Anti-Tumor Role of CAMK2B in Remodeling the Stromal Microenvironment and Inhibiting Proliferation in Papillary Renal Cell Carcinoma.
The tumor microenvironment (TME) is variable across tumor types and has diverse effects on malignant progression, based on the type and number of infiltrating stromal cells. In particular, TME effector genes and their competitive endogenous RNA (ceRNA) networks play a critical role in regulating malignant tumor progression. However, the core effector molecules involved in TME modulation of kidney renal papillary cell carcinoma (KIRP) are poorly understood. To address this question, a cohort containing 233 KIRP patients was derived from The Cancer Genome Atlas (TCGA) database, and the data were processed using the ESTIMATE algorithm. We further evaluated the relationship between immune scores (ISs) and stromal scores (SSs) and disease progression and found that high SSs were associated with a poor prognosis in KIRP. Differentially expressed genes (DEGs) were therefore screened based on SS scores, resulting in 2509 DEGs, including 1668 mRNAs, 783 long noncoding (lnc)RNAs, and 58 micro (mi)RNAs. DEGs were then filtered using the random variance and subjected to hierarchical clustering using EPCLUST. Weighted gene co-expression network analysis (WGCNA) was used to assess the prognostic capacity of these DEGs and identify target ceRNA networks, and lncRNA GUSBP11/miR-432-5p/CAMK2B in the turquoise module was selected as a promising ceRNA network. From this analysis CAMK2B was selected as the core gene predicted to be involved in stromal TMA regulation. We therefore explored the expression and function of CAMK2B in vitro and in vivo and provide evidence that this protein promotes stromal TME remodulation and inhibits proliferation in KIRP. Lastly, we show that vascular endothelial growth factor (VEGF), transforming growth factor (TGF)β, and close homolog of L1 (CHL1) act as downstream effectors of CAMK2B in KIRP. Thus, in this study, we show that the TME determines prognosis of KIRP patients via the core effector molecule CAMK2B, which mediates both microenvironmental remodeling and tumor progression. Based on these findings, we propose that remodeling of the stromal microenvironment could represent an improved therapeutic approach relative to immunotherapy for KIRP.


Assessment and response to spiritual pain: part I.
Spiritual pain or suffering is common. Cicely Saunders described persons with "total pain" including the physical, psychological, social, and spiritual dimensions. Yet, a construct for what it is, and how to respond, is not so common. In this paper, I hypothesize that the components of spiritual pain can be summarized in the following manner. Spiritual pain or Suffering = ((Awareness of death + Loss of Relationships + Loss of Purpose + Loss of Control))/(Life affirming and transcending Purpose + Internal Sense of Control). Thus, an assessment of spiritual pain or suffering should examine the degree to which the individual is experiencing each of these components and their relationship to each other. Further, each of these components is dynamic, always in process, both within and between the components. A second paper will examine the sufferer's religious responses and suggested pastoral responses.


Maintenance oral sulfasalazine prolongs remission in ulcerative proctitis and proctosigmoiditis.
We have retrospectively compared the effectiveness of five different regimens for inducing and maintaining clinical remission in 206 patients with idiopathic proctitis (n = 115) and proctosigmoiditis (n = 91). The five therapeutic regimens were: corticosteroid enemas, 5-aminosalicylic acid (5-ASA) enemas, oral 5-ASA (sulfasalazine or mesalamine), corticosteroid enemas plus oral 5-ASA, or 5-ASA enemas plus oral 5-ASA. Clinical remission was achieved within 28 days of therapy in 47%, and eventually in 94% of these patients. No significant differences in efficacy were found among the five regimens. Most patients ultimately experienced a recurrence of symptoms, but the duration of remission was significantly longer with maintenance oral sulfasalazine or mesalamine (17.2 months) than with no therapy (11.8 months), P less than 0.01. We conclude that several regimens are equally effective in inducing remission of proctitis and proctosigmoiditis, although prolonged therapy may be needed to accomplish this goal. Maintenance oral 5-ASA significantly prolongs symptomatic remission in proctitis and proctosigmoiditis.


[The role of the sarcocyst surface apparatus in utilizing the host cell muscle structures].
The participation of the sarcocyst surface apparatus (SSA) of two sarcosporidian species, Sarcocystis muris and S. ovifelis (Coccidia, Sporozoa, Apicomplexa), in degradation of disrupted host cell substances was investigated. After degradation, these substances are transported through the membrane of the SSA to the sarcocyst ground substance (GS), but this process cannot be regarded as endocytosis. At first, the transported substances were found in SSA pits in the form of fibrillar structures. Later on, these were seen as twisted up granules. In some cases, such granules restore their fibrillar shape, penetrate through the SSA membrane and appear in the sarcocyst GS. In other cases, the small granules may be released from SSA pits directly to the sarcocyst GS. Besides, two SSA primembrane layers were seen to disappear during the transportation of host cell substances. In addition, multimembrane structures (membranous whorls) were first demonstrated between the plasmalemma and inner membrane complex of the zoite pellicle. Multimembrane structures were found, in addition, in the zoite cytoplasm in connection with micronemes. These structures resembling chloroplast granae of thylakoids may presumably fill the gap in membrane pool of the SSA contributing to its renewal.


Osmotic regulation of hepatic betaine metabolism.
Betaine critically contributes to the control of hepatocellular hydration and provides protection of the liver from different kinds of stress. To investigate how the hepatocellular hydration state affects gene expression of enzymes involved in the metabolism of betaine and related organic osmolytes, we used quantitative RT-PCR gene expression studies in rat hepatoma cells as well as metabolic and gene expression profiling in primary hepatocytes of both wild-type and 5,10-methylenetetrahydrofolate reductase (MTHFR)-deficient mice. Anisotonic incubation caused coordinated adaptive changes in the expression of various genes involved in betaine metabolism, in particular of betaine homocysteine methyltransferase, dimethylglycine dehydrogenase, and sarcosine dehydrogenase. The expression of betaine-degrading enzymes was downregulated by cell shrinking and strongly induced by an increase in cell volume under hypotonic conditions. Metabolite concentrations in the culture system changed accordingly. Expression changes were mediated through tyrosine kinases, cyclic nucleotide-dependent protein kinases, and JNK-dependent signaling. Assessment of hepatic gene expression using a customized microarray chip showed that hepatic betaine depletion in MTHFR(-/-) mice was associated with alterations that were comparable to those induced by cell swelling in hepatocytes. In conclusion, the adaptation of hepatocytes to changes in cell volume involves the coordinated regulation of betaine synthesis and degradation and concomitant changes in intracellular osmolyte concentrations. The existence of such a well-orchestrated response underlines the importance of cell volume homeostasis for liver function and of methylamine osmolytes such as betaine as hepatic osmolytes.


Assessment of varicella vaccine effectiveness in Germany: a time-series approach.
A multivariate time-series regression model was developed in order to describe the 2005-2008 age-specific time-course of varicella sentinel surveillance data following the introduction of a varicella childhood vaccination programme in Germany. This ecological approach allows the assessment of vaccine effectiveness under field conditions by relating vaccine coverage in cohorts of 24-month-old children to the mean number of cases per reporting unit in the sentinel network. For the 1-2 years age group, which is directly affected by the vaccination programme, a one-dose vaccine effectiveness of 83·2% (95% CI 80·2-85·7) was estimated which corresponds to previous approaches assessing varicella vaccine effectiveness in the field in the USA.


Deliberate self-injury functions and their clinical correlates among adolescent psychiatric inpatients.
The aim of the study was to analyze the relationships between clinical variables (the severity of depression symptoms, feelings towards the body, dissociation, number and type of traumatic events) and deliberate self-injury functions. Moreover, we investigated whether the of group self-mutilating adolescents is internally diverse in terms of how important individual functions of self-mutilation are, and whether the subgroups singled out by these functions differ between each other in terms of clinical variables. The Inventory of Statements about Self-Injury was used. Characterizations of examined individuals and other research tools are included in our previous article (year, issue, pages). Associated with negative feelings towards the body are the functions of self-injuries (anti-dissociation, self-punishment) that can be described as interpersonal. High levels of depression symptoms (self-depreciation included) are mainly associated with the self-injury functions: self-punishment, anti-dissociation, establishing interpersonal boundaries. Affect regulation becomes more important as a function of self-inflicted injuries in cases of biological dysregulation and intense dissociative symptoms. The adolescents psychiatric inpatients are internally diverse in terms of dominant functions of self-injuries, which can be categorized into intra- and interpersonal. Intrapersonal functions dominate when an individual experiences severe depression, dissociative symptoms, and negative feelings towards the body. In cases of moderate intensity of depression, dissociative symptoms and negative feelings towards the body, both intrapersonal and interpersonal functions of self-mutilation are similarly important. Further research is required to explain the lowest severity of depression symptoms, dissociative symptoms and negative feelings towards the body co-occurs with no awareness of self-injuries functions.


Palladium-Promoted DNA-Compatible Heck Reaction.
Optimal conditions for palladium-promoted Heck reaction on DNA were developed with good to excellent conversions. Versatility with either DNA-conjugated styrene/acrylamide or aryl iodide and a broad substrate scope of the corresponding coupling partners were established. Furthermore, robustness of the Heck reaction conditions on single-strand DNA and feasibility for DNA-encoded library production were demonstrated.


A missed opportunity--lessons learnt from a chlamydia testing observation study in general practice.
Chlamydia is the most frequently notified sexually transmissible infection in Australia and occurs most commonly in young people. Up to 80% of chlamydia infections are asymptomatic. The Royal Australian College of General Practitioners recommends annual chlamydia testing for all sexually active people aged less than 25 years. This study explored potential structural or procedural barriers that might inhibit chlamydia testing in young women in general practice. The chlamydia testing pathways of 12 general practices were examined using a comprehensive practice assessment tool. The pathways of these clinics were compared to a best practice testing pathway, and clinics were offered tailored advice to help improve their practice pathway. Clinics were followed up at 2 months. Little change to existing practices had been made. Clinics employing a practice manager were better equipped to enable systems for chlamydia testing to be developed. Results are discussed in light of May's normalisation theory, which states that changing practices requires shared understanding and commitment by all staff. It is unlikely that chlamydia testing rates in general practice will reach the levels required to reduce the burden of chlamydia without a coordinated clinic level approach.


