[The integration of psychiatry services in the general hospital].
This work consist of a bibliographic review about the inclusion of the psychiatry in general hospitals. Through it we were able to approach some historical aspects concerning the presence of mentally ill people in general hospitals, the creation and organization of psychiatric units in general hospitals, the hospitalization of psychiatric patients in institutions lacking specific units and the services of psychiatric interconsultation. The work consists of a part of a Master's dissertation in which we observed that there is a great amount of literature about the subject; however, all of them under the view of the nursing team. No references were found about the viewpoint of the mentally ill person about the hospitalization in a general hospital.


Decreased NO signaling leads to enhanced vasoconstrictor responsiveness in skeletal muscle arterioles of the ZDF rat prior to overt diabetes and hypertension.
Approximately 40% of patients with type 2 diabetes present with concurrent hypertension at the time of diabetes diagnosis. Increases in peripheral vascular resistance and correspondingly enhanced vasoconstrictor capacity could have profound implications for the development of hypertension and the progression of insulin resistance to overt diabetes. The purpose of this study was to determine whether skeletal muscle arteriolar vasoconstrictor dysfunction precedes or occurs concurrently with the onset of diabetes and hypertension. Male Zucker diabetic fatty (ZDF) rats were studied at 7, 13, and 20 wk of age to represent prediabetic and short-term and long-term diabetic states, respectively. Conscious mean arterial pressure (MAP), fasted plasma insulin and glucose, vasoconstrictor responses, and passive mechanical properties of isolated skeletal muscle arterioles were measured in prediabetic, diabetic, and age-matched control rats. Elevated MAP was manifest in short-term diabetes (control 117 +/- 1, diabetic 135 +/- 3 mmHg) and persisted with long-term diabetes (control 113 +/- 2, diabetic 135 +/- 3 mmHg). This higher MAP was preceded by augmented arteriolar vasoconstrictor responses to norepinephrine and endothelin-1 and followed by diminished beta-adrenergic vasodilation and enhanced myogenic constriction in long-term diabetes. Furthermore, we demonstrate that diminished nitric oxide (NO) signaling underlies the increases in vasoconstrictor responsiveness in arterioles from prediabetic and diabetic rats. Arteriolar stiffness was not different between control and prediabetic or diabetic rats at any time point studied. Collectively, these results indicate that increases in vasoconstrictor responsiveness resulting from diminished NO signaling in skeletal muscle arterioles precede the development of diabetes and hypertension in ZDF rats.


Targeted treatment for unresectable EGFR mutation-positive stage III non-small cell lung cancer: Emerging evidence and future perspectives.
Epidermal growth factor receptor (EGFR) mutations are detected in up to one third of patients with unresectable stage III non-small cell lung cancer (NSCLC). The current standard of care for unresectable stage III NSCLC is consolidation durvalumab for patients who have not progressed following concurrent chemoradiotherapy (the 'PACIFIC regimen'). However, the benefit of immunotherapy, specifically in patients with EGFR mutation-positive (EGFRm) tumors, is not well characterized, and this treatment approach is not recommended in these patients, based on a recent ESMO consensus statement. EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated significant improvements in patient outcomes in EGFRm metastatic NSCLC. The benefits of these agents have also translated to patients with EGFRm early-stage resectable disease as adjuvant therapy. The role of EGFR-TKIs has yet to be prospectively characterized in the unresectable setting. Preliminary efficacy signals for EGFR-TKIs in unresectable EGFRm stage III NSCLC have been reported from a limited number of subgroup and retrospective studies. Several clinical trials are ongoing assessing the safety and efficacy of EGFR-TKIs in this patient population. Here, we review the current management of unresectable EGFRm stage III NSCLC. We outline the rationale for investigating EGFR-TKI strategies in this setting and discuss ongoing studies. Finally, we discuss the evidence gaps and future challenges for treating patients with unresectable EGFRm stage III NSCLC.


Functional role of the alpha-chain of complement receptor type 3 in human eosinophil-dependent antibody-mediated cytotoxicity against schistosomes.
The participation of complement receptor type 3 (CR3) in antibody-dependent effector function of human eosinophils against parasites was studied by using monoclonal antibodies directed against various surface molecules. Both adherence and cytotoxicity of hypodense eosinophils to IgE-coated schistosomula of Schistosoma mansoni were strongly inhibited by anti-CR3 antibodies (OKM1 or Mo1). The specificity of the inhibitory effect for the alpha-chain of CR3 was shown by the lack of inhibition of anti-beta-chain or anti-LFA1 alpha-chain monoclonal antibodies, although these antigens were expressed on human eosinophils. These results associated to previous works on IgE receptors demonstrate that both receptor for Fc fragments of IgE and CR3 are essential in IgE-dependent cytotoxicity of human eosinophils. Flow microfluorometry analysis revealed that hypodense eosinophils were more intensively stained by OKM1 antibodies than the normodense populations. In the case of IgG-mediated cytotoxicity by normodense eosinophils, only the enhancement of cytotoxicity due to monokine activation was inhibited by anti-CR3 alpha-chain antibodies. These findings suggest an increased expression of CR3 on eosinophils after activation either in vivo or in vitro. The participation of CR3 in IgE-mediated cytotoxicity against schistosomes was also required in the case of blood monocytes but not for platelet-mediated killing, which does not require prior adherence. The biologic role of CR3 is therefore extended to effector mechanisms involving eosinophils and two different isotypes of antibodies and possibly implied in immunity against schistosomes.


Impact of protocolized diuresis for de-resuscitation in the intensive care unit.
Administration of diuretics has been shown to assist fluid management and improve clinical outcomes in the critically ill post-shock resolution. Current guidelines have not yet included standardization or guidance for diuretic-based de-resuscitation in critically ill patients. This study aimed to evaluate the impact of a multi-disciplinary protocol for diuresis-guided de-resuscitation in the critically ill. This was a pre-post single-center pilot study within the medical intensive care unit (ICU) of a large academic medical center. Adult patients admitted to the Medical ICU receiving mechanical ventilation with either (1) clinical signs of volume overload via chest radiography or physical exam or (2) any cumulative fluid balance ≥ 0 mL since hospital admission were eligible for inclusion. Patients received diuresis per clinician discretion for a 2-year period (historical control) followed by a diuresis protocol for 1 year (intervention). Patients within the intervention group were matched in a 1:3 ratio with those from the historical cohort who met the study inclusion and exclusion criteria. A total of 364 patients were included, 91 in the protocol group and 273 receiving standard care. Protocolized diuresis was associated with a significant decrease in 72-h post-shock cumulative fluid balance [median, IQR - 2257 (- 5676-920) mL vs 265 (- 2283-3025) mL; p < 0.0001]. In-hospital mortality in the intervention group was lower compared to the historical group (5.5% vs 16.1%; p = 0.008) and higher ICU-free days (p = 0.03). However, no statistically significant difference was found in ventilator-free days, and increased rates of hypernatremia and hypokalemia were demonstrated. This study showed that a protocol for diuresis for de-resuscitation can significantly improve 72-h post-shock fluid balance with potential benefit on clinical outcomes.


Percutaneous transluminal rotational atherectomy for coronary artery disease.
This is an update of the review on 'Percutaneous transluminal rotational atherectomy for coronary artery disease' first published in The Cochrane Library Issue 4, 2003. Percutaneous transluminal coronary rotational atherectomy (PTCRA) debulks atherosclerotic plaque from coronary arteries using an abrasive burr. On rotation, the burr selectively removes hard tissue. PTCRA has been used both as an alternative to and in conjunction with balloon angioplasty to open up blocked coronary arteries. Its ongoing effectiveness and safety compared with other modes of removing atherosclerotic plaques is reviewed. To assess the effects of PTCRA for coronary artery disease in patients with non-complex and complex lesions (e.g. ostial, long or diffuse lesions or those arising from in-stent re-stenosis) of the coronary arteries. For the original review, we searched the Heart Group Specialised Register; The Cochrane Library to Issue 2, 2001; and MEDLINE, CINAHL, EMBASE and Current Contents to December 2002 and reviewed reference lists for relevant articles. For the current review, we searched the same registries from 2002 to 2012 and reviewed reference lists for relevant articles. We included randomised and quasi-randomised controlled trials of PTCRA compared with placebo, no treatment or another intervention and excluded cross-over trials. Two review authors independently extracted data and assessed the risk of bias of the studies identified. Data were extracted independently by two review authors. We asked authors of trials to provide information when missing data were encountered. Statistical summaries used risk ratios (RR) and weighted mean differences. We included 12 trials enrolling 3474 patients. The overall risk of bias was unclear for the majority of articles due to a lack of reported data; however, the authors determined that this would be unlikely to impact negatively as most data outcomes were objective (e.g. death vs. no death). There was no evidence of the effectiveness in improving patient outcomes of PTCRA in non-complex lesions. In complex lesions, there were no statistically significant differences in re-stenosis rates at six months (RR 1.05; 95% confidence interval (CI) 0.83 to 1.33) and at one year (RR 1.21; 95% CI 0.95 to 1.55) in those receiving PTCRA with adjunctive balloon angioplasty (PTCA) (PTCRA/PTCA) compared to those receiving PTCA alone. Morphological characteristics distinguishing complex lesions have not been examined in parallel-arm randomised controlled trials. The evidence for the effectiveness of PTCRA in in-stent re-stenosis is unclearCompared to angioplasty alone, PTCRA/PTCA did not result in a statistically significant increase in the risk of major adverse cardiac events (myocardial infarction (MI), emergency cardiac surgery or death) during the in-hospital period (RR 1.27; 95% CI 0.86 to 1.90). Compared to angioplasty, PTCRA was associated with nine times the risk of an angiographically detectable vascular spasm (RR 9.23; 95% CI 4.61 to 18.47), four times the risk of perforation (RR 4.28; 95% CI 0.92 to 19.83) and about twice the risk of transient vessel occlusions (RR 2.49; 95% CI 1.25 to 4.99) while angiographic dissections (RR 0.48; 95% CI 0.34 to 0.68) and stents used as a bailout procedure (RR 0.29; 95% CI 0.09 to 0.87) were less common. When conventional PTCA is feasible, PTCRA appears to confer no additional benefits. There is limited published evidence and no long-term data to support the routine use of PTCRA in in-stent re-stenosis. Compared to angioplasty alone, PTCRA/PTCA did not result in a higher incidence of major adverse cardiac events, but patients were more likely to experience vascular spasm, perforation and transient vessel occlusion. In certain circumstances (e.g. patients ineligible for cardiac surgery, those with architecturally complex lesions, or those with lesions that fail PTCA), PTCRA may achieve satisfactory re-vascularisation in subsequent procedures.


