Randomised controlled trial of cultural-adapted and programme-adopted cognitive behavioural therapy for children and adolescents' anxiety in Japan: protocol for a Multi-, Inter-, and Cross-cultural Clinical Child Study (MIXCS).
The primary objective of the Multi-, Inter-, and Cross-cultural Clinical Child Study (MIXCS) is to evaluate the hypothesis that the effects of cultural-adapted cognitive behavioural therapy (CA-CBT) and programme-adopted cognitive behavioural therapy (PA-CBT) for children and adolescents' anxiety are both superior to a psychological control (moral education control: MEC) for reducing child and adolescent anxiety disorders and symptoms as well as related constructs. The secondary objective is to explore commonalities and differences in therapy factors between CA-CBT and PA-CBT. The study has been designed as a randomised, controlled and assessor masked multicentre superiority trial with three groups: CA-CBT, PA-CBT and MEC. Primary outcome is remission of primary anxiety disorders evaluated by independent evaluators. Secondary outcomes are clinician's severity ratings, child self-reported anxiety symptoms, depressive symptoms, cognitive errors and family accommodation, as well as parent-reported anxiety symptoms, and family accommodation. Competence and adherence of treatment, therapy factors in treatment sessions are also measured based on behavioural observation. Finally, satisfaction and comprehension are collected. We aim to recruit at least 99 families for the analysis. Treatment will be delivered weekly for 10 sessions and assessment will be conducted 2 weeks before the treatment (pre), 3 months after the base date when the treatment starts (post), 6 months (six months follow-up) and 12 months (12 months follow-up) after the postassessment. The MIXCS study was approved by Doshisha University Research Ethics Review Committee, Kwansei Gakuin University Institutional Review Board for Medical and Biological Research Involving Human Subjects and Shinshu University Certified Review Board of Clinical Research. Regardless of the results, the primary outcome will be published in a journal, and if the efficacy and effectiveness of CA-CBT and/or PA-CBT are empirically supported, the authors will encourage dissemination of the programmes including the assessment system through key stakeholders in education, health, and welfare areas. UMIN000038128.


Transcription initiation in the Escherichia coli K-12 malI-malX intergenic region and the role of the cyclic AMP receptor protein.
The Escherichia coli K-12 malI-malX intergenic region contains two divergent promoters, which have been investigated by both mutational and biochemical analysis. The malX promoter drives transcription initiation from a location that is 43 bp upstream from the malX translation start codon. Expression from the malX promoter is dependent on binding of the cyclic AMP receptor protein (CRP) to a DNA site centred 41.5 bp upstream of the transcript start. The malI promoter drives transcription initiation from a location 85 bp upstream from the malX transcript start and it is active without the CRP. Expression from the malI promoter can be stimulated by the CRP. Mutational analysis suggests that the malI promoter has an unusual organization.


Thyroid carcinoma: results from surgical treatment in 211 consecutive patients.
A retrospective study was undertaken of 211 patients who were operated on for thyroid carcinoma. The revised histological diagnoses were papillary (n = 167), follicular (n = 26), medullary (n = 9) and undifferentiated (n = 9). No patient was lost to follow up (mean 10 years). In 162 patients a palpable neck mass was the only clinical presentation of disease (76%). Fine needle aspiration cytology was increasingly used throughout the period. Total thyroidectomy was done in 167 (79%), hemi or subtotal thyroidectomy in 22 (10%), the remaining received palliative treatment. Accidental unilateral vocal cord paralysis occurred in 3 (1.4%). Total thyroidectomy was followed by permanent hypoparathyroidism in 19 (11%). The tumour recurred in 37 (19%), and 23 of the patients died thyroid cancer (11%). The disease specific mortality for patients with undifferentiated tumours was 77% compared with 8% for patients with differentiated tumours. In the latter group, death of cancer was correlated significantly with age, sex, tumour size, presence of regional metastases, and palliative treatment.


Glucose homeostasis, beta cell function, and insulin resistance in relation to vitamin D status after gestational diabetes mellitus.
We wanted to determine vitamin D status after gestational diabetes mellitus (GDM) and to evaluate whether levels of 25-hydroxyvitamin D3 (25OHD3 ) are associated with beta cell function, insulin resistance or a diagnosis of diabetes after GDM. Glucose homeostasis was assessed during a 75-g oral glucose tolerance test one to two years after delivery in 376 women with previous GDM (287 European and 78 non-European, including 33 Arab and 35 Asian women). Insulin resistance was estimated using homeostasis model assessment of insulin resistance (HOMA-IR). The insulinogenic index (I/G30) and the disposition index [(I/G30)/HOMA-IR] were used to calculate insulin secretion. Concentrations of serum 25OHD3 were determined. Mean (±SD) 25OHD3 concentration was 50.0 ± 22.3 nmol/L and differed significantly among subgroups of body mass index, ethnicity, and glucose tolerance status; 53% had 25OHD3 levels <50 nmol/L and 87% had 25OHD3 levels <75 nmol/L. There was a negative correlation between 25OHD3 concentration and HOMA-IR (p < 0.001) and a positive correlation between 25OHD3 and disposition index (p = 0.002) in univariable regression analysis. Correlations attenuated after adjustment for body mass index. In univariable regression analysis, 25OHD3 concentrations were significantly associated with diabetes after GDM (p = 0.004). However, in a multivariable model, non-European origin, HOMA-IR and insulinogenic index were significantly associated with postpartum diabetes, whereas 25OHD3 concentrations were not. Vitamin D deficiency/insufficiency in previous GDM cases appears to be associated with beta cell dysfunction and insulin resistance, but not with postpartum diabetes when factors well known to influence type-2 diabetes were adjusted for.


Pretransplant donor-specific anti-HLA antibodies as predictors of early allograft rejection in ABO-compatible liver transplantation.
The significance of preexisting donor-specific HLA antibodies (HLA-DSAs) for liver allograft function is unclear. Our previous studies have shown that humoral alloreactivity frequently accompanies acute cellular rejection (ACR). In the present study, we set out to determine whether pretransplant HLA-DSAs correlate with clinically significant ACR in the first 90 days after transplantation and, if so, to determine their predictive values. Class I HLA-DSAs and class II HLA-DSAs were determined by single-antigen bead flow cytometry for 113 consecutive adult transplants. A statistical analysis was performed for data from 109 consecutive patients with graft survival greater than or equal to 90 days. All patients who developed biochemical graft dysfunction underwent liver biopsy for hematoxylin-eosin and complement component 4d staining. Cox proportional hazards models and associated hazard ratios revealed a significant association of pretransplant HLA-DSAs with clinically significant ACR: this association started with a mean fluorescence intensity (MFI) as low as 300 for both class I (hazard ratio = 2.7, P < 0.01) and class II (hazard ratio = 6.0, P < 0.01). Pretransplant HLA-DSAs were associated with an increased risk of ACR: P < 0.01 for class I (42% versus 18%), P < 0.001 for class II (37% versus 7%), and P < 0.001 for either class I or II (36% versus 3%). Class I or II HLA-DSAs with an MFI ≥ 1000 had the best positive predictive value for clinically significant ACR at 46%, whereas class I or II HLA-DSAs with an MFI ≥ 300 had the best negative predictive value at 97.1%. Although our study was based on consecutive patients, it was limited by the relatively low number of single-center subjects. In conclusion, the present study indicates that pretransplant HLA-DSAs, even at low levels of allosensitization, correlate with the risk of clinically significant ACR. Our findings suggest that anti-human leukocyte antigen antibodies could serve as donor-specific markers of immunoreactivity to the liver graft.


Perception of premature infants' mothers on home visits before and after hospital discharge.
To understand the meaning of home visits by neonatal nurses for mothers of premature babies. A qualitative study was conducted with 21 mothers of families participating in a project that supported families of premature infants, born at a university hospital in the city of Londrina, Brazil. Data collection was conducted through semi-structured individual interviews, using a form with the identification data of mothers and an interview script. Three themes were revealed: the home visit as a support to the family, individualized home care, feeling cared for and supported in performing the baby's care. The home visit from the perspective of longitudinal care was a powerful resource that promoted the link between families and nurses, decreasing doubts, fears and anxieties of the mother. In addition, home care was provided and adherence to care and treatment was encouraged.


The frequency of cricopharyngeal dysfunction on videofluoroscopic swallowing studies in patients with dysphagia.
Dysphagia associated with cricopharyngeal dysfunction (CPD) is of particular interest to the otolaryngologist because it may respond to cricopharyngeal myotomy. There is a wide variation in the reported incidence of cricopharyngeal dysfunction in patients with dysphagia. This can be attributed to the different populations being studied, the lack of uniform criteria for diagnosis, and to different techniques used to evaluate patients. We have reviewed videofluoroscopic swallowing studies (VSS) conducted on 443 consecutive patients with complaints of dysphagia to identify the incidence of cricopharyngeal dysfunction. The patient population consists of 443 veterans with complaints of dysphagia who were evaluated by videofluoroscopic swallowing studies at the Department of Veterans Affairs Medical Center, East Orange, NJ, between November 1988 and March 1993. Cricopharyngeal dysfunction was diagnosed radiologically as the appearance of a shelf in the posterior column of barium at the level of the cricoid cartilage. It was identified in 10 of 177 (5.7%) patients with neurological disorders, in 7 of 142 (4.9%) patients with head and neck or esophageal tumors, and in 11 of 124 (8.9%) patients with other medical problems. These results do not support the notion that cricopharyngeal dysfunction is an important factor in a significant proportion of patients with dysphagia. It is recognized that videofluoroscopy may not always detect cricopharyngeal dysfunction and that better criteria for identifying this entity are needed.


Avian tuberculosis in pigs: Mycobacterium intracellulare infection in a breeding herd.
Lymphadenitis of pigs caused by Mycobacterium intracellulare is widely recognised in continental Europe but this is the first report of it in England. No disease was seen on the farm but condemnations of tissues and organs at the slaughterhouse were often than 100 a week and in one week were in excess of 200. The loss was greater to the slaughterhouse than to the farmer because of the constant disruption to the production line. There was no evidence that diseased pigs performed less well than healthy pigs. M intracellulare types 4 and 6 and M xenopi were isolated from diseased pigs. The source of the infection was traced to the sawdust bedding supplied by a local sawmill set in the middle of a forest. Changing the bedding to straw halted the outbreak. From the sawdust M avium types 1 and 4, M fortuitum and M intracellulare type 4 were isolated. The wildlife round the sawmill was investigated as a source of infection. Although M intracellulare type 4 and M avium were isolated from moles and a hedgehog, it was concluded that the wildlife was not involved. There was no evidence of pig to pig transmission.


