Efficient and compact source of tuneable ultrafast deep ultraviolet laser pulses at 50 kHz repetition rate.
Deep ultraviolet (DUV) laser pulses with tuneable wavelength and very short duration are a key enabling technology for next-generation technology and ultrafast science. Their generation has been the subject of extensive experimental effort, but no technique demonstrated thus far has been able to meet all requirements in one light source. Here we demonstrate a bright, efficient, and compact source of tuneable DUV ultrafast laser pulses based on resonant dispersive wave emission in hollow capillary fiber. In a total footprint of only 120cm×75cm, including the ytterbium-based drive laser, we generate pulses between 208nm and 363nm at 50kHz repetition rate with a total efficiency of up to 3.6%. Down-scaling of the DUV generation reduces the required energy sufficiently to enable the generation of two-color few-femtosecond DUV pulses.


Novel in-frame deletion mutation in FLCN gene in a Korean family with recurrent primary spontaneous pneumothorax.
Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant disease presenting with skin fibrofolliculomas, pulmonary cysts, primary spontaneous pneumothorax (PSP), and renal cancer. It is caused by germline mutations in the FLCN gene, which encodes folliculin. Here we report a novel in-frame deletion mutation p.F143del (c.427_429delTTC) in exon 6 of FLCN gene in the proband and her two sisters. The proband was a 40-year-old Korean woman who presented with right-sided pneumothorax and papular lesions on the face and neck area but without renal cancer. Her father also had a history of PSP and died of renal cancer at the age of 75. Her older sisters have been treated for recurrent PSP but did not have skin lesions suspicious of fibrofolliculoma. The relative expression of FLCN was significantly reduced in the proband and one of the sibling who was confirmed to have FLCN mutation. In-frame deletions in the FLCN gene have rarely been reported but have been shown to impose significant effect on protein stability of FLCN. Identification of a novel genotype in BHDS will provide clues to the phenotype-genotype relations and may aid in explaining the molecular pathogenesis of diseases related to FLCN mutation.


Differentiation of mouse embryonic stem cells into blood.
Embryonic stem (ES) cells can be maintained as pluripotent stem cells or induced to differentiate into many different somatic cell types. As ES-derived somatic cells can potentially be used for cell transplantation or cell-based therapy, ES cells have gained much scientific and general public attention. Successful derivation of blood from ES cells for tissue engineering will require a comprehensive understanding of inductive signals and downstream effectors involved in blood lineage development. Ideally, directed differentiation of ES cells into blood and isolation of pure hematopoietic progenitors will enhance our ability to utilize ES-derived blood cells for future clinical applications. The protocols provided in this unit describe methods of maintaining and differentiating mouse ES cells as well as identifying and isolating hematopoietic progenitors by utilizing flow cytometry and progenitor assays.


Modification of β-Sheet Forming Peptide Hydrophobic Face: Effect on Self-Assembly and Gelation.
β-Sheet forming peptides have attracted significant interest for the design of hydrogels for biomedical applications. One of the main challenges is the control and understanding of the correlations between peptide molecular structure, the morphology, and topology of the fiber and network formed as well as the macroscopic properties of the hydrogel obtained. In this work, we have investigated the effect that functionalizing these peptides through their hydrophobic face has on their self-assembly and gelation. Our results show that the modification of the hydrophobic face results in a partial loss of the extended β-sheet conformation of the peptide and a significant change in fiber morphology from straight to kinked. As a consequence, the ability of these fibers to associate along their length and form large bundles is reduced. These structural changes (fiber structure and network topology) significantly affect the mechanical properties of the hydrogels (shear modulus and elasticity).


Aggressive and violent incidents: perceptions of training and support among staff caring for older people and people with head injury.
Reported rates of workplace violence are increasing and studies of violence and aggression to health service staff in the United Kingdom have largely focused upon mental health and accident and emergency units. The study of violence and aggression in other specialties has been neglected. This paper reports the findings from a survey of staff perceptions of training and support in an elderly care and head injury unit. Staff in a care of older people and head injury unit, half of whom were nurses, were surveyed to identify their experiences of violence and aggression in the workplace, their receipt of training, the relevance of training and knowledge of support services. An anonymous semi-structured questionnaire was sent to all nursing, therapy and psychology staff in the unit. Quantitative data were analysed by SPSS and content analysis was adopted for the qualitative data. Just over half the participants had experienced an incident of violence or aggression in the past 12 months. Training was judged to be relevant by almost 90% of respondents but was not always delivered in line with trust guidance. Staff who had been involved in incidents were more likely to identify training needs. A higher percentage of nurses than other professions were involved in incidents, but they were not as aware of the staff support department as other professional groups. The findings indicate that care of older people and head injury units should examine more closely the delivery of staff training on violence and aggression, and invite staff to identify their training needs. A national survey of approaches to staff support may be worthwhile. Staff who had received training judged it to be relevant to their working situations, but outstanding training needs should be identified and addressed. Confidential staff support facilities should be well publicized.


Chronic Cavitary Pulmonary Aspergillosis: A Case Report and Review of the Literature.
BACKGROUND Aspergillus spores have the ability to affect patients with or without intact immune systems; because of this disease's wide patient involvement it deserves a place on the differential diagnosis list, with endocarditis and tuberculosis, for those presenting with new pulmonary nodules or cavitation. CASE REPORT This case report involves the presentation, diagnosis, and treatment of a 69-year-old female who presented with new rapidly progressing cavitary lung lesions in the setting of copious administration of systemic steroid use. Given the patient's past history of alcoholism and environmental exposure, her case was not straight forward in regard to a diagnosis. Ultimately, she was diagnosed with chronic cavity pulmonary aspergillosis in the setting of chronic immunosuppression secondary to systemic steroid administration. Due to her convoluted medical history and the poor differential diagnosis list, there was a delay in final diagnosis. CONCLUSIONS This case report and clinical review aims to prevent anchoring when the patient's presentation is not straight forward and aims to remind the clinician of the importance of a differential diagnosis.


Vesicle formation of single-chain amphiphilic 4-dodecylbenzene sulfonic acid in water and micelle-to-vesicle transition induced by wet-dry cycles.
Simple single-chain amphiphiles (SCAs) can form vesicular structures in their single-component aqueous solutions, which has attracted great attention, but the understanding of their aggregation behavior is still limited. In this work, the aggregation behavior of 4-dodecylbenzene sulfonic acid (DBSA), a typical simple SCA, in water was investigated. The structure and properties of the aggregates formed were determined. In particular, the effect of wet-dry cycles on the structures of aggregates was examined. The mechanisms of aggregate formation and structural transition were discussed. It was found that the increase of DBSA concentration can drive the occurrence of a micelle-to-vesicle transition, showing a critical micelle concentration and critical vesicle concentration of ∼0.53 and 2.14 mM, respectively. The vesicles formed coexist with micelles in solution, with a unilamellar structure and ∼80 nm size, and exhibit size-selective permeability. In addition, the vesicles show remarkable stability upon long-term storage, exposure to high temperature, and freeze-thaw cycles. The H-bonding interaction between DBSA species and the interdigitated structure of alkyl chains in bilayers play a key role in the formation and stability of DBSA vesicles. Interestingly, it was found that the wet-dry cycle can induce a micelle-to-vesicle transition and an obvious increase in the size of the original vesicles, accompanied by the formation of some multilamellar vesicles. This work provides a better understanding of the aggregation behavior of simple SCAs in their single-component aqueous solutions.


Forsythia fructus inhibits the mast-cell-mediated allergic inflammatory reactions.
Mast cells are key as effector cells in the early phase allergic inflammation and in diverse immunological and pathological processes. Forsythia fructus (F. fructus) has used as a traditional medicine for inflammatory diseases. In the present study, we determined the effect of F. fructus extracts on compound 48/80-induced paw oedema and vascular permeability in vivo. In addition, we investigated in vitro whether F. fructus has inhibitory effects on compound 48/80-induced histamine releases from rat peritoneal mast cells (RPMC), and on phorbol 12-myristate 13-acetate (PMA) plus A23187-induced tumor necrosis factor-alpha (TNF-alpha) releases from human mast cells (HMC-1). In mice orally administrered F. fructus (100 microg/g) for 1 h, compound-48/80-induced oedema and vascular permeability were significantly reduced rather than those receiving intravenous injection of ketotifen, mast cell stabilizer. F. fructus dose-dependently inhibited the histamine release induced by compound 48/80 from RPMCs. Moreover, F. fructus had no cytotoxic effects on cell viability and had inhibitory effects on TNF-alpha secretion from HMC-1. These results suggest that F. fructus is a potential herb medicine for treatment of inflammatory diseases through downmodulating mast cell activation.


[Physiotherapeutic treatment of gastroduodenal ulcer].
The review presents 69 references of current literature on the problem of gastroduodenal ulcer physiotherapy which has a good potential of impact on gastroduodenal motility, lipid peroxidation, microcirculation, physiological and reparative regeneration of epithelial and glandular cells. The choice of a physiotherapeutic method depends on the disease stage and to a less extent on location of the ulcer defect.


Pediatric Supratentorial Ependymoma: Surgical, Clinical, and Molecular Analysis.
Pediatric supratentorial ependymomas (SEs) have distinct molecular and behavioral differences from their infratentorial counterparts. To present our experience with pediatric SEs over a 24-yr period. Clinical, operative, and radiographic information was abstracted retrospectively. Our primary outcomes were progression-free survival (PFS) and overall survival (OS). Detection of C11orf95-RELA rearrangement was performed using interphase fluorescence in situ hybridization (iFISH). Seventy-three patients were identified (41 female, 32 male); median age was 6.7 yrs (range, 1 mo-18.8 yr); median follow-up was 8.3 yrs (range, 2.0-26.3). Fifty-eight (79.5%) of 73 patients underwent gross total resection (GTR); no patient with subtotal resection had greater than 1 cm3 of residual tumor; 42 patients (57.5%) experienced subsequent disease progression with 17 patients ultimately dying of their disease. Median PFS was 3.7 yrs. Molecular analysis was available for 51 patients (70%). On bivariate analysis, PFS and OS were not statistically affected by age, tumor grade, or extent of resection, although there was a clinically significant trend for the latter in favor of aggressive resection on PFS (P = .061). Children with RELA fusion had significantly higher PFS (P = .013) than those without, although there was no difference in OS when compared with those with no C11orf95-RELA fusion or C11orf95 gene rearrangement alone. In our series, GTR may be associated with better PFS, but did not impact OS. Surprisingly, RELA fusion was not found to be a negative prognostic factor, raising the possibility that the deleterious effects may be overcome by aggressive resection.