High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease.
Most patients diagnosed with primary chronic cold agglutinin disease (CAD) have a clonal lymphoproliferative bone marrow disorder. Treatment with rituximab is the only well-documented effective therapy, leading to 45%-60% partial responses (PR). Complete responses (CR) are rare, and median response duration is only 11 months. In a prospective multicenter trial, 29 patients received rituximab 375 mg/m(2) on days 1, 29, 57 and 85; and fludarabine orally, 40 mg/m(2) on days 1-5, 29-34, 57-61 and 85-89. Twenty-two patients (76%) responded, 6 (21%) achieving CR and 16 (55%) PR. Among 10 patients nonresponsive to rituximab monotherapy, 1 achieved CR and 6 PR. Median increase in hemoglobin level was 3.1 g/dL among the responders and 4.0 g/dL in those who achieved CR. Lower quartile of response duration was not reached after 33 months. Estimated median response duration was more than 66 months. Grade 3-4 hematologic toxicity occurred in 12 patients (41%). In conclusion, fludarabine and rituximab combination therapy is very efficient in patients with CAD. Toxicity may be a concern, and benefits should be carefully weighed against risks in very old and comorbid patients. It remains to be established whether the combination should be first-line or an efficient second-line therapy in CAD patients requiring treatment.


Protocol: a 'One health' two year follow-up, mixed methods study on antibiotic resistance, focusing children under 5 and their environment in rural India.
Antibiotic resistance has been referred to as 'the greatest malice of the 21st century' and a global action plan was adopted by the World Health Assembly in 2015. There is a wealth of independent studies regarding antibiotics and resistant bacteria in humans, animals and their environment, however, integrated studies are lacking, particularly ones that simultaneously also take into consideration the health related behaviour of participants and healthcare providers. Such, 'One health' studies are difficult to implement, because of the complex teamwork that they entail. This paper describes the protocol of a study that investigates 'One health' issues regarding antibiotic use and antibiotic resistance in children and their environment in Indian villages. Both quantitative and qualitative studies are planned for a cohort of children, from 6 villages, and their surrounding environment. Repeated or continues data collection is planned over 2 years for quantitative studies. Qualitative studies will be conducted once. Studies include parents' health seeking behavior for their children (1-3 years of age at the onset), prescribing pattern of formal and informal healthcare providers, analysis of phenotypic antibiotic resistance of Escherichia coli from samples of stool from children and village animals, household drinking water, village source water and waste water, and investigation on molecular mechanisms governing resistance. Analysis of interrelationship of these with each other will also be done as basis for future interventions. Ethics approval has been obtained from the Institutional Ethics Committee R.D. Gardi Medical College, Ujjain, India (No: 2013/07/17-311). The findings of the study presented in this protocol will add to our knowledge about the multi-factorial nature of causes governing antibiotic use and antibiotic resistance from a 'One health' perspective. Our study will be the first of its kind addressing antibiotic use and resistance issues related to children in a One-health approach, particularly for rural India.


Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia Group B Study 9663.
The mechanisms responsible for prostate cancer androgen independence are diverse. Mutations of the androgen receptor (AR) gene that broaden ligand specificity have been implicated. Bone marrow specimens containing prostate tumor were obtained from men undergoing antiandrogen withdrawal for AR sequence analysis and clinical correlation. Eligible men enrolled on a trial of antiandrogen withdrawal had a minimum prostate-specific antigen (PSA) level of 5 ng/dL that was increasing on castration therapy including an antiandrogen. With informed consent, marrow biopsies were obtained to collect prostate tumor. Additional samples were obtained from men enrolled on chemotherapy trials. AR cDNA or DNA was polymerase chain reaction-amplified, cloned, and sequenced. The AR CAG repeat length was recorded. One hundred eighty-four bone marrow biopsies were obtained, and 48 had prostate tumor detected by light microscopy. The ARs from these 48 samples were sequenced. Overall, five (10%) of 48 tumors had mutated ARs. AR point mutations were detected in the hormone-binding domain involved in transcription factor binding. Three mutations were novel in prostate cancer. One tumor sample had a CAG repeat length of 21, compared with germline length of 22 repeats. There was no association between detectability of AR mutations and antiandrogen withdrawal response or survival. These data suggest that AR mutations are present in approximately 10% of patients with prostate cancer who experience treatment failure with hormone therapy that included an antiandrogen. Mutations in the AR likely confer a growth advantage for a subset of progressive prostate cancers. Correlation of AR mutation with antiandrogen withdrawal response or survival could not be made.


The Effect of a Community-Based Self-Help Intervention: Korean Americans With Type 2 Diabetes.
Korean Americans are one of the most underserved ethnic/linguistic minority groups owing to cultural and institutional barriers; there is an urgent need for culturally competent diabetes management programs in the Korean American community for those with type 2 diabetes. The purpose of this study was to test the effectiveness of a community-based, culturally tailored, multimodal behavioral intervention program in an ethnic/linguistic minority group with type 2 diabetes. An RCT with waitlist comparison based on the Predisposing, Reinforcing, and Enabling Constructs in Education/environmental Diagnosis and Evaluation (PRECEDE)-Policy, Regulatory, and Organizational Constructs in Educational and Environmental Development (PROCEED) and self-help models. Data were collected between September 2010 and June 2013 and were analyzed in August-December 2014. Statistical significance was set at p<0.05. In a naturally occurring community setting, a total of 250 Korean Americans with type 2 diabetes were randomized into an intervention group (n=120) or a control group (n=130). The intervention consisted of key self-management skill-building activities through 12 hours of group education sessions, followed by integrated counseling and behavioral coaching by a team of RNs and community health workers. Primary (clinical) outcomes were hemoglobin A1c, glucose, total cholesterol, and low-density lipoprotein at baseline and at 3, 6, 9, and 12 months. Secondary (psychosocial and behavioral) outcomes included diabetes-related quality of life, self-efficacy, adherence to diabetes management regimen, and health literacy. During the 12-month project, the intervention group demonstrated 1.0%-1.3% (10.9-14.2 mmol/mol) reductions in hemoglobin A1c, whereas the control group achieved reductions of 0.5%-0.7% (5.5-7.7 mmol/mol). The differences between the two groups were statistically significant. The intervention group showed statistically significant improvement in diabetes-related self-efficacy and quality of life when compared with the control group. RN/community health worker teams equipped with culturally tailored training can be effective in helping an ethnic/linguistic minority group manage diabetes in the community.


The Dynamic Regulatory Genome of Capsaspora and the Origin of Animal Multicellularity.
The unicellular ancestor of animals had a complex repertoire of genes linked to multicellular processes. This suggests that changes in the regulatory genome, rather than in gene innovation, were key to the origin of animals. Here, we carry out multiple functional genomic assays in Capsaspora owczarzaki, the unicellular relative of animals with the largest known gene repertoire for transcriptional regulation. We show that changing chromatin states, differential lincRNA expression, and dynamic cis-regulatory sites are associated with life cycle transitions in Capsaspora. Moreover, we demonstrate conservation of animal developmental transcription-factor networks and extensive network interconnection in this premetazoan organism. In contrast, however, Capsaspora lacks animal promoter types, and its regulatory sites are small, proximal, and lack signatures of animal enhancers. Overall, our results indicate that the emergence of animal multicellularity was linked to a major shift in genome cis-regulatory complexity, most notably the appearance of distal enhancer regulation.


Risk analysis of the governance system affecting outcomes in the Great Barrier Reef.
The state and trend of the Great Barrier Reef's (GBR's) ecological health remains problematic, influencing United Nations Educational, Scientific and Cultural Organization (UNESCO) statements regarding GBR governance. While UNESCO's concerns triggered separate strategic assessments by the Australian and Queensland governments, there has been no independent and integrated review of the key risks within the overall system of governance influencing GBR outcomes. As a case study of international significance, this paper applies Governance Systems Analysis (GSA), a novel analytical framework that identifies the governance themes, domains and subdomains most likely to influence environmental and socio-economic outcomes in complex natural systems. This GBR-focussed application of GSA identifies governance subdomains that present high, medium, or low risk of failure to produce positive outcomes for the Reef. This enabled us to determine that three "whole of system" governance problems could undermine GBR outcomes. First, we stress the integrative importance of the Long Term Sustainability Plan (LTSP) Subdomain. Sponsored by the Australian and Queensland governments, this subdomain concerns the primary institutional arrangements for coordinated GBR planning and delivery, but due to its recent emergence, it faces several internal governance challenges. Second, we find a major risk of implementation failure in the achievement of GBR water quality actions due to a lack of system-wide focus on building strong and stable delivery systems at catchment scale. Finally, we conclude that the LTSP Subdomain currently has too limited a mandate/capacity to influence several high-risk subdomains that have not been, but must be more strongly aligned with Reef management (e.g. the Greenhouse Gas Emission Management Subdomain). Our analysis enables exploration of governance system reforms needed to address environmental trends in the GBR and reflects on the potential application of GSA in other complex land and sea-scapes across the globe.


Immunohistochemical evaluation of estrogen and progesterone receptor content in 183 patients with endometrial carcinoma. Part I: Clinical and histologic correlations.
A series of 183 cases of primary endometrial carcinomas were immunohistochemically stained for estrogen receptors (ERs) and progesterone receptors (PRs) using formalin-fixed, paraffin-embedded sections. All specimens were obtained from uterine curettages performed at the time of the initial diagnosis or initial therapy. The ER and PR content in the malignant and benign components (benign epithelium, stroma, and myometrium) was evaluated separately for positivity and divided into three groups according to the percentage of positive cells and the intensity of the nuclear stain. Endometrioid-type adenocarcinoma had the highest degree of positivity for both receptors, followed by adenosquamous carcinoma, serous carcinoma, and clear cell carcinoma. The positivity for ERs and PRs of the malignant component was statistically correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage (P less than 0.01), FIGO grade (P less than 0.001), and nuclear grade (P less than 0.0001) of the tumors. The degrees of ER and PR positivity of the malignant component correlated with each other (P less than 0.0001). There was no association between the depth of myometrial tumor invasion and either receptor status of the malignant component. There was a significant association between the presence of lymph vessel invasion and the positivity for PR. Positivity for PR correlated negatively with the patients' ages (P less than 0.004). The results of this study indicate that immunohistochemical analysis of sex steroid receptor status on formalin-fixed, paraffin-embedded tissue offers an excellent alternative to the standard biochemical procedure.