A method for examining surface and interface irregularities after photorefractive keratectomy and laser in situ keratomileusis: predictor of optical and functional outcomes.
To develop a system for the examination of the ablated surface after photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK) and to correlate the surface regularity to the functional outcome. A Nidek Eas-1000 Anterior Eye Segment Analysis System was used to examine the ablated surface or the interface regularity immediately after PRK and LASIK. Eighty eyes were evaluated and divided into three study groups; group 1; regularity (18 eyes), group 2; mild irregularity (32 eyes) group 3; severe irregularity (30 eyes). At 12 months postoperatively, group 1 (regularity) showed the best percentage of eyes with 0 haze (100%) and with a refraction +/- 1.00 D of plano (89%); group 2 (mild irregularity) 84% had 0 haze and 62% were +/- 1.00 D of plano; group 3 (severe irregularity) 27% had 0 haze and 47% were +/- 1.00 D of plano. The patients with no postoperative irregularity had a sharply lower incidence of haze and a better refractive outcome with respect to plano, confirming the influence of ablation regularity on the results and the importance of this analysis in clinical practice.


Evaluation of alkylresorcinols in adipose tissue biopsies as a long-term biomarker of whole-grain wheat and rye intake in free-living Swedish men and women.
Wheat and rye, the most consumed whole grains (WG) in the Nordic countries, contain alkylresorcinols (AR) in their bran. AR concentrations in human adipose tissue might reflect long-term WG rye and wheat intake. We aimed to evaluate AR concentrations in adipose tissue biopsies as a long-term biomarker of WG wheat and rye intake in free-living Swedish men and women. Cross-sectional study. AR concentrations in adipose tissue biopsies were analysed and compared with long-term WG intake assessed by three FFQ (repeated over a period of 14 years in men, 17 years in women) and with plasma AR concentrations. The Cohort of Swedish Men between 1997 and 2010 and the Swedish Mammography Cohort between 1987 and 2003, Sweden. Men (n 149) and women (n 109). Long-term WG rye intake estimated with repeated FFQ correlated (r=0·31-0·41, P<0·01) with adipose-tissue AR concentrations, while WG wheat intake correlated only weakly (r=0·17-0·33, P<0·05). Total AR concentration in adipose tissue was 61 % lower in women than in men at similar energy-adjusted WG wheat and rye intakes, but plasma concentrations were similar. AR concentrations in adipose tissue correlated well with plasma concentrations (r=0·49-0·81, P<0·001). AR in adipose tissue reflected long-term WG rye but not WG wheat intake, probably due to poor precision in estimating WG wheat intake by FFQ. AR in adipose tissue appears promising as a biomarker of long-term WG rye intake but should be adjusted for sex.


Interface Study on the Effect of Carbon and Boron Carbide Diffusion Barriers in Sc/Si Multilayer System.
Sc/Si multilayers are one of the promising material combinations commonly used in the spectral range of 35-50 nm. However, diffusion and silicidation at the interfaces of Sc/Si multilayers limit widespread applications of this material combination. To improve the properties of Sc/Si multilayers, the scheme of barrier layers is utilized. In this work, a series of Sc/Si multilayers with boron carbide and carbon barrier layers were designed and fabricated to compare the properties including interface quality and thermal stability. The effect on the multilayer structure and quality before and after annealing were investigated by using grazing-incidence X-ray reflection, X-ray diffraction, rocking-curve X-ray diffuse scattering, transmission electron microscopy, and selected area electron diffraction. The results indicate that severe interdiffusion and crystallization occur in the multilayer with a carbon barrier after annealing. However, a boron carbide barrier layer improves thermal stability up to 550 °C since the interfaces remain abrupt and clear after annealing. The multilayer quality is confirmed to be improved significantly.


Impact of pre-treatment in GnRH-antagonist cycles triggered with GnRH agonist on reproductive outcomes.
Pre-treatment (PT) therapies in IVF are known to be used as pre-stimulation modality to improve cycle outcomes. This study aims to assess whether PT in GnRH antagonist cycles triggered with GnRH-agonist impact oocyte maturation response. Data were retrospectively collected for patients who underwent GnRH antagonist cycle with agonist triggering with and without PT. The patients were allocated to groups according to their PT status. The primary outcome evaluated was suboptimal maturation response. Suboptimal maturation to trigger was defined as no oocyte upon retrieval when adequate response was expected. The study population included 196 patients who underwent GnRH antagonist cycle with agonist triggering. The study group included 69 patients who received PT. The control group included 127 patients with no PT. In univariate analysis, the PT group significantly displayed suboptimal response compared to the controls (p = 0.008). All the patients in the study group with suboptimal response (with or without hCG re-triggering) were treated with GnRH-agonist as PT. Basal and pre-trigger LH values were significantly lower in the study group compared to controls (p < 0.001). Multivariate regression analysis revealed that PT with GnRH agonist was a significant predictor for suboptimal response. Pre-treatment, and particularly the use of GnRH-agonist as PT in antagonist cycles triggered with agonist, increases the risk of suboptimal response to GnRH-agonist trigger. This might be explained by prolonged pituitary suppression, which lasts beyond the PT cessation.


Optimization of recombinant t-PA secretion from seeded vascular grafts.
Seeding of vascular grafts with genetically engineered endothelial cells (EC) secreting anticoagulant or fibrinolytic agents offers a potential means of improving patency rates. Prior to the initiation of in vivo studies, we examined cell retention and tissue plasminogen activator (t-PA) secretion from small-diameter synthetic graft segments seeded with sheep venous EC genetically engineered to secrete human t-PA. Following retroviral-mediated gene transfer, EC were seeded at varying densities onto 4-mm-diameter synthetic graft segments of different composition, achieving confluent coverage of all materials. t-PA production from seeded grafts was evaluated under both static conditions and after flow exposure, for up to 3 days after seeding. t-PA secretion varied directly with increasing seeding density for all graft types, reaching a maximum of 20 ng/cm2/24 hr. t-PA secretion correlated highly with the number of seeded cells as determined by measurement of DNA from lysates of seeded grafts (r2 = 0.90, P < 0.0001). For all graft types tested, approximately 50% of seeded cells were retained after exposure to flow in vitro. Retained EC remained viable as determined by t-PA secretion. The rate of t-PA secretion from collagen-impregnated Dacron grafts was higher than that obtained with other materials both under static conditions and after flow exposure. This higher rate was most likely due to the higher surface area presented by the Dacron grafts. These data demonstrate that small-diameter prosthetic graft materials can be coated with a layer of EC that (i) remains metabolically active and capable of secreting a fibrinolytic agent, and (ii) remains adherent to the graft surface after exposure to flow. These experiments provide a foundation for in vivo studies in which grafts are seeded with EC genetically engineered to increase local fibrinolysis.


Ocellatuperoxides A-F, Uncommon Anti-Tumoral γ-Pyrone Peroxides from a Photosynthetic Mollusk Placobranchus ocellatus.
Six new pairs of γ-pyrone polypropionate enantiomers with an unusual peroxyl bridge at the side chain, namely (±)-ocellatuperoxides A-F (1-6), were isolated and characterized from the South China Sea photosynthetic mollusk Placobranchus ocellatus. Extensive spectroscopic analysis, single crystal X-ray diffraction analysis, ECD- (electronic circular dichroism) comparison, and TDDFT (time-dependent density functional theory) ECD computation were used to determine the structures and absolute configurations of new compounds. In a cell viability assay, several compounds showed considerable anti-tumoral effects on human non-small cell lung cancer cells A549 with Gefitinib (7.4 μM) and Erlotinib (2.1 μM) as positive controls. Further RNA-sequencing analysis and gene expression evaluation indicated that the anti-tumoral activity of the most effective compound 3 was associated with the regulation of several important genes, such as FGFR1 and HDAC5.


Food allergen avoidance: risk assessment for life.
The skills and knowledge required to carry out food allergen avoidance are becoming increasingly sophisticated. It is not enough to know the names of a handful of dishes which contain a known allergen as an ingredient. Many lifestyles now depend on food prepared away from the home. New product development has introduced a wide range of ingredients and dishes which are labour saving, exciting and innovative. Product traceability now depends on advanced technological support as it struggles to keep up with foods manufactured, prepared and served in ever more complex circumstances. Consumers are now faced with 'a jungle of choices'. However, those individuals who need to avoid a known allergen, particularly in trace quantities, often find that the food choice deemed suitable is poor, and the information available inadequate or even dangerously misleading. There are two important groups for whom this situation is a major concern. Thousands of families with young children are forced to live with the possibility that everyday foods may be contaminated by a known allergen which could kill in minutes. They live on their nerves, reading every packet and resorting to hyperprotective childcare and vigilance. In addition, the youngest independent consumers, teenagers and those in their twenties, may have little first-hand experience of food preparation. They may be ill-equipped in food-allergen risk assessment. Sadly, those who die from anaphylaxis or allergen-triggered asthma are often in this age-group. Current initiatives to support consumers at risk include a recognised standard for manufacturers seeking to eliminate an allergen from their production, and the integration of food allergy into training for caterers and food standards enforcement professionals.


Detection of micrometastases in lung cancer with magnetic nanoparticles and quantum dots.
Detection of micrometastases plays an important role in early-stage and recurrent cancer diagnosis. In the study, a new method of screening micrometastases of lung cancer in peripheral blood by magnetic nanoparticles (MNPs) and quantum dots (QDs) was developed to achieve early diagnosis and recurrence prevention. MNPs were prepared by combining miniemulsion polymerization and Stöber coating methods. QDs were prepared by using Cd(Ac)(2) · 2H(2)O and oxygen-free NaHTe with thioglycolic acid as the stabilizer. The carbodiimide-mediated condensation method was used to couple pan-cytokeratin (pan-ck) antibody (Ab) to the surface of the MNPs, and Lunx and SP-A Abs to the surface of the QDs. After four kinds of epithelial tumor cells were enriched by MNPs coupled with pan-ck Ab (MNP-pan-ck), lung cancer cells A549 and SPC-A-1 were successfully identified by QDs with double-labeled Abs. Finally, 32 patients with non-small cell lung cancer (NSCLC) were collected, out of 26 cases with the enriched circulating tumor cells (CTCs), 21 cases were successfully identified by QDs. Therefore, a new method was established in which MNP-pan-ck collected CTCs and QDs with double-labeled Abs could be used simultaneously to identify CTCs from NSCLC patients.


