significant (P < 0.0001). (1)H-based MR elastography can noninvasively measure the shear stiffness of human lung parenchyma in vivo and can quantitate the change in shear stiffness due to respiration. The values obtained were consistent with previously reported in vitro assessments of cadaver lungs. Further work is required to increase the flexibility of the current acquisition and to investigate the clinical potential of lung MRE.


Observations of the PCB distribution within and in-between ice, snow, ice-rafted debris, ice-interstitial water, and seawater in the Barents Sea marginal ice zone and the North Pole area.
To evaluate the two hypotheses of locally elevated exposure of persistent organic pollutants (POPs) in ice-associated microenvironments and ice as a key carrier for long-range transport of POPs to the Arctic marginal ice zone (MIZ), dissolved and particulate polychlorinated biphenyls (PCBs) were analyzed in ice, snow, ice-interstitial water (IIW), seawater in the melt layer underlying the ice, and in ice-rafted sediment (IRS) from the Barents Sea MIZ to the high Arctic in the summer of 2001. Ultra-clean sampling equipment and protocols were specially developed for this expedition, including construction of a permanent clean room facility and a stainless steel seawater intake system on the I/B ODEN as well as two mobile 370 l ice-melting systems. Similar concentrations were found in several ice-associated compartments. For instance, the concentration of one of the most abundant congeners, PCB 52, was typically on the order of 0.1-0.3 pg l(-1) in the dissolved (melted) phase of the ice, snow, IIW, and underlying seawater while its particulate organic-carbon (POC) normalized concentrations were around 1-3 ng gPOC(-1) in the ice, snow, IIW, and IRS. The solid-water distribution of PCBs in ice was well correlated with and predictable from K(ow) (ice log K(oc)-log K(ow) regressions: p<0.05, r2=0.78-0.98, n=9), indicating near-equilibrium partitioning of PCBs within each local ice system. These results do generally not evidence the existence of physical microenvironments with locally elevated POP exposures. However, there were some indications that the ice-associated system had harbored local environments with higher exposure levels earlier/before the melting/vegetative season, as a few samples had PCB concentrations elevated by factors of 5-10 relative to the typical values, and the elevated levels were predominantly found at the station where melting had putatively progressed the least. The very low PCB concentrations and absence of any significant concentration gradients, both in-between different matrices and over the Eurasian Arctic basin scale, suggest that ice is not an important long-range transport purveyor of POPs to the Arctic MIZ ecosystem.


Highly selective detection of 2,4,6-trinitrophenol by using newly developed terbium-doped blue carbon dots.
The detection of nitroaromatic explosives is of great importance owing to their strong explosive power and harmfulness in terms of the environment, homeland security and public safety. Herein, rare earth-doped carbon dots with multifunctional features were firstly prepared by simply keeping the mixture of terbium(iii) nitrate pentahydrate and citric acid at 190 °C for 30 min. The as-prepared terbium doped carbon dots (Tb-CDs), through a rapid and simple direct carbonization route, have a size of about 3 nm, and exhibit excitation wavelength dependent emission of blue fluorescence, are stable, and can be applied for the selective and colorimetric detection of 2,4,6-trinitrophenol (TNP) in the range of 500 nM-100 μM with a limit of detection of 200 nM based on the inner filtering effect (IFE) of the excitation and emission bands of Tb-CDs by TNP and the electron transfer (ET) from Tb-CDs to TNP, giving a precise and highly reproducible result for detecting complex water samples.


Adiposomes from Obese-Diabetic Individuals Promote Endothelial Dysfunction and Loss of Surface Caveolae.
Glycosphingolipids (GSLs) are products of lipid glycosylation that have been implicated in the development of cardiovascular diseases. In diabetes, the adipocyte microenvironment is characterized by hyperglycemia and inflammation, resulting in high levels of GSLs. Therefore, we sought to assess the GSL content in extracellular vesicles derived from the adipose tissues (adiposomes) of obese-diabetic (OB-T2D) subjects and their impact on endothelial cell function. To this end, endothelial cells were exposed to adiposomes isolated from OB-T2D versus healthy subjects. Cells were assessed for caveolar integrity and related signaling, such as Src-kinase and caveolin-1 (cav-1) phosphorylation, and functional pathways, such as endothelial nitric oxide synthase (eNOS) activity. Compared with adiposomes from healthy subjects, OB-T2D adiposomes had higher levels of GSLs, especially LacCer and GM3; they promoted cav-1 phosphorylation coupled to an obvious loss of endothelial surface caveolae and induced eNOS-uncoupling, peroxynitrite generation, and cav-1 nitrosylation. These effects were abolished by Src kinase inhibition and were not observed in GSL-depleted adiposomes. At the functional levels, OB-T2D adiposomes reduced nitric oxide production, shear response, and albumin intake in endothelial cells and impaired flow-induced dilation in healthy arterioles. In conclusion, OB-T2D adiposomes carried a detrimental GSL cargo that disturbed endothelial caveolae and the associated signaling.