Patients With Ulcerative Colitis and Primary Sclerosing Cholangitis Frequently Have Subclinical Inflammation in the Proximal Colon.
Patients with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) have a high risk of colonic neoplasia. Neoplasia frequently develops in the proximal colon in patients with PSC. Histologic inflammation is an independent risk factor for the development of neoplasia; we investigated whether patients with UC and PSC have more subclinical disease activity than patients with UC alone. We performed a retrospective analysis of data from 143 patients (205 examinations) with ulcerative pancolitis who were in clinical remission and treated at a tertiary medical center from May 2011 through May 2016. Endoscopic and histologic activity were compared between patients with PSC (from 36 examinations) and without PSC (from 169 examinations). Disease activity was scored per colonic segment using a modified Mayo endoscopic subscore and histologic assessment. In each colonic segment, differences in disease activity and the degree of discordance between endoscopic and histologic inflammation among UC patients with and without PSC were compared. Patients with UC-PSC had significantly more subclinical endoscopic (odds ratio [OR], 4.21; 95% CI, 1.67-10.63) and histologic activity (OR, 5.13; 95% CI, 2.25-11.68) in the right colon, as well as greater degree of histologic than endoscopic inflammation in the proximal colon (OR, 3.14, 95% CI, 1.24-7.97), compared with patients without PSC. Patients with UC-PSC had significantly less histologic activity in the rectum on multivariate analysis (OR, 0.24; 95% CI, 0.08-0.72). Patients with UC and PSC who are in clinical remission are significantly more likely to have endoscopic and histologic inflammation in the right colon than patients with UC without PSC. Our findings provide insight into cause of colorectal cancer in UC patients with PSC.


Regulation of COX Assembly and Function by Twin CX9C Proteins-Implications for Human Disease.
Oxidative phosphorylation is a tightly regulated process in mammals that takes place in and across the inner mitochondrial membrane and consists of the electron transport chain and ATP synthase. Complex IV, or cytochrome c oxidase (COX), is the terminal enzyme of the electron transport chain, responsible for accepting electrons from cytochrome c, pumping protons to contribute to the gradient utilized by ATP synthase to produce ATP, and reducing oxygen to water. As such, COX is tightly regulated through numerous mechanisms including protein-protein interactions. The twin CX9C family of proteins has recently been shown to be involved in COX regulation by assisting with complex assembly, biogenesis, and activity. The twin CX9C motif allows for the import of these proteins into the intermembrane space of the mitochondria using the redox import machinery of Mia40/CHCHD4. Studies have shown that knockdown of the proteins discussed in this review results in decreased or completely deficient aerobic respiration in experimental models ranging from yeast to human cells, as the proteins are conserved across species. This article highlights and discusses the importance of COX regulation by twin CX9C proteins in the mitochondria via COX assembly and control of its activity through protein-protein interactions, which is further modulated by cell signaling pathways. Interestingly, select members of the CX9C protein family, including MNRR1 and CHCHD10, show a novel feature in that they not only localize to the mitochondria but also to the nucleus, where they mediate oxygen- and stress-induced transcriptional regulation, opening a new view of mitochondrial-nuclear crosstalk and its involvement in human disease.


Orthodontic-surgical treatment: neuromuscular evaluation in open and deep skeletal bite patients.
The aim of this study was to compare electromyographic data of two groups of patients (open and deep skeletal bite) before and after surgical orthodontic treatment. All patients who underwent orthognathic surgery at the Department of Orthodontics (University of Milan) were subjected to periodic electromyographic evaluation of the masticatory muscles (masseter and anterior temporal muscles) and to electrokinesiographic evaluation of mandibular movements. The sample comprised 72 patients (35 open skeletal bite patients and 37 deep skeletal bite patients) at the end of craniofacial growth. The electromyographic instruments used in the study included a Freely and a K6-I electromyograph. Statistical evaluation was carried out with Student's t tests for independent samples. Lots of differences between open and deep skeletal bite patients have been underlined by the analysis of the electromyographic data obtained. These results have been obtained with both electromyographic systems. Muscular activity in microvolts is higher in deep skeletal bite patients at the beginning of the treatment than in open bite ones, but during the following phases of the treatment, the two values became similar. Morphologic differences between open and deep bite patients can also be demonstrated by instrumental examinations, and their correction after surgical treatment is observable on electromyographic and electrognatographic exams.


[Susceptibility of community-acquired pneumonia pathogens to azithromycin].
Two hundred and sixty eight microbial strains were tested for their antibiotic susceptibility. Azithromycin (sumamed) was shown to have an efficient inhibitory action on pneumococci, streptococci and hemophilic bacilli. Doxycycline and gentamicin were not sufficiently active against gram-positive cocci, the same as trimethoprime/sulfamethoxazole which was equally not sufficiently active against hemophilic bacilli. Adequate therapy of bronchopulmonary diseases requires the pathogen antibioticograms.


[Iosif Vasil'evich Bertenson, an organizer of forensic medical examination in the Sankt-Peterburg region].
The paper describes the life and professional work of I.V. Bertenson, MD, the first medical inspector of the Sankt-Peterburg guberniya (region), distinguished forensic medical examiner, surgeon, hygienist, historian of medicine and organizer of health services in this country. The versatile activities of I.V. Bertenson are exemplified by his work as the editor of the journal "Arkhiv sudebnoy meditsiny and obshchestvennoy gigieny (Archive of Forensic Medicine and Public Hygiene)", and the chairman of the 5th Pirogov Congress. The materials for the paper were borrowed from the Sankt-Peterburg Central State Archive and pre-revolutionary press publications.


Challenges and current advances in the methodology of thyroglobulin measurements.
Thyroglobulin (Tg) is a large protein secreted exclusively by the thyroid gland. In a clinical setting, it is measured for the purpose of follow-up of thyroidectomy patients. However, Tg measurements are often impeded by the presence of Tg autoantibodies and/or heterophylic antibodies that interfere with most measuring platforms. This presents a global problem in thyroid cancer patients who need to be postoperatively monitored for recurrent or residual disease. Therefore, in this paper we offer an overview of the existing methodologies and alternative approaches for Tg measurements that are a focus of research worldwide. These include Tg mRNA measurements, exosomal Tg detection, the use of alternative analytes (liquid biopsies) and the development of new approaches for preanalytical sample treatment.


Responding to mental health needs of Syrian refugees in Turkey: mhGAP training impact assessment.
About 1468 Syrian and Turkish doctors, serving in primary health care, have received the mhGAP training during 2016-2019. As additional training needs were identified, MoH and WHO wanted to understand the usefulness of the training and its impact in responding to the mental health needs of Syrian refugees in Turkey. A five component assessment was done in 2019, consisting of feedback of trainees, assessment of increase in knowledge; utilization of service; compliance to treatment guidelines and service user satisfaction. The purpose was to understand the perception of participants on the training; estimate the knowledge gained-attributable to the training; estimate the increase in mental health cases identified and treated; compliance with treatment guidelines; as well as perception of the services received by end-beneficiaries. Results indicate that most of the respondents were happy with the training, but preferred additional mhGAP training as a refresher course in the future. There was knowledge gained due to the training, 9% for the Syrian and 5% for Turkish doctors. The knowledge gained has helped the practicing doctors to be more attentive and increase the numbers of cases diagnosed after the training for almost all groups of diagnoses. Most doctors, observed during practice, comply with the guidelines shared during the training, but improvement is still needed when it comes to prescription and treatment of certain conditions. The average number of mental health cases identified increased by 38 (%27) cases in the year following the training. We observed over 70% compliance with guidelines for 9 out of 12 criteria in question. The results of the patient exit interviews indicate a high level of satisfaction with the MHPSS services provided. About 95% of beneficiaries were happy with the quality of the service, and 92% having their needs met. The mhGAP training was found useful. More training should be conducted to fill in the gap in service provision and meet the mental needs of Syrian refugees in Turkey.


The Time is Ripe for a Consensus Definition of Clinical Recovery in First-episode Psychosis: Suggestions Based on a 10-Year Follow-up Study.
A consensus definition of clinical recovery in first-episode psychosis (FEP) is required to improve knowledge about recovery rates in this population. To propose criteria for a future consensus definition, this study aims to investigate rates of clinical recovery when using a standard definition (full psychotic symptom remission and adequate functioning for minimum one year) across both affective and nonaffective FEP groups (bipolar spectrum and schizophrenia spectrum disorders). Second, we aim to explore changes in rates when altering the standard definition criteria. Third, to examine the extent to which healthy controls meet the functioning criteria. In total, 142 FEP participants and 117 healthy controls preselected with strict criteria, were re-assessed with structured clinical interviews at 10-year follow-up. A total of 31.7% were in clinical recovery according to the standard definition, with significantly higher recovery rates in bipolar (50.0%) than in schizophrenia spectrum disorders (22.9%). Both groups' recovery rates decreased equally when extending duration and adding affective symptom remission criteria and increased with looser functioning criteria. In healthy controls, 18.8% did not meet the standard criteria for adequate functioning, decreasing to 4.3% with looser criteria. Findings suggest that clinical recovery is common in FEP, although more in bipolar than in schizophrenia spectrum disorders, also when altering the recovery criteria. We call for a future consensus definition of clinical recovery for FEP, and suggest it should include affective symptom remission and more reasonable criteria for functioning that are more in line with the general population.