Promoter-regulated in vivo asymmetric self-assembly strategy to synthesize heterogeneous nanoparticles for signal amplification.
Signal amplification is commonly used to enhance the sensitivity of biological analysis. Here, we present a strategy involving in vivo asymmetric self-assembly combined with promoter strength regulation to synthesize heterogeneous nanoparticles for signal amplification. Two expression vectors were constructed by genetically inserting, respectively, signal and binding molecules into the hepatitis B core antigen protein (HBcAg) structure. Because of differential expression of the two recombinant proteins in the presence of a strong promoter (T7) and a weak promoter (Tac-1) and spontaneous asymmetric self-assembly in vivo, heterogeneous HBcAg nanoparticles (NPs) with a high ratio of signal-bearing to target-binding molecules were obtained. These nanoparticles contained a large number of green fluorescent proteins as signal molecules and a small number of B1 immunoglobulin-binding domains from protein G for antibody binding, thus enabling sensitive immunoassays. As a proof of concept, improved sensitivity for antibody detection was achieved using the heterogeneous nanoparticle conjugated with a secondary antibody molecule.


Screening instruments for depression in primary care: a concise review for clinicians.
Depression is prevalent across the life span worldwide. It is a common problem encountered in primary care settings. The World Health Organization recommends the integration of mental health into general health care in order to seal the existing gap between the number of patients who need mental health care and those who actually receive it. Addressing the burden of mental health problems in primary care settings has its limitations, particularly because of the time constraints in busy primary care clinics as well as the inadequate training of staff and physicians in mental health disorders. That is why reliable, brief, and easy to administer depression screening instruments are important in helping physicians identify patients at risk. The 2-item Patient Health Questionnaire (PHQ-2) is a suitable primary screening tool for depression. If positive, other tools should be administered, such as the PHQ-9 in adults, the PHQ-9 or Geriatric Depression Scale-15 in older adults, or the Arroll's help question or the Edinburgh Postnatal Depression Scale in ante- or postpartum women. Patients with positive scores ought to be interviewed more thoroughly. Computerized depression screening instruments that are interfaced or integrated into electronic health records seem to be promising steps toward optimizing diagnosis, treatment, and follow-up. The availability of adequate management and follow-up are ethical requirements for the utilization of any screening instrument for depression.


Synthesis of Some Novel Fused Pyrimido[4″,5″:5',6']-[1,2,4]triazino[3',4':3,4] [1,2,4]triazino[5,6-b]indoles with Expected Anticancer Activity.
Our current goal is the synthesis of polyheterocyclic compounds starting from 3-amino-[1,2,4]triazino[5,6-b]indole 1 and studying their anticancer activity to determine whether increasing of the size of the molecules increases the anticancer activity or not. 1-Amino[1,2,4]triazino[3',4':3,4]-[1,2,4]triazino[5,6-b]indole-2-carbonitrile (4) was prepared by the diazotization of 3-amino[1,2,4]-triazino[5,6-b]indole 1 followed by coupling with malononitrile in basic medium then cyclization under reflux to get 4. Also, new fused pyrimido[4″,5″:5',6'][1,2,4]triazino-[3',4':3,4][1,2,4]triazino[5,6-b]indole derivative 6 was prepared and used to obtain polycyclic heterocyclic systems. Confirmation of the synthesized compounds' structures was carried out using elemental analyses and spectral data (IR, ¹H-NMR and 13C-NMR and mass spectra). The anticancer activity of some of the synthesized compounds was tested against HepG2, HCT-116 and MCF-7 cell lines. The anticancer screening results showed that some derivatives display good activity which was more potent than that of the reference drug used. Molecular docking was used to predict the binding between some of the synthesized compounds and the prostate cancer 2q7k hormone and breast cancer 3hb5 receptors.


Sialic acid binding domains of CD22 are required for negative regulation of B cell receptor signaling.
CD22, a negative regulator of B cell antigen receptor signaling, binds glycoconjugates terminating in alpha2, 6 sialic acid. The physiological ligand(s) for CD22 remain unknown. We asked whether the sialic acid binding domains are necessary for CD22 to function as a negative regulator. We generated two mutants that lack sialic acid binding activity and expressed them in a novel CD22(-/-) murine B cell line. Anti-IgM activated B cells expressing either CD22 mutant had greater Ca(2+) responses than cells expressing wild-type CD22. Each variant also had reduced CD22 tyrosine phosphorylation and Src homology 2 domain-containing protein tyrosine phosphatase-1 association. These data suggest that the alpha2, 6 sialic acid ligand binding activity of CD22 is critical for its negative regulatory functions.


Carbon cycle instability and orbital forcing during the Middle Eocene Climatic Optimum.
The Middle Eocene Climatic Optimum (MECO) is a global warming event that occurred at about 40 Ma. In comparison to the most known global warming events of the Paleogene, the MECO has some peculiar features that make its interpretation controversial. The main peculiarities of the MECO are a duration of ~500 kyr and a carbon isotope signature that varies from site to site. Here we present new carbon and oxygen stable isotopes records (δ13C and δ18O) from three foraminiferal genera dwelling at different depths throughout the water column and the sea bottom during the middle Eocene, from eastern Turkey. We document that the MECO is related to major oceanographic and climatic changes in the Neo-Tethys and also in other oceanic basins. The carbon isotope signature of the MECO is difficult to interpret because it is highly variable from site to site. We hypothesize that such δ13C signature indicates highly unstable oceanographic and carbon cycle conditions, which may have been forced by the coincidence between a 400 kyr and a 2.4 Myr orbital eccentricity minimum. Such forcing has been also suggested for the Cretaceous Oceanic Anoxic Events, which resemble the MECO event more than the Cenozoic hyperthermals.


Special Populations Networks: themes and lessons learned.
The Special Populations Networks (SPN) Program was a 5-year, nationwide project funded by the National Cancer Institute to reduce cancer-related health disparities in minority and other underserved communities by building community health infrastructure, improving cancer awareness and use of cancer screening services, and increasing the cadre of minority junior scientists studying disparities issues. Through collaborations with a wide range of community and academic partners, the 18 grantee organizations: 1) developed culturally sensitive cancer communications approaches and materials; 2) conducted outreach and educational activities appropriate to their communities' needs and diverse cultures; and 3) trained and mentored young minority investigators who succeeded in winning support for pilot projects addressing local cancer health disparities issues, trained and deployed lay health workers, and worked with community and health provider organizations to improve understanding of cancer risk in these populations and encourage participation in appropriate clinical trials. SPN activities were grounded in community-based participatory research principles and practice. This overview highlights major project themes, provides examples of differing individual grantee approaches to similar issues, and describes key lessons learned, as reported by the SPN projects, that may guide future programmatic and research efforts to eliminate cancer health disparities in the United States. Cancer 2006. Published 2006 by the American Cancer Society.


A large-scale Boolean model of the rheumatoid arthritis fibroblast-like synoviocytes predicts drug synergies in the arthritic joint.
Rheumatoid arthritis (RA) is a complex autoimmune disease with an unknown aetiology. However, rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) play a significant role in initiating and perpetuating destructive joint inflammation by expressing immuno-modulating cytokines, adhesion molecules, and matrix remodelling enzymes. In addition, RA-FLS are primary drivers of inflammation, displaying high proliferative rates and an apoptosis-resistant phenotype. Thus, RA-FLS-directed therapies could become a complementary approach to immune-directed therapies by predicting the optimal conditions that would favour RA-FLS apoptosis, limit inflammation, slow the proliferation rate and minimise bone erosion and cartilage destruction. In this paper, we present a large-scale Boolean model for RA-FLS that consists of five submodels focusing on apoptosis, cell proliferation, matrix degradation, bone erosion and inflammation. The five-phenotype-specific submodels can be simulated independently or as a global model. In silico simulations and perturbations reproduced the expected biological behaviour of the system under defined initial conditions and input values. The model was then used to mimic the effect of mono or combined therapeutic treatments and predict novel targets and drug candidates through drug repurposing analysis.


Effects of rigid plate fixation and subsequent removal on craniofacial growth in rabbits.
To examine the effects of rigid plate fixation (RPF) and subsequent removal on craniofacial growth in rabbits. Randomized controlled experiment. Thirty-two 6-week-old male New Zealand white rabbits. Group 1 underwent exposure of the left nasofrontal suture and midzygomatic arch; group 2, RPF of the left nasofrontal suture and midzygomatic arch areas; group 3, single osteotomy at left nasofrontal suture and double osteotomies at midzygomatic arch with RPF of osteotomies; and group 4, controls. At 11 weeks of age, the RPF was removed. Animals were killed at 20 weeks of age. Linear and 3-dimensional measurements (euclidean distance matrix analysis) were used to evaluate craniofacial regions. In comparison with control animals, linear data showed shortening of the left nasal bone in group 3. Groups 1 through 3 also exhibited shortening of the left zygomatic arch, orbital diameter, and anterior midfacial height. Euclidean distance matrix analysis showed significant restrictive shape alterations on both the ipsilateral and contralateral sides in groups 1 through 3. In comparison with animals in which RPF was left in place, linear data showed significant shortening of the orbital diameter in groups 1 through 3 and of anterior midface height in groups 2 and 3. Euclidean distance matrix analysis showed significant restrictive shape alterations on both contralateral and ipsilateral sides. Rather than preventing restrictive growth disturbances to the growing midface in rabbits, RPF with subsequent removal produces a greater amount of restrictive shape alteration than RPF that is left in place.


A theoretically exact reconstruction algorithm for helical cone-beam differential phase-contrast computed tomography.
Differential phase-contrast computed tomography (DPC-CT) reconstruction problems are usually solved by using parallel-, fan- or cone-beam algorithms. For rod-shaped objects, the x-ray beams cannot recover all the slices of the sample at the same time. Thus, if a rod-shaped sample is required to be reconstructed by the above algorithms, one should alternately perform translation and rotation on this sample, which leads to lower efficiency. The helical cone-beam CT may significantly improve scanning efficiency for rod-shaped objects over other algorithms. In this paper, we propose a theoretically exact filter-backprojection algorithm for helical cone-beam DPC-CT, which can be applied to reconstruct the refractive index decrement distribution of the samples directly from two-dimensional differential phase-contrast images. Numerical simulations are conducted to verify the proposed algorithm. Our work provides a potential solution for inspecting the rod-shaped samples using DPC-CT, which may be applicable with the evolution of DPC-CT equipments.