Orientation-averaged light-extinction characteristics of compound particles including aggregate effects.
Orientation-averaged light-extinction characteristics of compound sulfate-carbon-soot particles have been analyzed with a discrete-dipole algorithm (DDSCAT code) for r1/r2 (ratio of primary-particle radius to secondary-particle radius) in the range 7 to 1 and for wavelengths from 0.4 to 0.8 microm. It was found that compound particles above a particle radius of approximately 0.2 microm exhibit light-extinction characteristics that closely match those of a pure sulfate particle. The shielding of the carbon particle by the primary particle apparently reduces the absorption effect of the soot particle over the range of all possible orientations. In light of the fact that soot particles tend to be small in comparison with host sulfate particles, the light-extinction characteristics of compound particles are dictated by the optical properties of the host particles. This result has been applied for aerosol aggregates with log-normal size distributions. For r1/r2 > or = 2 the aggregate extinction coefficient of a group of compound particles remains within 12% of that of a group consisting only of sulfate particles. This allows for effective calculation of the overall aerosol light extinction on the basis of the optical and geometrical properties of the constituent particles without having to include a compound-geometry effect.


Utility of multiphase contrast enhancement patterns on CEH-EUS for the differential diagnosis of IPMN-derived and conventional pancreatic cancer.
Intraductal papillary mucinous neoplasm (IPMN) is reported as a high-risk factor for pancreatic cancer (PC) that includes IPMN-derived cancers (IPMC) and the development of invasive pancreatic ductal adenocarcinoma (PDAC) concomitant with IPMN. Since invasive IPMC and PDAC exhibit different oncological behaviors, their differentiation is clinically important. We aimed to investigate the use of contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) for the differential diagnosis between invasive IPMC and PDAC. This study involved 183 consecutive patients with PC (invasive IPMC: 42, PDAC concomitant with IPMN: 9, without IPMN: 132) who underwent CEH-EUS preoperatively. While investigating the patterns, enhanced effects in the solid part of the tumor were compared with those in the surrounding pancreatic parenchyma after administration of Sonazoid® and evaluated as hyperenhanced, isoenhanced, or hypoenhanced. We retrospectively compared the enhanced pattern of CEH-EUS by using multiphasic analysis and clinicopathological factors between invasive IPMC and PDAC. In multiphase evaluations at 20, 40 and 60 s in CEH-EUS, 75.2% (106/141) of PDACs were hypoenhanced (-) at ≥2 of the 3 time points, with significant differences from those of invasive IPMC (P < 0.001). The solid tumor diameter was significantly larger in PDAC than in invasive IPMC, and the tumor stage and preoperative serum carbohydrate antigen 19-9 level were higher. After propensity score matching of stage and solid tumor diameter, contrast enhancement patterns were significantly more persistent in invasive IPMC than in PDAC (P = 0.0013). Multiphase evaluation using CEH-EUS is a useful method for differentiating between invasive IPMC and PDAC.


Seroprevalence of Toxoplasma gondii infection in pet dogs in Lanzhou, Northwest China.
In recent years, surveys of Toxoplasma gondii infection in dogs have been reported worldwide, including China. However, little is known about the prevalence of T. gondii in pet dogs in Northwest China. In the present study, the prevalence of T. gondii in pet dogs in Lanzhou, China was investigated using the modified agglutination test (MAT). In this survey, antibodies to T. gondii were found in 28 of 259 (10.81%) pet dogs, with MAT titers of 1:20 in 14 dogs, 1:40 in nine, 1:80 in four, and 1:160 or higher in one dog. The prevalence ranged from 6.67% to 16.67% among dogs of different ages, with low rates in young pet dogs, and high rates in older pet dogs. The seroprevalence in dogs >3 years old was higher than that in dogs ≤1 years old, but the difference was not statistically significant (P >0.05). The seroprevalence in male dogs was 12.50% (17 of 136), and in female dogs it was 8.94% (11 of 123), but the difference was not statistically significant (P >0.05). A high prevalence of T. gondii infection was found in pet dogs in Lanzhou, Northwest China, which has implications for public health in this region. In order to reduce the risk of exposure to T. gondii, further measures and essential control strategies should be carried out rationally in this region.


Nonalcoholic steatohepatitis: a toxic liver disease in industrial workers.
Occupational/environmental exposure to hepatotoxins has recently been implicated in nonalcoholic steatohepatitis (NASH). The aims of this study were to determine the presence and frequency of NASH in a large group of workers chronically exposed to several volatile petrochemical products in an industrial area in north-east Brazil and to observe its course in workers removed from the work environment. 1500 asymptomatic workers were screened with standard liver blood tests during 1994-5. Those with elevated transaminases (>3x normal) on 3 occasions were evaluated further both clinically and with serum HBsAg, anti-HCV, ferritin, lipids and autoantibody determination. Patients with either no etiological diagnosis, positive HBsAg/anti-HCV serology and/or excess alcohol intake underwent liver biopsy. Those with obesity, diabetes or an isolated abnormal GGT were excluded. Of workers diagnosed as having NASH (compatible histology and no excess alcohol intake), a proportion were removed from the work environment and evaluated monthly with liver blood tests and a repeat liver biopsy 8-14 months later. 112 workers had abnormal transaminases and 32 fulfilled the criteria for liver biopsy. 20 of these were classified as NASH, the remainder had viral hepatitis (n = 6), alcoholic liver disease (n = 5) or portal vein thrombosis (n = 1). In all of the 10/20 who were removed from the work environment, their aminotransferases and GGT gradually decreased and their histology improved. These results demonstrate that NASH can occur following chronic exposure to volatile petrochemical substances in the workplace. Exposed workers should be regularly screened for the presence of liver damage and ideally removed from the work environment where possible.


Cooperative problem solving by tufted capuchin monkeys (Cebus apella): spontaneous division of labor, communication, and reciprocal altruism.
Using an experimentally induced cooperation task, the authors investigated whether tufted capuchin monkeys (Cebus apella) share the following 3 characteristics of cooperation with humans: division of labor, communication, and reciprocal altruism. In Experiment 1, the authors trained individual monkeys to perform the necessary sequence of actions for rewards and tested them in pairs to assess whether they could solve the task by spontaneously dividing the sequence of actions. All pairs solved this task. In Experiment 2, monkeys worked in the cooperation task and a task requiring no partner help. They looked at the partner significantly longer in the former task than in the latter, but communicative intent could not be determined. In Experiment 3, only 1 of 2 participants obtained a reward on each trial. Monkeys maintained cooperation when their roles were reversed on alternate trials. Their cooperative performances demonstrated division of labor; results suggest task-related communication and reciprocal altruism.


Transepithelial glucose transport in cell culture.
Pig kidney cell line LLC-PK1 cultured on a collagen-coated membrane filter formed a continuous sheet of oriented asymmetrical epithelial cells joined by circumferential occluding junctions. In the presence of 5.5 mM D-glucose, a potential difference (PD) of 2.8 mV, apical bath negative, short-circuit current Isc of 13.2 microA . cm-2, and transepithelial resistance of 211 omega . cm2 were recorded. Isc and PD were reduced by phlorizin added to the apical bath but were unaffected when phlorizin was placed in the basolateral bath. Ouabain or the replacement of Na by tris-(hydroxymethyl)aminomethane or choline abolished the Isc. The sugar concentrations required to produce the half-maximal Isc were 0.13 mM beta-methyl-D-glucoside, 0.28 mM D-glucose, 0.65 mM alpha-methyl-D-glucoside, 0.77 mM 6-deoxy-D-glucose, 4.8 mM D-galactose, and 29 mM 3-O-methylglucose. When [Na] was reduced, the D-glucose required for half-maximal SCC increased. Isotopically 3H- and 14C-labeled D-glucose were used to determine simultaneous bidirectional fluxes; a resultant net apical-to-basolateral flux was present and could be abolished by phlorizin. The transported isotope cochromatographed with labeled D-glucose, indicating negligible metabolism. The cell culture model provides advantages for investigation of mechanisms of transepithelial glucose transport.


HIV-1 viral protein R causes peripheral nervous system injury associated with in vivo neuropathic pain.
Painful peripheral neuropathy has become the principal neurological disorder in HIV/AIDS patients. Herein, we investigated the effects of a cytotoxic HIV-1 accessory protein, viral protein R (Vpr), on the peripheral nervous system (PNS). Host and viral gene expression was investigated in peripheral nerves from HIV-infected individuals and in HIV-infected human dorsal root ganglion (DRG) cultures by RT-PCR and immunocytochemistry. Cytosolic calcium ([Ca(2+)]) fluxes and neuronal membrane responses were analyzed in cultured DRGs. Neurobehavioral responses and cytokine levels were assessed in a transgenic mouse model in which the vpr transgene was expressed in an immunodeficient background (vpr/RAG1(-/-)). Vpr transcripts and proteins were detected in peripheral nerves and DRGs from HIV-infected patients. Exposure of rat or human cultured DRG neurons to Vpr rapidly increased [Ca(2+)] and action potential frequency while increasing input resistance. HIV infection of human DRG cultures caused neurite retraction (P<0.05), accompanied by induction of interferon-α (IFN-α) transcripts (P<0.05). vpr/RAG1(-/-) mice expressed Vpr together with increased IFN-α (P<0.05) in the PNS and also exhibited mechanical allodynia, unlike their vpr/RAG1(-/-) littermates (P<0.05). Herein, Vpr caused DRG neuronal damage, likely through cytosolic calcium activation and cytokine perturbation, highlighting Vpr's contribution to HIV-associated peripheral neuropathy and ensuing neuropathic pain.


Alternative energy futures: the case for electricity.
The energy trends of the past and their likely evolution in the next 50 years have been analyzed in the light of technological progress. It is concluded that society will tend to become less centralized than in the past and that it is possible to have future per capita values of energy consumption at the world level similar to those at present, with a substantial redistribution to allow for economic growth of the less developed countries. A condition for this is increasing penetration of electricity. The rationale for the suggested scenario is described, and prospects for electricity for both the industrialized and developing countries are discussed.


