Fisetin, a dietary phytochemical, overcomes Erlotinib-resistance of lung adenocarcinoma cells through inhibition of MAPK and AKT pathways.
Erlotinib (Tarceva) is a selective epidermal growth factor receptor tyrosine kinase inhibitor for treatment of non-small cell lung cancer (NSCLC). However, its efficacy is usually reduced by the occurrence of drug resistance. Our recent study showed that a flavonoid found in many plants, Fisetin, might have a potential to reverse the acquired Cisplatin-resistance of lung adenocarcinoma. In the present study, we aimed to test whether Fisetin could have the ability to reverse Erlotinib-resistance of lung cancer cells. Erlotinib-resistant lung adenocarcinoma cells, HCC827-ER, were cultured from the cell line HCC827, and the effects of Fisetin and Erlotinib on the cell viability and apoptosis were evaluated. The possible signaling pathways in this process were also detected. As expected, the results showed that Fisetin effectively increased sensitivity of Erlotinib-resistant lung cancer cells to Erlotinib, possibly by inhibiting aberrant activation of MAPK and AKT signaling pathways resulted from AXL suppression. In conclusion, Fisetin was a potential agent for reversing acquired Erlotinib-resistance of lung adenocarcinoma. Inactivation of AXL, MAPK and AKT pathways might play a partial role in this process.


Urinary detection of type IV collagen and its increase in glomerulonephritis.
Type IV collagen is the major component of the glomerular extracellular matrix. The nature of type IV collagen antigens in the urine from various forms of glomerulonephritis was studied using enzyme-linked immunosorbent assay for monoclonal antibodies to the 7S domain and some of the non-7S and non-NC1 domains. The size distribution of antigenic material in urinary samples from a patient with IgA nephropathy was analyzed by gel filtration chromatography. The results demonstrated a single peak at 340 kDa, suggesting the measurement of almost intact type IV collagen molecules. The urinary concentration of type IV collagen in patients with membranous nephropathy and chronic renal failure was significantly increased compared with that of normal controls. Measurement of the urinary concentrations of type IV collagen is useful in the diagnosis of glomerular disease, particularly in cases where invasive methods are contraindicated and clinically membranous nephropathy is suspected.


Nurses' influence on quality of care in postoperative pain management: a phenomenological study.
The aims of this study were to describe a group of nurses' influence on the quality of care in postoperative pain management and to elucidate the meaning of exercising this influence. Fifteen protocols, written by experienced clinical nurses, describing complex postoperative pain situations where the nurses' actions influenced the outcome were analysed by using two different phenomenological methods. The results showed that the general meaning structure of the nurses' influence on the quality of care in postoperative pain management consisted of (i) the nurses' perception of an unsatisfactory situation concerning the pain management of the surgical patients; (ii) that the nurses personally intervened; and (iii) that they changed the outcome of the situation in a positive direction. The meaning of exercising this influence was interpreted as an aspiration to relieve the patients from their suffering by exercising professional skills and knowledge in a creative, problem-solving, caring process.


Genome-wide promoter methylation analysis in neuroblastoma identifies prognostic methylation biomarkers.
Accurate outcome prediction in neuroblastoma, which is necessary to enable the optimal choice of risk-related therapy, remains a challenge. To improve neuroblastoma patient stratification, this study aimed to identify prognostic tumor DNA methylation biomarkers. To identify genes silenced by promoter methylation, we first applied two independent genome-wide methylation screening methodologies to eight neuroblastoma cell lines. Specifically, we used re-expression profiling upon 5-aza-2'-deoxycytidine (DAC) treatment and massively parallel sequencing after capturing with a methyl-CpG-binding domain (MBD-seq). Putative methylation markers were selected from DAC-upregulated genes through a literature search and an upfront methylation-specific PCR on 20 primary neuroblastoma tumors, as well as through MBD- seq in combination with publicly available neuroblastoma tumor gene expression data. This yielded 43 candidate biomarkers that were subsequently tested by high-throughput methylation-specific PCR on an independent cohort of 89 primary neuroblastoma tumors that had been selected for risk classification and survival. Based on this analysis, methylation of KRT19, FAS, PRPH, CNR1, QPCT, HIST1H3C, ACSS3 and GRB10 was found to be associated with at least one of the classical risk factors, namely age, stage or MYCN status. Importantly, HIST1H3C and GNAS methylation was associated with overall and/or event-free survival. This study combines two genome-wide methylation discovery methodologies and is the most extensive validation study in neuroblastoma performed thus far. We identified several novel prognostic DNA methylation markers and provide a basis for the development of a DNA methylation-based prognostic classifier in neuroblastoma.