Etiologies and predictors of ST-segment elevation myocardial infarction.
Rapid diagnosis of ST-segment elevation myocardial infarction (STEMI) is essential for the appropriate management of patients. We investigated the prevalence, etiologies and predictors of false-positive diagnosis of STEMI and subsequent inappropriate catheterization laboratory activation in patients with presumptive diagnosis of STEMI. Four hundred fifty-five consecutive patients (62±13 years, 345 males) with presumptive diagnosis of STEMI between August 2008 and November 2010 were included. A false-positive diagnosis of STEMI was made in 34 patients (7.5%) with no indication of coronary artery lesion. Common causes for the false-positive diagnosis were coronary spasm in 10 patients, left ventricular hypertrophy in 5 patients, myocarditis in 4 patients, early repolarization in 3 patients, and previous myocardial infarction and stress-induced cardiomyopathy in 2 patients each. In multivariate logistic regression analysis, symptom-to-door time >12 hours {odds ratio (OR) 4.995, 95% confidence interval (CI) 1.384-18.030, p=0.014}, presenting symptom other than chest pain (OR 7.709, 95% CI 1.255-39.922, p=0.027), absence of Q wave (OR 9.082, CI 2.631-31.351, p<0.001) and absence of reciprocal changes on electrocardiography (ECG) (OR 17.987, CI 5.295-61.106, p<0.001) were independent predictors of false-positive diagnosis of STEMI. In patients whom STEMI was planned for primary coronary intervention, the false-positive diagnosis of STEMI was not rare. Correct interpretation of ECGs and consideration of ST-segment elevation in conditions other than STEMI may reduce inappropriate catheterization laboratory activation.


[Diagnosis and management of von Willebrand disease].
von Willebrand disease (VWD) is an inherited bleeding disorder resulting from either a quantitative or a qualitative deficiency in the plasma glycoprotein von Willebrand factor (VWF). A diagnosis of VWD can be made when a patient presents with appropriate bleeding and VWF <30 IU/dl. However, persons with VWF levels of 30-50 IU/dl cannot be precluded from the diagnosis of VWD. Desmopressin acetate (DDAVP) or VWF-containing factor VIII (pdVWF/FVIII) concentrate is used for treating VWD. The effect of DDAVP varies among individuals; a trial should be performed while in a nonbleeding state. For patients in whom DDAVP is invalid or those that require long-term management of hemostasis, pdVWF/FVIII is administered. The treatment of the hype rmenorrhea is the hope of every pregnant patient with VWD. When a patient with VWD becomes pregnant, VWF and FVIII should be regularly monitored throughout pregnancy. During childbirth, pdVWF/FVIII concentrate should be administered to achieve VWF and FVIII levels of ≥50 IU/dl before delivery.


Evaluation of the Beckman Coulter AcT 5 diff AL hematology analyzer in a hospital setting.
The Coulter AcT 5-part differential (5 diff) autoloader (AL) hematology analyzer from Beckman Coulter (Fullerton, CA, USA) was evaluated at the Florida Medical Center in Fort Lauderdale, Florida, an acute care hospital facility. The AcT 5 diff AL is a new, fully automated bench-top 5-part differential hematology analyzer with automatic loading and sampling. It is designed as a front-line instrument for small- to medium-sized laboratories or as a backup in larger laboratories. We evaluated the performance of the AcT 5 diff AL for complete blood counts (CBCs). The Coulter Onyx AL was used as the reference instrument and the 5-part differential against the reference 400-cell manual differential count (2 operators x 200 cells). A total of 140 patient samples were analyzed in the study, with most of the samples obtained from our own laboratory workload. We supplemented this dataset with pediatric and oncology samples from nearby practices. All samples were analyzed within 4 hours of collection, and the AcT 5 diff AL demonstrated excellent accuracy with correlation values (r) > 0.98 for all directly measured CBC parameters (white blood cell count, red blood cell count, hemoglobin, mean corpuscular volume, and platelets). Reproducibility studies on the AcT 5 diff AL also showed excellent results, with coefficients of variation much lower than the manufacturer's specifications. Initial differential comparisons showed good correlations for neutrophils, lymphocytes, and eosinophils (r = 0.84, 0.96, and 0.88, respectively) with a lower correlation for monocytes (r = 0.43). On subsequent review and data analysis we found differential discrepancies in 39 of the 140 samples, for which all showed multiple morphological flags, R diff flags, or poor scatterplot separations indicating that the AcT 5 diff AL differential was likely to be inaccurate and that a morphological assessment and differential was necessary. Given the acutecare setting that our laboratory serves and the skewing of the dataset of our study because of the addition of abnormal pediatric and oncology cases, these abnormal sample results were not surprising. These 39 samples all had markedly abnormal differentials with either increased numbers of immature and/or abnormal cells due to such conditions as end-stage liver disease, respiratory failure, renal failure, sepsis and pneumonia, high white blood cell leukemias, and a variety of other acute illnesses. Reanalysis of the differential data, excluding these 39 grossly abnormal samples with R flags and multiple flags, showed the AcT 5 diff AL differential gave very good correlations for neutrophils, lymphocytes, monocytes, and eosinophils (r = 0.93, 0.97, 0.66, and 0.85, respectively). Our technologists were also impressed with the reliability of the AcT 5 diff AL, its ease of use and transfer from stand-by to ready mode, the user friendliness of the software, and the clarity of the printed report. We concluded that the AcT 5 diff AL gives accurate and precise CBC and 5-part differential results and is an excellent, easy-to-use instrument ideally suited for small- to moderate-sized hospital laboratories, as a back-up in a large hospital laboratory, or for use in physician office laboratories.


Nephromegaly in infancy and early childhood: a risk factor for Wilms tumor in Beckwith-Wiedemann syndrome.
Beckwith-Wiedemann Syndrome (BWS) is an overgrowth syndrome associated with macrosomia, omphalocele, macroglossia, visceromegaly and Wilms tumor (WT). We conducted a case-control study in children with BWS to examine whether nephromegaly increases the risk of WT. The BWS Registry was used to identify control and case patients. Control patients were defined as children with BWS who were older than 6 years and had no imaging evidence of renal disease or previous WT and for whom complete records were available; 31 patients met these criteria. Case patients were defined as children with BWS who had WT and screening renal imaging before the diagnosis of WT; 12 of these patients had serial screening images before diagnosis of WT and comprised the study population. Only renal images obtained before the diagnosis of WT was made were used to assess renal length. All 12 patients with WT had nephromegaly (> or =95th percentile of age adjusted renal length) on serial screening studies. Only four of 31 control patients (specificity = 86%) had nephromegaly resulting in an odds ratio of 72 (95% confidence interval = 13-391) for the risk of WT with nephromegaly. In patients with BWS, persistent nephromegaly is a strong risk factor for the development of WT. If screening for WT is done in this population, infants with nephromegaly should be considered those at greatest risk for WT, and screening may be best targeted at this group.


Usefulness of multi-detector row computed tomography for accurate preoperative assessment of pancreatic adenocarcinoma: report of a case.
A 74-year-old female underwent surgical treatment for adenocarcinoma of the pancreatic head. Preoperative multi-detector row computed tomography (MD-CT) demonstrated tumor invasion into the accessory right colic vein and the branch of the middle colic artery (MCA), which was not detected by digital subtraction angiography. MD-CT showed anatomical variants in the left hepatic artery arising from the left gastric artery, and the right posterior hepatic artery arising from the superior mesenteric artery. Three-dimensional reconstruction CT generated a clear picture of the anatomy of the region concerned, which is essential for a safe operation. The MD-CT findings were highly consistent with the intraoperative findings. We have demonstrated that MD-CT is an important and highly accurate modality for pancreatic surgery.


Risk factors for early complications following arthroplasty in elderly patients with a femoral neck fracture.
Early complications after arthroplasty for geriatric femoral neck fractures are known to negatively affect postoperative recovery and increase postoperative mortality. Identifying risk factors associated with early complications after arthroplasty may offer an opportunity to address and prevent these complications in many patients. To evaluate preoperative risk factors for early complications after arthroplasty in elderly patients with a femoral neck fracture. 119 elderly patients with femoral neck fractures who had been treated with arthroplasty (hemiarthroplasty or total hip arthroplasty) between December 2015 and December 2018 were retrospectively analysed. Early complications were defined as any complications that did not exist preoperatively, and occurred during hospital stay after arthroplasty Preoperative clinical, epidemiological and laboratory data were collected. Binary univariable and multivariable logistic regression analysis were applied to identify predictors of early complications after arthroplasty for geriatric femoral neck fractures. Median age of all patients was 80.0 (IQR 74.0-84.0) years. We identified 28 (23.5%) early complications after arthroplasty. Univariable logistic regression analysis found that preoperative body mass index (BMI p= 0.031), C-reactive protein (CRP p= 0.017) and serum Albumin (p= 0.006) were potential risk factors for early complications. Then preoperative BMI, CRP and serum Albumin were stratified and used for multivariable logistic regression analysis The multivariate logistic regression analysis showed that preoperative higher BMI (⩾ 28 kg/m2; OR 10.440; 95% CI 2.674-41.170; p= 0.001) and lower serum Albumin (⩽ 35 g/L; OR 3.933; 95% CI 1.509-10.800; p= 0.006) were independent risk factors for early complications after arthroplasty in geriatric femoral neck fractures. However, preoperative higher CRP levels (> 10 mg/L; OR 1.139; 95% CI 1034-1428; p= 0.833) was found to be not an independent risk factor for early complications. Our results demonstrate that obesity and hypoalbuminemia are independent predictors for early complications during hospital stay after arthroplasty, which should be meticulously noted to minimize these risk factors in geriatric femoral neck fractures.


Terminological collocations in medical latin and english: a comparative study.
The present paper examines the linguistic status of terminological collocations in medical Latin and English, discusses the most productive term-formation models and ways of Latin-English translation. The authors aim to provide the comparative analysis of Latin and English terminological collocations and suggest their classification in terms of the idiomaticity level and semantic valency. The research is based on the corpus of terminological collocations in Latin and English medical discourse using structural, etymological, typological, comparative methods, as well as the method of semantic analysis and conceptual metaphor theory. The research has resulted in the delineation of the following groups of terminological collocations in medical Latin and English: (1) terminological collocations with lower degree of idiomaticity - analytical units whose semantics correlates with the amount of free meanings of the components; (2) terminological collocations with semantic cohesion of the components due to metaphorical nature of the terminological element with active / passive valency; (3) clinical idioms - terminological collocations with higher degree of idiomaticity. Within the latter group, we suggest to discern eponymic, toponymic, zoomorphic, botanic and mythonimic subtypes of terminological collocations. A promising area of future research is the development of bilingual explanatory dictionaries with Latin and English equivalents of terminological collocations, as well as the information about the semantics of their components.