Prehospital nausea and vomiting after trauma: Prevalence, risk factors, and development of a predictive scoring system.
Nausea and vomiting are common problems in trauma patients and potentially dangerous during trauma resuscitation. These symptoms are present in up to 10% of ambulance patients, but their prevalence in trauma patients is largely unknown. The aim of this study was to determine the prevalence of prehospital nausea and vomiting in trauma patients and evaluate antiemetic usage. Prospective, cohort study of trauma resuscitation patients transported by ambulance to a major trauma centre. Patients with hemodynamic instability (systolic blood pressure <90, heart rate >120) or Glasgow Coma Scale score <14 on arrival were excluded. Nausea, vomiting, and antiemetic use were recorded. Convenience sample of 196 trauma resuscitation patients (68% men; age, 42 ± 18 years, mean Injury Severity Score 8 ± 7) were interviewed over the 5-month study period, of a total 369 admitted trauma patients (53%). Seventy-five (38%) patients reported some degree of nausea, 57 (29%) moderate or severe nausea, and 15 (8%) vomited. Older age and female gender were associated with vomiting (p < 0.01). Seventy-nine patients (40%) received a prophylactic antiemetic. Of these, four became nauseous (5%), compared with 71 of 117 (61%) for patients not given an antiemetic (p < 0.0001). Prehospital nausea and vomiting are more common in our cohort of trauma patients than the reported rates in the literature for nontrauma patients transported to hospital by ambulance. Only 40% of patients receive prophylactic antiemetics, but those patients are less likely to develop symptoms. V, epidemiological study.


Ten-Year Follow-up of 9-Valent Human Papillomavirus Vaccine: Immunogenicity, Effectiveness, and Safety.
The 9-valent human papillomavirus (9vHPV) vaccine Phase III immunogenicity study in 9- to 15-year-old boys and girls was extended to assess immunogenicity and effectiveness through 10 years after the last vaccine dose (NCT00943722). Boys (n = 301) and girls (n = 971) who received three 9vHPV vaccine doses in the base study (day 1, months 2 and 6) enrolled in the extension. Serum was collected through month 126 for antibody assessments by competitive Luminex immunoassay and immunoglobulin G-Luminex immunoassay. For effectiveness analysis starting at age 16 years, genital swabs were collected (to assess HPV DNA by polymerase chain reaction) and external genital examinations conducted every 6 months. Primary analyses were conducted in per-protocol populations. Geometric mean antibody titers peaked around month 7, decreased sharply between months 7 and 12, then gradually through month 126. Seropositivity rates remained ≥81% by competitive Luminex immunoassay and ≥95% by immunoglobin G-Luminex immunoassay at month 126 for each 9vHPV vaccine type. After up to 11.0 (median 10.0) years of follow-up postdose 3, there were no cases of HPV6/11/16/18/31/33/45/52/58-related high-grade intraepithelial neoplasia or condyloma in males or females. Incidence rates of HPV6/11/16/18/31/33/45/52/58-related 6-month persistent infection in males and females were low (54.6 and 52.4 per 10000 person-years, respectively) and within ranges expected in vaccinated cohorts, based on previous human papillomavirus vaccine efficacy trials. The 9vHPV vaccine demonstrated sustained immunogenicity and effectiveness through ∼10 years post 3 doses of 9vHPV vaccination of boys and girls aged 9 to 15 years.


Comparison of Carrier and de novo Pathogenic Variants in a Chinese DMD/BMD Cohort.
Background: Duchenne and Becker muscular dystrophy (DMD/BMD) are X-linked recessively inherited neuromuscular disorders caused by deletions, duplications, or small mutations in the DMD gene. With advances in prenatal diagnosis decreasing the number of affected offspring from carrier mothers, the frequency of de novo variants could increase. Therefore, determining the differences between the carrier and de novo variants of the DMD gene, which are rarely explored, is important for trial planning and genetic diagnosis in the future. Methods: A total of 440 patients, 349 of whom had DMD and 91 had BMD, diagnosed in our department between 2012 and 2019, along with their respective mothers, were included in this study. Multiplex ligation-dependent probe amplification was used to detected deletions and duplications in patients and their mothers. Small mutations were detected using next-generation sequencing in the patients, followed by Sanger sequencing in the mothers. Results: Deletions, duplications, and small mutations were identified in 204, 46, and 99 of the 349 patients with DMD and in 50, 10, and 31 of the 91 patients with BMD, respectively. De novo deletions were more concentrated in hotspot regions than carrier deletions of DMD/BMD. No clear bias was observed in the variant distribution between carriers, de novo duplications, and small mutations in DMD/BMD. The carrier frequency of DMD (61.6%) was lower than that of BMD (69.2%), but the difference was not statistically significant. The carrier frequency of deletions of the DMD gene (51.2%) was significantly lower than those of duplications (75%) and small mutations (81.5%). Conclusion: Compared to de novo deletions, deletions from carrier mothers had a wider distribution. Moreover, there was no significant difference between the carrier frequencies of DMD and BMD. Duplications and small mutations were more commonly inherited, while deletions were present de novo.


Ezrin is Significantly Overexpressed in Luminal A, Luminal B, and HER2 Subtype Breast Cancer.
Ezrin, a membrane-linking protein, has been shown to play an important role in the carcinogenesis of infiltrating breast ductal carcinoma and its strong expression has been used to predict poor prognosis in patients with breast carcinoma. In this study, we compared ezrin protein distribution pattern in benign breast disease and breast cancer molecular subtypes and evaluated their association with clinicopathologic variables. A total of 376 breast cases (142 benign and 234 malignant cases) were studied. Immunohistochemical analysis for ezrin was performed and its expression was observed in terms of its distribution, intensity, and proportion of cells reactive for ezrin. Ezrin was expressed in all benign cases and 91.7% of malignant cases. Apical staining was positively associated with benign breast disease, whereas membranous and cytoplasmic staining were more frequently observed in malignant cases, specifically of hormone receptor-positive subtypes (luminal A and luminal B). Ezrin was significantly overexpressed in luminal A, luminal B, and HER2 subtypes. Reduced ezrin expression was significantly associated with triple-negative breast cancer molecular subtype. No significant association was demonstrated between ezrin expression and Her2 gene amplification, tumor grading, or staging.


Successful treatment of granulomatosis with polyangiitis with hydropneumothorax using corticosteroids and immunosuppressant.
Pneumothorax and pleural effusion is a rare and serious complication of granulomatosis with polyangiitis (GPA). The present study reported a case with a history of sinusitis for 20 years, dry cough for three years and exacerbated purulent nasal discharge and recurrent skin ulcers for two years. The patient experienced sudden difficulty in breathing two months prior to presentation. Lung computed tomography (CT) showed multiple bilateral lung nodules and cavitary nodules as well as right hydropneumothorax. Paranasal sinus CT showed soft tissue infiltration. The cytoplasmic pattern of anti-neutrophil cytoplasmic antibody (c-ANCA) was positive and anti-proteinase 3 (PR3) antibodies, erythrocyte sedimentation rate and C-reactive protein were elevated. After pleural drainage and methylprednisolone pulse treatment, followed by cyclophosphamide and cyclosporine, the patient's symptoms were ameliorated, lungs were re-expanded, and c-ANCA, PR3 and inflammatory markers returned to normal levels.


Relationship of Th17/Treg Cells and Radiation Pneumonia in Locally Advanced Esophageal Carcinoma.
Radiation pneumonia is a main side-effect that has limited the clinical usage of radiotherapy in locally advanced esophageal carcinoma. T helper cells 17 (Th 17) and T regulatory cells (Tregs) play an important role in inflammatory diseases. The balance between Treg and Th17 cells is a key factor in the progression of many inflammatory and autoimmune diseases. Whether Tregs and Th17 cells are predictive factors of radiation pneumonia has not yet been reported. In this study, we investigated the relationships of Treg/Th17 cells and radiation pneumonia in patients with locally advanced esophageal cancer who received radiotherapy. One hundred and forty-eight patients with locally advanced esophageal cancer who received radical and palliative radiotherapy were enrolled. The levels of Th17 and Treg cells in the blood of patients were detected using flow cytometry at the time point of pre-radiotherapy, 1st, 2nd, 3rd, 4th, 5th and 6th week from the start of radiation and 4 weeks after completion of radiotherapy. Radiation pneumonia was evaluated according to Radiation Therapy Oncology Group's acute radiation pneumonia standards, with the endpoint being grade 2 or above radiation pneumonia. There were 24 cases of radiation pneumonia in 148 cases of locally advanced esophageal cancer patients who underwent radiotherapy. Th17 cells increased and, in contrast, Treg cells decreased in the radiation pneumonia group. The change in the ratio of Th17/Treg was more pronounced and the difference was statistically significant from the 5th week after irradiation compared to patients with no radiation pneumonia (p<0.05). There was no significant difference in dosimetric parameters, including V5, V20, V30 and mean lung dose (MLD) and clinical factors, such as gender, age, smoking history, history of surgery and chemotherapy. The ratio of Th17/Treg cells may be an effective predictive factor of radiation pneumonia.


[Graves' disease in preschool children].
Graves' disease, which is the main cause of hyperthyroidism in the pediatric age group, is very rare in pre-school children. We describe the cases of four girls, aged less than 6 years old, out of a total of 30 patients diagnosed with Graves' disease between 1985 and 2004. Investigations were motivated by tachycardia, chronic diarrhea, language development delay or thyroid nodules detected by cervical ultrasonography. In three of the four patients height and bone age were advanced. In all patients goiter was small or absent. None of the patients had ophthalmic disease. In all patients free T3 and T4 were elevated and thyroid-stimulating hormone was suppressed. Three patients were positive for thyroid-stimulating immunoglobulins (the method was not available for the oldest case). Two patients showed complete resolution after 5 years of treatment with carbimazole. The remaining two patients are still under treatment and no adverse effects have been documented.


[Risk Factors for Surgical Site Infection after Conversion from Laparoscopic to Open Cholecystectomy].
Objective To investigate the incidence of surgical site infection(SSI)following conversion from laparoscopic to open cholecystectomy and to analyze the related risk factors. Methods The clinical data of 179 patients who had experienced conversion from laparoscopic to open cholecystectomy in Peking Union Medical College Hospital from January 2014 to August 2019 were analyzed retrospectively.Univariate and multivariate logistic regression analyses were performed to evaluate the associations between clinical variables and SSI. Results The incidence of SSI was 19.0%(34/179)after conversion from laparoscopic to open cholecystectomy.The multivariable analysis demonstrated that preoperative endoscopic retrograde cholangiopancreatography(ERCP)(OR=4.208,95% CI:1.590-11.135,P=0.004)was the only independent risk factor of SSI. Conclusions The incidence of SSI after conversion from laparoscopic to open cholecystectomy increased remarkably,especially in those who had preoperative ERCP.Preventive interventions should be taken to reduce the incidence of SSI.