Use of exploratory factor analysis to ascertain the correlation between the activities of rheumatoid arthritis and infection by human parvovirus B19.
We evaluated a possible correlation between the clinical activities of rheumatoid arthritis (RA) and human parvovirus B19 (B19) infection using exploratory factor analysis (EFA). RA patients were organized into two groups: 100 patients in the main group and 97 in the RA(DAS28) group. Four subgroups were defined from the main group according to the presence or absence of certain infection-specific markers: group I comprised 43 patients who had IgG antibodies against B19; group II, 25 patients with active B19 infection (B19-specific IgM antibodies and/or plasma viremia); group III, 19 patients with latent/persistent B19 infection (virus-specific sequences in peripheral blood leukocytes' DNA with or without B19-specific IgG antibodies), and group IV, 13 patients without infection markers. The RA(DAS28) group was divided into four subgroups similarly to the main group: group I, 35; group II, 31; group III, 19; and group IV, 12 patients. Disease-specific clinical values in both groups were analyzed employing EFA, and the RA(DAS28) group was additionally assessed using Disease Activity Score (DAS)28. RA activity was higher in patients who had markers of B19 infection. The highest activity of RA in both study groups was in patients with latent/persistent infection. In the RA(DAS28) group, according to DAS28, the highest activity of RA was in patients with active B19 infection. Using EFA and DAS28, a correlation between the clinical activity of RA and B19 infection was confirmed. These data suggest that EFA is applicable for medico-biological studies.


Cloning and characterisation of malE in Burkholderia pseudomallei.
No recombinant protein is available for serodiagnosis or skin test in the diagnosis of melioidosis. This report describes the cloning of the malE gene, which encodes an immunogenic protein of Burkholderia pseudomallei. Bi-directional DNA sequencing of malE revealed that the gene contained a single open reading frame encoding 416 amino acid residues with a predicted molecular mass of 44.4 kDa. BLAST analysis showed that the putative protein encoded by malE is homologous to the maltose-binding protein (MBP) of other bacteria. It has 48% and 63% amino acid identity and similarity with the MBP of Brucella abortus, and malE complementation assay showed that it partially complemented the function of the MBP of Escherichia coli. Several highly conserved regions among the MBP of B. pseudomallei, Br. abortus, Salmonella enterica serotype Typhimurium, E. coli and Enterobacter aerogenes were observed. These regions represent signatures A, B, C, D and F identified in the MBP of E. coli. Further sequence analysis revealed that the first 24 amino acid residues of the MBP of B. pseudomallei probably represent the N-terminal signal peptide of the protein. Similar to the signal peptide of the MBP of E. coli, Ent. aerogenes and S. Typhimurium, the MBP of B. pseudomallei contains two basic residues in the first eight amino acids, followed by a hydrophobic core, with the last three amino acids in the signal peptide being Ala-Gln-Ala, conforming to the consensus sequence Ala-X-Ala at positions -3 to -1 relative to the site of proteolytic cleavage for recognition by signal peptidase I. Further studies on serodiagnosis of melioidosis with recombinant MBP should be performed.


The development of the Chondrocranium in the golden hamster, Mesocricetus auratus (Waterhouse).
3 -stages of development of the chondrocranium of the golden hamster have been described. The chondrocrania of the gerbil, mouse and white rat have been compared with the chondrocranium of the golden hamster and the main differences noted. In several respects, the chondrocranium of the golden hamster is primitive.


Diversity and genetic structure of mangaba remnants in states of northeastern Brazil.
In this study, we analyzed the genetic diversity and structure of remnants of mangaba populations in states of northeastern Brazil by applying 9 microsatellite markers previously developed to establish conservation strategies for germplasm and species preservation. Six to 20 individuals per population were analyzed, with a total of 94 individuals and 6 populations from the states of Ceará, Pernambuco, and Sergipe, Brazil. The intra-population positive fixation index (f) in all populations indicated inbreeding resulting from the lack of random mating. The mean genetic diversity index values GST, FST, and RST estimated for divergence among the 6 populations were 0.14 (P < 0.05), revealing moderate genetic differentiation. The smallest FST value (P ≥ 0.05) was observed between the Jacarecoara and Tapera populations (0.005) and the highest between the Barra dos Coqueiros and Jacarecoara populations (0.287). The Jacarecoara population was the most divergent among the populations analyzed. According to analysis of molecular variance results, the largest variation percentage resulted from variability within populations (83.18%). Bayesian clustering analysis showed the formation of 2 sets (K = 2). Our results are important for developing strategies for in situ conservation of the species, seed collection, and ex situ conservation. For both methods, conservation of the greatest possible genetic variability of the species is essential.


Luminescent tris(8-hydroxyquinolates) of bismuth(III).
Luminescent homoleptic bismuth(III) complexes have been synthesized by adding several functionalized 8-hydroxyquinolate ligands to bismuth(III) chloride in a 3:1 mole ratio in either ethanol or tetrahydrofuran (THF) solvent. These complexes have been characterized by single-crystal X-ray diffraction (XRD) analysis, UV-vis spectroscopy, fluorescence spectroscopy, and density functional theory (DFT) calculations to determine their structures and photophysical properties. Reversible dimerization of the mononuclear tris(hydroxyquinolate) complexes was observed in solution and quantified using UV-vis spectroscopy. The fluorescence spectra show a blue shift for the monomer compared with homoleptic aluminum(III) hydroxyquinolate compounds. Four dimeric compounds and one monomeric isomer were characterized structurally. The bismuth(III) centers in the dimers are bridged by two oxygen atoms from the substituted hydroxyquinolate ligands. The more sterically hindered quinolate complex, tris(2-(diethoxymethyl)-8-quinolinato)bismuth, crystallizes as a monomer. The complexes all exhibit low-lying absorption and emission spectral features attributable to transitions between the HOMO (π orbital localized on the quinolate phenoxide ring) and LUMO (π* orbital localized on the quinolate pyridyl ring). Excitation and emission spectra show a concentration dependence in solution that suggests that a monomer-dimer equilibrium occurs. Electronic structure DFT calculations support trends seen in the experimental results with a HOMO-LUMO gap of 2.156 eV calculated for the monomer that is significantly larger than those for the dimers (1.772 and 1.915 eV). The close face to face approach of two quinolate rings in the dimer destabilizes the uppermost occupied quinolate π orbitals, which reduces the HOMO-LUMO gap and results in longer wavelength absorption and emission spectral features than in the monomer form.


The swiss transplant cohort study: lessons from the first 6 years.
Prospective cohort studies significantly contribute to answering specific research questions in a defined population. Since 2008, the Swiss Transplant Cohort Study (STCS) systematically enrolled >95 % of all transplant recipients in Switzerland, collecting predefined data at determined time points. Designed as an open cohort, the STCS has included >3900 patients to date, with a median follow-up of 2.96 years (IQR 1.44-4.73). This review highlights some relevant findings in the field of transplant-associated infections gained by the STCS so far. Three key general aspects have crystallized: (i) Well-run cohort studies are a powerful tool to conduct genetic studies, which are crucially dependent on a meticulously described phenotype. (ii) Long-term real-life observations are adding a distinct layer of information that cannot be obtained during randomized studies. (iii) The systemic collection of data, close interdisciplinary collaboration, and continuous analysis of some key outcome data such as infectious diseases endpoints can improve patient care.


The impact of charismatic leadership on followers' initiative-oriented behavior: a study in German hospitals.
Organizations in the health care sector are undergoing extensive structural reforms. To face these challenges, management initiatives that foster employees' commitment to and support for organizational change are needed in hospitals. In literature, a charismatic leadership style has proved to be especially helpful in times of crisis and change as well as an essential antecedent of followers' discretionary behavior in organizations. Thus, the aim of the study was to investigate charismatic leadership as a means to enhance followers' initiative-oriented behavior in hospitals. In the hospital context, two situational conditions have to be taken into account. We hypothesized that both employees' job autonomy and stress in the workplace will moderate the positive relationship between charismatic leadership and followers' initiative-oriented behavior. We investigated 543 members of medical staff (physicians and nurses) in six German hospitals by using a questionnaire. The hypotheses were tested by conducting hierarchical regression analyses and interpreting main effects and interactions effects. Charismatic leadership significantly predicted followers' initiative-oriented behavior. Moreover, our study confirmed the moderating effect of job autonomy. However, the moderating effect of followers' stress was not confirmed by our data. First, the results of our investigation point at the positive impact that charismatic leaders have on followers' initiative-oriented behavior in the hospital. Several studies have shown that training can improve leaders' abilities in charismatic leadership. Thus, a suggestion for supervisor development from this is not only to provide professional training but also to intensify efforts in training specialized on charismatic leadership. Second, to support followers' participation in change processes, hospital managers should consider if and how the degree of followers' job autonomy can be enhanced.


CBP (CREB binding protein) integrates NF-kappaB (nuclear factor-kappaB) and glucocorticoid receptor physical interactions and antagonism.
Nuclear factor-kappaB (NF-kappaB) and the glucocorticoid receptor (GR) are transcription factors with opposing actions in the modulation of immune/inflammatory responses. NF-kappaB induces the expression of proinflammatory genes, while GR suppresses immune function in part by suppressing expression of the same genes. Previously, we demonstrated that physiological antagonism between NF-kappaB and GR is due to a mutual transcriptional antagonism that requires the p65 subunit of NF-kappaB and multiple domains of GR (1). To elucidate the mechanism(s) of NF-kappaB p65 and GR transcriptional antagonism, we analyzed the interactions of wild-type p65 and p65 RHD (rel homology domain, a dominant negative mutant of p65 which lacks a transactivation domain) with GR. We show that p65RHD blocks p65-mediated transactivation, yet does not block the repression of GR transactivation by p65, indicating that transcriptional activity by p65 is not required to repress GR function. Both p65 and p65 RHD physically interact with GR, but only intact p65 represses GR-mediated signaling, implicating the p65 transactivation domain in the transcriptional repression of GR. To further characterize p65-GR interactions, we examined the role of the transcriptional co-integrator CREB binding protein (CBP) in their mutual antagonism. GR-mediated repression of p65 transactivation and p65-mediated repression of GR transactivation, as well as the physical interaction between NF-kappaB and GR, are enhanced by CBP. GR bound to the antagonist RU 486, although transcriptionally inactive, retains the ability to repress p65 transactivation. However, CBP does not physically interact with antagonist-bound GR and does not enhance its repressive effect on p65. These data suggest that CBP functions as an integrator of p65/GR physical interaction, rather than as a limiting cofactor for which p65 and GR compete.