Forest restoration and fuels reduction work: Different pathways for achieving success in the Sierra Nevada.
Fire suppression and past selective logging of large trees have fundamentally changed frequent-fire-adapted forests in California. The culmination of these changes produced forests that are vulnerable to catastrophic change by wildfire, drought, and bark beetles, with climate change exacerbating this vulnerability. Management options available to address this problem include mechanical treatments (Mech), prescribed fire (Fire), or combinations of these treatments (Mech + Fire). We quantify changes in forest structure and composition, fuel accumulation, modeled fire behavior, intertree competition, and economics from a 20-year forest restoration study in the northern Sierra Nevada. All three active treatments (Fire, Mech, Mech + Fire) produced forest conditions that were much more resistant to wildfire than the untreated control. The treatments that included prescribed fire (Fire, Mech + Fire) produced the lowest surface and duff fuel loads and the lowest modeled wildfire hazards. Mech produced low fire hazards beginning 7 years after the initial treatment and Mech + Fire had lower tree growth than controls. The only treatment that produced intertree competition somewhat similar to historical California mixed-conifer forests was Mech + Fire, indicating that stands under this treatment would likely be more resilient to enhanced forest stressors. While Fire reduced modeled wildfire hazard and reintroduced a fundamental ecosystem process, it was done at a net cost to the landowner. Using Mech that included mastication and restoration thinning resulted in positive revenues and was also relatively strong as an investment in reducing modeled wildfire hazard. The Mech + Fire treatment represents a compromise between the desire to sustain financial feasibility and the desire to reintroduce fire. One key component to long-term forest conservation will be continued treatments to maintain or improve the conditions from forest restoration. Many Indigenous people speak of "active stewardship" as one of the key principles in land management and this aligns well with the need for increased restoration in western US forests. If we do not use the knowledge from 20+ years of forest research and the much longer tradition of Indigenous cultural practices and knowledge, frequent-fire forests will continue to be degraded and lost.


Size-dependent sex change can be the ESS without any size advantage of reproduction when mortality is size-dependent.
Almost all models of sex change evolution assume that reproductive rate increases with body size. However, size-dependent sex changing plants often show size-independent reproductive success, presumably due to pollen limitation. Can the observed size-dependent sex change pattern be the ESS in this case? To answer this question, we analyze a game model of size-dependent sex expression in plants. We assume: (1) reproductive rate is perfectly independent of size; (2) mortality decreases with size in the same way for both sexes; (3) growth rates decrease at maturity, more for females than males. We show that the ESS is size-dependent sex expression: small individuals are vegetative, intermediate individuals are male, and large individuals are female. These results demonstrate that mortality is important in size-dependent sex allocation even when mortality rate is independent of sex. They also offer an explanation of why we see populations in poor environments to have sex ratios more biased toward the first sex relative to high quality environments.


The chemical effect goes resonant - a full quantum mechanical approach on TERS.
Lately, experimental evidence of unexpectedly extremely high spatial resolution of tip-enhanced Raman scattering (TERS) has been demonstrated. Theoretically, two different contributions are discussed: an electromagnetic effect, leading to a spatially confined near field due to plasmonic excitations; and the so-called chemical effect originating from the locally modified electronic structure of the molecule due to the close proximity of the plasmonic system. Most of the theoretical efforts have concentrated on the electromagnetic contribution or the chemical effect in case of non-resonant excitation. In this work, we present a fully quantum mechanical description including non-resonant and resonant chemical contributions as well as charge-transfer phenomena of these molecular-plasmonic hybrid systems at the density functional and the time-dependent density functional level of theory. We consider a surface-immobilized tin(ii) phthalocyanine molecule as the molecular system, which is minutely scanned by a plasmonic tip, modeled by a single silver atom. These different relative positions of the Ag atom to the molecule lead to pronounced alterations of the Raman spectra. These Raman spectra vary substantially, both in peak positions and several orders of magnitude in the intensity patterns under non-resonant and resonant conditions, and also, depending on, which electronic states are addressed. Our computational approach reveals that unique - non-resonant and resonant - chemical interactions among the tip and the molecule significantly alter the TERS spectra and are mainly responsible for the high, possibly sub-Angstrom spatial resolution.


Predictive validity of the HCR-20 for violent and non-violent sexual behaviour in a secure mental health service.
Violent and non-violent sexual behaviour is a fairly common problem among secure mental health service patients, but specialist sexual violence risk assessment is time-consuming and so performed infrequently. We aimed to establish whether a commonly used violence risk assessment tool, the Health Clinical Risk management 20(HCR-20), has predictive validity specifically for inappropriate sexual behaviour. A pseudo-prospective cohort design was used for a study in the adult wards of a large provider of specialist secure mental health services. Routine clinical team HCR-20 assessments were extracted from records, and incidents involving inappropriate sexual behaviour were recorded for the 3 months following assessment. Of 613 patients, 104 (17%) had engaged in at least one inappropriate sexual behaviour; in 65 (10.6%), the sexual act was violent. HCR-20 total score, clinical and risk management subscales, predicted violent and non-violent sexual behaviour. The negative predictive value of the HCR-20 for inappropriate sexual behaviour was over 90%. Prediction of violent sexual behaviour may be regarded as well within the scope of the HCR-20 as a structured professional judgement tool to aid violence risk prediction, but we found that it also predicts behaviours that may be of concern but fall below the violence threshold. High negative predictive values suggest that HCR-20 scores may have some utility for screening out patients who do not require more specialist assessment for inappropriate sexual behaviour. Copyright © 2015 John Wiley & Sons, Ltd.


Is Playing Soccer More Osteogenic for Females Before the Pubertal Spurt?
The aims of this study were to assess bone mass in children and adolescent soccer players and to evaluate the influence of both gender and pubertal status on bone mass. A total of 110 soccer players (75 males / 35 females; 12.73 ± 0.65 / 12.76 ± 0.59 years) participated in this cross-sectional study. They were divided into two groups according to their pubertal status. Bone and lean masses were measured with Dual-energy X-ray Absorptiometry. An independent t-test and an adjusted by subtotal lean and training experience multivariate analysis of covariance were used to analyse the differences in bone mass values between genders and maturity status. Female soccer players presented higher bone mass values than their male counterparts in most of the measured weight-bearing sites. Moreover, when stratifying by pubertal status, peripubertal and postpubertal females had higher subtotal body and lumbar spine bone mass than males. Comparing between pubertal status groups before adjustment, both male and female postpubertal players showed higher bone mass than their pubertal counterparts. After adjusting, these differences disappeared and, in fact results were inverted as bone mass at the femoral neck was higher in both male and female peripubertal soccer players than in postpubertal players. Bone mass seems to be more intensely stimulated by playing soccer in female than male players, particularly in the lumbar spine. The results of peripubertal players showing higher bone mass at the femoral neck after adjusting suggest that playing soccer during the peripubertal stage could be an effective activity to achieve optimal bone mass values.


Uncovering the Dynamic Mechanisms of the Pseudomonas Aeruginosa Quorum Sensing and Virulence Networks Using Boolean Modelling.
Pseudomonas aeruginosa is an opportunistic pathogen with a large repertoire of virulence factors that allow it to cause acute and chronic infections. Treatment of P. aeruginosa infections often fail due to its antibiotic resistance mechanisms, thus novel strategies aim at targeting virulence factors instead of growth-related features. Although the elements of the virulence networks of P. aeruginosa have been identified, how they interact and influence the overall virulence regulation is unclear. In this study, we reconstructed the signaling and transcriptional regulatory networks of 12 acute and 8 chronic virulence factors, and the 4 quorum sensing systems of P. aeruginosa. Using Boolean modelling, we showed that the static interactions and the time when they take place are important features in the quorum sensing network. We also found that the virulence factors of the acute networks are under strict repression or non-strict activation, while those of most of the chronic networks are under repression. In conclusion, Boolean modelling provides a system-level view of the P. aeruginosa virulence and quorum sensing networks to gain new insights into the various mechanisms that support its pathogenicity. Thus, we suggest that Boolean modelling could be used to guide the design of new treatments against P. aeruginosa.


Nonpharmacological Cognitive Impairment Prevention Interventions in Older Adults Undergoing Cardiac Surgery: A Systematic Review.
More than 1 million individuals undergo cardiothoracic surgery for coronary artery bypass graft or valve repair/replacement annually in the United States. There is an increased risk of developing serious cognitive impairment post cardiothoracic surgery. Pharmacological interventions and surgical techniques were associated with improvements in cognitive function in previous systematic reviews. However, a gap in the literature exists regarding how nonpharmacological interventions can mitigate cognitive impairment in adults undergoing cardiac surgery. The aim of this study was to explore the effectiveness of nonpharmacological interventions to reduce the detrimental effects of cardiac surgery on cognitive function in patients after cardiothoracic surgery. CINAHL, MEDLINE, PubMed, EMBASE, PsycINFO, and Web of Science databases were searched following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines from January 2011 to February 2022. Nineteen studies were included in this review. Researchers defined cognitive impairment differently across studies. Various interventions were used to reduce cognitive impairment post cardiothoracic surgery, with the most common being remote ischemic limb conditioning. The interventions used to reduce cognitive impairment were heterogeneous in outcomes, measurements, and time of assessment, but only 2 interventions were associated with a reduction in cognitive impairment. This review is a unique synthesis of the quality of interventions that address broader components of cognition. Researchers used various interventions to reduce cognitive impairment; the outcomes, instruments, and time interval for measurements were heterogeneous. Researchers should conduct future studies at multiple time intervals, using a comprehensive measure of cognitive impairment to better understand the impact of cognitive impairment interventions postoperatively.


Changes in somatosensory evoked potentials and Hoffmann reflexes during fast isometric contraction of foot plantarflexor in humans.
In the present study, the extent to which the early component of somatosensory evoked potentials (SEPs) and the Hoffmann (H-) reflex induced by stimulation of the posterior tibial nerve are altered during the ascending and descending phases of fast plantarflexion was investigated. SEPSs and H-reflex of the soleus following tibial nerve stimulation were examined during fast plantarfiexion when performed by nine normal subjects. The analyses focused on differences in amplitude modulation of the P30-P40 component of SEP and the H-reflex between the ascending and descending phases of full-wave rectified and averaged soleus electromyographic (EMG) activity. The H-reflex amplitude was significantly increased and decreased during the ascending and descending phases more than under resting control conditions, respectively. The reduction of SEP amplitude was 49% for the ascending phase and 83% for the descending phases with respect to the resting situation. Modulation of SEP during the ascending and descending phases was robustly retained even during ischemic nerve blockade of large diameter afferent fibers. These findings suggest that the transmission of afferent inputs from muscle spindles to motoneurons and to the somatosensory cortex during fast isometric contraction of the plantar flexor is regulated in a time-dependent fashion by descending commands.