Isolation of ALU1-P gene encoding a protein with aluminum tolerance activity from Arthrobacter viscosus.
We isolated a DNA fragment (ALU1-P) encoding a protein with an activity of aluminum tolerance from an Al tolerant soil microorganism, Arthrobacter viscosus. This microorganism was isolated from acidic tea field soils. The cloned DNA is composed of 1090 nucleotides, which has one open-reading frame without any stop codon. However, when the DNA fragment was transferred into Escherichia coli, a microorganism susceptible to Al toxicity, it endowed E. coli with Al tolerance. The deduced amino acid sequence of the DNA showed 65% identity with the protein of YbaX gene in Escherichia coli, and 51.1% identity with YB91 Haein hypothetical protein of HI1191 gene in Haemophilus influenzae. The ALU1-P gene in the expression vector produced a protein of 192 amino acids deriving a molecular weight of 21.3 kDa by using the stop codon in vector. The ALU1-P gene is a new one that has the characteristic of Al tolerance.


Cholinergic input to dopaminergic neurons in the substantia nigra: a double immunocytochemical study.
In order to determine whether the cholinergic fibres that innervate the substantia nigra make synaptic contact with dopaminergic neurons of the substantia nigra pars compacta, a double immunocytochemical study was carried out in the rat and ferret. Sections of perfusion-fixed mesencephalon were incubated first to reveal choline acetyltransferase immunoreactivity to label the cholinergic terminals and then tyrosine hydroxylase immunoreactivity to label the dopaminergic neurons. Each antigen was localized using peroxidase reactions but with different chromogens. At the light microscopic level, in confirmation of previous observations, choline acetyltransferase-immunoreactive axons and axonal boutons were found throughout the substantia nigra. The highest density of these axons was found in the pars compacta where they were often seen in close apposition to tyrosine hydroxylase-immunoreactive cell bodies and dendrites. In the ferret where the choline acetyltransferase immunostaining was particularly strong, bundles of immunoreactive fibres were seen to run through the reticulata perpendicular to the pars compacta. These bundles were associated with tyrosine hydroxylase-immunoreactive dendrites that descended into the reticulata. The choline acetyltransferase-immunoreactive fibres made "climbing fibre"-type multiple contacts with the tyrosine hydroxylase positive dendrites. At the electron microscopic level the choline acetyltransferase-immunoreactive axons were seen to give rise to vesicle-filled boutons that formed asymmetrical synaptic specializations with nigral dendrites and perikarya. The synapses were often associated with sub-junctional dense bodies. On many occasions the postsynaptic structures contained the tyrosine hydroxylase immunoreaction product, thus identifying them as dopaminergic. It is concluded that at least one of the synaptic targets of cholinergic terminals in the substantia nigra are the dendrites and perikarya of dopaminergic neurons and that in the ferret at least, the dendrites of dopaminergic neurons that descend into the pars reticulata receive multiple synaptic inputs from individual cholinergic axons.


Efficient organic sensitizers with pyridine-N-oxide as an anchor group for dye-sensitized solar cells.
Five organic dyes with pyridine-N-oxide as the anchor group and electron acceptor have been synthesized and applied in dye-sensitized solar cells (DSSCs). Benzothiadiazole was introduced in the conjugation system to increase the electron withdrawing properties, FTIR spectra showed that the coordination was between the pyridine-N-oxide and the Brønsted acid site on the TiO2 surface. The relationship between different dye structures and the performance of the DSSCs was investigated systematically. The location of the thiophene unit was studied, and the direct linkage of benzothiadiazole with pyridine-N-oxide was beneficial to broaden the absorption. The donor-acceptor-acceptor-configured dye WL307, which has 2-ethylhexyloxy chains in the donor part, showed the best efficiency of 6.08% under 100 mW cm(-2) light illumination. The dye series showed a fairly good stability during the one month test period.


Intrauterine maxillary development and maxillary dental arch biometry: a fetal cadaver study.
This study's goal was to determine normal maxillary development on fetal cadavers. This study was carried out on 45 fetuses aged between the 17th - 40th weeks of gestation (24 male, 21 female). The distance between the widest left and right points of the maxillary dental arch (MDA) on the transverse plane, the distance of the papilla incisiva (PI) to the widest left and right points of the maxillary dental arch (MDAW), and the PI and posterior nasal spine (PNS) were measured. The average arch forms of the MDA were created according to trimester groups using the MATLAB program. The one-way ANOVA test was used to make a comparison between trimester groups, and ANOVA followed by post hoc analysis using the Bonferroni test was applied for comparisons. Pearson's correlation analysis was used for correlation analysis. The data in the present study did not differ between genders. In the comparison between trimester groups, we did not find any difference between the 3rd trimester and full-term groups only in the PI-MDAW measurement. Other parameters increased with age. In the correlation analysis, the measurement values by age showed a strong positive correlation. The MDAW exhibited the best correlation with age (rweek = 0.919). When the average MDA forms created using the MATLAB program were evaluated, it was observed that the PI-MDAW of the average MDA in the 3rd trimester and full-term intersected. This study provides a basis for a better understanding of fetal maxillary growth processes and can be useful to standardize the detection of malformations or intrauterine growth restrictions.