[Change in reproductive partner among women delivering at a Metropolitan Santiago public hospital].
Previous studies in Metropolitan Santiago, showed that at least 10% of mothers changed their reproductive partner. To study the frequency of reproductive partner change and its associated factors among women delivering in a public hospital. We interviewed 859 non primiparous women that gave birth to a child in a public hospital of Metropolitan Santiago, between March 2001 and February 2002. Mean maternal age rose according to birth order from 27.4 to 33.6 years from the second to the fourth sibling. Married women were the largest group and single ones decreased from the second to the third sibling. Twenty two percent had some activity out of home and those with a high birth order (fourth or more) exhibited poorer schooling. Unwanted pregnancies increased with birth order, reaching 55% among "fourth and over" births. Thirty four percent of women delivering their second child, changed their partner. Among women delivering their third child, 38.6% had one sibling with a different father; 20.4% had changed partner during their second pregnancy and 20% during the current one. Among those in the "fourth and over, group, 56.1% had at least one sibling with a different father; 18.3% had changed partner in the second sibling; 15%, in the third and 27.8%, in the fourth and over. In all birth orders, mothers with activity out of home exhibited a higher frequency of partner change. The most common reasons to change partner were infidelity, abandon or a personal decision, while economic reasons were uncommon. A great number of children are exposed to bonding ruptures and to the consequential mental health or behavioral problems.


Excessive Treadmill Training Produces different Cardiac-related MicroRNA Profiles in the Left and Right Ventricles in Mice.
High-volume training followed by inadequate recovery may cause overtraining. This process may undermine the protective effect of regular exercise on the cardiovascular system and may increase the risk of pathological cardiac remodelling. We evaluated whether chronic overtraining changes cardiac-related microRNA profiles in the left and right ventricles. C57BL/6 mice were divided into the control, normal training, and overtrained by running without inclination, uphill running or downhill running groups. After an 8-week treadmill training protocol, the incremental load test and training volume results showed that the model had been successfully established. The qRT-PCR results showed increased cardiac miR-1, miR-133a, miR-133b, miR-206, miR-208b and miR-499 levels in the left ventricle of the downhill running group compared with the left ventricle of the control group. Similarly, compared with the control group, the downhill running induced increased expression of miR-21, miR-17-3p, and miR-29b in the left ventricle. Unlike the changes in the left ventricle, no difference in the expression of the tested miRNAs was observed in the right ventricle. Briefly, our results indicated that overtraining generally affects key miRNAs in the left ventricle (rather than the right ventricle) and that changes in individual miRNAs may cause either adaptive or maladaptive remodelling with overtraining.


Higher organ donation consent rates by relatives of potential uncontrolled donors versus potential controlled donors after death.
Refusal to consent to organ donation is an important cause of the persisting gap between the number of potential organ donors and effectuated donors. In the Netherlands, organ donors include both uncontrolled donors: donors who die unexpectedly after cardiac death (DCD), after failed resuscitation and donors in whom death can be expected and donors after brain death, and controlled DCD donors: those who die after the withdrawal of treatment. Different donor type implies a different setting in which relatives are requested to consent to organ donation. It is unknown whether the setting influences the eventual decision for donation or not. Therefore, we compared the consent rate in potential donors who died unexpectedly (UD group) and in whom death was expected. A total of 523 potential organ donors between 2003 and 2011 in the 715-bed Maastricht University Medical Centre, the Netherlands were included. Both the patients' registration in the national donor register (DR) and the relatives' refusal rate in the two groups were retrospectively assessed using data from the donation application database. There were 109 unexpected and 414 expected potential donors The potential donors in the UD group were younger (mean age 52 versus 55 years, P = 0.032) and more often male (68 versus 52%, P = 0.003). There were no significant differences in registration in the DR between the groups. The relatives' consent rate in non-registered potential donors, or those who mandated the relatives for that decision, was higher in the UD group (53 versus 29%, P < 0.001). Less than 50% of the potential donors were registered in the national DR. Therefore, the relatives have an important role in the choice for organ donation. The relatives of potential donors who died unexpectedly consented more often to donation than those in whom death was expected.


Gibberellin application ameliorates the adverse impact of short-term flooding on Glycine max L.
Flooding is an abiotic stress that creates hypoxic conditions triggered by redox potential leading to restricted growth and grain yield in plants. In the current study, we have investigated the effect of exogenous gibberellins (GA4+7) on soybean under flooding stress. A regulatory role of GAs on biochemical changes in soybean plants [including chlorophyll contents, endogenous bioactive GA1 and GA4, endogenous jasmonic acid (JA) and abscisic acid (ABA)] has been elucidated after 3 and 6 h of flooding stress. The modulation of stress-related bio-chemicals and their genetic determinants [for instance, ABA (Timing of CAB expression1-TOC1, ABA-receptor-ABAR) and NO (S-nitrosoglutathione reductase-GSNOR1, NO overproducer1-NOX, and nitrite reductase-NR)] in response to short-term flooding stress were also explored. The current study showed that exogenous GAs rescued chlorophyll contents, enhanced endogenous bioactive GA1 and GA4 levels, endogenous jasmonic acid (JA) and checked the rate of ABA biosynthesis under short-term flooding. The exo-GAs induced the glutathione activity and reduced the resulting superoxide anion contents during short-term flooding in Pungsannamul soybean. Exo-GAs also triggered the endogenous S-nitrosothiols (precursor for increased NO production) that have been decreased over the time. Moreover, the exo-GAs could impinge a variety of biochemical and transcriptional programs that are ameliorative to plant growth during short-term flooding stress. The presence of GA1 and GA4 also confirms the presence of both C13-hydroxylation pathway and non-C13-hydroxylation pathway in soybean, respectively.


A Qualitative Study of the Feasibility and Acceptability of Implementing 'Sit-To-Stand' Desks in Vocational Education and Training.
While it has been shown that interrupting a person's sedentary behaviour has the potential to improve cognitive, physical and mental health, a large part of time that students spend in school is sedentary. As research has shown that approximately 80% of vocational education and training (VET) students have an unhealthy sedentary lifestyle, implementing "sit-to-stand" (StS) desks could interrupt sedentary behaviour and promote healthier behaviour. Therefore, the acceptability and feasibility of using such desks in the VET setting should be investigated. Using semi-structured focus group interviews analysed via deductive content analysis, the opinions of 33 students for the following topics were assessed: (1) usage of the standing option of the desks (2) reasons for standing in class (3) experienced effect of standing behind the desk, and (4) fostering future StS desks usage. Although VET students are aware of the potential benefits of using StS desks, they need to be actively stimulated and motivated by teachers to use them. In addition, time is needed to get into the habit of standing. Thus, for successful implementation of StS desks in the VET setting, all stakeholders (i.e., students, teachers, schoolboards) should be actively involved in stimulating the healthy behaviour of VET students.


Growth, Biomass Partitioning, and Photosynthetic Performance of Chrysanthemum Cuttings in Response to Different Light Spectra.
Chrysanthemum (Chrysanthemum morifolium) is among the most popular ornamental plants, propagated mainly through stem cuttings. There is a lack of information regarding the impact of the lighting environment on the successful production of cuttings and underlying mechanisms. The light spectrum affects plant morphology, growth, and photosynthesis. In the present study, chrysanthemum, cv. 'Katinka' cuttings, were exposed to five lighting spectra, including monochromatic red (R), blue (B) lights, and multichromatic lights, including a combination of R and B (R:B), a combination of R, B, and far red (R:B:FR) and white (W), for 30 days. B light enhanced areal growth, as indicated by a higher shoot mass ratio, while R light directed the biomass towards the underground parts of the cuttings. Monochromatic R and B lights promoted the emergence of new leaves. In contrast, individual leaf area was largest under multichromatic lights. Exposing the cuttings to R light led to the accumulation of carbohydrates in the leaves. Cuttings exposed to multichromatic lights showed higher chlorophyll content than monochromatic R- and B-exposed cuttings. Conversely, carotenoid and anthocyanin contents were the highest in monochromatic R- and B-exposed plants. B-exposed cuttings showed higher photosynthetic performance, exhibited by the highest performance index on the basis of light absorption, and maximal quantum yield of PSII efficiency. Although R light increased biomass toward roots, B light improved above-ground growth, photosynthetic functionality, and the visual performance of Chrysanthemum cuttings.


Comparison of GCaMP3 and GCaMP6f for studying astrocyte Ca2+ dynamics in the awake mouse brain.
In recent years it has become increasingly clear that astrocytes play a much more active role in neural processes than the traditional view of them as supporting cells suggests. Although not electrically excitable, astrocytes exhibit diverse Ca2+ dynamics across spatial and temporal scales, more or less dependent on the animal's behavioral state. Ca2+ dynamics range from global elevations lasting multiple seconds encompassing the soma up to the finest processes, to short elevations restricted to so-called microdomains within fine processes. Investigations of astrocyte Ca2+ dynamics have particularly benefitted from the development of Genetically-Encoded Calcium Indicators (GECIs). GECI expression can be achieved non-invasively in a cell type-specific manner and it can be genetically targeted to subcellular domains. The GCaMP family, a group of GECIs derived from the green fluorescent protein, has experienced some of the fastest advancements during the past decade. As a consequence we are now facing the challenge of needing to compare published data obtained with different versions of GECIs. With the intention to provide some guidance, here we compared Ca2+ dynamics across scales in awake transgenic mice expressing either the well-established GCaMP3, or the increasingly popular GCaMP6f, specifically in astrocytes. We found that locomotion-induced global Ca2+ elevations in cortical astrocytes displayed only minor kinetic differences and their apparent dynamic ranges for Ca2+ sensing were not different. In contrast, Ca2+ waves in processes and microdomain Ca2+ transients were much more readily detectable with GCaMP6f. Our findings suggest that behavioral state-dependent global astrocyte Ca2+ responses can be studied with either GCaMP3 or GCaMP6f whereas the latter is more appropriate for studies of spatially restricted weak and fast Ca2+ dynamics.