68Ga-DOTATOC PET/CT Imaging in Solitary Fibrous Tumor of the Pleura.
Here we describe a 77-year-old man with a solitary fibrous tumor of the pleura showing increasing tracer uptake at Ga-DOTATOC PET/CT, demonstrating that solitary fibrous tumor of the pleura may overexpress somatostatin receptors, therefore mimicking neuroendocrine tumors at somatostatin receptor PET/CT.


Impact of drug-eluting stents on the comparative effectiveness of coronary artery bypass surgery and percutaneous coronary intervention.
Drug-eluting stents (DES) have largely replaced bare-metal stents (BMS) for percutaneous coronary intervention (PCI). It is uncertain, however, whether introduction of DES had a significant impact on the comparative effectiveness of PCI versus coronary artery bypass graft surgery (CABG) for death and myocardial infarction (MI). We identified Medicare beneficiaries aged ≥66 years who underwent multivessel CABG or multivessel PCI and matched PCI and CABG patients on propensity score. We defined the BMS era as January 1999 to April 2003 and the DES era as May 2003 to December 2006. We compared 5-year outcomes of CABG and PCI using Cox proportional hazards models, adjusting for baseline characteristics and year of procedure and tested for a statistically significant interaction (P(int)) of DES era with treatment (CABG or PCI). Five-year survival improved from the BMS era to the DES era by 1.2% for PCI and by 1.1% for CABG, and the CABG:PCI hazard ratio was unchanged (0.90 vs 0.90; P(int) = .96). Five-year MI-free survival improved by 1.4% for PCI and 1.1% for CABG, with no change in the CABG:PCI hazard ratio (0.81 vs 0.82; P(int) = .63). By contrast, survival-free of MI or repeat coronary revascularization improved from the BMS era to the DES era by 5.7% for PCI and 0.9% for CABG, and the CABG:PCI hazard ratio changed significantly (0.50 vs 0.57, P(int) ≤ .0001). The introduction of DES did not alter the comparative effectiveness of CABG and PCI with respect to hard cardiac outcomes.


Reduction in Fracture Resistance of the Root with Aging.
The incidence of vertical root fracture in endodontically treated teeth increases with patient age. This study evaluated the microstructure, chemical composition, and mechanical properties of radicular dentin as a function of aging. Single-rooted teeth were obtained from adult donors ranging from age 15 to older than 80 years. Beams were extracted from the middle third of the root and subjected to 4-point flexure to failure to evaluate strength of dentin in terms of donor age. Based on the strength distribution, the fatigue strength of root tissue from young (≤30 years) and old (≥55 years) donor teeth was evaluated via cyclic flexure loading. The microstructure and chemical composition of radicular dentin from the 2 groups were evaluated as a function of distance from the root apex using microscopy and Raman spectroscopy, respectively. The strength decreased with age by approximately 25 MPa per decade, which resulted in a significant difference (P ≤ .0001) between the young (199 ± 36 MPa) and old (122 ± 11 MPa) groups. There was also a significant difference (P ≤ .0001) in fatigue strength between the young and old age groups. Both the mineral-to-collagen ratio and degree of cross-linking increased with age, with the largest changes identified in the apical and middle thirds, respectively. There is a reduction in the damage tolerance of radicular dentin with increasing age. This degradation appears to result from changes in the microstructure, corresponding chemical composition, and increase in collagen cross-linking with age, and is most severe near the root apex.


Cell lines cultured at high density are resistant to lysis by tumor necrosis factor and natural cytotoxic cells.
It has been suggested that natural cytotoxic (NC) cell activity and tumor necrosis factor (TNF), the molecular mediator of NC activity, are capable of protecting individuals against the progression of incipient tumors or could be useful in cancer therapy regimens. Much of this speculation arises as a result of in vitro studies, on a variety of tumor cells, demonstrating the cytolytic and cytostatic properties of NC and TNF activities. Here, evidence is presented showing that certain mouse fibroblast cell lines, generally considered sensitive to NC and TNF lysis, are quite resistant to these lytic activities when cultured at high cell density. Although a soluble factor that renders these same target cells resistant to NC and TNF lysis has been described, no such factor is involved in this high density-induced resistance. Rather, it appears that cell to cell contact of the targets is critical. Moreover, the induced resistance to NC and TNF lysis does not result from loss of either NC recognition determinants or TNF receptors by the target cells, but is the consequence of increased expression of a protein synthesis-dependent resistance mechanism. These observations raise the issue of the in vivo phenotype of cells characterized in vitro as sensitive to NC and TNF lysis. It is entirely possible that certain cells which are considered sensitive to NC and TNF activities are, in fact, resistant to these cytolytic activities when growing as tumors (i.e., at high cell density). Should this be the so, NC and TNF cytolytic activities may not function in vivo or may function only via some indirect means.


Spatiotemporal expression of extracellular matrix components during the chondrogenic and osteogenic phases of bone healing.
In this study, we investigated the cascade of events involved in the early phases of bone healing in rats, especially the transition from chondrogenesis to osteogenesis, which involves cellular and extracellular matrix (ECM) components. We used a standardized closed tibial fracture model in Wistar rats, which was divided into nine groups of five animals each, and the fracture area was evaluated at 0, 12, 24, 48, 72, 96, 144, 192, and 240 hours post-injury. Histological, histochemical, immunohistochemical and morphometric techniques were used to evaluate the proliferating cell nuclear antigen (PCNA), transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), type I procollagen (procoll-I), type I collagen (coll-I), and type II collagen (coll-II) expression at every time point. TGF-β expression peaked after 144 hours, in the initial chondrogenic phase. VEGF expression reached the first peak at 96-144 hours post-injury, in the initial chondrogenic phase and the second peak at 240 hours, in the osteogenic phase. Except at 48 hours, PCNA expression increased gradually from 12 hours and peaked at 96 hours in the prechondrogenic phase, and then decreased gradually until 240 hours in the osteogenic phase. Total collagen (T-coll) and coll-II reached an expression peak at 144 hours, in the chondrogenic phase. No differences were observed between their expression from 12 hours to 72 hours and at 240 hours post-injury. The results suggest that spatiotemporal expression of ECM components during the chondrogenic and osteogenic phases of bone healing depends on several combined and orchestrated factors. A better understanding of the coordinated participation of cells and ECM components in the early bone healing process may provide new insights into the etiology of abnormal or delayed fracture healing.


Effects of spray drying process parameters on the solubility behavior and physical stability of solid dispersions prepared using a laboratory-scale spray dryer.
The purpose of this study is to determine the process parameters of the laboratory-scale spray dryer affecting the solubility behavior and physical stability of solid dispersions. Solid dispersions of the model drug (nilvadipine or nifedipine) and hypromellose (HPMC) (w/w: 1/1) were prepared using the laboratory-scale spray dryer. As process parameters, nitrogen flow rate, sample concentration and pump speed were investigated. The samples were characterized by dissolution tests, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), scanning electron microscope (SEM), and nanoscale thermal analysis (Nano-TA). The physical stability was monitored after 7 months storage at 25°C. Solubility behavior and physical stability were improved by setting the low nitrogen flow rate and high sample concentration. DSC showed that the physical state depends on the spray drying conditions, whereas, every sample showed the similar morphology from SEM results. The difference of solubility behavior and physical stability were found to come from the microstructural phase separation of the spray dried particles using a novel analytical technique (Nano-TA). This study demonstrated that nitrogen flow rate and sample concentration should be the critical parameters for the enhancements of the solubility and physical stability of solid dispersions.


Modulation of jejunal ion and water absorption by endogenous angiotensin after dehydration.
In the pentobarbital sodium-anesthetized rat, dehydration for 24 h increased ion and water absorption from the jejunum. Dehydration also elevated plasma concentrations of angiotensin peptides and plasma renin activity but did not significantly alter plasma aldosterone concentrations. Infusion of tyramine, norepinephrine, and angiotensin II (AII) also stimulated jejunal absorption in a manner similar to dehydration. The elevation of jejunal absorption in response to dehydration is totally inhibited by the converting enzyme inhibitor captopril and the angiotensin receptor antagonist [lle7]AIII. Thus, increased jejunal absorption following dehydration is mediated by the renin-angiotensin system and is not secondary to either aldosterone or to antidiuretic hormone release. Further experiments demonstrated that the increase in jejunal absorption in response to dehydration was unaffected by propranolol but was totally abolished by phentolamine, prazosin, and peripheral sympathectomy. It is proposed that AII stimulates jejunal absorption by enhancing transepithelial transport processes and/or by altering the balance of Starling forces governing fluid absorption across enteric capillaries. Angiotensin thus appears to be a physiologically important mediator of jejunal absorption in states characterized by extracellular volume depletion.


Adaptation to climate change through seasonal migration revealed by climatic versus demographic niche models.
Predicting the geographic range of species and their response to climatic variation and change are entwined goals in conservation and evolutionary ecology. Species distribution models (SDMs) are foundational in this effort and used to visualize the geographic range of species as the spatial representation of its realized niche. SDMs are also used to forecast range shifts under climate change, but often in the absence of empirical evidence that climate limits population growth. We explored the influence of climate on demography, seasonal migration, and the extent of the geographic range in song sparrows (Melospiza melodia), a species thought to display marked local adaptation to regional climate. To do so, we developed SDMs to predict the demographic and climate niches of migratory and resident song sparrows across our study area in western North America from California to Alaska, using 48 years of demographic data from a focal population in British Columbia and 1.2 million continental-scale citizen science observations. Spatial agreement of our demographic and climate niche models in the region of our focal population was strong (76%), supporting the hypothesis that demographic performance and the occurrence of seasonal migration varied predictably with climatic conditions. In contrast, agreement at the northern (58%) and southern (40%) extents of our study area was lower, as expected if the factors limiting population growth vary regionally. Our results support the hypothesis that local climate drives spatial variation in the occurrence of seasonal migration in song sparrows by limiting the fitness of year-round residents, and suggest that climate warming has favored range expansions and facilitated an upward shift in elevational range song sparrows that forgo seasonal migration. Our work highlights the potential role of seasonal migration in climate adaptation and limits on the reliability of climate niche models not validated with demographic data.