[Action of morphine and fentanyl during the electrostimulation of biologically active points].
Experiments on rabbits showed the summation of analgesia induced by electric stimulation of biologically active points (BAP) and by administration of morphine and fentanil within a certain dosage range. The differences recorded in cortical evoked potentials in response to excitation of BAP and of an active point of the rabbit forefoot were levelled off in the presence of morphine administration.


Endodermal sinus tumor diagnosed in pregnancy: a case report.
Pure endodermal sinus tumor (EST) of the ovary is an uncommon germ cell tumor characterized by rapid growth. Its occurrence during pregnancy is extremely rare. The case of a 34-year-old woman with EST stage IC diagnosed in the 22nd week of gestation is presented. She received four cycles of cisplatin monotherapy during pregnancy. Further, three cycles of combination chemotherapy (cisplatin, bleomycin, and etoposide) were administered. Twenty-eight months posttreatment the patient was in complete remission with good health. A healthy female infant was delivered by cesarean section in the 35th week of pregnancy. The child showed normal laboratory, pediatric, and neurologic examination at the time of discharge from hospital and during the first and second years of her life. We conclude that the prognosis of EST is very good if patient receives adjuvant therapy. Cisplatin monotherapy seems to be effective and safe during pregnancy.


Component-based modeling and reachability analysis of genetic networks.
Genetic regulatory networks usually encompass a multitude of complex, interacting feedback loops. Being able to model and analyze their behavior is crucial for understanding their function. However, state space explosion is becoming a limiting factor in the formal analysis of genetic networks. This paper explores a modular approach for verification of reachability properties. A framework for component-based modeling of genetic regulatory networks, based on a modular discrete abstraction, is introduced. Then a compositional algorithm to efficiently analyze reachability properties of the model is proposed. A case study on embryonic cell differentiation involving several hundred cells shows the potential of this approach.


Accelerated decline in lung function in cigarette smokers is associated with TP53/MDM2 polymorphisms.
In vitro studies have shown that p53 mediates a protective response against DNA damage by causing either cell-cycle arrest and DNA repair, or apoptosis. These responses have not yet been demonstrated in humans. A common source of DNA damage in humans is cigarette smoke, which should activate p53 repair mechanisms. As the level of p53 is regulated by MDM2, which targets p53 for degradation, the G-allele of a polymorphism in intron 1 of MDM2 (rs2279744:G/T), that results in higher MDM2 levels, should be associated with a reduced p53 response and hence more DNA damage and corresponding tissue destruction. Similarly, the alleles of rs1042522 in TP53 that encode arginine (G-allele) or proline (C-allele) at codon 72, which cause increased pro-apoptotic (G-allele) or cell-cycle arrest activities (C-allele), respectively, may moderate p53's ability to prevent DNA damage. To test these hypotheses, we examined lung function in relation to cumulative history of smoking in a population-based cohort. The G-alleles in MDM2 and TP53 were found to be associated with accelerated smoking-related decline in lung function. These data support the hypothesis that p53 protects from DNA damage in humans and provides a potential explanation for the variation in lung function impairment amongst smokers.


TCRgammadelta + T lymphocytes in unexplained recurrent spontaneous abortions.
It is generally accepted that the immune system and cellular immunity in particular are involved in the mechanisms affecting the outcome of gestation. In order to evaluate a putative role of lymphocytes in the immunological mechanisms of unexplained recurrent spontaneous abortions (URSA), we studied peripheral blood lymphocyte subpopulations in 244 women with URSA and 44 controls. Direct immunofluorescence in whole blood with the appropriate combinations of monoclonal antibodies and flow cytometry was used. The study showed: a) a statistically significant increase of the mean CD4/CD8 ratio (2.12+/-0.84 vs 1.85+/-0.63, P = 0,039); b) a statistically significant decrease of the mean value of the percentage of CD5+ CD19+ lymphocytes (0.4+/-0.6 vs 1.4+/-0.78, P < 0.0001); and c) a statistically significant increase of the percentage of T lymphocytes expressing TCRgammadelta (4.68+/-3.19 vs 2.61+/-1.14, P < 0.0001). It should be noted that a statistically significant high number of women with URSA (72/195, 36.9%) showed an increased percentage of TCRgammadelta T cells (> or = 5%, where 5 equals the mean value + 2 standard deviations (SD) of the mean value of controls), whereas such a high percentage was not found in any control subject. It seems that women who experienced URSA comprise a heterogeneous population, as far as immunological parameters are concerned. At least in a subgroup of them, TCRgammadelta + T cells could be considered to play a role in the immune pathogenesis of fetal loss.


A three-dimensional in vitro model of tumor cell intravasation.
Metastasis is the cause of over 90% of all human cancer deaths. Early steps in the metastatic process include: the formation of new blood vessels, the initiation of epithelial-mesenchymal transition (EMT), and the mobilization of tumor cells into the circulation. There are ongoing efforts to replicate the physiological landscape of human tumor tissue using three-dimensional in vitro culture models; however, few systems are able to capture the full range of authentic, complex in vivo events such as neovascularization and intravasation. Here we introduce the Prevascularized Tumor (PVT) model to investigate early events of solid tumor progression. PVT spheroids are composed of endothelial and tumor cells, and are embedded in a fibrin matrix containing fibroblasts. The PVT model facilitates two mechanisms of vessel formation: robust sprouting angiogenesis into the matrix, and contiguous vascularization within the spheroid. Furthermore, the PVT model enables the intravasation of tumor cells that is enhanced under low oxygen conditions and is also dependent on the key EMT transcription factor Slug. The PVT model provides a significant advance in the mimicry of human tumors in vitro, and may improve investigation and targeting of events in the metastatic process.


Phase I trial of the murine monoclonal anti-GD2 antibody 14G2a in metastatic melanoma.
In a phase I trial, 12 patients with GD2 antigen-positive metastatic melanoma received the murine anti-GD2 monoclonal antibody 14G2a. The monoclonal antibody was administered in four doses over an 8-day period with total dose ranging from 10 to 120 mg. All patients receiving greater than 10 mg of 14G2a experienced transient abdominal/pelvic pain during the antibody infusion. Five patients had a delayed extremity pain syndrome following the third and fourth antibody infusion. Four of the five patients developed neurological toxicity, including two patients with significant although reversible motor neuropathy. Two of the patients developed hyponatremia secondary to a syndrome of inappropriate antidiuretic hormone. All 12 patients developed high levels of human anti-14G2a antibody. The plasma half-life of 14G2a was 42 +/- 6 (SD) h. One patient each had a partial response, mixed response, and stable disease, respectively. The very modest antitumor activity accompanied by dose-limiting neurological toxicity at total doses greater than 80 mg may restrict the clinical utility of murine 14G2a.


Multiple imaging modality-guided radiofrequency ablation combined with transarterial chemoembolization for hepatocellular carcinoma in special locations.
We aimed to evaluate the safety and effectiveness of radiofrequency ablation (RFA) combined with transarterial chemoembolization (TACE) guided by multiple imaging modalities for hepatocellular carcinomas (HCCs) in special (i.e., high-risk or unfavorable) locations compared with those in conventional locations. A total of 122 HCC patients were enrolled, including 85 patients (69.7%) with HCC in conventional locations and 37 (30.3%) with HCC in special locations. The clinical data, overall survival (OS), progression-free survival (PFS), and procedure-related adverse events were analyzed. RFA combined with TACE was successfully performed in all patients. Three complications (2.5%) occurred, with no significant difference between the conventional (n=1, 1.2%) and special (n=2, 5.4%) locations (P = 0.218). Complete tumor necrosis rate was not significantly different between the conventional (n=73, 85.9%) and special (n=34, 91.9%) locations at one-month imaging (P = 0.353). After a follow-up of 3-48 months, the PFS was 17 months for patients with HCC in conventional locations and 14 months for patients with HCC in special locations; one-year PFS rate was 68.1% in the conventional location group, not significantly (P = 0.741) different from 59.1% in the special location group. The OS was 28 months in the conventional location group while 32 months in the special location group. The cumulative one- and two-year OS rates were 89.9% and 63.3%, respectively, in the conventional location group, not significantly different from 96.3% and 65% in the special location group (P = 0.273). Age (P = 0.043) and tumor size (P < 0.001) were significant prognostic factors for OS, and tumor size (P < 0.001) was the only significant prognostic factor for PFS. RFA guided by multiple imaging modalities combined with TACE may be safe and effective for treating HCCs in special locations.


Genetic basis for divergence in developmental gene expression in two closely related sea urchins.
The genetic basis for divergence in developmental gene expression among species is poorly understood, despite growing evidence that such changes underlie many interesting traits. Here we quantify transcription in hybrids of Heliocidaris tuberculata and Heliocidaris erythrogramma, two closely related sea urchins with highly divergent developmental gene expression and life histories. We find that most expression differences between species result from genetic influences that affect one stage of development, indicating limited pleiotropic consequences for most mutations that contribute to divergence in gene expression. Activation of zygotic transcription is broadly delayed in H. erythrogramma, the species with the derived life history, despite its overall faster premetamorphic development. Altered expression of several terminal differentiation genes associated with the derived larval morphology of H. erythrogramma is based largely on differences in the expression or function of their upstream regulators, providing insights into the genetic basis for the evolution of key life history traits.


Neurobiology: motor control of flexible octopus arms.
Animals with rigid skeletons can rely on several mechanisms to simplify motor control--for example, they have skeletal joints that reduce the number of variables and degrees of freedom that need to be controlled. Here we show that when the octopus uses one of its long and highly flexible arms to transfer an object from one place to another, it employs a vertebrate-like strategy, temporarily reconfiguring its arm into a stiffened, articulated, quasi-jointed structure. This indicates that an articulated limb may provide an optimal solution for achieving precise, point-to-point movements.


Progesterone and oestradiol increase cytosolic Ca2+ in single rat hepatocytes.
Progesterone (300-400 microM) and oestradiol (25-200 microM) induce a prompt rise in the cytosolic free Ca2+ concentration (free Ca) in single rat hepatocytes, but testosterone, cortisol and dexamethasone do not. These increases are dependent on the presence of extracellular Ca2+. Both progesterone and oestradiol block phenylephrine-induced free Ca oscillations. These data suggest a certain specificity of the response of free Ca to steroids and may explain some of the non-genomic effects of these steroids on hepatocytes.