Characteristics of vibrator use by gay and bisexually identified men in the United States.
Recent reports indicate that vibrator use during solo and partnered sexual activities is common among heterosexual men and women in the United States. However, little research has comprehensively assessed vibrator use among gay and bisexually identified men. This study sought to document the extent to which gay and bisexually identified men report using vibrators, the sexual and relational situations within which they use them, and how men use vibrators on their own and their partners' bodies. Data were collected from 25,294 gay and bisexually identified men from 50 U.S. states and from the District of Columbia via an internet-based survey. Measures included sociodemographics, health-related indicators, sexual behaviors, and those related to recent and past use of vibrators during solo and partnered sexual interactions with other men. Approximately half (49.8%) of gay and bisexually identified men reported having used vibrators. Most men who had used a vibrator in the past reported use during masturbation (86.2%). When used during partnered interactions, vibrators were incorporated into foreplay (65.9%) and intercourse (59.4%). Men reported frequent insertion of vibrators into the anus or rectum when using them during masturbation (87.3%), which was also common during partnered interactions (∼60%), but varied slightly for casual and relationship sex partners. For both masturbation and partnered interactions, men overwhelmingly endorsed the extent to which vibrator use contributed to sexual arousal, orgasm, and pleasure. Vibrator use during both solo and partnered sexual acts was common among the gay and bisexually identified men in this sample and was described by men as adding to the quality of their sexual experiences.


Penetration of light into multiple scattering media: model calculations and reflectance experiments. Part I: the axial transfer.
The article presents two general equations of radiation penetration into layers of diffuse reflectors. One of the equations describes the depth origins of reflection, the other the depth profiles of absorption. The equations are evaluated within the theory of radiative transfer applying various degrees of analytical approximations and Monte Carlo simulations. The data are presented for different scattering and absorption coefficients, arbitrary layer thicknesses, collimated and diffused irradiation, and anisotropic forward scattering. The calculated mean depths of reflection are always lower than the mean depths of absorption. For nearly non-absorbing layers, the mean depths of absorption are about one third of the physical layer thickness. In contrast, penetration saturates for strong absorbers at very low depth levels. From the simulated data, methods are derived for the determination of the penetration depth from reflectance and transmittance data of thin layers or from radially diffused reflectance profiles upon spot irradiation. The methods are experimentally verified for a series of metal oxide powders with particle sizes ranging from much smaller to much larger than the wavelength of irradiation and for microcrystalline cellulose stained with different concentrations of an organic dye.


Dynamics of the time-resolved stimulated Raman scattering spectrum in presence of transient vibronic inversion of population on the example of optically excited trans-β-apo-8'-carotenal.
We have studied the effect of transient vibrational inversion of population in trans-β-apo-8(')-carotenal on the time-resolved femtosecond stimulated Raman scattering (TR-FSRS) signal. The experimental data are interpreted by applying a quantum mechanical approach, using the formalism of projection operators for constructing the theoretical model of TR-FSRS. Within this theoretical frame we explain the presence of transient Raman losses on the Stokes side of the TR-FSRS spectrum as the effect of vibrational inversion of population. In view of the obtained experimental and theoretical results, we conclude that the excited S2 electronic level of trans-β-apo-8(')-carotenal relaxes towards the S0 ground state through a set of four vibrational sublevels of S1 state.


Aneurysm expansion and retroperitoneal hematoma after thrombolysis for stent-graft limb occlusion caused by distal endograft migration.
To describe a complication of thrombolytic therapy used to treat graft limb occlusion precipitated by distal migration and kinking of an abdominal aortic stent-graft. A 5.5-cm abdominal aortic aneurysm (AAA) in a 66-year-old woman was treated with Vanguard bifurcated stent-graft. At the 1-year follow-up, she complained of left leg claudication. Computed tomography (CT) showed a 36% reduction in maximum AAA diameter, but the stent-graft had migrated distally approximately 5 mm, and the left graft limb was occluded. Thrombolysis was initiated, but after approximately 8 hours, abdominal pain began. Emergent CT scanning revealed rapid aneurysm expansion and a retroperitoneal hematoma. Thrombolytic treatment was stopped; transfusions and thrombogenic drugs were given to restore hemodynamic stability. The aneurysm began to decrease in size. The occluded graft limb had been reopened by the lytic therapy, uncovering a stenosis in the native artery distal to the graft limb. Stent placement restored outflow. The retroperitoneal hematoma resolved over time, and the aneurysm sac shrank to its prelytic diameter. The patient is well with a functioning endograft 18 months after the occlusion (30 months after stent-grafting). Caution must be taken when using thrombolysis in patients with endovascular aortic grafts because unexpected bleeding complications might arise. Thrombectomy, femorofemoral bypass, or stent or stent-graft extensions might be safer alternatives for treating occluded stent-graft limbs.


Animal models for motor neuron disease.
Motor neuron disease is a general term applied to a broad class of neurodegenerative diseases that are characterized by fatally progressive muscular weakness, atrophy, and paralysis attributable to loss of motor neurons. At present, there is no cure for most motor neuron diseases, including amyotrophic lateral sclerosis (ALS), the most common human motor neuron disease--the cause of which remains largely unknown. Animal models of motor neuron disease (MND) have significantly contributed to the remarkable recent progress in understanding the cause, genetic factors, and pathologic mechanisms proposed for this class of human neurodegenerative disorders. Largely driven by ALS research, animal models of MND have proven their usefulness in elucidating potential causes and specific pathogenic mechanisms, and have helped to advance promising new treatments from "benchside to bedside." This review summarizes important features of selected established animal models of MND: genetically engineered mice and inherited or spontaneously occurring MND in the murine, canine, and equine species.


In Silico Structural and Biochemical Functional Analysis of a Novel CYP21A2 Pathogenic Variant.
Classical congenital adrenal hyperplasia (CAH) caused by pathogenic variants in the steroid 21-hydroxylase gene (CYP21A2) is a severe life-threatening condition. We present a detailed investigation of the molecular and functional characteristics of a novel pathogenic variant in this gene. The patient, 46 XX newborn, was diagnosed with classical salt wasting CAH in the neonatal period after initially presenting with ambiguous genitalia. Multiplex ligation-dependent probe analysis demonstrated a full deletion of the paternal CYP21A2 gene, and Sanger sequencing revealed a novel de novo CYP21A2 variant c.694-696del (E232del) in the other allele. This variant resulted in the deletion of a non-conserved single amino acid, and its functional relevance was initially undetermined. We used both in silico and in vitro methods to determine the mechanistic significance of this mutation. Computational analysis relied on the solved structure of the protein (Protein-data-bank ID 4Y8W), structure prediction of the mutated protein, evolutionary analysis, and manual inspection. We predicted impaired stability and functionality of the protein due to a rotatory disposition of amino acids in positions downstream of the deletion. In vitro biochemical evaluation of enzymatic activity supported these predictions, demonstrating reduced protein levels to 22% compared to the wild-type form and decreased hydroxylase activity to 1-4%. This case demonstrates the potential of combining in-silico analysis based on evolutionary information and structure prediction with biochemical studies. This approach can be used to investigate other genetic variants to understand their potential effects.


Addressing quadruple aims through primary care and public health collaboration: ten Canadian case studies.
Health systems in Canada and elsewhere are at a crossroads of reform in response to rising economic and societal pressures. The Quadruple Aim advocates for: improving patient experience, reducing cost, advancing population health and improving the provider experience. It is at the forefront of Canadian reform debates aimed to improve a complex and often-fragmented health care system. Concurrently, collaboration between primary care and public health has been the focus of current research, looking for integrated community-based primary health care models that best suit the health needs of communities and address health equity. This study aimed to explore the nature of Canadian primary care - public health collaborations, their aims, motivations, activities, collaboration barriers and enablers, and perceived outcomes. Ten case studies were conducted in three provinces (Nova Scotia, Ontario, and British Columbia) to elucidate experiences of primary care and public health collaboration in different settings, contexts, populations and forms. Data sources included a survey using the Partnership Self-Assessment Tool, focus groups, and document analysis. This provided an opportunity to explore how primary care and public health collaboration could serve in transforming community-based primary health care with the potential to address the Quadruple Aims. Aims of collaborations included: provider capacity building, regional vaccine/immunization management, community-based health promotion programming, and, outreach to increase access to care. Common precipitators were having a shared vision and/or community concern. Barriers and enablers differed among cases. Perceived barriers included ineffective communication processes, inadequate time for collaboration, geographic challenges, lack of resources, and varying organizational goals and mandates. Enablers included clear goals, trusting and inclusive relationships, role clarity, strong leadership, strong coordination and communication, and optimal use of resources. Cases achieved outcomes addressing the Q-Aims such as improving access to services, addressing population health through outreach to at-risk populations, reducing costs through efficiencies, and improving provider experience through capacity building. Primary care and public health collaborations can strengthen community-based primary health care while addressing the Quadruple Aims with an emphasis on reducing health inequities but requires attention to collaboration barriers and enablers.


Effects of acute ethanol exposure on cytokine production by primary airway smooth muscle cells.
Both chronic and binge alcohol abuse can be significant risk factors for inflammatory lung diseases such as acute respiratory distress syndrome and chronic obstructive pulmonary disease. However, metabolic basis of alcohol-related lung disease is not well defined, and may include key metabolites of ethanol [EtOH] in addition to EtOH itself. Therefore, we investigated the effects of EtOH, acetaldehyde [ACE], and fatty acid ethyl esters [FAEEs] on oxidative stress, endoplasmic reticulum (ER) stress, AMP-activated protein kinase (AMPK) signaling and nuclear translocation of phosphorylated (p)-NF-κB p65 in primary human airway smooth muscle (HASM) cells stimulated to produce cytokines using LPS exposure. Both FAEEs and ACE induced evidence of cellular oxidative stress and ER stress, and increased p-NF-κB in nuclear extracts. EtOH and its metabolites decreased p-AMPKα activation, and induced expression of fatty acid synthase, and decreased expression of sirtuin 1. In general, EtOH decreased secretion of IP-10, IL-6, eotaxin, GCSF, and MCP-1. However, FAEEs and ACE increased these cytokines, suggesting that both FAEEs and ACE as compared to EtOH itself are proinflammatory. A direct effect of EtOH could be consistent with blunted immune response. Collectively, these two features of EtOH exposure, coupled with the known inhibition of innate immune response in our model might explain some clinical manifestations of EtOH exposure in the lung.