The Impact of Antihypertensive Medications on Bone Mineral Density and Fracture Risk.
This review summarizes the impact of thiazide diuretics on fracture risk in older hypertensive individuals. We performed a post hoc evaluation of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, a randomized, prospective, double blind hypertension study comparing a thiazide-like diuretic, a calcium channel blocker (CCB), and an angiotensin converting enzyme inhibitor (ACEi). We examined the risk of hip and pelvic fractures during the in-trial period (n = 22,180 participants; mean 4.9-year follow-up) and during the post-trial period using national data bases (n = 16,622 participants) (mean total follow-up 7.8 years). During the trial, participants randomized to the thiazide diuretic versus the CCB or the ACEi had a lower risk of fracture on adjusted analyses (HR 0.79 [95% CI, 0.63, 0.98], p = 0.04). Risk of fracture was significantly lower in participants randomized to the diuretic as compared to those randomized to the ACEi (HR 0.75 [95% CI, 0.58, 0.98]; p = 0.04), but not significantly different compared to the CCB (HR 0.87 [95% CI, 0.71, 1.09]; p = 0.17). Over the entire trial and post-trial period of follow-up, the cumulative incidence of fractures was non-significantly lower in participants assigned to the diuretic vs assignment to the ACEi or the CCB (HR 0.87 [0.74-1.03], p = 0.10) and versus each medication separately. These findings establish a benefit for thiazide diuretic treatment for the prevention of fractures versus other commonly used antihypertensive medications using prospective, randomized data. The effects of the thiazide diuretic on bone appear to be long lasting.


[Unawareness for homonymous visual field defect].
There was no report which dealt with the relationship between emotional state, degree of defective visual search, severity of hemianopic dyslexia, the episode when the patient became aware of the defect, and unawareness of visual loss in homonymous hemifield. To investigate the relationship between degree of awareness and those factors that might be responsible for the unawareness, including the aspects listed above. Four patients with visual field defects caused by a brain lesion after a stroke was investigated. Self rating of emotional state, search performance for an object among many placed on a table, and for text reading, as well as visual field, visual positive phenomena, and hemispatial neglect were evaluated. Degree of unawareness for field loss was evaluated by modified version of the method of Bisiach et al. (1985). In addition, the episodes when the patient became aware of the defect were asked. In accordance with the previous studies, we found no relationship between the degree of awareness of field defect and anatomic lesions, co-existence of hemispatial neglect, or the degree of awareness of hemiplegia. However, the patient with neglect was unaware of their troubles in vision at all, whereas the patients without neglect were aware of the troubles but misinterpreted them as problems of the eyes including acuity. In accordance with previous studies, co-existence of visual hallucinations or illusions seemed to be associated with awareness of visual field defect. No relationship was found between the degree of awareness of field defect and emotional state, degree of field loss, degree of defective visual search, or severity of hemianopic dyslexia. Their responses to the inquiry about the degree of awareness of field defect were not consistent. Thus, the awareness of the field defect seemed to be difficult to be kept firmly in their mind. On the other hand, the patients could remember the episode when they became aware of the defect for the first time, being able to specify time, place, and situation. Levine (1990) suggested that the sensory loss in this sort of patients was never phenomenally immediate but instead must be discovered by observation and inference. Non-specificity of the lesion, qualitative difference in awareness between the patient with and without hemispatial neglect, association of positive visual phenomena and awareness, fluctuation of awareness, and dependence of awareness on personal experiences found in our patients, can be explained with this 'discovery' hypothesis.


Cost-effectiveness of ceftolozane/tazobactam compared with piperacillin/tazobactam as empiric therapy based on the in-vitro surveillance of bacterial isolates in the United States for the treatment of complicated urinary tract infections.
A challenge in the empiric treatment of complicated urinary tract infection (cUTI) is identifying the initial appropriate antibiotic therapy (IAAT), which is associated with reduced length of stay and mortality compared with initial inappropriate antibiotic therapy (IIAT). We evaluated the cost-effectiveness of ceftolozane/tazobactam compared with piperacillin/tazobactam (one of the standard of care antibiotics), for the treatment of hospitalized patients with cUTI. A decision-analytic Monte Carlo simulation model was developed to compare the costs and effectiveness of empiric treatment with either ceftolozane/tazobactam or piperacillin/tazobactam in hospitalized adult patients with cUTI infected with Gram-negative pathogens in the US. The model applies the baseline prevalence of resistance as reported by national in-vitro surveillance data. In a cohort of 1000 patients, treatment with ceftolozane/tazobactam resulted in higher total costs compared with piperacillin/tazobactam ($36,413 /patient vs. $36,028/patient, respectively), greater quality-adjusted life years (QALYs) (9.19/patient vs. 9.13/patient, respectively) and an incremental cost-effectiveness ratio (ICER) of $6128/QALY. Ceftolozane/tazobactam remained cost-effective at a willingness to pay of $100,000 per QALY compared to piperacillin/tazobactam over a range of input parameter values during one-way and probabilistic sensitivity analysis. Model results show that ceftolozane/tazobactam is likely to be cost-effective compared with piperacillin/tazobactam for the empiric treatment of hospitalized cUTI patients in the United States.