Down regulation of genes involved in T cell polarity and motility during the induction of heart allograft tolerance by allochimeric MHC I.
The allochimeric MHC class I molecule [alpha1h1/u]-RT1.Aa that contains donor-type (Wistar Furth, WF; RT1u) epitopes displayed on recipient-type (ACI, RT1a) administered in conjunction with sub-therapeutic dose of cyclosporine (CsA) induces indefinite survival of heterotopic cardiac allografts in rat model. In vascularized transplantation models, the spleen contributes to graft rejection by generating alloantigen reactive T cells. The immune response in allograft rejection involves a cascade of molecular events leading to the formation of immunological synapses between T cells and the antigen-presenting cells. To elucidate the molecular pathways involved in the immunosuppressive function of allochimeric molecule we performed microarray and quantitative RTPCR analyses of gene expression profile of splenic T cells from untreated, CsA treated, and allochimeric molecule + subtherapeutic dose of CsA treated animals at day 1, 3 and 7 of post transplantation. Allochimeric molecule treatment caused down regulation of genes involved in actin filament polymerization (RhoA and Rac1), cell adhesion (Catna1, Vcam and CD9), vacuolar transport (RhoB, Cln8 and ATP6v1b2), and MAPK pathway (Spred1 and Dusp6) involved in tubulin cytoskeleton reorganization and interaction between actin and microtubule cytoskeleton. All these genes are involved in T cell polarity and motility, i.e., their ability to move, scan and to form functional immunological synapse with antigen presenting cells (APCs). These results indicate that the immunosuppressive function of allochimeric molecule may depend on the impairment of T cells' movement and scanning ability, and possibly also the formation of immunological synapse. We believe that these novel findings may have important clinical implications for organ transplantation.


[Late results of a mammary-coronary anastomosis].
Remote results of the treatment of 102 patients with mammary-coronary anastomosis for chronic coronary insufficiency, pre-infarction state and acute transmural myocardial infarction created in 1964-1976 are investigated. The observations continued from 5 to 16 years. In most cases mammary-coronary anastomosis was created without an artificial blood circulation on the contracting heart. An original model of the apparatus for suturing the vessels was used. More than 70% of the patients are alive (up to 16 years after operation) or survived from 5 to 16 years. In 40% of the living patients there is no stenocardia and they do not use nitroglycerin. Some patients were operated urgently in 1968-1975 for extensive transmural myocardial infarction. After creation of the mammary-coronary anastomosis the infarction was found to disappear. The patients are still alive.


[Decreased myocardial uptake of meta-iodobenzylguanidine in an autopsy-confirmed case of corticobasal degeneration with Lewy bodies restricted to the sympathetic ganglia].
We report on an autopsy case of corticobasal degeneration (CBD) with Lewy bodies in only the sympathetic ganglia. A 79-year-old man showed walking disturbance as an initial symptom, and developed dementia and bradykinesia within the next 2 years. Neurological examination revealed parkinsonism-like akinesia and rigidity in the trunk and neck without resting tremor. Brain magnetic resonance imaging showed frontal lobe atrophy predominantly on the right side. Cardiac uptake of meta-iodobenzylguanidine (MIBG) was reduced (H/M ratio: 1.14). A diagnosis of dementia with Lewy bodies (DLB) was made, but L-dopa treatment was not effective. Seven years later he died of pneumonia. On pathological examination, the frontal cortex and white matter were degenerated, predominantly on the right side. Gallyas-Braak silver staining and AT-8 immunostaining revealed neurofibrillary tangles, pretangles, argyrophilic threads, and astrocytic plaques in the cerebral cortex and basal ganglia, confirming the diagnosis of CBD. Lewy bodies, which were not seen in the central nervous system, were seen only in the sympathetic ganglia, and a severe loss of nerve fibers was apparent in the sympathetic nerve endings in the heart. MIBG is currently used to differentiate DLB from other parkinsonisms, such as CBD, multiple system atrophy, and progressive supranuclear palsy, because reduced cardiac uptake of MIBG represents a pathological change in the sympathetic nerve endings in the heart. However, the distribution of Lewy bodies cannot be determined from this finding. Thus, MIBG should not be used alone to confirm a diagnosis of DLB; other neurodegenerative diseases with incidental Lewy body disease, as in the present case, must be also considered.


Virulence plasmid stability in environmentally occurring Bacillus anthracis from North East Turkey.
The Bacillus anthracis virulence plasmid pXO2, which encodes for a polypeptide capsule, can be lost during long term laboratory storage. To determine if pXO2 is lost in nature we screened B. anthracis isolates obtained from B. anthracis spores from contaminated animal burial sites in Turkey for their ability to express a capsule upon primary culture. A total of 672 B. anthracis colonies were examined of which ten produced a mixed mucoid (capsule +ve)/non-mucoid (capsule -ve) phenotype and a further one colony yielded non-mucoid colonies upon repeated culture. Screening by PCR using pXO2 specific primers revealed that seven of these isolates had eliminated the plasmid. Of the four colonies which were positive by PCR, one regained the ability to express a capsule upon repeated culture suggesting that the defect was reversible. This is an important observation as capsule expression is a principal marker of virulence and in the absence of PCR serves as a key diagnostic marker. The results of this preliminary study suggest that pXO2 is lost in nature and that further studies are need to determine the mechanisms by which this occurs.


Chemography of natural product space.
We present the application of the generative topographic map algorithm to visualize the chemical space populated by natural products and synthetic drugs. Generative topographic maps may be used for nonlinear dimensionality reduction and probabilistic modeling. For compound mapping, we represented the molecules by two-dimensional pharmacophore features (chemically advanced template search descriptor). The results obtained suggest a close resemblance of synthetic drugs with natural products in terms of their pharmacophore features, despite pronounced differences in chemical structure. Generative topographic map-based cluster analysis revealed both known and new potential activities of natural products and drug-like compounds. We conclude that the generative topographic map method is suitable for inferring functional similarities between these two classes of compounds and predicting macromolecular targets of natural products.


Characterization of Leishmania colombiensis sp. n (Kinetoplastida: Trypanosomatidae), a new parasite infecting humans, animals, and phlebotomine sand flies in Colombia and Panama.
Characterization of Leishmania colombiensis sp.n. is presented, which on the basis of biological and molecular criteria, appears to be a new member of the L. braziliensis complex. A total of nine isolates of the new parasite were made in Colombia and Panama between 1980 and 1986: two from human cases of cutaneous leishmaniasis, six from phlebotomine sand flies, and one from a sloth. Although most closely related to L. lainsoni, L. colombiensis sp.n. is clearly distinguishable from other members of the genus by its reactivity with monoclonal antibodies, isoenzyme electrophoresis, and restriction endonuclease fragment patterns of kinetoplast DNA (k-DNA).


Integrating dissemination and implementation sciences within Clinical and Translational Science Award programs to advance translational research: Recommendations to national and local leaders.
The National Center for Advancing Translational Sciences (NCATS) has defined translation as the process of turning observations into interventions that are adopted, sustained, and improve health. Translation must attend to research and community systems and context at multiple levels, and to key stakeholders. Dissemination and implementation (D&I) sciences are informed by an understanding of the critical role of people and systems in disseminating, adopting, and sustaining innovations within real-world settings. Thus, the D&I sciences provides a set of principles that can guide the translational work of Clinical and Translational Science Award (CTSA) programs from basic research to public health. In this special communication, our cross-domain working group of the CTSA consortium, comprised of experts in methods and processes, workforce development, evaluation, stakeholder engagement, and D&I sciences, share a vision of how CTSAs can enhance translation across the translational spectrum through the integration of D&I sciences into the critical areas of methods and processes, workforce development, and evaluation. We propose a set of recommendations for NCATS national and local leaders that are intended to move D&I sciences out of a position of unfamiliarity and ancillary value and into the core identity of who CTSAs are, how they think, and what they do, to advance translation and health.


Development of the Flu-PRO: a patient-reported outcome (PRO) instrument to evaluate symptoms of influenza.
To develop content validity of a comprehensive patient-reported outcome (PRO) measure following current best scientific methodology to standardize assessment of influenza (flu) symptoms in clinical research. Stage I (Concept Elicitation): 1:1 telephone interviews with influenza-positive adults (≥18 years) in the US and Mexico within 7 days of diagnosis. Participants described symptom type, character, severity, and duration. Content analysis identified themes and developed the draft Flu-PRO instrument. Stage II (Cognitive Interviewing): The Flu-PRO was administered to a unique set of influenza-positive adults within 14 days of diagnosis; telephone interviews addressed completeness, respondent interpretation of items and ease of use. Samples: Stage I: N = 46 adults (16 US, 30 Mexico); mean (SD) age: 38 (19), 39 (14) years; % female: 56%, 73%; race: 69% White, 97% Mestizo. Stage II: N = 34 adults (12 US, 22 Mexico); age: 37 (14), 39 (11) years; % female: 50%, 50%; race: 58% White, 100% Mestizo. Symptoms identified by >50%: coughing, weak or tired, throat symptoms, congestion, headache, weakness, sweating, chills, general discomfort, runny nose, chest (trouble breathing), difficulty sleeping, and body aches or pains. No new content was uncovered during Stage II; participants easily understood the instrument. Results show the 37-item Flu-PRO is a content valid measure of influenza symptoms in adults with a confirmed diagnosis of influenza. Research is underway to evaluate the suitability of the instrument for children and adolescents. This work can form the basis for future quantitative tests of reliability, validity, and responsiveness to evaluate the measurement properties of Flu-PRO for use in clinical trials and epidemiology studies.


The surface (S)-layer gene cspB of Corynebacterium glutamicum is transcriptionally activated by a LuxR-type regulator and located on a 6 kb genomic island absent from the type strain ATCC 13032.
The surface (S)-layer gene region of the Gram-positive bacterium Corynebacterium glutamicum ATCC 14067 was identified on fosmid clones, sequenced and compared with the genome sequence of C. glutamicum ATCC 13032, whose cell surface is devoid of an ordered S-layer lattice. A 5.97 kb DNA region that is absent from the C. glutamicum ATCC 13032 chromosome was identified. This region includes cspB, the structural gene encoding the S-layer protomer PS2, and six additional coding sequences. PCR experiments demonstrated that the respective DNA region is conserved in different C. glutamicum wild-type strains capable of S-layer formation. The DNA region is flanked by a 7 bp direct repeat, suggesting that illegitimate recombination might be responsible for gene loss in C. glutamicum ATCC 13032. Transfer of the cloned cspB gene restored the PS2(-) phenotype of C. glutamicum ATCC 13032, as confirmed by visualization of the PS2 proteins by SDS-PAGE and imaging of ordered hexagonal S-layer lattices on living C. glutamicum cells by atomic force microscopy. Furthermore, the promoter of the cspB gene was mapped by 5' rapid amplification of cDNA ends PCR and the corresponding DNA fragment was used in DNA affinity purification assays. A 30 kDa protein specifically binding to the promoter region of the cspB gene was purified. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry and peptide mass fingerprinting of the purified protein led to the identification of the putative transcriptional regulator Cg2831, belonging to the LuxR regulatory protein family. Disruption of the cg2831 gene in C. glutamicum resulted in an almost complete loss of PS2 synthesis. These results suggested that Cg2831 is a transcriptional activator of cspB gene expression in C. glutamicum.