Enhanced expression of neutral endopeptidase (NEP) in airway epithelium in biopsies from steroid- versus nonsteroid-treated patients with atopic asthma.
The expression of the endogenous neuropeptide-degrading enzyme, neutral endopeptidase (NEP; CALLA, CD10, E.C.22.214.171.124) on cultured human airway epithelial cells can be upregulated by corticosteroids. We examined whether NEP expression in the airway epithelium or lamina propria in bronchial biopsies is enhanced in atopic asthmatics on regular inhaled steroids as compared with those without steroid treatment. Forty nonsmoking adults (age 19 to 48 yr) with mild to moderate asthma (forced expiratory volume in 1 s > or = 50% pred., histamine PC20 range 0.02 to 7.6 mg/ml) with (n = 23) or without (n = 17) regular inhaled steroids treatment entered the study. Biopsies were taken at (sub)segmental level from the right lower lobe, the middle lobe, and the main carina. Immunohistochemical staining was performed on cryostat sections using the VIL-A1 monoclonal antibody against CD10 (NEP). Intra- and inter-observer repeatability of a semiquantitative scoring method was good as assessed by weighted kappa (kappa(w) ranging from 0.66 to 0.81). In the airway epithelium, NEP-positive sites were within the basal layer and, in contrast with studies applying other antibodies, also at apical sites and within the lamina propria. In both the epithelium and lamina propria, NEP expression was not significantly different between the three biopsy sites (Friedman's nonparametric two-way analysis of variance; P > 0.68), nor was expression in the lamina propria associated with inhaled steroid usage (Mann-Whitney U test; P = 0.98). However, NEP expression was significantly enhanced in the airway epithelium in patients using inhaled steroids as compared with nonsteroid users (mean rank: 23.4 and 15.5, respectively; P = 0.02). Among nonsteroid-using subjects, NEP expression was related to symptoms and the methacholine PC20 (Rs: -0.69 and 0.49, respectively; P < or = 0.04). We conclude that the expression of NEP is enhanced in airway epithelium in bronchial biopsy specimens from patients with atopic asthma who are regularly using inhaled steroids as compared with patients who do not. This fits the hypothesis that the anti-inflammatory effect of corticosteroids within the airways is partially mediated by the upregulation of the endogenous neuropeptide-degrading enzyme NEP.


Perinatal and maternal morbidity and mortality among term singletons following midcavity operative vaginal delivery versus caesarean delivery.
To quantify severe perinatal and maternal morbidity/mortality associated with midcavity operative vaginal delivery compared with caesarean delivery. Population-based, retrospective cohort study. British Columbia, Canada. Term, singleton deliveries (2004-2014) by attempted midcavity operative vaginal delivery or caesarean delivery in the second stage of labour, stratified by indication for operative delivery (n = 10 901 deliveries; 5057 indicated for dystocia, 5844 for fetal distress). Multinomial propensity scores and mulitvariable log-binomial regression models were used to estimate adjusted rate ratios (ARR) and 95% confidence intervals (95% CI). Composite severe perinatal morbidity/mortality (e.g. convulsions, severe birth trauma and perinatal death) and severe maternal morbidity (e.g. severe postpartum haemorrhage, shock, sepsis and cardiac complications). Among deliveries with dystocia, attempted midcavity operative vaginal delivery was associated with higher rates of severe perinatal morbidity/mortality compared with caesarean delivery (forceps ARR 2.11, 95% CI 1.46-3.07; vacuum ARR 2.71, 95% CI 1.49-3.15; sequential ARR 4.68, 95% CI 3.33-6.58). Rates of severe maternal morbidity/mortality were also higher following midcavity operative vaginal delivery (forceps ARR 1.57, 95% CI 1.05-2.36; vacuum ARR 2.29, 95% CI 1.57-3.36). Among deliveries with fetal distress, there were significant increases in severe perinatal morbidity/mortality following attempted midcavity vacuum (ARR 1.28, 95% CI 1.04-1.61) and in severe maternal morbidity following attempted midcavity forceps delivery (ARR 2.34, 95% CI 1.54-3.56). Attempted midcavity operative vaginal delivery is associated with higher rates of severe perinatal morbidity/mortality and severe maternal morbidity, though these effects differ by indication and instrument. Perinatal and maternal morbidity is increased following midcavity operative vaginal delivery.


The immunosuppressive activity of heat shock protein 70.
Heat shock protein 70 (HSP70) has previously been described as a potent antitumour vaccine. The mechanism relied on the ability of tumour derived HSP70 to associate with antigenic peptides, which, when cross presented, elicited a T cell mediated antitumour response. Subsequently, HSP70 was incorrectly described as a potent adjuvant of innate immunity, and although mistakes in the experimental approaches were exposed and associated with endotoxin contamination in the recombinant HSP70 specimen, questions still remain regarding this matter. Here we review only publications that have cautiously addressed the endotoxin contamination problem in HSP70 in order to reveal the real immunological function of the protein. Accordingly, "endotoxin free" HSP70 stimulates macrophages and delivers antigenic peptides to APCs, which effectively prime T cells mediating an antitumour reaction. Conversely, HSP70 has potent anti-inflammatory functions as follows: regulating T cell responses, reducing stimulatory capacity of DCs, and inducing development of immunosuppressive regulatory T cells. These activities were further associated with the immune evasive mechanism of tumours and implicated in the modulation of immune reactivity in autoimmune diseases and transplant-related clinical conditions. Consequently, the role of HSP70 in immune regulation is newly emerging and contrary to what was previously anticipated.


Coding Client Language in Motivational Interviewing for HIV Medication Adherence Using Self-Determination Theory.
Both motivational interviewing (MI) and self-determination theory (SDT) emphasise the importance of an individual's autonomy. SDT proposes that motivation is on a continuum with autonomous motivation (AM) at the self-determined end of the spectrum. Whether client speech reflects AM is not coded in MI process studies, however, as it is subsumed under the broader category of change talk (CT). We aimed to code naturalistic speech within MI sessions for HIV medication (antiretroviral) adherence according to whether expressed motivation was autonomous or controlled. We then assessed relationships between adherence and both autonomous/controlled motivational speech (AM/CM) and CT. We developed a new coding tool (the SDT coding system: SDTCS) to measure naturally occurring AM speech and CM speech expressed during an MI session targeting antiretroviral (ART) adherence with 62 adults living with HIV (16 female; mean age 40 years). We coded the same sessions using the motivational interviewing skills code (MISC) 2.5 and then examined relationships with on-time ART adherence. The SDTCS was developed using a combined inductive and deductive approach. Adequate reliability estimates were achieved and the measure possessed good content validity. Naturally occurring AM speech had a stronger relationship to ART adherence in the week after the MI session than CM speech. There was also some evidence that the relationship between AM speech and adherence was stronger than between CT and adherence. Future refinement and extension of the SDTCS could allow for a more nuanced understanding of client motivational speech that is currently provided by existing coding tools.


Late preterm birth, maternal depression, and risk of preschool psychiatric disorders.
Preterm children are at greater risk for psychiatric disorders, including anxiety disorders and attention-deficit/hyperactivity disorder (ADHD), than their term-born peers. Prior research has focused primarily on children born at early gestational ages. Less is known about the rate of psychiatric disorders among late preterm or early term children. In addition, whether a history of maternal depression also associated with prematurity has an impact on the risk for psychiatric disorders remains underexplored. Preschoolers between ages 3 and 6 years (N = 306) were recruited for a study examining preschool depression that included healthy and disruptive preschoolers. Preschoolers were placed in the following groups: late preterm (34-36 weeks, n = 39), early term (37-39 weeks, n = 78), and full term (40-41 weeks, n = 154). DSM-IV psychiatric disorders were assessed via the Preschool Age Psychiatric Assessment. Maternal history of psychiatric disorders was assessed using the Family Interview for Genetic Studies. Late preterm children had higher rates of any Axis I psychiatric diagnosis (odds ratio = 3.18, 95% confidence interval = 1.09-4.76) and of any anxiety disorder (odds ratio = 3.74, 95% confidence interval = 1.59-8.78) than full term children after adjusting for gender, ethnicity, family income, and IQ. There were no differences in rates of psychiatric diagnoses between early term and full term children. A history of maternal depression mediated the relationship between late preterm birth and anxiety disorders in preschoolers. Late preterm children were at increased risk for anxiety disorders at preschool age. A history of maternal depression mediated this association. Findings confirm the extension of the risk of psychiatric disorders associated with prematurity to the late preterm group, and suggest that maternal depression may play a key role in this risk trajectory.


Efflux Pump Overexpression Contributes to Tigecycline Heteroresistance in Salmonella enterica serovar Typhimurium.
Bacterial heteroresistance has been identified in several combinations of bacteria and antibiotics, and it complicated the therapeutic strategies. Tigecycline is being used as one of the optimal options for the treatment of infections caused by multidrug-resistant Salmonella. This study investigated whether heterorresistance to tigecycline exists in a Salmonella enterica serovar Typhimurium strain harboring the oqxAB-bearing IncHI2 plasmid pHXY0908. MIC and population analyses were performed to evaluate population-wide susceptibility to tigecycline. The effects of efflux pumps on MIC levels were assessed using the efflux pump inhibitor Phe-Arg-β-naphthylamide, measuring intracellular tigecycline accumulation as well as mRNA levels of regulatory and efflux pump genes. DNA sequencing of regulatory regions were performed and plasmid curing from a resistant strain provided an appropriate control. Results showed that MICs of a parental strain with and without pHXY0908 as well as a plasmid-cured strain 14028/Δp52 were 0.5, 1, and 1 μg/mL, respectively. Population analysis profiling (PAP) illustrated that only the pHXY0908-containg strain was heteroresistant to tigecycline. A fraction of colonies exhibited stable profiles with 4- to 8-fold increases in MIC. The frequencies of emergence of these isolates were higher in the plasmid-containing strain pHXY0908 than either the parental or the 14028/Δp52 strain. Phe-Arg-β-naphthylamide addition restored tigecycline susceptibility of these isolates and intracellular tigecycline accumulation was reduced. Heteroresistant isolates of the strain containing pHXY0908 also had elevated expression of acrB, ramA, and oqxB. DNA sequencing identified numerous mutations in RamR that have been shown to lead to ramA overexpression. In conclusions, heteroresistance to tigecycline in Salmonella enterica serovar Typhimurium was manifested in a plasmid-bearing strain. Our results suggest that this phenotype was associated with overexpression of the AcrAB-TolC and OqxAB efflux pumps.


[Role and results of surgery in Crohn disease in adults].
Because of new medical treatments, the authors propose a review of the principal surgical indications in Crohn's disease in adults and the current prognosis based on the literature. Schematically, these indications correspond to failures of drug treatment, apart from emergency situations. Relapses are still very frequent, but may remain responsive to medical treatment. However, coloproctectomy, a fairly invasive operation, provides the best results in the colonic forms.