An Autosomal Translocation 73,XY,t(12;20)(q11;q11) in an Infertile Male Llama (Lama glama) With Teratozoospermia.
Structural chromosome abnormalities, such as translocations and inversions occasionally occur in all livestock species and are typically associated with reproductive and developmental disorders. Curiously, only a few structural chromosome aberrations have been reported in camelids, and most involved sex chromosomes. This can be attributed to a high diploid number (2n = 74) and complex chromosome morphology, which makes unambiguous identification of camelid chromosomes difficult. Additionally, molecular tools for camelid cytogenetics are sparse and have become available only recently. Here we present a case report about an infertile male llama with teratozoospermia and abnormal chromosome number 2n = 73,XY. This llama carries an autosomal translocation of chromosomes 12 and 20, which is the likely cause of defective spermatogenesis and infertility in this individual. Our analysis underlines the power of molecular cytogenetics methods over conventional banding-based chromosome analysis for explicit identification of normal and aberrant chromosomes in camelid karyotypes. This is the first case of a translocation and the first autosomal aberration reported in any camelid species. It is proof of principle that, like in other mammalian species, structural chromosome abnormalities contribute to reproductive disorders in camelids.


Activity of dietary fatty acids on FFA1 and FFA4 and characterisation of pinolenic acid as a dual FFA1/FFA4 agonist with potential effect against metabolic diseases.
Various foods are associated with effects against metabolic diseases such as insulin resistance and type 2 diabetes; however, their mechanisms of action are mostly unclear. Fatty acids may contribute by acting as precursors of signalling molecules or by direct activity on receptors. The medium- and long-chain NEFA receptor FFA1 (free fatty acid receptor 1, previously known as GPR40) has been linked to enhancement of glucose-stimulated insulin secretion, whereas FFA4 (free fatty acid receptor 4, previously known as GPR120) has been associated with insulin-sensitising and anti-inflammatory effects, and both receptors are reported to protect pancreatic islets and promote secretion of appetite and glucose-regulating hormones. Hypothesising that FFA1 and FFA4 mediate therapeutic effects of dietary components, we screened a broad selection of NEFA on FFA1 and FFA4 and characterised active compounds in concentration-response curves. Of the screened compounds, pinolenic acid, a constituent of pine nut oil, was identified as a relatively potent and efficacious dual FFA1/FFA4 agonist, and its suitability for further studies was confirmed by additional in vitro characterisation. Pine nut oil and free and esterified pure pinolenic acid were tested in an acute glucose tolerance test in mice. Pine nut oil showed a moderately but significantly improved glucose tolerance compared with maize oil. Pure pinolenic acid or ethyl ester gave robust and highly significant improvements of glucose tolerance. In conclusion, the present results indicate that pinolenic acid is a comparatively potent and efficacious dual FFA1/FFA4 agonist that exerts antidiabetic effects in an acute mouse model. The compound thus deserves attention as a potential active dietary ingredient to prevent or counteract metabolic diseases.


An Atypical Case of Warfarin-Induced Skin Necrosis.
Skin necrosis is a relatively rare, potentially fatal side effect of warfarin. It is most commonly reported within 10 days of initiation of therapy in warfarin-naïve patients. We report an atypical case of warfarin-induced skin necrosis upon recommencement of warfarin in a non-naïve warfarin patient.


Trends in spending for substance abuse treatment, 1986-2003.
Since 1987, public and private investment in substance abuse (SA) treatment has not kept pace with other health spending. SA treatment spending in the United States grew from $9.3 billion in 1986 to $20.7 billion in 2003. The average annual total growth rate was 4.8 percent. In comparison, total U.S. health care spending grew by 8.0 percent. As a result of the slower growth of SA spending compared to that for all health care, SA spending fell as a share of all health spending from 2.1 percent in 1986 to 1.3 percent in 2003.


Adolescent Understanding and Acceptance of the HPV Vaccination in an Underserved Population in New York City.
Background. HPV vaccination may prevent thousands of cases of cervical cancer. We aimed to evaluate the understanding and acceptance of the HPV vaccine among adolescents. Methods. A questionnaire was distributed to adolescents at health clinics affiliated with a large urban hospital system to determine knowledge pertaining to sexually transmitted diseases and acceptance of the HPV vaccine. Results. 223 adolescents completed the survey. 28% were male, and 70% were female. The mean age for respondents was 16 years old. Adolescents who had received the HPV vaccine were more likely to be female and to have heard of cervical cancer and Pap testing. Of the 143 adolescents who had not yet been vaccinated, only 4% believed that they were at risk of HPV infection and 52% were willing to be vaccinated. Conclusions. Surveyed adolescents demonstrated a marginal willingness to receive the HPV vaccine and a lack of awareness of personal risk for acquiring HPV.


Inequalities in healthy life expectancy by social class and area type: England, 2001-03.
Healthy life expectancy (HLE) is an important indicator which combines longevity with health status. This article examines inequalities in HLE by socio-economic position in England, and between Local Authorities (LAs) in the deprived 'Spearhead group' and other LAs. Census and vital event data available from the ONS Longitudinal Study were used to calculate estimates of HLE based on general health status for each Registrar General's Social Class (RGSC) in 2001-03, in England as a whole and within the 'Spearhead group' and non-Spearhead LAs. A predominantly linear relationship was present with HLE increasing with rising social class. The differences observed in HLE at birth and at age 65 between people assigned to the professional and unskilled manual social classes were statistically significant and substantial, demonstrating a clear social inequality in the amount of life, the quality of those years lived, the absolute number of healthy life years, and thus the relative proportion of life spent in 'Good' or 'Fairly Good' health.HLEs at birth were statistically significantly higher for women than for men in the non-Spearhead LAs for all social classes; however, in the 'Spearhead group' of areas higher HLEs in women were only present among the skilled non-manual, skilled manual and partly skilled social classes. This suggests that an interaction effect between sex and area in the level of HLE may be operating.The magnitude of inequality in HLE between professionals and the unskilled manual class in the proportion of life spent in 'Good' or 'Fairly Good' health also varied between the 'Spearhead group' and non-Spearhead LAs: among men, a difference of 6.6 per cent was present in non-Spearhead LAs, compared with 10.6 per cent in the 'Spearhead group'; among women, the equivalent differences were 5.3 per cent and 7.6 per cent. The within-class HLEs for men and women were lower in the 'Spearhead group' compared with the non-Spearhead LAs, and statistically significantly lower among the intervening social classes for men; among women they are significant for all social classes other than the professional class. The scale of inequalities shown is important for policy responses and understanding of differences in service needs.


Indirect fluorescence antibody studies of porcine cytomegalo virus infections in the Netherlands.
Sera from 683 pigs of 41 swine herds with clinical atrophic rhinitis (AR), from 477 pigs of 37 herds with no AR history, from 267 breeding sows and breeding boars for slaughtering, from 22 boars at an artificial insemination centre, and from 103 SPF pigs were tested for the presence of antibodies to porcine cytomegalo virus (PCMV). The herds examined were spread all over the Netherlands. For the presence of antibodies to PCMV the indirect fluorescence antibody test was used. To obtain the antigen, the PCMV had been grown in pig lung macrophage cultures in Petri dishes for 10--12 days. These macrophages were dropped into the wells of slides. The serum dilution 1:20 of all the 103 sera from SPF pigs were negative, but 93 per cent of the other sera were positive. No marked differences were found between swine herds with clinical atrophic rhinitis and herds with no AR history. The FA titres in both types of herds seem to be at a comparable level.


Expression of neuromedin B in adipose tissue and its regulation by changes in energy balance.
Bombesin is one of the most powerful substances showing anorexic effects in the hypothalamus (Moody TW & Merali Z 2004 Bombesin-like peptides and associated receptors within the brain: distribution and behavioral implications. Peptides 25 511-520). In mammals, neuromedin B (NMB) is one member of a family of bombesin-like peptides, which have been shown to reduce food intake when administered systemically. Using Taqman real-time PCR with specific primers, we report the expression of NMB mRNA in both human and rodent adipose tissue. Expression of NMB in rodent epididymal adipose tissue was higher than in other tissues studied. Expression of NMB in adipose tissue appears to be regulated by changes in energy balance and leptin. It is decreased fourfold in the epididymal fat depot of ob/ob mice when compared with the same fat depot in lean mice. It is further decreased with the intra-peritoneally (i.p.) administration of leptin in both lean and obese ob/ob mice. This may relate to its function in food intake regulation or to changes in energy expenditure. We demonstrate that NMB expression in rodent adipose tissue is decreased in cold exposed animals. However, when we investigated the effects of NMB on resting metabolic rate by i.p. injection, there was no effect on oxygen consumption, RQ or physical activity when compared with saline-treated controls. In conclusion, NMB is expressed in both human and rodent adipose tissue and appears to be regulated by changes in energy balance. Given its anorexic effects centrally, it may form part of a new adipose tissue--hypothalamic axis regulating food intake.


A long-term, controlled-outcome analysis of in utero versus neonatal cleft lip repair using an ovine model.
Successful open repair of a cleft lip in utero has the advantage of scarless wound healing in the fetus. Unfortunately, no long-term outcome studies have been performed to evaluate the efficacy of these repairs. Moreover, no study to date has compared the long-term results of an in utero cleft lip repair to a similar, control-matched, newborn cleft repair. This study was performed to evaluate the 9-month outcome of in utero cleft lip surgery compared with an identical cleft lip repair performed on infant lambs. In utero epithelialized cleft lips were created through an open hysterotomy in sixteen 65-day-old fetal lambs (term = 140 days) using methods described by Longaker et al. Eight of 16 animals underwent subsequent in utero repair of these clefts at 90 days gestational age. The repair of the remaining eight animals was delayed until 1 week postpartum. At 9 months, the animals were analyzed for changes in lip contour and for the degree of scarring by hematoxylin and eosin and Masson's trichrome collagen staining. Two animals in each group died from preterm labor. Of the animals that survived to term, all repaired lips had some degree of abnormality postoperatively. One of six lips repaired in utero dehisced before delivery. Three of six neonatal repairs dehisced in the first postoperative month. In the remaining animals with intact lip repairs, the vertical lip height on the repaired side was an average of 9 to 12 mm shorter than the normal lip in both the in utero and neonatally repaired animals. Phenotypically, the postnatally repaired animals had more lip distortion and visible notching. Histologically, the in utero repair was scarless and the neonatal repairs had scar throughout the entire vertical height of the lip with an associated loss of hair in this region. Maxillary growth was also evaluated. There was no inhibition of maxillary growth in the animals that underwent in utero cleft lip repair. However, in the neonatal repair group, significant maxillary retrusion was evident. Compared with the cleft side of the maxilla, horizontal growth was decreased by 11 percent (p = 0.01). Compared with the intrauterine repair group, there was a 17-percent decrease in horizontal maxillary width (p = 0.01). Straight-line in utero repair of a cleft lip produces a better long-term result in terms of maxillary growth than a similar repair performed postnatally in the ovine model. There was no diminution in maxillary growth in the animals treated in utero. Histologically, in utero repair of clefts was indeed scarless. However, both lip repairs produced lips that were significantly shorter than their contralateral noncleft sides. This degree of lip shortening would require a secondary lip revision, thereby defeating the purpose of performing an intrauterine repair. Comparisons now need to be made between in utero and neonatal repairs using a Millard-type rotation advancement technique before intrauterine treatment can be considered to be more beneficial than our current treatment modalities.