Enhancing the value of mortality data for health systems: adding Circumstances Of Mortality CATegories (COMCATs) to deaths investigated by verbal autopsy.
Half of the world's deaths and their causes pass unrecorded by routine registration systems, particularly in low- and middle-income countries. Verbal autopsy (VA) collects information on medical signs, symptoms and circumstances from witnesses of a death that is used to assign likely medical causes. To further contextualise information on mortality, understanding underlying determinants, such as logistics, barriers to service utilisation and health systems responses, is important for health planning. Adding systematic methods for categorising circumstantial determinants of death to conventional VA tools is therefore important. In this context, the World Health Organization (WHO) leads the development of international standards for VA, and added questions on the social and health systems circumstances of death in 2012. This paper introduces a pragmatic and scalable approach for assigning relevant Circumstances Of Mortality CATegories (COMCATs) within VA tools, and examines their consistency, reproducibility and plausibility for health policy making, as well as assessing additional effort and cost to the routine VA process. This innovative COMCAT model is integrated with InterVA-5 software (which processes WHO-2016 VA data), for assigning numeric likelihoods to six circumstantial categories for each death. VA data from 4,116 deaths in the Agincourt Health and Socio-Demographic Surveillance System in South Africa from 2012 to 2016 were used to demonstrate proof of principle for COMCATs. Lack of resources to access health care, poor recognition of diseases and inadequate health systems responses ranked highest among COMCATs in the demonstration dataset. COMCATs correlated plausibly with age, sex, causes of death and local knowledge of the demonstration population. The COMCAT approach appears to be plausible, feasible and enhances the functionality of routine VA to account for critical limiting circumstances at and around the time of death. It is a promising tool for evaluating progress towards the Sustainable Development Goals and the roll-out of Universal Health Coverage.


Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway.
Quiescent T cells can be induced to express many genes by mitogen or antigen stimulation. The messenger RNAs of some of these genes undergo relatively rapid degradation compared to messenger RNAs from constitutively expressed genes. A T cell activation pathway that specifically regulates the stability of messenger RNAs for the lymphokines interleukin-2, interferon-gamma, tumor necrosis factor-alpha, and granulocyte-macrophage colony-stimulating factor is induced by stimulation of the CD28 surface molecule. This pathway does not directly affect the steady-state messenger RNA level, transcription, or messenger RNA half-life of other T cell activation genes, including c-myc, c-fos, IL-2 receptor, and the 4F2HC surface antigen. These data show that stimuli received at the cell surface can alter gene expression by inducing specific changes in messenger RNA degradation.


Rapidly progressive paraplegia due to an extradural lumbar meningocele mimicking a cyst. Case report.
Unlike arachnoid meningoceles, arachnoid cysts frequently cause local pressure effects probably because there is no free communication between the cyst and the subarachnoid space. Following the first detailed description of cystic lesions of spinal nerve roots by Tarlov in 1938, a simplified classification of spinal meningeal cysts was developed in 1988, containing three major categories. The authors report on a lumbar intraspinal extradural meningocele that caused incomplete paraplegia in an otherwise healthy 31-year-old man in whom magnetic resonance imaging revealed stigmata of Scheuermann disease. Intraoperatively, the lesion was classified as a transitional-type lesion, in accordance with Type IA of the Nabors classification, because a communication with the subarachnoid space was observed. After complete removal of the meningocele, the patient's recovery was prompt and complete.