Angry characters and frightened souls: Patients and family explanatory models of bipolar disorder in Taiwan.
Bipolar disorder (BD) affects a significant proportion of Taiwanese individuals (Weissman et al., 1996; Yang, Yeh, & Hwu, 2012). Psychotropic medications are typically the mainstay of treatment for BD, and there is an abundance of international research on biological etiology and medication options. However, there is comparatively little research on psychosocial aspects of BD, including how it is understood and managed within families. As culture provides the context in which psychiatric disease is managed, there is a need to identify distinct Chinese psychosocial perspectives that might shed light on intervention options. This research explored how Taiwanese patients and family members comprehend and cope with BD. A sample of 42 participants, including 20 Taiwanese patients diagnosed with Bipolar Disorder-I (BD-I) for at least 4 years, and 22 family members, participated in separate interviews on explanatory models of illness. Qualitative thematic analysis focused on features that were distinct from those in current Western research literature. Five themes were identified that represented Taiwanese conceptualizations of BD, notions of etiology, views regarding treatment, and the difficulties in managing the disorder. Participants used Chinese language terms and descriptions of BD that reflected greater concerns about irritability, anger, and family conflict than about other symptoms, and participants also emphasized characterological trait descriptions of the condition. Their responses reflected their acceptance of lifelong family responsibility for caretaking, clashing beliefs regarding biomedical versus traditional Chinese medical and spiritual models of etiology and cure, profound concerns about the effects of psychiatric medication on the liver and kidney systems, and a focus on stress rather than genetic or biological models of etiology.


Single-centre experience with intradetrusor injection of onabotulinumtoxinA: a retrospective study of the years 2003-2012 in a Danish population.
This study aimed to evaluate the efficacy of treatment for incontinence due to neurogenic detrusor overactivity (NDO) and idiopathic detrusor overactivity (IDO) with onabotulinumtoxinA (BoNT-A) at Aarhus University Hospital, Skejby, Denmark. The data were collected retrospectively by systematic review of the patient records from March 2003 to May 2012. Patients treated with BoNT-A over the age of 18 years were included. Treatment indication, diagnosis, adverse events, treatment interval, duration of effect and effect grade were registered. Follow-up data were collected by a telephone interview 4 weeks after treatment. The study identified 219 patients, who received a total of 657 treatments during the period. Full effect of the treatment was experienced in 71%, intermediate effect was seen in 16% and low effect in 3%. There was no difference in effect duration between the IDO and NDO groups. The most common adverse event was the need to perform clean intermittent self-catheterization; 27% of all patients experienced this. Urinary tract infections were reported in 5% of procedures and significant haematuria in 1%. These findings correspond with the results of other published studies. BoNT-A is a safe and effective treatment for incontinence in IDO and NDO.


Characterization of K(ATP)-channels in rat basilar and middle cerebral arteries: studies of vasomotor responses and mRNA expression.
Changes in the activity of K+ channels represent a major mechanism that regulates vascular tone. Cerebrovascular adenosine 5'-triphosphate-sensitive K+(K(ATP)) channels were characterized in studies of the molecular expression and vasomotor reactivity to different K(ATP) channel openers in rat basilar and middle cerebral arteries. Both arteries showed strong mRNA expression of the subunits of the pore-forming inward-rectifying K+ channel type 6.1 (Kir6.1), Kir6.2 and the connected sulfonylurea receptor (SUR) subunits, SUR1 and SUR2B, while only weak bands for SUR2A were seen. The K(ATP) channel openers induced relaxation of prostaglalndin F2alpha-precontracted isolated basilar and middle cerebral arteries with the order of potency N-Cyano-N-(1,1-dimethylpropyl)-N''-3pyridylguanidine (P-1075)>levcromakalim>N-(4-Phenylsulfonylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (ZM226600)>pinacidil>diazoxide. The responses induced by levcromakalim, ZM226600 and diazoxide were significantly more potent in basilar arteries than in middle cerebral arteries, while pinacidil and P-1075 were equipotent. Endothelium removal decreased (P<0.05) the sensitivity (pIC50) of basilar arteries, but not of middle cerebral arteries, to pinacidil, levcromakalim, P-1075 and ZM226600. The maximum relaxant response to P-1075 was stronger (P<0.005) in basilar arteries with endothelium than without endothelium. Correlation of the relaxant potency of K(ATP) channel openers in rat basilar and middle cerebral arteries with historical measurements of affinity obtained in COS-7 cell lines expressing either SUR1, SUR2A or SUR2B showed that vasodilatation by K(ATP) channel openers correlated with binding to either the SUR2A or the SUR2B subunit. Glibenclamide was a blocker of relaxation induced by pinacidil, levcromakalim, P-1075 and ZM226600 in basilar arteries. Only a weak antagonistic effect of glibenclamide on pinacidil-, levcromakalim- and ZM226600-induced relaxations was found in middle cerebral arteries. The subunit profile and the observed pharmacological properties suggest that the K(ATP) channels expressed in rat basilar and middle cerebral artery are likely to be composed of SUR2B co-associated with Kir6.1 or Kir6.2. In basilar arteries, but not in middle cerebral arteries, endothelial K(ATP) channels may be involved.


Skeletal dysplasias with osteopenia in the newborn: the value of alkaline phosphatase.
Alkaline phosphatase is a commonly measured enzyme in clinical practice. Normal, excessively elevated and depressed serum or plasma levels have clinical value in the approach to the differential diagnosis of skeletal dysplasias associated with osteopenia in the newborn period. Two cases are described to illustrate this contention. In the first case we describe a neonate with congenital hypophosphatasia and markedly depressed levels of plasma alkaline phosphate, and in the second case we report a patient with a fracture of the femur, congenital rickets and an elevated alkaline phosphate level. In skeletal dysplasias with osteopenia, the nature of the abnormality in alkaline phosphate values, in association with that of calcium and phosphate, is an invaluable diagnostic aid in differential diagnosis.


Machine learning for the prediction of antimicrobial stewardship intervention in hospitalized patients receiving broad-spectrum agents.
A significant proportion of inpatient antimicrobial prescriptions are inappropriate. Post-prescription review with feedback has been shown to be an effective means of reducing inappropriate antimicrobial use. However, implementation is resource intensive. Our aim was to evaluate the performance of traditional statistical models and machine-learning models designed to predict which patients receiving broad-spectrum antibiotics require a stewardship intervention. We performed a single-center retrospective cohort study of inpatients who received an antimicrobial tracked by the antimicrobial stewardship program. Data were extracted from the electronic medical record and were used to develop logistic regression and boosted-tree models to predict whether antibiotic therapy required stewardship intervention on any given day as compared to the criterion standard of note left by the antimicrobial stewardship team in the patient's chart. We measured the performance of these models using area under the receiver operating characteristic curves (AUROC), and we evaluated it using a hold-out validation cohort. Both the logistic regression and boosted-tree models demonstrated fair discriminatory power with AUROCs of 0.73 (95% confidence interval [CI], 0.69-0.77) and 0.75 (95% CI, 0.72-0.79), respectively (P = .07). Both models demonstrated good calibration. The number of patients that would need to be reviewed to identify 1 patient who required stewardship intervention was high for both models (41.7-45.5 for models tuned to a sensitivity of 85%). Complex models can be developed to predict which patients require a stewardship intervention. However, further work is required to develop models with adequate discriminatory power to be applicable to real-world antimicrobial stewardship practice.


Androgen receptor expression in cervical intraepithelial neoplasia and invasive squamous cell carcinoma of the cervix.
If in vitro studies have demonstrated a potential interaction between human papillomavirus (HPV) and androgen receptor (AR), their expression in vivo during cervical carcinogenesis remains unknown. To clarify the issue, we have tested by immunohistochemistry the expression status of AR in low-grade cervical intraepithelial neoplasia (LSIL-CIN1) (n=30), high-grade cervical intraepithelial neoplasia (HSIL-CIN2/3) (n=30), and invasive squamous cell carcinoma (ISCC) (n=13). All the patients with these lesions have got a corresponding liquid-based cytology and were proved to be HPV positive by using hybrid capture II methodology with probes against high-risk oncogenic HPVs (HR-HPVs). Thirty cases of normal exocervix epithelium served as controls. The evaluation of AR expression was performed by using H-score system, and an H-score >50 was considered positive. Androgen receptor expression was observed in 100% of normal epithelium (30/30) and LSIL (30/30), but only in 63% of HSIL (19/30) and 23% of ISCC (3/13). A statistically significant difference (P<0.05) concerning this expression was found between normal epithelium and HSIL or ISCC, between LSIL and HSIL or ISCC, and between HSIL and ISCC. To the best of our knowledge, this is the first study describing that the loss of AR expression is a frequent and common event in HSIL and ISCC resulting probably from complex interactions between HR-HPVs and these receptors. These data provide new insights concerning a potential role of androgen and AR in cervical carcinogenesis, which should be confirmed in furthers studies.


Effects of adding steroids, in vitro irradiation, or both to cyclosporine immunosuppression in the murine laryngeal transplantation model.
Adding oral prednisone or in vitro organ irradiation to an immunosuppressive regimen for laryngeal transplantation may allow cyclosporine dosage to be decreased without compromising organ rejection rates. Using an established rat laryngeal transplant model, we sought to determine whether combined immunosuppressive regimens decreased rejection rates. Twenty-two treatment groups of 10 animals each were studied. Cyclosporine was administered at 2 different historically low dosages (1.5 and 2 mg/kg per day) alone, in combination with prednisone, and with in vitro irradiation of the harvested larynx. At 15 days after transplantation, cyclosporine combined with prednisone did not significantly alter the mean severity of rejection. At 30 days after transplantation, rats treated with a combination of cyclosporine 2 mg/kg and prednisone 1 mg/kg showed the least amount of rejection. Rejection rates were significantly higher with 2 mg/kg cyclosporine alone (p < .00024). Irradiation did not significantly decrease the severity of rejection. These results demonstrate that at 1 month after transplantation, a combined steroid and cyclosporine regimen reduces the severity of rejection after laryngeal transplantation in an animal model. Our findings suggest that laryngeal transplant patients may be treated with low cyclosporine doses without experiencing organ rejection if steroids are added to the immunosuppressive regimen.


Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
Several pharmacological treatment options are available for type 2 diabetes; however, many patients do not achieve optimum glycaemic control and therefore new therapies are necessary. We assessed the efficacy and safety of semaglutide, a glucagon-like peptide-1 (GLP-1) analogue in clinical development, compared with insulin glargine in patients with type 2 diabetes who were inadequately controlled with metformin (with or without sulfonylureas). We did a randomised, open-label, non-inferiority, parallel-group, multicentre, multinational, phase 3a trial (SUSTAIN 4) at 196 sites in 14 countries. Eligible participants were insulin-naive patients with type 2 diabetes, aged 18 years and older, who had insufficient glycaemic control with metformin either alone or in combination with a sulfonylurea. We randomly assigned participants (1:1:1) to either subcutaneous once-weekly 0·5 mg or 1·0 mg semaglutide (doses reached after following a fixed dose-escalation regimen) or once-daily insulin glargine (starting dose 10 IU per day, then titrated weekly to a pre-breakfast self-measured plasma glucose target of 4·0-5·5 mmol/L [72-99 mg/dL]) for 30 weeks. In all treatment groups, previous background metformin and sulfonylurea treatment was continued throughout the trial. We did the randomisation using an interactive voice or web response system. The primary endpoint was change in mean HbA1c from baseline to week 30 and the confirmatory secondary endpoint was the change in mean bodyweight from baseline to week 30. We assessed efficacy and safety in the modified intention-to-treat population (mITT; all randomly assigned participants who were exposed to at least one dose of study drug) and used a margin of 0·3% to establish non-inferiority in HbA1c reduction. This trial is registered with ClinicalTrials.gov, number NCT02128932. Between Aug 4, 2014, and Sept 3, 2015, we randomly assigned 1089 participants to treatment; the mITT population consisted of 362 participants assigned to 0·5 mg semaglutide, 360 to 1·0 mg semaglutide, and 360 to insulin glargine. 49 (14%) participants assigned to 0·5 mg semaglutide discontinued treatment prematurely, compared with 55 (15%) assigned to 1·0 mg semaglutide, and 26 (7%) assigned to insulin glargine. Most discontinuations were due to adverse events-mostly gastrointestinal with semaglutide, and others such as skin and subcutaneous tissue disorders (eg, rash, pruritus, and urticaria) with insulin glargine. From a mean baseline HbA1c of 8·17% (SD 0·89), at week 30, 0·5 and 1·0 mg semaglutide achieved reductions of 1·21% (95% CI 1·10-1·31) and 1·64% (1·54-1·74), respectively, versus 0·83% (0·73-0·93) with insulin glargine; estimated treatment difference versus insulin glargine -0·38% (95% CI -0·52 to -0·24) with 0·5 mg semaglutide and -0·81% (-0·96 to -0·67) with 1·0 mg semaglutide (both p<0·0001). Mean bodyweight at baseline was 93·45 kg (SD 21·79); at week 30, 0·5 and 1·0 mg semaglutide achieved weight losses of 3·47 kg (95% CI 3·00-3·93) and 5·17 kg (4·71-5·66), respectively, versus a weight gain of 1·15 kg (0·70-1·61) with insulin glargine; estimated treatment difference versus insulin glargine -4·62 kg (95% CI -5·27 to -3·96) with 0·5 mg semaglutide and -6·33 kg (-6·99 to -5·67) with 1·0 mg semaglutide (both p<0·0001). Severe or blood glucose-confirmed hypoglycaemia was reported by 16 (4%) participants with 0·5 mg semaglutide and 20 (6%) with 1·0 mg semaglutide versus 38 (11%) with insulin glargine (p=0·0021 and p=0·0202 for 0·5 mg and 1·0 mg semaglutide vs insulin glargine, respectively). Severe hypoglycaemia was reported by two (<1%) participants with 0·5 mg semaglutide, five (1%) with 1·0 mg semaglutide, and five (1%) with insulin glargine. Six deaths were reported: four (1%) in the 0·5 mg semaglutide group (three cardiovascular deaths, one pancreatic carcinoma, which was assessed as being possibly related to study medication) and two (<1%) in the insulin glargine group (both cardiovascular death). The most frequently reported adverse events were nausea with semaglutide, reported in 77 (21%) patients with 0·5 mg and in 80 (22%) with 1·0 mg, and nasopharyngitis reported in 44 (12%) patients with insulin glargine. Compared with insulin glargine, semaglutide resulted in greater reductions in HbA1c and weight, with fewer hypoglycaemic episodes, and was well tolerated, with a safety profile similar to that of other GLP-1 receptor agonists. Novo Nordisk A/S.


Antinuclear autoantibodies in uveitis.
We have studied 44 sera of patients with uveitis, and controls for the presence of ANF and other antinuclear antibodies (ss-DNA, ds-DNA, Poly (I), Poly (G), RNP, Sm, histones) and for the presence of a common anti-DNA idiotype (16/6 Id) employing the ELISA method. Various incidences of antinuclear antibodies were found in sera of patients with uveitis. The uveitis specimens were found to have high titers of autoantibodies to ss-DNA, ds-DNA, Poly (I), histones and Poly (G). High titers of anti-Sm antibodies were detected only in 9% of the uveitis patients, which is markedly lower than the reported percentage of anti-Sm antibodies in SLE. No significant differences were found in the incidence of antinuclear antibodies between sera of patients with localized uveitis and uveitis concomitant with a systemic disorder. Similarly, no relationship was found between location of uveitis (anterior versus posterior) and autoantibody profile. Our results imply that despite considering uveitis as a specific organ malady, it should be regarded serologically as an autoimmune condition.


Highly sensitive and specific microRNA expression profiling using BeadArray technology.
We have developed a highly sensitive, specific and reproducible method for microRNA (miRNA) expression profiling, using the BeadArray technology. This method incorporates an enzyme-assisted specificity step, a solid-phase primer extension to distinguish between members of miRNA families. In addition, a universal PCR is used to amplify all targets prior to array hybridization. Currently, assay probes are designed to simultaneously analyse 735 well-annotated human miRNAs. Using this method, highly reproducible miRNA expression profiles were generated with 100-200 ng total RNA input. Furthermore, very similar expression profiles were obtained with total RNA and enriched small RNA species (R(2) >or= 0.97). The method has a 3.5-4 log (10(5)-10(9) molecules) dynamic range and is able to detect 1.2- to 1.3-fold-differences between samples. Expression profiles generated by this method are highly comparable to those obtained with RT-PCR (R(2) = 0.85-0.90) and direct sequencing (R = 0.87-0.89). This method, in conjunction with the 96-sample array matrix should prove useful for high-throughput expression profiling of miRNAs in large numbers of tissue samples.


[Diffuse type of gastric cancer adenocarcinoma in 10 years old boy: report of a case].
We report a rare case of diffuse type of gastric cancer with signet ring cells in 10 years old boy who was admitted with a 12 months history with weight loss, dysphagia to solids first and to liquids later, anorexia, fatigue, dizziness, vomiting and later, with pain in the left upper quadrant. On examination, he appeared pale, malnourished, with café-au- lait spots over the trunk and extremities. Laboratory tests showed; Hb 7.5 g, albumin 2.62 g, Thevenon positive on stools. Abdominal ultrasound examination showed periaortic masses and diffuse space occupying lesions in the liver. Endoscopic examination of the stomach showed multiple elevated tumor lesions. One located at 3 cm on the subcardial region presented irregular borders, partially eroded, that bleed easily when rubbing its surface. Multiple biopsy samples were taken. They showed a diffuse gastric signet cell type carcinoma of the stomach. Immunohistochemistry was positive to CK 8. The patient died a year later with wide spread metastasis. The boy was born through a normal delivery after a normal pregnancy to a primipara mother. His family history recorded a grandmother aunt dying of gastric cancer.


Bis(10-methylacridinium)s as a versatile platform for redox-active functionalized dyes and novel structures.
10-Methylacridinium is a stable aromatic cation exhibiting yellow-orange color and strong green fluorescence (FL), and can be used as a versatile building block in constructing a wide variety of novel π-electron systems. The dications with the two chromophores connected by a proper π spacer undergo reversible "dyrex" (dynamic redox) behavior, and C-C bond formation/cleavage is accompanied by their redox reactions. The prototype is biphenyl-2,2'-diylbis(10-methylacridinium), which exhibits electrochromic response with ON/OFF switching of FL during the reversible interconversion with the di(spiroacridan)-type electron donor. Slight structural alteration under the concept of "MFMS" (maximum function on the minimum skeleton) endowed the dyrex system with metal-binding or chiroptical properties, which could be modified by the redox reactions. Some of the di(spiroacridan) derivatives generated from bis(10-methylacridinium)s have extreme structural parameters, such as the greatest C-C bond length ever reported.


Measurement system errors explained.
Most temperature measurements are not so much concerned with absolute accuracy as repeatability, since focused on is whether the temperature is stable, moving up or moving down and by what rate of change. This is not the case, however, with temperature measurement within sterilisers, stresses Ted Baker, managing director, Isopharm Sentry.


Synergistic effect of vasoactive intestinal peptides on TNF-alpha-induced IL-6 synthesis in osteoblasts: amplification of p44/p42 MAP kinase activation.
We previously showed that tumor necrosis factor-alpha (TNF-alpha) stimulates synthesis of interleukin-6 (IL-6), a potent bone resorptive agent, via p44/p42 mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase/Akt in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the effect of vasoactive intestinal peptide (VIP) on TNF-alpha-induced IL-6 synthesis in these cells. VIP, which by itself slightly stimulated IL-6 synthesis, synergistically enhanced the TNF-alpha-induced IL-6 synthesis in MC3T3-E1 cells. The synergistic effect of VIP on the TNF-alpha-induced IL-6 synthesis was concentration-dependent in the range between 1 and 70 nM. We previously reported that VIP stimulated cAMP production in MC3T3-E1 cells. Forskolin, a direct activator of adenylyl cyclase, or 8-bromoadenosine-3',5'-cyclic monophosphate (8bromo-cAMP), a plasma membrane-permeable cAMP analogue, markedly enhanced the TNF-alpha-induced IL-6 synthesis as well as VIP. VIP markedly up-regulated the TNF-alpha-induced p44/p42 MAP kinase phosphorylation. The Akt phosphorylation stimulated by TNF-alpha was only slightly affected by VIP. PD98059, a specific inhibitor of MEK1/2, significantly suppressed the enhancement of TNF-alpha-induced IL-6 synthesis by VIP. The synergistic effect of a combination of VIP and TNF-alpha on the phosphorylation of p44/p42 MAP kinase was diminished by H-89, an inhibitor of cAMP-dependent protein kinase. These results strongly suggest that VIP synergistically enhances TNF-alpha-stimulated IL-6 synthesis via up-regulating p44/p42 MAP kinase through the adenylyl cyclase-cAMP system in osteoblasts.