Roles for ordered and bulk solvent in ligand recognition and docking in two related cavities.
A key challenge in structure-based discovery is accounting for modulation of protein-ligand interactions by ordered and bulk solvent. To investigate this, we compared ligand binding to a buried cavity in Cytochrome c Peroxidase (CcP), where affinity is dominated by a single ionic interaction, versus a cavity variant partly opened to solvent by loop deletion. This opening had unexpected effects on ligand orientation, affinity, and ordered water structure. Some ligands lost over ten-fold in affinity and reoriented in the cavity, while others retained their geometries, formed new interactions with water networks, and improved affinity. To test our ability to discover new ligands against this opened site prospectively, a 534,000 fragment library was docked against the open cavity using two models of ligand solvation. Using an older solvation model that prioritized many neutral molecules, three such uncharged docking hits were tested, none of which was observed to bind; these molecules were not highly ranked by the new, context-dependent solvation score. Using this new method, another 15 highly-ranked molecules were tested for binding. In contrast to the previous result, 14 of these bound detectably, with affinities ranging from 8 µM to 2 mM. In crystal structures, four of these new ligands superposed well with the docking predictions but two did not, reflecting unanticipated interactions with newly ordered waters molecules. Comparing recognition between this open cavity and its buried analog begins to isolate the roles of ordered solvent in a system that lends itself readily to prospective testing and that may be broadly useful to the community.


Immune-related ocular toxicities in solid tumor patients treated with immune checkpoint inhibitors: a systematic review.
Immune-related ocular toxicities are uncommon but serious adverse events that may be associated with the use of immune checkpoint inhibitors. The objective of this review is to assess the incidence and risk of ocular toxicities which are potentially immune-related and occur with immune checkpoint treatment of solid tumors. Areas covered: PubMed database has been searched till June 2016. Prospective clinical trials reporting the occurrence of immune-related ocular toxicities in solid tumor patients treated with immune checkpoint inhibitors were included. Eleven trials with 4965 participants were included. These studies included one study for ipilimumab and tremelimumab, three studies for nivolumab, five studies for pembrolizumab and one study comparing pembrolizumab to ipilimumab. No atezolizumab studies were included. The most common ocular toxicities reported with these agents included uveitis and dry eyes. Pooled analysis for odds ratio of all-grade immune-related ocular toxicities is 3.40 [95% CI: 1.32-8.71; P = 0.01]. Expert commentary: Despite being uncommon, immune-related ocular toxicities (particularly uveitis and dry eyes) occur with a higher frequency in cancer patients treated immune checkpoint inhibitors compared to those treated with control regimens.


Metabolic effects and fate of succinic acid methyl esters in rat hepatocytes.
The metabolic fate and metabolic effects of succinic acid methyl esters were examined in rat isolated hepatocytes. Both the monomethyl ester (SAM) and dimethyl ester (SAD) of succinic acid inhibited D-glucose metabolism. Such an inhibition affected, in order of increasing severity, the direct incorporation of D-glucose into glycogen and futile cycling between the hexose and its 6-phosphate ester, the phosphorylation of D-glucose, the generation of triose phosphates from the hexose, and the production of 14C-labeled lactate, pyruvate, and amino acids from D-[U-14C]glucose and its oxidation. The dimethyl ester of [1,4-14C]succinic acid ([1,4-14C]SAD) or [2,3-14C]-succinic acid ([2,3-14C]SAD) was efficiently converted to acidic metabolites. The oxidation of [1,4-14C]SAD largely exceeded that of [2,3-14C]SAD. Inversely the generation of newly formed radioactive D-glucose and glycogen appeared higher in cells exposed to [2,3-14C]SAD, rather than [1,4-14C]SAD. It is proposed that SAM and SAD are suitable nutrients both to cover the energy need of hepatocytes and to act as gluconeogenic precursors.


Cerebellar metastases: diagnostic and management considerations.
Prompted by several unsatisfactory outcomes, we reviewed the records of 59 patients with cerebellar metastases (26 solitary) with respect to clinical presentation, diagnosis, and natural history. Eighty-seven percent of patients initially complained of headache, gait disturbance, and/or dizziness. At time of diagnosis, 92% of patients with solitary cerebellar metastases and 74% of the overall series complained of headache and/or difficulty walking. In three of four cases, magnetic resonance imaging (MRI) was superior to x-ray computed tomography (CT) in detecting the cerebellar lesions. Several patients acutely deteriorated during evaluation or at the initiation of radiation therapy. We conclude that a cancer patient presenting with headache and gait difficulty with or without nausea/vomiting and dizziness should promptly undergo head CT scanning, and that MRI is useful even if CT is negative. In addition, we recommend that patients with documented cerebellar metastases receive high-dose glucocorticoid therapy for 48 to 72 hours before beginning radiation therapy. The presence of symptomatic hydrocephalus or failure to respond to glucocorticoids initially are particularly ominous features that may be best managed by early neurosurgical consultation before beginning radiation therapy.


What is the economic case for treating obesity?
From both societal and payer perspectives, the economic effect of obesity in the United States is substantial, estimated at approximately 6% of our national health expenditure and cost of care in a major health maintenance organization. The number of physician visits related to obesity has increased 88% in a 6-year period. The morbidity cost (lost productivity) and functional capability of the patient with obesity is increasing rapidly (50% increase in lost productivity, 36% increase in restricted activity, and 28% increase in number of bed-days). Cost savings of treating obesity are comparable to those of treating other chronic diseases such as coronary heart disease and diabetes. Most studies indicate that most of the direct health care costs of obesity are from type 2 diabetes, coronary heart disease and hypertension. To date, however, there have been no published reports of the cost effectiveness of the medical management of obesity treatment. In conclusion, the cost of obesity is comparable to that of other chronic diseases, yet it receives disproportionately less attention. Cost effectiveness studies need to be initiated promptly.


Quantitative Proteomic Analysis of Differentially Expressed Proteins and Downstream Signaling Pathways in Chronic Bladder Ischemia.
Growing evidence suggests that ischemia may contribute to aging associated bladder dysfunction and lower urinary tract symptoms. Our goal was to determine the effects of chronic ischemia on bladder proteomic profiles and characterize downstream signaling pathways. Bilateral iliac artery atherosclerosis and chronic bladder ischemia were created in male Sprague Dawley® rats. At 8 weeks cystometrograms were obtained. Ischemic and control bladder tissues were then processed for label-free quantitative proteomic analysis. GO (Gene Ontology) and IPA (Ingenuity® Pathway Analysis) software were used to classify altered proteins in bladder ischemia. Western blot was done to confirm differentially expressed proteins. Tissue structure was examined by transmission electron microscopy. Chronic ischemia resulted in detrusor instability and noncompliance. Proteomic analysis revealed a total of 4,277 proteins in ischemic and 4,602 in control bladder tissues. In ischemic bladders 359 and 66 proteins were differentially expressed with a greater than twofold and fivefold change, respectively. On GO analysis differentially expressed proteins were associated with molecular signaling mechanisms underlying proteolysis and degenerative processes. Pathway and network analysis of ischemic tissues suggested that altered proteins are involved in ubiquitination, Nrf2 mediated oxidative stress response, cell death, glucose metabolism and cytoskeleton remodeling. Western blot verified changes in 4 representative proteins, including Nedd4l, Mpo, Ca3 and Fkbp5. Altered proteomic profile of the bladder was associated with widespread ultrastructural damage. Alterations of bladder proteomic profiles in ischemia may provide new insight into molecular pathways underlying bladder dysfunction and lower urinary tract symptoms in pelvic atherosclerosis.


Cervical spinal cord injury and the need for cardiovascular intervention.
The level of cervical spinal cord injury (CSCI) can be used to predict the need for a cardiovascular intervention. Retrospective review. Data included level of spinal cord injury, Injury Severity Score, lowest heart rate, and systolic blood pressure in the first 24 hours and intensive care unit course. The level of CSCI was divided into high (cord level C1-C5) or low (cord level C6-C7). Neurogenic shock was defined as bradycardia with hypotension. Statistical analysis was performed with the t test and the chi2 test. Level I trauma center. The patients studied were those with quadriplegia who experienced a CSCI and were admitted to the hospital between December 1, 1993, and October 31, 2001. Pressors, chronotropic agents, and pacemakers.Main Outcome Measure Use of a cardiovascular intervention in the presence of neurogenic shock. Eighty-three patients met the criteria for CSCI and quadriplegia, 62 in the high (C1-C5) and 21 in the low (C6-C7) level. There was no significant difference between the 2 groups in mean +/- SD age (38.2+/-17.8 vs 34.7+/-15.6 years; P=.43), mean +/- SD Injury Severity Score (35.7+/-17.5 vs 32.5+/-11.2; P=.44), mean +/- SD admission base deficit (-0.7+/-3.6 vs 0.7+/-2.7; P=.06), or mortality (12 [19%] of 62 patients vs 2 [10%] of 21 patients; P=.29). Neurogenic shock was present in 19 (31%) of the 62 patients with high CSCI and in 5 (24%) of the 21 patients with low CSCI (P=.56). There was a marked difference in the use of a cardiovascular intervention between those with a high and those with a low CSCI: 15 (24%) of 62 patients vs 1 (5%) of 21 patients (P=.02). Two patients with C1 through C5 spinal cord injuries required cardiac pacemakers. There was no significant difference in the frequency of neurogenic shock by injury level. Patients with a high CSCI (C1-C5) had a significantly greater requirement for a cardiovascular intervention compared with patients with lower injuries (C6-C7).


Behavior of amphotericin B lipid complex in plasma in vitro and in the circulation of rats.
Amphotericin B lipid complex (ABLC) shows reduced toxicity relative to that of amphotericin B deoxycholate (AmB-d) while maintaining antifungal activity. Rat blood or plasma was spiked with ABLC in vitro. Released amphotericin B was separated from the parent material by centrifugation. At early times (0 to 15 min) most (approximately 90%) of the amphotericin B was complexed. The amount of released amphotericin B increased gradually in a time- and temperature-dependent fashion. The released amphotericin B was associated with plasma lipoprotein and nonlipoprotein proteins. The area under the concentration-time curve from 0 to 24 h for total amphotericin B in whole blood of rats given a single intravenous bolus dose of 1 mg of ABLC per kg of body weight was fourfold lower than that in rats given 1 mg of AmB-d per kg. The complexed amphotericin B was rapidly removed from the circulation and was distributed to the tissues in these rats. Other rats were treated intravenously with ABLC (10 mg/kg/day) or AmB-d (0.5 mg/kg/day) daily for 15 days. Blood was collected at 15 and 180 min after administration of the last dose. The total levels of amphotericin B in the blood of the group given ABLC were about three to five times those in the group given AmB-d, and the concentration of released, protein-bound amphotericin B in the plasma of the group given ABLC was about one to two times that observed for the group given AmB-d, despite the 20-fold difference in dose. The relative protein distribution of amphotericin B in plasma was similar after ABLC or AmB-d administration under these steady-state conditions in vivo. The rapid uptake of complexed amphotericin B by tissues and the very low levels of circulating protein-bound amphotericin B in plasma after the administration of ABLC may explain, in part, the reduced toxicity and enhanced therapeutic index of this preparation.