Do we need regional guidelines for breast cancer management in the MENA region? MENA Breast Cancer Guidelines project.
Breast cancer is the most common cancer among females worldwide in general and in the Middle East and the North African region (MENA region) in particular. Management of breast cancer in the MENA region faces a lot of challenges, which include younger age at presentation, aggressive behaviour, lack of national breast screening programmes and lack of reliable data registries as well as socioeconomic factors. These factors make applying the international guidelines for breast cancer management very challenging. The aim of this project is to explore the need for a regional breast cancer guideline as well as to screen the clinical practice of breast cancer management in the MENA region. Three web-based designed surveys were sent to more than 600 oncologists in the MENA region from the period of August 2013 to October 2014. Full descriptive data and information regarding the application of international breast cancer guidelines were collected. The software was using the IP address to prevent duplication of collected data. Descriptive analysis and results were shown as numbers and percentages. During the period of the survey, 104 oncologists responded, representing around an 11% response rate. The majority of replies came from Egypt (59 responses (59%)), followed by Saudi Arabia (ten responses (9.6%)). Fifty-one per cent of responders had more than ten years of experience, and further 31.7% had 5-10 years of experience. Seventy-four per cent were working in governmental hospitals, which is our target sector. There was a major defect in having a genetic counsel unit (78.8% declared an absence of this service), presence of a national breast screening programme (55.8% declared an absence of this service), performing sentinel lymph node biopsy (43.3% declared an absence of this service). The need for regional guidelines for the management of breast cancer was agreed upon by 90.6% of responders. There is a clear need to improve the management of breast cancer in the MENA region. Creating a national breast screening programme and a reliable database is essential. A regional guideline is required to establish the best possible management of breast cancer according to the patients and disease specification as well as the regional socioeconomic factors and facilities available. There is also a need to improve clinical research that meets the region's needs.


Predicting pilot error: testing a new methodology and a multi-methods and analysts approach.
The Human Error Template (HET) is a recently developed methodology for predicting design-induced pilot error. This article describes a validation study undertaken to compare the performance of HET against three contemporary Human Error Identification (HEI) approaches when used to predict pilot errors for an approach and landing task and also to compare analyst error predictions to an approach to enhancing error prediction sensitivity: the multiple analysts and methods approach, whereby multiple analyst predictions using a range of HEI techniques are pooled. The findings indicate that, of the four methodologies used in isolation, analysts using the HET methodology offered the most accurate error predictions, and also that the multiple analysts and methods approach was more successful overall in terms of error prediction sensitivity than the three other methods but not the HET approach. The results suggest that when predicting design-induced error, it is appropriate to use a toolkit of different HEI approaches and multiple analysts in order to heighten error prediction sensitivity.


A formalin-inactivated whole SIV vaccine confers protection in macaques.
A vaccine against human immunodeficiency virus (HIV) would be highly effective in stopping the acquired immunodeficiency syndrome (AIDS) epidemic. A comprehensive evaluation of potential vaccine methodologies can be made by means of the simian model for AIDS, which takes advantage of the similarities in viral composition and disease potential between simian immunodeficiency virus (SIV) infection of rhesus macaques and HIV infection in humans. Immunization with a formalin-inactivated whole SIV vaccine potentiated with either alum and the Syntex adjuvant threonyl muramyl dipeptide (MDP) or MDP alone resulted in the protection of eight of nine rhesus monkeys challenged with ten animal-infectious doses of pathogenic virus. These results demonstrate that a whole virus vaccine is highly effective in inducing immune responses that can protect against lentivirus infection and AIDS-like disease.