Risk: benefit of treating high blood pressure in older adults.
Older people (those aged 65 years or over) comprise over 15% of the UK's population and this cohort is growing. Whilst at greatest risk from systemic arterial hypertension (hypertension), its resultant end organ damage and clinically significant cardiovascular disease, this group was initially neglected in clinical trials and thereby denied treatment, with the lack of evidence cited as justification. However since the 1960s, when the first landmark trials in severe diastolic hypertension were published, there has been a progressive attempt to understand the pathophysiology of hypertension and to expand the evidence base for treatment in older adults. In contrast to the participants of the very first randomized trials who had a mean age of 51 years, the recent Hypertension in the Very Elderly Trial demonstrated significant mortality and morbidity benefits from the treatment of both mixed systolic and diastolic hypertension, as well as isolated systolic hypertension in octogenarians. This review highlights the progressive evidence base behind the relative risks and benefits of treating hypertension in older adults.


Standard treatment of ulcerative colitis.
Ulcerative colitis (UC) is an idiopathic, chronic inflammation of the colon which may present with a range of mild to severe symptoms. The disease may be localized to the rectum or can be more extensive and involve the left side of the colon or the whole colon. Treatment in UC is directed towards inducing and maintaining remission of symptoms and mucosal inflammation. The key parameters to be assessed for the most appropriate treatment are the severity and extent of the inflammation. Meta-analyses of published trials have shown that topical treatment with 5-aminosalicylic acid (5-ASA) is the treatment of choice in active distal mild-to-moderate UC. Oral aminosalicylates are effective in both distal and extensive mild-to-moderate disease, but in distal disease, the rates of remission are lower than those obtained with topical 5-ASA. New steroids, such as budesonide and beclomethasone dipropionate (BDP), administered as enemas, constitute an alternative to 5-ASA therapy. In some studies, these have been shown to be as effective as conventional steroids but with significantly lower inhibition of plasma cortisol levels. Patients with unresponsive disease or those with more severe presentation will require oral corticosteroids and sometimes intravenous therapy. Approximately 10% of patients with unresponsive UC have severe attacks requiring hospitalization. Patients with severe disease should be managed jointly by a medical and surgical team, and intensive intravenous treatment should be started with high-dose steroids. Early recognition of failure of therapy will allow the introduction of immunosuppressive therapy with intravenous cyclosporine. Patients who respond are shifted to oral cyclosporine associated with azathioprine/6-mercaptopurine, whereas those who fail will require proctocolectomy. Oral aminosalicylates are the first-line therapy in maintenance of remission. Topical 5-ASA may play a role in distal disease. Patients who are steroid dependent can be started on azathioprine or 6-mercaptopurine although it may take up to 3 months for the treatment to become effective. They may have reversible immediate side effects, such as pancreatitis or bone marrow suppression, which disappear upon discontinuation of therapy. Close monitoring of these hematologic and biochemical parameters will improve safety. The use of biologic therapy with infliximab in more severe disease has not been established.


Pediatric clinical handover: a best practice implementation project.
Communication of information between and among healthcare providers is an essential element of patient care. Poor clinical handover has been associated with inaccurate clinical assessment and diagnosis, delays in diagnosis, medication errors and decreased patient satisfaction. Effective and efficient transition of patient care information requires an evidence-based handover approach. The aim of this evidence implementation project was to make a contribution to promote evidence-based practice in clinical handover in a pediatric setting and thereby enhance patient safety and service delivery. Seven criteria identified by the Joanna Briggs Institute were used to conduct an audit in the Gastroenterology Department, Children's Hospital of Fudan University, Shanghai, People's Republic of China. Twelve nurses and 260 handover sessions were involved. The JBI Practical Application of Clinical Evidence System and Getting Research into Practice audit tools for promoting change in health practice were used to ascertain compliance with the criteria before and after the implementation of best practice. The program included three phases and was conducted over six months. There were improvements with compliance for each criterion. Face-to-face communication, standardized documentation, identification of patients, care plan handover and transfer of responsibility reached 100% compliance. Detailed observations of the patient improved from 93% to 98%, and there was an 18% improvement for relevant history handover. This project has demonstrated that handover sessions can be more effective by translating evidence into practice through ongoing evidence-based audit. Nursing inter-shift handover requires the use of a highly valuable and important standardized tool. Further audits will need to be carried out in order to maintain the practice change, and ensure the sustainability of the project.


Selective regulation of Notch ligands during angiogenesis is mediated by vimentin.
Notch signaling is a key regulator of angiogenesis, in which sprouting is regulated by an equilibrium between inhibitory Dll4-Notch signaling and promoting Jagged-Notch signaling. Whereas Fringe proteins modify Notch receptors and strengthen their activation by Dll4 ligands, other mechanisms balancing Jagged and Dll4 signaling are yet to be described. The intermediate filament protein vimentin, which has been previously shown to affect vascular integrity and regenerative signaling, is here shown to regulate ligand-specific Notch signaling. Vimentin interacts with Jagged, impedes basal recycling endocytosis of ligands, but is required for efficient receptor ligand transendocytosis and Notch activation upon receptor binding. Analyses of Notch signal activation by using chimeric ligands with swapped intracellular domains (ICDs), demonstrated that the Jagged ICD binds to vimentin and contributes to signaling strength. Vimentin also suppresses expression of Fringe proteins, whereas depletion of vimentin enhances Fringe levels to promote Dll4 signaling. In line with these data, the vasculature in vimentin knockout (VimKO) embryos and placental tissue is underdeveloped with reduced branching. Disrupted angiogenesis in aortic rings from VimKO mice and in endothelial 3D sprouting assays can be rescued by reactivating Notch signaling by recombinant Jagged ligands. Taken together, we reveal a function of vimentin and demonstrate that vimentin regulates Notch ligand signaling activities during angiogenesis.


Emergent drug resistance with integrase strand transfer inhibitor-based regimens.
To estimate the incidence of and risk factors for emergent resistance to integrase strand transfer inhibitor (INSTI) and nucleoside(-tide) reverse transcriptase inhibitors (NRTI) in HIV-1-infected adults receiving an INSTI and two NRTIs. Retrospective cohort study. Persons aged at least 19 years were included if they received their first prescription for raltegravir, elvitegravir or dolutegravir in British Columbia, Canada in 2012-2014 and were followed to 31 December 2015. Emergent resistance was defined as new mutations conferring intermediate-high level NRTI or INSTI resistance (score ≥30, Stanford HIV Drug Resistance Algorithm v.7.0.1). First-year resistance rates and 95% confidence intervals (95% CI) were estimated for 'any' (INSTI or NRTI) resistance using Poisson regression. The relationship between any emergent resistance and explanatory variables was modeled by Cox proportional hazards. There were 270 raltegravir, 323 elvitegravir and 392 dolutegravir-treated persons who were predominantly male (77%), antiretroviral therapy (ART)-experienced (81%), with low prevalence of preexisting drug resistance (16%). INSTI and NRTI resistance emerged in both ART-experienced and ART-naive persons (including dolutegravir-treated ART-naive), with no statistically significant differences in 'any' resistance rates (95% CI) between INSTIs: raltegravir 3.80 (1.90, 7.60), elvitegravir 2.37 (1.06, 5.27) and dolutegravir 1.48 (0.62, 3.55)/100 person-years. The strongest factors associated with emergent resistance were CD4 less than 200 cells/μl, adjusted hazard ratio (95% CI) 10.46 (4.67, 23.41) and less than 80% adherence to the INSTI regimen hazard ratio 2.52 (1.11, 5.71). Incident drug resistance rates were low with 'real-world' use of INSTI-based regimens. However, incomplete ART adherence and low CD4 cell count were associated with increased resistance rates regardless of which INSTI was prescribed. Provide adherence support and monitor for drug resistance.


CD8+ T cell mediated noncytolytic inhibition of human immunodeficiency virus type I.
The development of cellular immune responses in primary human immunodeficiency virus type-1 (HIV-1) infection is accompanied by a dramatic decrease in plasma viremia and resolution of the acute clinical syndrome. The full nature of the immunological response and its consequences on HIV pathogenesis is still largely a mystery, but significant progress has been achieved in the characterization of some of the players involved. Several studies indicate that noncytolytic HIV suppression by CD8+ T lymphocytes may be inversely associated with viral load suggesting that this antiviral activity is important in host control of HIV replication. This review focuses on this antiviral activity by CD8+ T lymphocytes, which is distinct from that activity elicited by some cytolytic CD8+ T lymphocytes (CTLs).


Genetic-biochemical criteria for individual sensitivity in development of occupational bronchopulmonary diseases.
Human individual sensitivity to health-hazardous occupational factors and probability of developing chronic lung diseases depend on genetic variation of serum and erythrocytic proteins. The present work was aimed at studying the phenotypes of serum and erythrocytic proteins in patients with occupational respiratory diseases. We studied 7 highly polymorphic genetic systems the varieties of which may be connected with development of bronchopulmonary pathology (BPP) and the immune status of the body: proteinase inhibitor (Pi), third component of the complement (C3), transferrin (Tf), group-specific component of blood serum (Gc), haptoglobin (Hp), erythrocytic glyoxalase (Glo) and phosphoglucomutase (PGM) in patients with chronic bronchitis, silicosis, occupational bronchial asthma and in the control group consisting of Moscow population not exposed to occupational hazards and apparently healthy workers of an engineering plant. Considerable differences were revealed in genetic structure of the patients with bronchopulmonary pathology as compared with the apparently healthy people along a series of Integrated system: proteinase inhibitor (Pi), C3, Tf, Gc, PGM. Comparison of the study groups by significant differences in the aggregate of the genetic information obtained suggests that 5 (HP, C3, Tf, Pl, PGM1) of the 7 studied systems showed the hereditary features of silicosis. The gene carriers Hp*2, C3*F, PGM1*2-, TF*D, GC*R due to peculiar biochemical processes appear to have less adaptive potentialities and a greater likelihood of the disease on exposure to industrial factors. The examined patients with chronic bronchitis showed an increase in the variant of GC*2 and of a rare variants of proteins GC*R and Pi*S, the patients with occupational bronchial asthma showed an increase in the variant of Hp*2 and of a rare variant Pi*S. Such studies could be useful for assessment and forecast of individual risk of occupational diseases.