Isolated plantar fracture-dislocation of the middle cuneiform.
A previously unreported case of plantar dislocation of the medial cuneiform is described. The significance of this injury does not lie in its rarity, but in the amount of force required to cause such an injury. This large force may cause bony disruption, along with significant soft-tissue injury, and even compartment syndrome. Analysis of the preoperative evaluation, including the importance of a computed axial tomographicscan, operative intervention, and postoperative care are discussed.


Congenital heart disease; comments regarding incidence and natural history.
The incidence of congenital heart disease is approximately 1 per cent of all live births. Approximately 60 per cent of patients who die of congenital heart disease do so at less than two years of age. Very few patients with such lesions live beyond 45 years at the very most. In about 70 per cent of patients who are born with cardiac anomalies, the lesions are either of kinds that are already being operated upon successfully or for which operations are now being attempted and often are helpful.


Parabolic Viscosity Behavior of NaCl-Thickened Surfactant Systems upon Temperature Change.
The viscosity of household care products plays an important role in pleasant delivery using consumer experience at home. A novel solution to mitigate the sharp rising of viscosities at low temperatures of detergents was proposed. By designing the formulation of the surfactant blend, formulators can achieve acceptable viscosity profiles in the temperature range encountered in daily life. The verification and modulation of formulas bearing parabolic viscosity-temperature behavior were systematically studied, including in single, binary, and ternary systems, based on the modulation of sodium ethoxylated alkyl sulfate (AES) by other anions, zwitterions, and nonions. The R ratio theory was used to have a better understanding of the molecular assembly of surfactants behind the parabolic behavior exhibited in rheology analyses. One of the key findings is that the parabolic viscosity-temperature phenomenon could be easily observed in the highly hydrated ethoxylated anionic systems like AES-based systems. For those anions lacking ethoxylation, especially sodium linear alkylbenzene sulfonate (LAS), the monotonic variation of hydration affinity with temperature led to the disappearance of parabola in the observed temperature window (>0 °C). Moreover, salinity played an important role in the hydration affinity of the polar group and the interaction between the hydrophilic headgroups. A balanced salinity should be optimized to modulate the hydration affinity in a desired range so that the parabola could be easily tuned within the target temperature region. These findings provide opportunities for the formulators in the household care industry to design products with better pourability through carefully selecting a combination of surfactants and fine-tuning their ratios to improve consumer use experience, especially in winter.


The effect of low ionic strength extracellular solutions on the resting potential in skeletal muscle fibers.
Intracellular measurements of the resting potential were made in fibers of the frog sartorius muscle in solutions of varying salt composition and concentration to determine the effects of low ionic strength extracellular solutions on the resting potential. Changes in the glass microelectrode tip potential in low ionic strength solutions were minimized by adding ThCl(4) to the extracellular solution. These experimental conditions allowed measurement of the relationship of the resting potential to the concentration of the salt in the extracellular solution by replacing it with the nonionic substance, sucrose. Substitution of sucrose for the extracellular NaCl produced a stable depolarization which was logarithmically related to the NaCl concentration. Substitution of sucrose for choline Cl, instead of NaCl, produced the same degree of depolarization. When Na salts of anions less permeable than chloride (Br, I, NO(3)) were used, the resting potentials in 116 mM solutions were close to those with chloride (+/-3mv). The depolarizations produced in low ionic strength solutions of these salts were significantly less than those with chloride.


Interhemispheric lipoma associated with subcutaneous lipoma.
We report an extremely rare case of intracranial lipoma that was associated with subcutaneous lipoma situated on the anterior fontanelle. During ultrasonographic examination of the subcutaneous lesion, intracranial lipoma was incidentally diagnosed. Computed tomography revealed corpus callosum agenesis, interhemispheric lipoma extending into the choroid plexus. Magnetic resonance imaging demonstrated the subcutaneous lipoma and also the exact extent of the lesion. The pathogenesis of lipomas is discussed and the literature is reviewed.


[Safety and efficacy of rivaroxaban for prevention of deep vein thrombosis in patients with preoperative abnormal D-dimer after total knee arthroplasty].
To evaluate the safety and efficacy of rivaroxaban for prevention of deep vein thrombosis (DVT) in patients with preoperative abnormal D-dimer after total knee arthroplasty (TKA). Between August and September 2013, 60 consecutive patients with varus knee osteoarthritis undergoing unilateral TKA were enrolled in the study. According to the preoperative D-dimer level, the patients were divided into 2 groups: D-dimer normal group (control group, n = 41) and D-dimer abnormal group (test group, n = 19). No significant difference was found in gender, age, body mass index, and preoperative knee range of motion between 2 groups (P > 0.05). All patients underwent conventional primary TKA and anticoagulation therapy with rivaroxaban to prevent DVT. The tourniquet use time, postoperative hospitalization time, and total hospitalization time were compared between 2 groups. At 1, 3, and 5 days after operation, prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (FIB), and D-dimer were measured. Wound complications and DVT were observed. The postoperative hospitalization time of the test group was significantly longer than that of the control group (t = 2.327, P = 0.031), while the tourniquet use time and total hospitalization time showed no significant difference between 2 groups (P > 0.05). All the patients were followed up 6-8 months (mean, 7.2 months). Wound complications occurred in 3 cases (7.3%) of the control group and in 2 cases (10.5%) of the test group, showing no significant difference (χ2 = 0.175, P = 0.676). Color ultrasonography showed no pulmonary embolism and DVT at 6 weeks after TKA. There were significant differences in PT, TT, and FIB between at pre- and post-TKA in the same group, but no significant difference was found between 2 groups. The APTT and D-dimer had significant differences between at pre- and post-TKA in the same group, and between groups. There was no significant interaction effect between time and group for each index. Preoperative abnormal D-dimer level should not be regarded as a contraindication for TKA. The risks of DVT and wound complications in patients with abnormal D-dimer level are similar to patients with normal D-dimer level using rivaroxaban administration after TKA. It is unnecessary to conventional monitor D-dimer and other coagulation and hemorrhage laboratory tests in the patients after TKA.


[Interest of the cervical gland dissection after radiotherapy with or without chemotherapy].
The aim of this study was to evaluate the necessity and morbidity of neck dissection after radiation therapy within organ preservation treatment. We present a retrospective study of 64 patients, treated initially by radiotherapy with or without chemotherapy for squamous cell carcinoma of head and neck with cervical metastases (> 2 cm), who underwent post-radiation neck dissection between January 1992 and August 2000. Eight (13%) patients were classified T1, nineteen (30%) T2, twenty (31%) T3, eleven (17%) T4 and six (9%) Tx. Eleven patients had N1 neck disease (17%), fifteen patients N2a (24%), eleven patients N2b (17%) and twenty-seven patients N3 (42%). Follow-up ranged from 3 to 86 months with a mean of 39 months. The average length of time between neck dissection and the end of treatment was 60 days. Complications were recorded in 21 patients (33%). Forty-four (68%) of 64 patients had microscopic residual disease. Eight (72%) of 11 patients with N1 neck disease and 17 (63%) of 27 patients with N3 neck disease had pathology. Initial N status was not a predictive factor of microscopic residual disease (p = 0.51). There was no significant relationship between clinical residual adenopathy and microscopic residual disease (p = 0.53). Fourteen patients are still alive without recurrent disease. Eight (57%) of these 14 patients had a positive pathology at the time of neck dissection. The mean follow-up time of these patients is 32.6 months, with a follow up longer than 2 years for half of them (n = 7). Neck dissection after radiation was planned for all patients with an initial node > 2 cm in diameter regardless of clinical response in the neck. We confirm that neck dissection appears to be safe after radiotherapy and is necessary because it improves quality of life and prevents fatal evolution with uncontrollable neck disease.


The potential impacts of circadian rhythm disturbances on male fertility.
A circadian rhythm is an internalized timing system that synchronizes the cellular, behavioral, and physiological processes of organisms to the Earth's rotation. Because all physiological activities occur at a specific time, circadian rhythm disturbances can lead to various pathological disorders and diseases. Growing evidence has shown that the circadian clock is tightly connected to male fertility, and circadian perturbations contribute to infertility. The night shiftwork, insufficient sleep, and poor sleep quality are common causes of circadian disturbances, and many studies have reported that they impair sperm quality and increase the risk of male infertility. However, research on the impacts of light, body temperature, and circadian/circannual rhythms is relatively lacking, although some correlations have been demonstrated. Moreover, as the index of sperm quality was diverse and study designs were non-uniform, the conclusions were temporarily inconsistent and underlying mechanisms remain unclear. A better understanding of whether and how circadian disturbances regulate male fertility will be meaningful, as more scientific work schedules and rational lifestyles might help improve infertility.


INBREEDING AND VARIANCE EFFECTIVE SIZES FOR NONRANDOM MATING POPULATIONS.
Following an inbreeding approach and assuming discrete generations and autosomal inheritance involving genes that do not affect viability or reproductive ability, I have derived expressions for the inbreeding effective size, NeI , for a finite diploid population with variable census sizes for three cases: monoecious populations with partial selfing; dioecious populations of equal numbers of males and females with partial sib mating; and unequal numbers of males and females with random mating. For the first two cases, recurrence equations for the inbreeding coefficient are also obtained, which allow inbreeding coefficients to be predicted exactly in both early and late generations. Following the variance of change in gene frequency approach, a general expression for variance effective size, NeV , is obtained for a population with unequal numbers of male and female individuals, arbitrary family size distribution, and nonrandom mating. All the parameters involved are allowed to change over generations. For some special cases, the equation reduces to the simple expressions approximately as derived by previous authors. Comparisons are made between equations derived by the present study and those obtained by previous authors. Some of the published equations for NeI and NeV are shown to be incomplete or incorrect. Stochastic simulations are run to check the results where disagreements with others are involved.