Single-incision video-assisted thoracoscopic evaluation and emergent surgery for severe lung and chest wall injury after thoracic trauma in a water park.
Thoracic trauma is a challenging situation with potential severe chest wall and intrathoracic organ injuries. We present a case of emergent surgery in a 23-year-old man with hemorrhagic shock due to massive lung and chest wall injury after thoracic trauma in a water slide. We performed a SI-VATS approach in order to define intrathoracic and chest wall injuries, and once checked the extension of the chest wall injury, we added a middle size thoracotomy just over the affected area in order to stabilize rib fractures with Judet plates, that had caused massive laceration in left lower lobe (LLL) and injured the pericardium causing myocardical tear. After checking bronchial and vascular viability of LLL we suggested a lung parenchyma preserving technique with PTFE protected pulmonary primary suture in order to avoid a lobectomy. Chest tubes were removed on 3rd postoperative day and patient was discharged on 14th postoperative day. He has already recovered his normal activity 6 months after surgery.


Nutrition, Behavior Change and Physical Activity Outcomes From the PEARS RCT-An mHealth-Supported, Lifestyle Intervention Among Pregnant Women With Overweight and Obesity.
Background: Diet quality and physical activity positively impact pregnancy outcomes among women with obesity, but successful lifestyle interventions require intense clinician time. We aimed to investigate the impact of a behavioral-lifestyle intervention (PEARS) supported by a smartphone app among pregnant women with overweight and obesity, on nutrient intake, behavioral stage-of-change and physical activity. Methods: Pregnant women (BMI 25-39.9 kg/m2, measured, n = 565) were randomized at 15.6 weeks' gestation to the intervention (n = 278), or a control group (n = 287) (ISRCTN29316280). The intervention was grounded in behavior-change theory. Participants received nutrition (low glycaemic index and healthy eating) and exercise advice, a smartphone app and fortnightly emails. The control group received usual care which does not include dietary advice. At baseline and 28 weeks' gestation, dietary data were obtained through 3-day food diaries (n = 290 matched), and stage-of-change and physical activity data were self-reported. App usage data were collected. Results: There were no differences between the groups at baseline. Compared with the control group, the intervention group had improved dietary intakes post-intervention with; lower glycaemic index (MD -1.75); free sugars (%TE) (MD -0.98); fat (%TE) (MD -1.80); and sodium (mg) (MD -183.49). Physical activity (MET-minutes/week) was higher in the intervention group post-intervention (MD 141.4; 95% CI 62.9, 219.9). The proportion of participants at "maintenance" stage-of-change for physical activity was higher in the intervention group (56.3 vs. 31.2%). App use was associated with lower glycaemic index and less energy from free sugars, but not with physical activity. Conclusion: A behavioral-lifestyle intervention in pregnancy supported by a smartphone app improved dietary intakes, physical activity, and motivation to engage in exercise.


Exercise preconditioning against hydrogen peroxide-induced oxidative damage in proteins of rat myocardium.
Both regular physical exercise and low levels of H(2)O(2) administration result in increased resistance to oxidative stress. We measured the accumulation of reactive carbonyl derivatives and the activities of proteasome complex and DT-diaphorase in cardiac muscle of trained and untrained rats after chronic i.p. administration of 1 ml t-butyl H(2)O(2) (1 mmol/kg for 3 weeks every second day). Twenty-four rats were randomly assigned to a control group administered with saline, control administered with H(2)O(2), and exercised administered either saline or H(2)O(2). The activity of DT-diaphorase significantly increased in H(2)O(2) administered and exercised groups, indicating that an increase in H(2)O(2) levels stimulate the activity of this enzyme. The cardiac muscle of H(2)O(2) administered nonexercised animals accumulated significantly more carbonyl than control group (P < 0.05). The exercise and H(2)O(2) administration resulted in less oxidatively modified protein than found in nonexercised groups (P < 0.05). The peptide-like activity of proteasome complex was induced by the treatment of H(2)O(2) and exercise and exercise potentiate the effect of H(2)O(2). On the other hand, the chymotrypsin-like and trypsin-like activities were stimulated only by physical training and H(2)O(2) administration. The data suggest that chronic administration of H(2)O(2) after exercise training decreases the accumulation of carbonyl groups below the steady-state level and induces the activity of proteasome and DT-diaphorase. Hence, the stimulating effect of physical exercise on free radical generation is an important phenomenon of the exercise-induced adaptation process since it increases resistance to oxidative stress. Regular exercise training is a valuable physiological means of preconditioning the myocardium to prolonged oxidative stress.