Direct effects of neutrophil oxidants on elastase-induced extracellular matrix proteolysis.
Oxidant species produced by human polymorphonuclear leukocytes (PMN) inactivate alpha-1-protease inhibitor and thus may indirectly enhance neutrophil elastase-induced proteolysis. It is unclear, however, if PMN-derived oxidants directly enhance proteolysis of extracellular matrix by neutrophil elastase. Matrix was produced by neonatal rat aortic smooth muscle cells and pulse-labeled with 3H-lysine to allow identification of the collagen-specific amino acid, hydroxylysine (3H-HL), and the elastin specific amino acid, desmosine (3H-DES). The smooth muscle cells were lysed, and the remaining matrix was used as a culture surface and a proteolytic substrate for intact PMN and purified neutrophil elastase. Proteolysis of collagen and elastin were quantified by chromatographic separation of the marker amino acids 3H-HL and 3H-DES, which were released into the supernatant or remained in the matrix after a 3-h incubation at 37 degrees C. The peptide, formyl-methionine-leucine-phenylalanine (FMLP), produced more rapid release of myeloperoxidase than did phorbol myristate acetate (PMA), which produced more release of O2- and H2O2 than did FMLP. The percent release of total matrix 3H-DES in the presence of PMN + FMLP was 2.45 +/- 0.19% (mean +/- SE, n = 6) and with PMN + PMA it was 1.32 +/- 0.1% (n = 6, p less than 0.01). The release of matrix 3H-HL did not differ. Neutrophil cytoplasts, which produced O-2 and H2O2 but lacked azurophilic granules, did not significantly enhance either elastin or collagen degradation by purified neutrophil elastase (NE).(ABSTRACT TRUNCATED AT 250 WORDS)


Assembling nonspherical 2D binary nanoparticle superlattices by opposite electrical charges: the role of Coulomb forces.
High-quality approximately 16 nm c-In2O3 nanoctahedra and approximately 6 nm Pd spherical nanoparticles were synthesized via a high-temperature wet-chemical approach, and their electrophoretic mobilities in toluene were investigated, respectively. Opposite electrical charge-induced 2D binary nanoparticle superlattice patterns containing two such nanocomponents were prepared, for the first time. Three types of c-In2O3-skeleton-structure-contained assembly patterns were identified as well. It was further observed that the vertices of c-In2O3 nanoctahedra could have higher electrical charge density than that on edge or plane and the small Pd nanoparticles were "suspended" on the middle plane of the c-In2O3 nanoctahedra, apparently well above the substrate surface (support film) rather than sitting on it. The assembly structure study indicates that Coulomb forces resulted from the opposite electrical charges are the dominative driving forces to induce the formation of such nanoctahedra-nanospheres 2D binary nanoparticle superlattices.


[The G.E.R.U. retrospective study of 400 cases of urticaria].
The authors report on a study with computerised results of 400 urticaria and/or angioedema cases, which were explored in single dermatology center (Pr. J. SAYAG) by the members of GERU. The study was managed with a computerised file and was processed with Sesame software. The figures achieved are related to semilogic and paraclinical data and to etiological factors.


Molecular detection and isolation of facultatively methylotrophic bacteria, including Methylobacterium podarium sp. nov., from the human foot microflora.
This is the first study to demonstrate that diverse methylotrophic bacteria occur in the human foot microflora. Polymerase chain reaction (PCR) amplification of DNA from the soles and toe clefts of feet of five subjects indicated Methylobacterium strains to be present in all cases. Polymerase chain reaction amplification also showed the gene for the alpha-subunit of methanol dehydrogenase (mxaF) to be present in all samples. Two types of mxaF were recovered, one closest to that of Methylobacterium extorquens and the other most similar to that of Hyphomicrobium methylovorum. Numerous methylotrophic strains able to grow on methylamine were isolated with ease from the feet of nine volunteers. These were found by 16S rRNA analysis to be most closely related to Methylobacterium species, Brevibacterium casei, Pseudomonas strain NZ099 and P. migulae. Three strains from two subjects were of a novel species, Methylobacterium podarium sp. nov. This facultatively methylotrophic, obligately aerobic, pink-pigmented, non-motile rod grew with a wide range of multicarbon and one-carbon compounds including citrate, xylose, mono-, di-, and trimethylamine, dimethylsulphide, methanethiol, dimethylsulphoxide, dimethylsulphone and methanol.


Two complementary methods for predicting peptides binding major histocompatibility complex molecules.
Peptides that bind to major histocompatibility complex products (MHC) are known to exhibit certain sequence motifs which, though common, are neither necessary nor sufficient for binding: MHCs bind certain peptides that do not have the characteristic motifs and only about 30% of the peptides having the required motif, bind. In order to develop and test more accurate methods we measured the binding affinity of 463 nonamer peptides to HLA-A2.1. We describe two methods for predicting whether a given peptide will bind to an MHC and apply them to these peptides. One method is based on simulating a neural network and another, called the polynomial method, is based on statistical parameter estimation assuming independent binding of the side-chains of residues. We compare these methods with each other and with standard motif-based methods. The two methods are complementary, and both are superior to sequence motifs. The neural net is superior to simple motif searches in eliminating false positives. Its behavior can be coarsely tuned to the strength of binding desired and it is extendable in a straightforward fashion to other alleles. The polynomial method, on the other hand, has high sensitivity and is a superior method for eliminating false negatives. We discuss the validity of the independent binding assumption in such predictions.


Extracorporeal membrane oxygenation support for single lung transplantation in a patient with primary pulmonary hypertension.
Left single lung transplantation was performed under perioperative extracorporeal membrane oxygenation (ECMO) support for a patient of primary pulmonary hypertension. Continuous ECMO in this patient for one day after the transplantation decreased the pulmonary blood flow and probably served to minimize the potential complication of reperfusion edema of the graft. During this period, the ECMO was gradually weaned so that the grafted lung could adapt itself to the gradually increased blood flow through it. The patient was extubated without difficulty 2 days alter the removal of ECMO and made a smooth recovery.


The effect of contact stress on cartilage friction, deformation and wear.
Following hip hemiarthroplasty, a metal femoral head articulates against natural acetabular cartilage. Cartilage friction and wear may be influenced by variables including loading time, contact stress, contact area, sliding distance, and sliding speed. The aim of this study was to investigate the effect of these variables on cartilage friction, deformation and wear in a simulation using idealized geometry model. Bovine cartilage pins were reciprocated against metal plates to mimic a hemiarthroplasty articulation under static loading. The effective coefficient of friction (micro elf) under contact stresses (0.5 to 16 MPa), contact areas (12 and 64 mm2), stroke lengths (4 and 8 mm), sliding velocities (4 and 8 mm/s), and loading time (1 and 24 hours) were studied. The permanent deformation of cartilage (after 24 hours of recovery) with and without motion was recorded to assess cartilage linear wear. The micro eff was found to remain < 0.35 with contact stresses < or =4 MPa. Severe damage to the cartilage occurred at contact stresses > 8 MPa and significantly increased micro eff after 12 hours of reciprocation. In long-term, contact area had no significant effect on micro eff, and sliding distance and velocity only affected micro eff under low contact stresses. The cartilage linear wear increased with contact stress, sliding distance and velocity.


PREDICTIVE ACTIVATION BIOMARKERS OF TREATMENT-NAIVE ASYMPTOMATIC CHOROIDAL NEOVASCULARIZATION IN AGE-RELATED MACULAR DEGENERATION.
To assess the long-term evolution of treatment-naive quiescent choroidal neovascularization (CNV), in age-related macular degeneration (AMD), to identify predictive activation biomarkers. Patients with quiescent CNV underwent a comprehensive ophthalmological examination, including fluorescein and indocyanine green angiographies, structural optical coherence tomography (OCT), and OCT angiography. Qualitative and quantitative analyses of structural OCT and OCT angiography images were performed during the study period. At the last follow-up evaluation, the enrolled eyes were divided into two groups: eyes with quiescent CNV converting to exudative AMD (eAMD) and those not progressing to eAMD. Sixty-eight eyes of 68 patients were enrolled in the study. Mean follow-up duration was 40 ± 28 months using multimodal imaging and 22 ± 13 months using OCT angiography. On structural OCT, quiescent CNV not converting to eAMD showed a preferential growth of the pigment epithelium detachment greatest linear diameter (P = 0.009), whereas the eAMD group presented a preferential growth of the pigment epithelium detachment maximal height (P < 0.0001) during the study period. Quantitative analysis of choriocapillaris OCT angiograms confirmed the CNV area growth during follow-up (from 4.18 ± 4.77 mm at baseline to 5.10 ± 5.06 mm at the last follow-up visit; P = 0.02). A close follow-up is recommended to early identify predictive activation biomarkers of treatment-naive quiescent CNV.


ERK inhibitors as a potential new therapy for rheumatoid arthritis.
Rheumatoid arthritis (RA), a chronic and systemic autoimmune disease that leads to progressive articular destruction, is evoked by the concerted action of RA-related cells, such as T cells, synovial fibroblasts and macrophages. Although anticytokine biologics block the intercellular signal transduction of these RA-related cells and thereby exert a strong ameliorative effect on RA, there still remains a significant percentage of nonresponsive patients. In addition to these biologics that disrupt specific intercellular signals, extracellular signal-regulated kinase (ERK) inhibitors, which are believed to target the intracellular signals common to the diverse RA-related cells, are also used as a treatment for RA patients, including those who are nonresponsive to the anticytokine therapies. Recently, potent and selective inhibitors for ERK with the co-crystal structures have been reported. FR180204, an ERK inhibitor, has been shown to be effective against mouse collagen-induced arthritis, a representative animal model of RA. This compound also suppresses the antigen-specific activation of T cells, which play a central role in the initiation and progress of the disease. Information obtained from the co-crystal structures would contribute to the improvement of the chemical characteristics. Thus, with the discovery of new potential chemical entities, ERK inhibitors may emerge as a new therapeutic approach for the treatment of RA.


[Prothrombin time and its standardization: a potentiality to introduce INR method in criteria for disseminated intravascular coagulation].
Prothrombin time (PT) is widely utilized for evaluation of diseases with single or multiple coagulation factors disorders, such as severe liver dysfunction and disseminated intravascular coagulation (DIC). However, its standardization of reagent and method is not established yet for universal purpose except International Normalized Ratio (INR) for control of oral anticoagulant therapy (OAT). Neither Prothrombin time ratio adapted in Japanese criteria for DIC nor seconds method in criteria reported by the last SSC meeting is corrected between assays, therefore much dependence on these criteria causes risk of misdiagnosis. In order to resolve incoherence of method of PT, we performed this study for introducing INR method to diagnostic criteria for DIC. In our results, sensitivities of two reagents from human tissue factor (TF) to DIC model plasma with middle to low activities of multiple coagulation factors almost equal to plasma from patients with OAC, although other two reagents from rabbit TF show discrepancy of sensitivities between DIC and OAT plasma. These suggest a potentiality to introduce INR system to diagnosis of DIC when human TF is used as a PT reagent. Based on standardization of method, significance of PT in DIC criteria should be reevaluated in worldwide.


Challenges to sovereign ambitions: forces of convergence and divergence within the global pharmaceutical sector and the UK's withdrawal from the European Union.
This paper maps key regulatory, governance and legal challenges associated with the UK's withdrawal from the European Union (EU) in terms of convergent and divergent pressures within the global pharmaceutical sector. These include (i) convergent regulatory pressures associated with the European framework for pre-market licensing; (ii) convergent and divergent industry pressures with regard to drug discovery and manufacturing; and (iii) divergent and convergent market pressures associated with the supply, pricing and assessment of medicines. The UK's sovereign ambitions risk a loss of influence over the licensing and surveillance of pharmaceuticals under convergent regulatory and industry pressures to engage in unilateral participation in the European regime. Further, they also risk a loss of influence over processes for pricing and assessing the effectiveness of new treatment regimens under divergent market pressures from larger pharmaceutical markets outside the EU, notably the United States.