Infant outcomes of certified nurse midwife attended home births: United States 2000 to 2004.
Home births attended by certified nurse midwives (CNMs) make up an extremely small proportion of births in the United States (<1.0%) and are not supported by the American College of Obstetrics and Gynecology (ACOG). The primary objective of this analysis was to examine the safety of certified nurse midwife attended home deliveries compared with certified nurse midwife in-hospital deliveries in the United States as measured by the risk of adverse infant outcomes among women with term, singleton, vaginal deliveries. United States linked birth and infant death files for the years 2000 to 2004 were used for the analysis. Adverse neonatal outcomes including death were determined by place of birth and attendant type for in-hospital certified nurse midwife, in-hospital 'other' midwife, home certified nurse midwife, home 'other' midwife, and free-standing birth center certified nurse midwife deliveries. For the 5-year period there were 1 237 129 in-hospital certified nurse midwife attended births; 17 389 in-hospital 'other' midwife attended births; 13 529 home certified nurse midwife attended births; 42 375 home 'other' midwife attended births; and 25 319 birthing center certified nurse midwife attended births. The neonatal mortality rate per 1000 live births for each of these categories was, respectively, 0.5 (deaths=614), 0.4 (deaths=7), 1.0 (deaths=14), 1.8 (deaths=75), and 0.6 (deaths=16). The adjusted odds ratio (95% confidence interval) for neonatal mortality for home certified nurse midwife attended deliveries vs in-hospital certified nurse midwife attended deliveries was 2.02 (1.18, 3.45). Deliveries at home attended by CNMs and 'other midwives' were associated with higher risks for mortality than deliveries in-hospital by CNMs.


Novel integrative rehabilitation system for the upper extremity: Design and usability evaluation.
Design and test the usability of a novel virtual rehabilitation system for bimanual training of gravity supported arms, pronation/supination, grasp strengthening, and finger extension. A robotic rehabilitation table, therapeutic game controllers, and adaptive rehabilitation games were developed. The rehabilitation table lifted/lowered and tilted up/down to modulate gravity loading. Arms movement was measured simultaneously, allowing bilateral training. Therapeutic games adapted through a baseline process. Four healthy adults performed four usability evaluation sessions each, and provided feedback using the USE questionnaire and custom questions. Participant's game play performance was sampled and analyzed, and system modifications made between sessions. Participants played four sessions of about 50 minutes each, with training difficulty gradually increasing. Participants averaged a total of 6,300 arm repetitions, 2,200 grasp counts, and 2,100 finger extensions when adding counts for each upper extremity. USE questionnaire data averaged 5.1/7 rating, indicative of usefulness, ease of use, ease of learning, and satisfaction with the system. Subjective feedback on the custom evaluation form was 84% favorable. The novel system was well-accepted, induced high repetition counts, and the usability study helped optimize it and achieve satisfaction. Future studies include examining effectiveness of the novel system when training patients acute post-stroke.


Further delineation of Raine syndrome.
We report o a baby from an Arab family with Raine syndrome. The baby presented at birth with severe craniofacial anomalies including a wide anterior fontanelle, exophthalmos, severe depression of the nasal bridge with a hypoplastic midface, bilateral choanal atresia and a large protruding tongue. All the limbs were short and the thorax was small. Radiologically there was increased bone density in some bones, periosteal new bone formation and marked bowing of the femurs, tibiae, and ulnae. We suggest that osteosclerosis in Raine syndrome is not necessarily severe and generalized, and bowing of the long bones is another variable radiological feature of the syndrome.


[Maternal and neonatal Pasteurella multocida infection].
Materno-fetal infection due to Pasteurella multocida is rare; it may be severe in the neonate. A 27-year old woman was admitted at 37 weeks' gestation with a history of abdominal cramps. Twenty-four hours after delivery, the mother was febrile (40 degrees C) and was given intravenous cefotaxime (2 days), followed by cefpodoxime (15 days). The newborn was febrile and hypotonic 24 hours after birth; he received an infusion of hydroxyethylamidon and was given cefotaxime (3 days), netilmicin (6 days) and amoxicillin (10 days). Pasteurella multocida was isolated from placenta, blood and gastric fluid in the baby and in blood cultures and vaginal swab in the mother. It was established that the mother was bitten by her dog during the pregnancy and wounded a few days before delivery. This neonate was infected during the delivery and the source of mother's contamination was easy to determinate: pet animals were kept by the family and there was an history of wounds during her pregnancy.


Circadian acetylome reveals regulation of mitochondrial metabolic pathways.
The circadian clock is constituted by a complex molecular network that integrates a number of regulatory cues needed to maintain organismal homeostasis. To this effect, posttranslational modifications of clock proteins modulate circadian rhythms and are thought to convert physiological signals into changes in protein regulatory function. To explore reversible lysine acetylation that is dependent on the clock, we have characterized the circadian acetylome in WT and Clock-deficient (Clock(-/-)) mouse liver by quantitative mass spectrometry. Our analysis revealed that a number of mitochondrial proteins involved in metabolic pathways are heavily influenced by clock-driven acetylation. Pathways such as glycolysis/gluconeogenesis, citric acid cycle, amino acid metabolism, and fatty acid metabolism were found to be highly enriched hits. The significant number of metabolic pathways whose protein acetylation profile is altered in Clock(-/-) mice prompted us to link the acetylome to the circadian metabolome previously characterized in our laboratory. Changes in enzyme acetylation over the circadian cycle and the link to metabolite levels are discussed, revealing biological implications connecting the circadian clock to cellular metabolic state.


The management of musculoskeletal infection in HIV carriers.
Over a three-year period, the authors prospectively implemented a protocol for management of musculoskeletal sepsis (MSS) in HIV carriers in Yaounde, Cameroon. The diagnosis of MSS was based on conventional criteria. HIV carriage was screened by an ELISA test and confirmed with the Western Blot technique. The immune status was based on CD4 lymphocyte count by flow cytometry; patients were classified as non-immunodepressed (NID), mildly immunodepressed (MID), or severely immunodepressed (SID) based on their CD4 lymphocyte count, as the latter was respectively over 500, between 200 and 500 or less than 200 per ml. Infection was treated by surgical debridement followed by a long-course targeted antibiotic therapy. All SID patients and some MID patients with AIDS-related symptoms also had standard antiretroviral (ARV) therapy. Thirty-one of 294 patients seen with musculoskeletal sepsis during the study period and tested for HIV were found to be HIV carriers. Their mean age was 33 years; the male/female ratio was 1.58. The following clinical pictures were observed: chronic osteomyelitis (COM) in 32.3% of the cases, septic arthritis (SA) in 38.7%, soft tissue infection (STI) in 25.8%; the last case was a severe leg complication of Buruli Ulcer (BU). Among these 31 patients, 38.7% were classified as SID (5 COM, 4 SA, 2 STI and the BU patient), 25.8% as MID (2 COM, 4 SA, 2 STI) and 35.5% as NID (3 COM, 6 SA, 2 STI). The organisms involved were not specific. Fifteen patients were managed conventionally, while the other 16 had the usual treatment associated with ARV therapy. The immediate outcome of MSS was good in 29 patients, after a mean hospital stay of five weeks; in two cases of septic arthritis of the knee, a second debridement was needed, due to persistent drainage, and the sinuses all closed. Three months after discharge, one patient with COM of the humerus developed a low-flow fistula which was closed after a revision sequestrectomy. After one year, none of the patients complained of any symptom suggesting reactivation of their MSS. There is no evidence that HIV carriage is in itself a high risk factor for musculoskeletal sepsis; the incidence of HIV carriage was indeed virtually similar in the 294 patients with MSS and in the general population, i.e. around 10%. However, in order to improve the outcome following musculoskeletal infections in patients with HIV, their management should take into account their immune status, based on a CD4 lymphocyte count. NID patients should be treated as any other patients with MSS, while SID should have additional standard ARV treatment. For those who are MID, the indication for antiretroviral therapy should depend on the presence of one or more AIDS-related signs.


Ferroptosis Inducers for Prostate Cancer Therapy.
Lipid peroxidation-driven iron-dependent ferroptosis is a regulated cell death mechanism implicated in numerous diseases, such as neurological diseases, kidney injury, ischemia, and tumors, including prostate cancer. The cellular mechanisms of ferroptosis are strongly associated with iron, reactive oxygen species and amino acid metabolic pathways. Several compounds, namely ferroptosis inducers, impact these pathways and trigger ferroptosis by i) inhibiting Xc - transporter system, ii) impairing GPX4 functions and iii) oxidizing iron and polyunsaturated phospholipids. Preclinical studies show that in combination with conventional anticancer drugs, ferroptosis inducers are effective in prostate cancer and in combating the progression towards the castration-resistant disease. This review overviews the mechanisms implicated in ferroptosis and discusses the findings achieved in prostate cancer.


The case for hypoglycaemia as a proarrhythmic event: basic and clinical evidence.
Recent clinical studies show that hypoglycaemia is associated with increased risk of death, especially in patients with coronary artery disease or acute myocardial infarction. This paper reviews data from cellular and clinical research supporting the hypothesis that acute hypoglycaemia increases the risk of malignant ventricular arrhythmias and death in patients with diabetes by generating the two classic abnormalities responsible for the proarrhythmic effect of medications, i.e. QT prolongation and Ca(2+) overload. Acute hypoglycaemia causes QT prolongation and the risk of ventricular tachycardia by directly suppressing K(+) currents activated during repolarisation, a proarrhythmic effect of many medications. Since diabetes itself, myocardial infarction, hypertrophy, autonomic neuropathy and congestive heart failure also cause QT prolongation, the arrhythmogenic effect of hypoglycaemia is likely to be greatest in patients with pre-existent cardiac disease and diabetes. Furthermore, the catecholamine surge during hypoglycaemia raises intracellular Ca(2+), thereby increasing the risk of ventricular tachycardia and fibrillation by the same mechanism as that activated by sympathomimetic inotropic agents and digoxin. Diabetes itself may sensitise myocardium to the arrhythmogenic effect of Ca(2+) overload. In humans, noradrenaline (norepinephrine) also lengthens action potential duration and causes further QT prolongation. Finally, both hypoglycaemia and the catecholamine response acutely lower serum K(+), which leads to QT prolongation and Ca(2+) loading. Thus, hypoglycaemia and the subsequent catecholamine surge provoke multiple, interactive, synergistic responses that are known to be proarrhythmic when associated with medications and other electrolyte abnormalities. Patients with diabetes and pre-existing cardiac disease may therefore have increased risk of ventricular tachycardia and fibrillation during hypoglycaemic episodes.