Multiple mechanisms for stochastic resonance are inherent to sinusoidally driven noisy Hopf oscillators.
To ensure their sensitivity to weak periodic signals, some physical systems likely operate near a Hopf bifurcation. Many systems operating near such a bifurcation exhibit stochastic resonance, but it is unclear which mechanisms for resonance are inherent to the bifurcation. To address this question, we study the sinusoidally forced dynamics of noisy supercritical and subcritical Hopf oscillators. We find four qualitatively different mechanisms for stochastic resonance and determine the conditions for each type of resonance.


Reply letter to the editor concerning the article 'Safety of Sars-Cov-2 vaccines administration for adult patients with hereditary fructose intolerance'.
According to the current European medicines legislation, on the labeling is mandatory a warning contraindicating for hereditary fructose intolerance (HFI) patients medicines with oral or parenteral fructose and sorbitol, and oral sucrose, invert sugar, isomaltitol, lactitol and maltitol, but parenteral sucrose is not mentioned. Intravenous administration of sucrose does not increase blood glucose concentrations, because sucrose is poorly oxidized to CO2 and mainly excreted in the urine as a disaccharide; absence of enzimatic activity outside the gut explains why there is not a warning for parenteral sucrose presentations. For this reason, parenteral drugs with sucrose are allowed in HFI patients. Nevertheless, due to interindividual variability and the fact that not all parenterally administered sucrose is recovered in urine, HFI patients need to be closely monitored after parenteral administration of sucrose-containing drugs, especially when the amount exceeds the maximum permissible thresholds.


Postmenopausal Bleeding among Rural Women in Tamil Nadu, India: Mixed Methods Study.
Postmenopausal bleeding (PMB) is a common and early symptom of cervical and endometrial cancer. Its early detection can improve the cure rate and reduces mortality. The objective of the study is to find out the prevalence and determinants of PMB in a rural community setting and the reasons for not undergoing cervical cancer screening among postmenopausal women. A sequential exploratory mixed methods study where qualitative (group interviews) phase followed quantitative (survey) phase in the community. The survey was undertaken among the representative sample of 1,530 postmenopausal women in 34 villages of Villupuram district, Tamil Nadu. Data were collected by house-to-house survey. Bivariate and multivariate analysis was done using SPSS 24 software package. The prevalence of PMB was found to be 1.8%. Only 5.6% women had undergone screening. The majority did not go for screening due to lack of awareness, or they did not have any symptoms or feared about negative results. Occupation (daily wage laborers), use of oral contraceptive pills at least for 1 year, recurrent abortions (> three abortions), reproductive tract infection (more than 10 episodes in lifetime), abdominal obesity (increased waist-hip ratio), and underweight were identified as significant risk factors for PMB. Nearly 2% of women have PMB, and most of the factors identified as determinants are preventable. Cervical cancer screening rate was poor among the respondents and lack of awareness was stated as the major reason for it. Hence, the promotion of healthy lifestyles and contraceptives in early reproductive life and awareness for the need of early screening is recommended.


Viral infection transiently reverses activation receptor-mediated NK cell hyporesponsiveness in an MHC class I-independent mechanism.
Continuous engagement of the Ly49H activating receptor with its ligand (m157) in a transgenic mouse expressing m157 (m157-Tg) results in hyporesponsiveness of Ly49H(+) NK cells. The same interaction, during murine cytomegalovirus (MCMV) infection, leads to activation of Ly49H(+) NK cells. MCMV infection results in decreased MHC class I (MHC-I) expression on the infected cell as well as inflammatory responses, both of which do not take place in the uninfected m157-Tg mouse, potentially allowing for activation of NK cells in the context of MCMV infection. In this study, we demonstrated that viral infection transiently reverses activation receptor-mediated NK cell hyporesponsiveness in an MHC-I-independent mechanism. Furthermore, Ly49H(+) NK cells in an MHC-I-deficient environment remained hyporesponsive in the context of m157 expression, even when mature WT splenocytes were transferred into m157-Tg mice in an MHC-I-deficient environment. However, the administration of cytokines TNF-α, IL-12, and IFN-β resulted in a partial recovery from activation receptor-induced hyporesponsiveness. Thus, the release of the aforementioned cytokines during MCMV infection and not the downregulation of MHC-I expression appears to be responsible for partial resolution of Ly49H receptor-induced NK cell hyporesponsiveness.


An ultrahigh affinity d-peptide antagonist Of MDM2.
The oncoprotein MDM2 negatively regulates the activity and stability of the p53 tumor suppressor and is an important molecular target for anticancer therapy. Aided by mirror image phage display and native chemical ligation, we have previously discovered several proteolysis-resistant duodecimal d-peptide antagonists of MDM2, termed (D)PMI-α, β, γ. The prototypic d-peptide inhibitor (D)PMI-α binds ((25-109))MDM2 at an affinity of 220 nM and kills tumor cells in vitro and inhibits tumor growth in vivo by reactivating the p53 pathway. Herein, we report the design of a superactive d-peptide antagonist of MDM2, termed (D)PMI-δ, of which the binding affinity for ((25-109))MDM2 has been improved over (D)PMI-α by 3 orders of magnitude (K(d) = 220 pM). X-ray crystallographic studies validate (D)PMI-δ as an exceedingly potent inhibitor of the p53-MDM2 interaction, promising to be a highly attractive lead drug candidate for anticancer therapeutic development.


A high-temperature tolerant species in clade 9 of the genus Phytophthora: P. hydrogena sp. nov.
A previously unknown Phytophthora species was isolated from irrigation water in Virginia, USA. This novel species produces abundant noncaducous and nonpapillate sporangia in soil water extract solution. It sometimes produces chlamydospores and hyphal swellings in aged cultures and in Petri's solution. This species has optimum vegetative growth at 30 C and grows well at 35 C. The lowest and highest temperatures for growth are 5 and 40 C. All isolates examined in this study are compatibility type A1 and produce mostly plerotic oospores when paired with an A2 mating-type tester of P. cinnamomi. Sequence analyses of the rDNA internal transcribed spacer (ITS) regions and the mitochondrially encoded cytochrome c oxidase 1 (cox 1) gene placed this species in clade 9 of the genus Phytophthora. These characteristics support the description of this taxon as a new species for which we propose the name P. hydrogena sp. nov. Further phylogenetic and physiological investigations of clade 9 species revealed a high-temperature tolerant cluster including P. hydrogena, P. aquimorbida, P. hydropathica, P. irrigata, P. chrysanthemi, P. insolita, P. polonica and P. parsiana. These species all grow well at 35 C. The monophyly of the species in this heat-tolerant cluster except P. insolita and P. polonica is highly supported by the maximum-likelihood analyses of the ITS and cox 1 sequences.


Biomarker discovery in glomerular diseases using urinary proteomics.
Renal biopsy remains the gold standard test for definitive diagnosis of glomerular diseases. This invasive procedure; however, has a potential risk for serious complications and is contraindicated in some patients. It is therefore essential to search for noninvasive biomarkers for the diagnosis and prognosis of glomerular diseases. The urine is the most appropriate sample for biomarker discovery in glomerular diseases. Urinary proteomics has thus gained a wide acceptance and has been extensively applied to this area. This review focuses mainly on applications of proteomic technologies to urinary proteome profiling for biomarker discovery in various glomerular diseases, including diabetic nephropathy, IgA nephropathy, membranous nephropathy, focal segmental glomerulosclerosis, primary membranoproliferative glomerulonephritis, lupus nephritis, antiglomerular basement membrane disease, minimal change disease, and pediatric nephrotic syndrome. Recent findings from these studies are summarized and discussed. These data clearly underline the great promise of urinary proteomics in biomarker discovery for glomerular diseases.


Use of course-embedded projects for program assessment.
There is increasing demand on science faculty to develop authentic assessment measures for both individual courses and undergraduate programs. We report here on a quarter-long group project used in a neurophysiology course that can be used for either purpose. Small groups of four to five students critically analyze at least 10 articles from the primary scientific literature. The end result of this process is the equivalent of a scientific review article that is presented in two formats, a 10-min oral presentation and a scientific poster presentation. Students perform better on application tasks than on analysis, synthesis, or evaluation tasks associated with the project (P < 0.025) and generally respond positively to process questions (59-82%) but less positively to task questions (36-76%) about group dynamics. The cognitive skills and basic content knowledge required to complete this project are developed throughout the undergraduate program. Thus the project is a type of culminating program experience. However, the project also assesses basic course proficiency, because students cannot analyze primary neuroscience research without an understanding of neurophysiological principles.


[Photocoagulation in retinal branch vein occlusion (RBVO) (author's transl)].
54 cases of retinal branch vein occlusion, 19 of which received photocoagulation treatment, were reviewed to assess the value of photocoagulation in this disease. Our results suggest that the effect of photocoagulation in the treatment of macular edema is not convincing. This finding is in contrast to the main stream in literature. On the other hand the treatment's beneficial effect in destroying or preventing neovascularisations in the course of RBVO seems established and may even be enhanced with the technique described. On the basis of our results and theoretical considerations, some guidelines for the care and treatment of RBVO patients are suggested.


[ELEMENTS OF A SYSTEMATIC APPROACH TO HYGIENIC REGULATION OF XENOBIOTICS].
Hygienic standardization (HS) of chemicals remains to be the one of the effective ways to ensure chemical safety of the population. At that hygienic standards (such as maximum allowable concentrations--MACs) are interrelated and aggregated into the coherent systems. Therefore, the task of the study was in establishment of the logic of inter- standard relations between the existing standards and actualization of legitimate relations of the interrelations such as MACwz/MACatm, (i.e., to systematize standards) and so as CL₅₀/MACwz (reflecting the ratio of reliability). In the suggested systemic approach the benchmark indices of the proposed HS system are the values of the MACwz. Standards for other media, including atmosphere air may be only some compartments of MACwz. The performed studies and calculations allowed to justify and implement the system approach into the practice of HS in Ukraine. There is need for further search for additional solutions in nonreachability of LC₅₀ in the experiment, justification of standards for the population in the absence of MACwz, comparison with the data of normative databases of other countries. It is necessary to introduce the value of permissible deviation from the requirements of the systemness, to embody conditions (1)-(7) into the general principle of the prohibition of greater deviation and to harmonize acting and newly introduced standards within frameworks of modern ideology and methods of HS of harmful substances. This opens up broad prospects for the new phase of HS and a significant increase in the reliability of results obtained by the various methods and in different laboratories.