Excision and transposition of piggyBac transposable element in tobacco budworm embryos.
The TTAA-specific lepidopteran transposon piggyBac has already proved useful as a gene-transfer vector for efficient transformation of a wide variety of insects. Transposable element excision and transposition assays are useful indicators of an element's ability to be mobilized in vivo and, thus, potentially serve as a transforming vector. Here, we report that this transposon is capable of excision and transposition in tobacco budworm embryos with relatively low frequency.


Spontaneously ruptured choledochal cyst: Rare diagnosis on hepatic scintigraphy.
A 47-day-old female infant presented with congenital inguinal hernia, seizure on the 2(nd) day of life, fever, progressive jaundice, acholic stools and distension of abdomen. She was suspected to have choledochal cyst with extrahepatic biliary atresia (EHBA) and referred for an Hepatobiliary Tc-99m iminodiacetic acid (HIDA) scan. On HIDA scan, a functional diagnosis of ruptured choledochal cyst was made which was not possible on anatomical imaging like ultrasound (USG)/computed tomography (CT) scan. This was supported thereafter by bilious aspirate on abdominal paracentesis. Immediate laparotomy with T-tube insertion was done. The child improved dramatically after the procedure. Biliary peritonitis secondary to cyst perforation or rupture is a rare complication reported to occur in 1-2% cases of choledochal cyst. Early diagnosis and management is the key to reduce the morbidity and mortality.


The National Healthy Sleep Awareness Project Sleep Health Surveillance Questionnaire as an Obstructive Sleep Apnea Surveillance Tool.
To validate the previously published National Healthy Sleep Awareness Project (NHSAP) Surveillance and Epidemiology Workgroup questionnaire for ability to determine risk for moderate to severe obstructive sleep apnea (OSA). The NHSAP sleep questions, part of the next Behavioral Risk Factor Surveillance System (BRFSS), were constructed to mimic elements of the STOP sleep apnea questionnaire, and included number of days with sleep disruption and unintentional dozing and a history of snoring and apneas. The responses to four sleep questions from the BRFSS were collected from 352 adults undergoing in-laboratory polysomnography at Mayo Clinic, Rochester, Minnesota. Demographic and clinical information, including sex, age, body mass index (BMI), and presence of hypertension, which will be available in other parts of the complete BRFSS, were obtained by chart review. Univariate and logistic regression analyses were performed, and values of P < .05 were considered to be statistically significant. Fifty-five percent of subjects were men and 45% were women with a median age of 58 years and BMI 32.2 kg/m2. Sixty percent had no or mild OSA, and 40% had moderate to severe OSA. No single question was superior in screening for moderate to severe OSA, although a history of snoring and witnessed apneas was more likely to predict moderate to severe OSA. Male sex, age ≥ 50 years, BMI ≥ 30 kg/m2, presence of hypertension, and a history of snoring and witnessed apneas were the most highly weighted factors in predicting moderate to severe OSA. When each variable was dichotomized to a single point, a cutoff of 5 points significantly predicted a high risk of moderate to severe OSA with an odds ratio of 3.87 (2.39-6.27). Although many variables were positively associated with the apnea-hypopnea index, no single factor was superior in predicting moderate to severe OSA. Male sex, increased age, higher BMI, hypertension, and a history of snoring and witnessed apneas are the most highly predictive of moderate to severe OSA. Combined use of the NHSAP questionnaire and demographic and clinical characteristics could be considered for screening for moderate to severe OSA.


TLR4 Overexpression Aggravates Bacterial Lipopolysaccharide-Induced Apoptosis via Excessive Autophagy and NF-κB/MAPK Signaling in Transgenic Mammal Models.
Gram-negative bacterial infections pose a significant threat to public health. Toll-like receptor 4 (TLR4) recognizes bacterial lipopolysaccharide (LPS) and induces innate immune responses, autophagy, and cell death, which have major impacts on the body's physiological homeostasis. However, the role of TLR4 in bacterial LPS-induced autophagy and apoptosis in large mammals, which are closer to humans than rodents in many physiological characteristics, remains unknown. So far, few reports focus on the relationship between TLR, autophagy, and apoptosis in large mammal levels, and we urgently need more tools to further explore their crosstalk. Here, we generated a TLR4-enriched mammal model (sheep) and found that a high-dose LPS treatment blocked autophagic degradation and caused strong innate immune responses and severe apoptosis in monocytes/macrophages of transgenic offspring. Excessive accumulation of autophagosomes/autolysosomes might contribute to LPS-induced apoptosis in monocytes/macrophages of transgenic animals. Further study demonstrated that inhibiting TLR4 downstream NF-κB or p38 MAPK signaling pathways reversed the LPS-induced autophagy activity and apoptosis. These results indicate that the elevated TLR4 aggravates LPS-induced monocytes/macrophages apoptosis by leading to lysosomal dysfunction and impaired autophagic flux, which is associated with TLR4 downstream NF-κB and MAPK signaling pathways. This study provides a novel TLR4-enriched mammal model to study its potential effects on autophagy activity, inflammation, oxidative stress, and cell death. These findings also enrich the biological functions of TLR4 and provide powerful evidence for bacterial infection.


Clinicopathological significance and prognostic role of p-STAT3 in patients with hepatocellular carcinoma.
Constitutive activation of STAT3 through its phosphorylation (p-STAT3) plays a key role in the development and progression of various cancers. However, the relationship between p-STAT3 expression and the clinicopathological features and prognostic value in patients with hepatocellular carcinoma (HCC) remains controversial. We conducted a meta-analysis to evaluate the role of p-STAT3 in HCC. The PubMed, Cochrane Library, Web of Science, EMBASE, Chinese CNKI, and Chinese Wanfang databases were searched using the appropriate terms to find the relevant studies on p-STAT3 and HCC. The relationship between p-STAT3 expression and clinicopathological characteristics and prognostic value was established. Pool odds ratios (ORs) and hazard ratios (HRs) with 95% CIs were calculated using the STATA 14.2 software. The eight articles included in this meta-analysis comprised 752 patients. Expression of p-STAT3 was associated with incidence, age, liver cirrhosis, tumor size, vascular invasion, and TNM stage of HCC, but it was not related to gender, alpha-fetoprotein (AFP), hepatitis B surface antigen (HBsAg), number of tumors, and tumor differentiation. Additionally, the expression of p-STAT3 was related to a poor 3- and 5-year overall survival rate and disease-free survival rate. Expression of p-STAT3 was associated with the incidence, age, liver cirrhosis, tumor size, vascular invasion, and TNM stage. Thus, p-STAT3 can be a reliable prognostic biomarker for HCC. Further high-quality studies with larger numbers of patients are needed.


Effects of Physical Exercise on Neuroinflammation, Neuroplasticity, Neurodegeneration, and Behavior: What We Can Learn From Animal Models in Clinical Settings.
Physical exercise is a cornerstone in the management of many neurodegenerative disorders, such as Parkinson's disease, dementia, and stroke. However, much of its beneficial effects on improving motor functions and cognition as well as decreasing neurodegeneration and neuroinflammation are not yet well understood. The obvious limitations of studying the protective mechanisms behind exercise, for example, brain plasticity and neurodegeneration, could be overcome by generating novel animal models of neurodegenerative disorders. In this narrative review, we discuss the beneficial effects of exercise performed in animal models of neurodegenerative disorders and how the results from animal studies can be used in clinical settings. From preclinical studies, the positive effects of exercise have been related to increased levels of neurotrophic factors, elevated expression of anti-inflammatory cytokines, and reduced levels of pro-inflammatory cytokines and activated microglia. It is clear that parameters influencing the effect of exercise, such as intensity, still remain to be investigated in animal studies in order to find the optimal program that can be translated into exercise interventions for patients with neurodegenerative diseases.


Norcantharidin, a clinical used chemotherapeutic agent, acts as a powerful inhibitor by interfering with fibrinogen-integrin αIIb β3 binding in human platelets.
During platelet activation, fibrinogen binds to its specific platelet receptor, integrin αIIb β3 , thus completing the final common pathway for platelet aggregation. Norcantharidin (NCTD) is a promising anticancer agent in China from medicinal insect blister beetle. In this study, we provided the evidence to demonstrate NCTD (0.1-1.0 μM) possesses very powerful antiplatelet activity in human platelets; nevertheless, it had no effects on surface P-selectin expression and only slight inhibition on ATP-release reaction in activated platelets. Moreover, NCTD markedly hindered integrin αIIb β3 activation by interfering with the binding of FITC-labelled PAC-1. It also markedly reduced the number of adherent platelets and the single platelet spreading area on immobilized fibrinogen as well as clot retraction. Additionally, NCTD attenuated phosphorylation of proteins such as integrin β3 , Src and FAK in platelets spreading on immobilized fibrinogen. These results indicate that NCTD restricts integrin αIIb β3 -mediated outside-in signalling in human platelets. Besides, NCTD substantially prolonged the closure time in human whole blood and increased the occlusion time of thrombotic platelet plug formation and prolonged the bleeding time in mice. In conclusion, NCTD has dual activities, it can be a chemotherapeutic agent for cancer treatment, and the other side it possesses powerful antiplatelet activity for treating thromboembolic disorders.


Where will I go? Displaced nurses relate their experiences.
Registered nurses have been experiencing displacement, the nonvoluntary transfer or reassignment of the registered nurse to another unit or position, or layoff, termination, and severing of nursing personnel as a result of the closure of hospitals and other agencies and the physical relocation of departments or units. The purpose of this qualitative study is to describe the human experience of change from the perspective of displaced nurses. Thirteen registered nurses employed at eight metropolitan New York agencies described their experiences of displacement. Their interviews were analyzed using grounded theory methodology. Five themes emerged in the displacement experience: finding out, weighing options, coping with negative emotions and loss, support, and giving advice. Implications for education, practice, and research are discussed.