Notch Signaling and Maintenance of SOX2 Expression in Rat Anterior Pituitary Cells.
After publication of reports describing the presence of stem/progenitor cells among non-hormone-producing cells in the pituitary, the mechanism responsible for proliferation and differentiation generated considerable interest. Several studies have suggested that Notch signaling is involved. In the present study, we examined the histochemical relationship between Notch signaling molecules and the transcription factor SOX2 in rat pituitary. Combined in situ hybridization and immunohistochemistry showed that Notch2 mRNA and SOX2 were co-expressed at embryonic day 14.5 in most cells in the adenohypophyseal primordium. In adult rat pituitary, double immunohistochemistry showed that SOX2 and either Notch2 or the Notch signaling target HES1 were co-localized within cells with large oval nuclei in both the marginal cell layer and cell aggregates in the main part of the anterior lobe, which are believed to be stem cell niches. Furthermore, when the Notch signaling inhibitor DAPT was added to a primary culture of adult rat anterior pituitary cells, the proportion of SOX2-expressing cells within Notch2-positive cells was approximately 30% lower. These findings suggest that Notch signaling has a role in maintaining the stemness of precursor cells in the adult rat pituitary gland.


miR-17-92 plays an oncogenic role and conveys chemo-resistance to cisplatin in human prostate cancer cells.
The mir-17-92 cluster consists of six mature miRNAs and is implicated in diverse human cancers by targeting mRNAs involved in distinct pathways that either promote or inhibit carcinogenesis. However, the molecular mechanism underlying the mir-17-92 cluster-mediated pro-tumorigenic or anti-tumorigenic effects has not been clearly elucidated in prostate cancer. In the present study, the role of the mir-17-92 cluster in diverse aspects of prostate cancer cells has been thoroughly investigated. Forced introduction of the mir-17-92 cluster into the androgen-independent DU145 prostate cancer cells evidently promoted cell growth due to disruption of the balance between cellular proliferation and apoptosis. Overexpression of the mir-17-92 cluster significantly improved the migration and invasion of the DU145 cells, attributed to the induction of integrin β-1. Notably, the mir-17-92 cluster conveyed chemo-resistance to cisplatin. We demonstrated that the mir-17-92 cluster suppressed the expression of inhibitor of the AKT signaling pathway and activated the AKT pathway subsequently, which played a central role in regulating cellular proliferation, apoptosis and chemo-resistance. Continuously activated ERK1/2 signaling also contributed importantly to these processes. The present study provides key evidence for crucial oncogenic role of the miR-17-92 cluster in prostate cancer cells. Further investigations are warranted to determine whether miR-17-92 cluster can be targeted for future treatment of human prostate cancer.


The Costs and Benefits of SNOMED CT Implementation: An Economic Assessment Model.
As part of its investigations, the EU-funded ASSESS CT project developed an Economic Assessment Model for assessing SNOMED CT's and other terminologies' socio-economic impact in a systematic approach. Methodology and key elements of the model are presented: cost and benefit indicators for assessing deployment, and a cost-benefit analysis tool to collect, estimate, and evaluate data.


Nutrient History Affects the Response and Resilience of the Tropical Seagrass Halophila stipulacea to Further Enrichment in Its Native Habitat.
Eutrophication is one of the main threats to seagrass meadows, but there is limited knowledge on the interactive effects of nutrients under a changing climate, particularly for tropical seagrass species. This study aimed to detect the onset of stress in the tropical seagrass, Halophila stipulacea, by investigating the effect of in situ nutrient addition during an unusually warm summer over a 6-month period. We measured a suite of different morphological and biochemical community metrics and individual plant traits from two different sites with contrasting levels of eutrophication history before and after in situ fertilization in the Gulf of Aqaba. Nutrient stress combined with summer temperatures that surpassed the threshold for optimal growth negatively affected seagrass plants from South Beach (SB), an oligotrophic marine protected area, while H. stipulacea populations from North Beach (NB), a eutrophic and anthropogenically impacted area, benefited from the additional nutrient input. Lower aboveground (AG) and belowground (BG) biomass, reduced Leaf Area Index (LAI), smaller internodal distances, high sexual reproductive effort and the increasing occurrence of apical shoots in seagrasses from SB sites indicated that the plants were under stress and not growing under optimal conditions. Moreover, AG and BG biomass and internodal distances decreased further with the addition of fertilizer in SB sites. Results presented here highlight the fact that H. stipulacea is one of the most tolerant and plastic seagrass species. Our study further demonstrates that the effects of fertilization differ significantly between meadows that are growing exposed to different levels of anthropogenic pressures. Thus, the meadow's "history" affects it resilience and response to further stress. Our results suggest that monitoring efforts on H. stipulacea populations in its native range should focus especially on carbohydrate reserves in leaves and rhizomes, LAI, internodal length and percentage of apical shoots as suitable warning indicators for nutrient stress in this seagrass species to minimize future impacts on these valuable ecosystems.


Lipid profile and carotid intima-media thickness in a prospective cohort of very preterm subjects at age 19 years: effects of early growth and current body composition.
Cardiovascular disease (CVD) risk is associated with prenatal and infancy growth. However, the relative importance of these time periods for the CVD risk is uncertain. To elucidate this, we tested in a very preterm cohort the effects of birth weight for gestational age and weight gain between birth and 3 mo post-term (early postnatal weight gain) and between 3 mo and 1 y post-term (late infancy weight gain) on the lipid profile and carotid intima-media thickness (CIMT) at age 19 y. A less favorable lipid profile was strongly associated with higher current body mass index (BMI), greater waist circumference, and greater absolute fat mass. CIMT was positively associated with current height, and with low-density lipoprotein (LDL) cholesterol and apolipoprotein B (ApoB) levels, and LDL/high-density lipoprotein (HDL) cholesterol and ApoB/apolipoprotein AI (ApoAI) ratios. Lipid profile and CIMT were unrelated to gestational age, birth weight standard deviation score (SDS) and early postnatal weight gain. CIMT was positively associated with late infancy weight gain, but the relationship disappeared after correction for current height. Our findings in 19 y olds born very preterm argue for an effect of current body composition, rather than of early growth, on the CVD risk. Attempts to reduce the CVD risk in this specific population should focus on weight reduction in young adulthood rather than on optimizing the early growth pattern.


Tanshinone IIA Induces Heme Oxygenase 1 Expression and Inhibits Cyclic Strain-Induced Interleukin 8 Expression in Vascular Endothelial Cells.
Tanshinone IIA is the main effective component of Salvia miltiorrhiza, known as "Danshen," which has been used in many therapeutic remedies in traditional Chinese medicine. However, the direct effects of tanshinone IIA on vascular endothelial cells have not yet been fully described. In the present study, we demonstrated that tanshinone IIA increased heme oxygenase-1 (HO-1) expression in human umbilical vein endothelial cells. Western blot analyses and experiments with specific inhibitors indicated tanshinone IIA enhanced HO-1 expression through the activation of phosphoinositide 3-kinase (PI3K)/Akt and the subsequent induction of nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation. In addition, tanshinone IIA inhibited cyclic strain induced interleukin-8 (IL-8) expression. HO-1 silencing significantly abrogated the repressive effects of tanshinone IIA on strain-induced IL-8 expression, which suggests HO-1 has a role in mediating the effects of tanshinone IIA. This study reports for the first time that tanshinone IIA inhibits cyclic strain-induced IL-8 expression via the induction of HO-1 in endothelial cells, providing valuable new insight into the molecular pathways that may contribute to the effects of tanshinone IIA.


Aortic ring assay.
Angiogenesis, the sprouting of blood vessels from preexisting vasculature is associated with both natural and pathological processes. Various angiogenesis assays involve the study of individual endothelial cells in culture conditions (1). The aortic ring assay is an angiogenesis model that is based on organ culture. In this assay, angiogenic vessels grow from a segment of the aorta (modified from (2)). Briefly, mouse thoracic aorta is excised, the fat layer and adventitia are removed, and rings approximately 1 mm in length are prepared. Individual rings are then embedded in a small solid dome of basement matrix extract (BME), cast inside individual wells of a 48-well plate. Angiogenic factors and inhibitors of angiogenesis can be directly added to the rings, and a mixed co-culture of aortic rings and other cell types can be employed for the study of paracrine angiogenic effects. Sprouting is observed by inspection under a stereomicroscope over a period of 6-12 days. Due to the large variation caused by the irregularities in the aortic segments, experimentation in 6-plicates is strongly advised. Neovessel outgrowth is monitored throughout the experiment and imaged using phase microscopy, and supernatants are collected for measurement of relevant angiogenic and anti-angiogenic factors, cell death markers and nitrite.


A synthetic snRNA m3G-CAP enhances nuclear delivery of exogenous proteins and nucleic acids.
Accessing the nucleus through the surrounding membrane poses one of the major obstacles for therapeutic molecules large enough to be excluded due to nuclear pore size limits. In some therapeutic applications the large size of some nucleic acids, like plasmid DNA, hampers their access to the nuclear compartment. However, also for small oligonucleotides, achieving higher nuclear concentrations could be of great benefit. We report on the synthesis and possible applications of a natural RNA 5'-end nuclear localization signal composed of a 2,2,7-trimethylguanosine cap (m(3)G-CAP). The cap is found in the small nuclear RNAs that are constitutive part of the small nuclear ribonucleoprotein complexes involved in nuclear splicing. We demonstrate the use of the m(3)G signal as an adaptor that can be attached to different oligonucleotides, thereby conferring nuclear targeting capabilities with capacity to transport large-size cargo molecules. The synthetic capping of oligos interfering with splicing may have immediate clinical applications.