Monitoring of Venturia inaequalis harbouring the QoI resistance G143A mutation in French orchards as revealed by PCR assays.
Genetic resistance to QoI fungicides may account for recent failures to control Venturia inaequalis (Cooke) Winter in French orchards. Two PCR-based assays were developed to detect the G143A point mutation in the fungal mitochondrial cytochrome b gene. The mutation is known to confer a high level of resistance to QoI fungicides. Occurrence of the G143A mutation in French field isolates collected from 2004 to 2007 was monitored. The QoI-resistant cytochrome b allele was specifically detected either following the cleavage of the amplified marker by a restriction endonuclease (CAPS assay) or its amplification using an allele-specific PCR primer. Using either method, the G143A mutation was found in 42% of the 291 field samples originating from French orchards in which apple scab proved difficult to be controlled. Monitoring of the G143A mutation in orchards located in 15 French administrative regions indicated that the mutation was detected at least once in nine of the regions, and its presence ranged from 33% to 64% of the orchards analysed in 2004 and in 2007 respectively. The PCR-based methods developed in this study efficiently reveal the presence of the G143A mutation in French V. inaequalis field populations.


Normalisation of High Bone Remodelling due to Oestrogen Deficiency by Traditional Chinese Formulation Kang Shuai Lao Pian in Ovariectomised Rats.
Postmenopausal osteoporosis transpires due to excessive osteoclastic bone resorption and insufficient osteoblastic bone formation in the presence of oestrogen insufficiency. Kang Shuai Lao Pian (KSLP) is a red ginseng-based traditional Chinese medicine known for its anti-ageing properties. However, studies on its effect on bone loss are lacking. Thus, the current study examined the skeletal protective effects of KSLP in an ovariectomised rodent bone loss model. Three-month-old female Sprague Dawley rats (n=42) were randomised into baseline, sham and ovariectomised (OVX) groups. The OVX rats were supplemented with low- (KSLP-L; 0.15 g/kg), medium- (KSLP-M; 0.30 g/kg), high-dose KSLP (KSLP-H; 0.45 g/kg) or calcium carbonate (1% w/v). The daily supplementation of KSLP was performed via oral gavage for eight weeks. Gavage stress was stimulated in the ovariectomised control with distilled water. The rats were euthanised at the end of the study. Whole-body and femoral bone mineral content and density scans were performed at baseline and every four weeks. Blood samples were obtained for the determination of bone remodelling markers. Histomorphometry and biomechanical strength testing were performed on femurs and tibias. High bone remodelling typically due to oestrogen deficiency, indicated by the elevated bone formation and resorption markers, osteoclast surface, single-labelled surface and mineralising surface/bone surface ratio, was observed in the untreated OVX rats. Whole-body BMD adjusted to body weight and Young's modulus decreased significantly in the untreated OVX rats. High-dose KSLP supplementation counteracted these degenerative changes. In conclusion, KSLP improves bone health by normalising bone remodelling, thereby preventing bone loss and decreased bone strength caused by oestrogen deficiency. Its anti-osteoporosis effects should be validated in patients with postmenopausal osteoporosis.


Lesion topographies in multiple sclerosis diagnosis: A reappraisal.
To assess the contributions of cortico-juxtacortical and corpus callosum lesions to multiple sclerosis diagnosis and to compare the value of ≥1 vs ≥3 periventricular lesions in clinically isolated syndromes (CIS). Step 1: We evaluated lesion topography classifications in 657 patients with CIS with stepwise Cox proportional hazards regression models considering second attack as the outcome. Step 2: We established 2 dissemination in space (DIS) versions according to the periventricular lesion cutoffs of ≥1 and ≥3 and assessed their performance at 10 years with second attack as the outcome, first individually and then combined with dissemination in time (DIT) in all cases (n = 326), by age, and by CIS topography. Step 1: The models (hazard ratios [95% confidence interval]) favored ≥1 over ≥3 periventricular lesions (2.5 [1.7-3.6]) and cortico-juxtacortical over juxtacortical lesions (1.4 [1.0-1.8]). Callosal lesions were not selected. Step 2: DIS specificity with ≥1 periventricular lesions was slightly lower than with ≥3 (59.1 vs 61.4) and the same after adding DIT (88.6). Regarding age, ≥3 periventricular lesions improved DIS specificity over ≥1 lesions in the 40-49 years of age bracket (66.7 vs 58.3). This difference disappeared when adding DIT (83.3). Optic neuritis had a similar pattern when evaluating CIS topographies. Our results comply with the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) consensus recommendation of combining cortical and juxtacortical lesions into a single term when possible. Concerning periventricular lesions, maintaining the current ≥1 cutoff in the McDonald criteria does not compromise specificity in typical CIS cases, but attention should be paid to older patients or optic neuritis cases.


EXO70C2 Is a Key Regulatory Factor for Optimal Tip Growth of Pollen.
The exocyst, a eukaryotic tethering complex, coregulates targeted exocytosis as an effector of small GTPases in polarized cell growth. In land plants, several exocyst subunits are encoded by double or triple paralogs, culminating in tens of EXO70 paralogs. Out of 23 Arabidopsis thaliana EXO70 isoforms, we analyzed seven isoforms expressed in pollen. Genetic and microscopic analyses of single mutants in EXO70A2, EXO70C1, EXO70C2, EXO70F1, EXO70H3, EXO70H5, and EXO70H6 genes revealed that only a loss-of-function EXO70C2 allele resulted in a significant male-specific transmission defect (segregation 40%:51%:9%) due to aberrant pollen tube growth. Mutant pollen tubes grown in vitro exhibited an enhanced growth rate and a decreased thickness of the tip cell wall, causing tip bursts. However, exo70C2 pollen tubes could frequently recover and restart their speedy elongation, resulting in a repetitive stop-and-go growth dynamics. A pollen-specific depletion of the closest paralog, EXO70C1, using artificial microRNA in the exo70C2 mutant background, resulted in a complete pollen-specific transmission defect, suggesting redundant functions of EXO70C1 and EXO70C2. Both EXO70C1 and EXO70C2, GFP tagged and expressed under the control of their native promoters, localized in the cytoplasm of pollen grains, pollen tubes, and also root trichoblast cells. The expression of EXO70C2-GFP complemented the aberrant growth of exo70C2 pollen tubes. The absent EXO70C2 interactions with core exocyst subunits in the yeast two-hybrid assay, cytoplasmic localization, and genetic effect suggest an unconventional EXO70 function possibly as a regulator of exocytosis outside the exocyst complex. In conclusion, EXO70C2 is a novel factor contributing to the regulation of optimal tip growth of Arabidopsis pollen tubes.


Increased Risky Choice and Reduced CHRNB2 Expression in Adult Male Rats Exposed to Nicotine Vapor.
While the cognitive enhancing effects of nicotine use have been well documented, it has also been shown to impair decision making. The goal of this study was to determine if exposure to nicotine vapor increases risky decision making. The study also aims to investigate possible long-term effects of nicotine vapor exposure on the expression of genes coding for cholinergic and dopaminergic receptors in brain. Thirty-two adult male Sprague Dawley rats were exposed to 24 mg/mL nicotine vapor or vehicle control, immediately followed by testing in the probability discounting task for 10 consecutive days. Fifty-four days after the 10-day vapor exposure, animals were sacrificed and expression of genes coding for the α4 and β2 cholinergic receptor subunits, and dopamine D1 and D2 receptors, were analyzed using RT-PCR. Exposure to nicotine vapor caused an immediate and transient increase in risky choice. Analyses of gene expression identified significant reductions in CHRNB2 and DRD1 in the nucleus accumbens core and CHRNB2 and DRD2 in the medial prefrontal cortex of rats previously exposed to nicotine vapor, relative to vehicle controls. Results provide data on the negative cognitive effects of nicotine vapor exposure and identify cholinergic and dopaminergic mechanisms that may affected with repeated use.


Metal- and photo-induced cleavage of DNA by podophyllotoxin, etoposide, and their related compounds.
Podophyllotoxin (PD) and its derivative etoposide (VP-16), a clinically useful anticancer drug, exhibit different mechanisms of action. PD binds specifically to tubulin to prevent its polymerization, whereas VP-16 lacks this action. The DNA strand breakage caused by VP-16 is thought to be due to its interaction with topoisomerase II or to free radical formation by oxidation of its 4'-phenolic hydroxyl group to a semiquinone free radical. We have demonstrated that PD, VP-16, 4'-demethylepipodophyllotoxin (DEPD), and syringic acid (SA) exhibit no DNA-cleaving activity but, in the presence of metal ions such as Cu2+ and Fe3+, DEPD and SA form metal complexes, which in turn show high activity for DNA strand scission at pH 7.8 under air. Furthermore, it was found that DNA cleavage was greatly promoted by irradiation with UV light. The PD-Fe3+ system at pH 7.8 showed very low DNA-cleaving activity, but irradiation with UV light in the system induced almost complete DNA breakage. DNA cleavages were significantly inhibited in the presence of hydroxyl radical scavengers, such as sodium benzoate and dimethylurea, in the Cu(2+)-SA and Fe(3+)-PD systems, with or without UV irradiation. These reactions were investigated by optical and ESR spectra, coupled with ESR spin-trapping techniques, by which the formation of hydroxy radicals was clearly detected in all systems. These findings have led us to a new proposal of the metal- and photo-induced mechanism for understanding the antitumor action of PD, VP-16, and their related compounds.