[Antibody persistence following primary vaccination with hepatitis B vaccine among normal and high-responder adults: a 5-year follow-up study].
To evaluate the 5-year antibody persistence and the risk factors associated with the persistence after primary vaccination of hepatitis B vaccine (HepB) among normal or high-response adults. A total of 24 237 healthy adults who had no histories of hepatitis B infection and hepatitis B vaccination, resided in the local area for more than six months and were aged 18-49 years were selected from 79 villages in north of Zhangqiu county, Shandong province, China in 2009. Blood samples were obtained and hepatitis B surface antigen (HBsAg), antibody against hepatitis B surface antigen (anti-HBs) and antibody against hepatitis B core antigen (anti-HBc) were detected using ELISA method. A total of 11 590 persons who were negative for all of these indicators were divided into four groups by cluster sampling methods. Each group was vaccinated with one of the following four types of HepB at 0-1-6 months schedule: 20 μg HepB derived in Saccharomyces cerevisiae (HepB-SC), 20 μg HepB derived in Chinese hamster ovary cell (HepB-CHO), 10 μg HepB-SC and 10 μg HepB derived in Hansenula polymorpha (HepB-HP). The normal and high-responder was followed up and their demographic characteristic (including age, gender), histories of hepatitis B infection, hepatitis B vaccination, smoking, drinking and chronic diseases were investigated. Blood samples were collected one month (T1) and five years (T2) and anti-HBs, anti-HBc and HBsAg (if anti-HBs<10 mU/ml) were detected by CMIA. A total of 1 902 participants were followed up and the risk factors associated with positive rate of anti-HBs and GMC of anti-HBs were identified by multiple logistic regression analysis and multifactor linear regression model analysis, respectively. Among 1 902 adults, 824 (43.32%) were male and 1 078 (56.68%) were female. The anti-HBs positive rate was 100% at T1 and it decreased to 73.29% (1 394 cases) at T2. The corresponding GMC was decreased from 1 527.15 (95%CI: 1 437.84-1 622.01) mU/ml at T1 to 35.07 (95%CI: 32.20-38.19) mU/ml at T2. When comparing with those vaccinated 20 μg HepB-SC, the significantly lower positive rate at T2 was observed in those vaccinated 10 μg HepB-SC group and 10 μg HepB-HP group. The OR (95% CI) was 0.41 (0.28-0.61) and 0.27 (0.18-0.39), respectively. The GMC of anti-HBs was also significantly lower among those vaccinated 10 μg HepB-SC and 10 μg HepB-HP. The b (95%CI) was -0.20 (-0.28- -0.12) and -0.36 (-0.44- -0.29) , respectively. When comparing with those occasionally drinking, the significantly lower positive rate at T2 was observed in those regular drinking. The OR(95%CI) was 0.51(0.30-0.87). The GMC of anti-HBs in age group of 18-29 was significantly higher than those in 40-49 age group; the b (95%CI) was -0.10(-0.18- -0.01). When comparing with those whose anti-HBs titer was less than 999 mU/ml at T1, the significantly higher positive rate of anti-HBs at T2 was observed in those whose anti-HBs titer was 1 000-1 999 mU/ml, those whose anti-HBs titer was 2 000-2 999 mU/ml and those whose anti-HBs titer was ≥10 000 mU/ml. The OR (95%CI) was 10.11 (6.90-14.82), 20.42 (13.98-29.82) and 54.58 (22.08-134.92), respectively. When comparing with those whose anti-HBs titer was ≤999 mU/ml at T1, the GMC of anti-HBs at T2 was also significantly higher among those whose anti-HBs titer at T1 was 1 000-1 999 mU/ml, those whose anti-HBs titer at T1 was 2 000-2 999 mU/ml and those whose anti-HBs titer at T1 was ≥10 000 mU/ml. The b (95%CI) was 0.55 (0.47-0.62), 0.94 (0.88-1.00) and 1.63 (1.54-1.72), respectively. Nobody was found positive to HBsAg at T2 and the conversion rate of anti-HBc was 3.89% (74/1 902) at T2. Anti-HBs GMC decreased rapidly at T2 among normal and high-responder adults, while the positive rate of anti-HBs still kept at a high level. The antibody persistence among normal and high-responder adults at T2 was associated with HepB type, age, history of drinking and GMC of anti-HBs at T1.


Post-training intrahippocampal infusion of nicotine prevents spatial memory retention deficits induced by the cyclo-oxygenase-2-specific inhibitor celecoxib in rats.
Recently, we demonstrated that intrahippocampal infusion of the cyclo-oxygenase (COX)-2-specific inhibitor celecoxib impaired spatial memory retention in the Morris water maze. In the present work, we investigated the effects of nicotine, infused in the rat dorsal hippocampus several minutes after infusion of celecoxib, on memory retention in the Morris water maze. Rats were trained for 3 days; each day included two blocks, and each block contained four trials. Test trials were conducted 48 h after surgery. As expected, bilateral intrahippocampal infusion of celecoxib (19 microg/side; 0.1 m) increased escape latency and travel distance in rats, indicating significant impairment of spatial memory retention. We also examined the effects of bilateral infusion of nicotine (0.5, 1.0 and 2.0 microg/side) on memory retention. Infusion of 1 microg nicotine significantly decreased escape latency and travel distance but not swimming speed, compared with controls, suggesting memory retention enhancement by nicotine at this concentration. In separate experiments, bilateral infusion of nicotine, infused 5 min after 0.1 m (19 microg/side) celecoxib infusion, was associated with escape latency, travel distance and swimming speed profiles very similar to those in control animals. Brain tissue sections from several of these animals were subjected to immunohistochemical staining analysis with anti-COX-2 antibodies. Quantification analysis by optical density measurements showed that the celecoxib infusion reduced the immunoreactivity of COX-2-containing neurons in the CA1 area of the hippocampus compared with controls, although this reduction was not significant. However, infusion of a combination of celecoxib and nicotine significantly increased this immunoreactivity compared with levels in control and celecoxib-infused groups. These results suggest that nicotine prevented or reversed the adverse effects of celecoxib on spatial memory retention and protected or restored the immunostaining pattern of COX-2 neurons in the rat dorsal hippocampus.


Schizophrenia--a follow-up study of results of treatment.
This is the second article from a study of the outcome of five different methods of treatment for schizophrenia; patients were followed up over a period of two to five years after first admission and the first release. Patients who had been originally treated in hospital with psychotherapy alone stayed longer in hospital over the follow-up period than those who had received electroconvulsive therapy (ECT), drug alone, or drug plus psychotherapy. Those who had been treated with milieu therapy also had a longer stay dated from the time of admission. Patients treated initially with drugs or ECT showed a trend toward spending less time in hospital after their release.


[Adhesive properties of the upper surface of fibroblasts and epithelium in cultures].
Adhesive properties of the upper surface of cultured normal and neoplastic epithelial cells and of fibroblasts were studied. It was shown that the attachment of prelabeled homo- and heterologous cells introduced into epithelial sheets were very low as compared with the free substratum and dense cultures of fibroblasts. The upper surface of cells of cultured anaplastic hepatoma 22a was adhesive for prelabeled cells. Morphological characteristics of the studied cultures were compared. It was found that low adhesiveness of the upper surface of epithelial sheets correlated with the formation of firm intercellular contacts which remained unbroken during migration into the wound. It is suggested that when epithelial cells make contacts with each other, their surface is subdivided into two types of regions: areas of low adhesiveness (the upper surface), and those of firm intercellular contacts. This may cause the formation of monolayer epithelial sheet.


Identification of specific sites of hormonal regulation in spermatogenesis in rats, monkeys, and man.
A detailed understanding of the hormonal regulation of spermatogenesis is required for the informed assessment and management of male fertility and, conversely, for the development of safe and reversible male hormonal contraception. An approach to the study of these issues is outlined based on the use of well-defined in vivo models of gonadotropin/androgen deprivation and replacement, the quantitative assessment of germ cell number using stereological techniques, and the directed study of specific steps in spermatogenesis shown to be hormone dependent. Drawing together data from rat, monkey, and human models, we identify differences between species and formulate an overview of the hormonal regulation of spermatogenesis. There is good evidence for both separate and synergistic roles for both testosterone and follicle-stimulating hormone (FSH) in achieving quantitatively normal spermatogenesis. Based on relatively selective withdrawal and replacement studies, FSH has key roles in the progression of type A to B spermatogonia and, in synergy with testosterone, in regulating germ cell viability. Testosterone is an absolute requirement for spermatogenesis. In rats, it has been shown to promote the adhesion of round spermatids to Sertoli cells, without which they are sloughed from the epithelium and spermatid elongation fails. The release of mature elongated spermatids from the testis (spermiation) is also under FSH/testosterone control in rats. Data from monkeys and men treated with steroidal contraceptives indicate that impairment of spermiation is a key to achieving azoospermia. The contribution of 5alpha-reduced androgens in the testis to the regulation of spermatogenesis is also relevant, as 5alpha-reduced androgens are maintained during gonadotropin suppression and may act to maintain low levels of germ cell development. These concepts are also discussed in the context of male hormonal contraceptive development.


Cardiovascular risk factors in HIV-infected patients.
Highly active antiretroviral therapy (HAART) commonly leads to persistent dyslipidemia and insulin resistance that appear likely to confer an increased incidence of cardiovascular disease (CVD). Both protease inhibitors (PIs) and, to a lesser extent, nucleoside analog reverse transcriptase inhibitors (NRTIs) appear to be involved, through direct metabolic effects of PIs and an indirect effect of PI and NRTI-related lipodystrophy. Several studies have found a variable relationship between CVD incidence and HAART, but these studies were not prospective and may not have been adequately powered. A variety of treatment strategies have been evaluated for dyslipidemia and insulin resistance, including lifestyle changes, drugs, and antiretroviral switching, but their relative safety, efficacy and roles are unclear. Although treatment of dyslipidemia and insulin resistance is commonly recommended, it should be remembered that such therapy is likely to be of greater benefit in those with a greater perceived CVD risk (i.e., multiple risk factors) and the lowest risk of HIV disease progression.


Nonenzymatic Target-Driven DNA Nanomachine for Monitoring Malathion Contamination in Living Cells and Bioaccumulation in Foods.
Intensive applications of toxic malathion pesticides bring a vital threat to the environment and health. Hence, a credible and sensitive strategy is urgently needed for the respective detection of malathion. In this work, an aptamer-based nonenzymatic autonomous DNA walking machine was fabricated for monitoring trace malathion contamination in cells and foods. Along with the machine walking driven by malathion-triggered reaction entropy, multiple fluorescent signal outputs were thermodynamically generated for signal amplification. The proposed stable DNA nanomachine achieved satisfactory results with a detection limit of 81.9 pg L-1 for testing malathion, which could be applied to actual samples including apple juice, paddy water, and paddy soil. Furthermore, the high stability, sensitivity, and biocompatibility of the nanomachine enabled monitoring of the malathion contamination in living cells and bioaccumulation in lettuce without additional purification. Consequently, with these excellent performances, it is strongly anticipated that the DNA walking machine has tremendous potential to be extended to general platforms against pesticides to avoid malathion-contaminated agricultural production for environmental safety and human health.


[SSBT (severely suppressed bone turnover) ].
Atypical fractures of femoral shaft and pelvis occurred on the long-term bisphosphonate treatment patients have been first reported in 2005. Since then many cases have been reported, while the number of atypical fractures is small compared with that of bisphosphonate treatment patients. It is speculated that accumulation of microdamage induced by severely suppressed bone turnover causes clinical fatigue fracture.