Experimental determination of the lidar overlap profile with Raman lidar.
The range-dependent overlap between the laser beam and the receiver field of view of a lidar can be determined experimentally if a pure molecular backscatter signal is measured in addition to the usually observed elastic backscatter signal, which consists of a molecular component and a particle component. Two methods, the direct determination of the overlap profile and an iterative approach, are presented and applied to a lidar measurement. The measured overlap profile accounts for actual system alignment and for all system parameters that are not explicitly known, such as actual laser beam divergence and spatial intensity distribution of the laser light.


Migration, medical education, and health care: a view from Pakistan.
To review physician flows in Pakistan in the contexts of capacity to educate and provide for anticipated health needs. Literature review was used to refine estimates and assumptions about physician supply and demand. Net physician supply was calculated from data on physician inflows and estimates of migration and other causes of physician loss. Projections of anticipated needs up to 2020 were calculated, assuming different levels of physician need or demand. Reasons for emigration were extracted from interviews, questionnaires, and reports; health indicators and migration figures were obtained from literature and Web sites. Approximately 74,000 physicians were practicing in Pakistan in 2005. Annually, local medical schools and international medical graduate certification provide 5,400 physicians, soon to reach 6,800; 1,150 physicians emigrate; and an estimated 570 physicians stop practicing for various reasons. The current ratio (0.473) of physicians to 1,000 population is inadequate to maintain the nation's health. Future Physician Workforce Shortages (PWSs) for Pakistan range between 57,900 and 451,102 physicians in 2020, depending on assumptions about future need. Pakistan cannot meet its needs for health care given the current levels of production and dependency on physicians in the organization of the system. Although outmigration contributes to the problem, it is the growing demand for health care from increases in population; adverse conditions that generate ill-health; and increasing expectations that dramatically increase the PWSs. The anticipated shortfall in Pakistan reflects a global pattern. Definition of physician roles and improvement of standards through refined assessment require serious consideration.


Transcription factor AP-4 contains multiple dimerization domains that regulate dimer specificity.
Enhancer binding protein AP-4 is a transcription factor that activates both viral and cellular genes by binding to the symmetrical DNA sequence, CAGCTG. Here, we report the molecular cloning and characterization of human AP-4 cDNAs. The deduced amino acid sequence reveals that AP-4 is a helix-loop-helix (HLH) protein. Like other members of this family, the AP-4 HLH motif and the adjacent basic domain are necessary and sufficient to confer site-specific DNA binding. However, unlike other HLH proteins, AP-4 also contains two additional protein dimerization motifs consisting of leucine repeat elements LR1 and LR2. The analysis of various deletion and point mutants for their ability to dimerize in the presence or absence of DNA reveals several unusual features. Although the HLH basic region is sufficient for DNA recognition and binding, dimer formation between different truncated versions of AP-4 in solution requires an intact LR1 or LR2 domain. AP-4 is unable to form heterodimers with other helix-loop-helix family members such as the immunoglobulin enhancer binding factor, E12. In contrast, an AP-4 derivative, delta C222, which lacks LR1 and LR2 but retains an intact HLH, can form heterodimers with E12. Moreover, AP-4 molecules containing LR2 or LR1 are unable to form mixed dimers with carboxy-terminally truncated AP-4 molecules such as delta C222, but retain the ability to form complexes with longer versions of AP-4 that contain LR1 and/or LR2. Our findings strongly suggest that AP-4 contains multiple protein-protein interfaces that function to promote homodimer formation and restrict heterocomplexes. These findings provide a mechanism by which different members of the helix-loop-helix family of transcription factors can form functional dimers in a specific fashion with their appropriate partners to control transcriptional networks during cellular differentiation.


Spermiogenesis and exchange of basic nuclear proteins are impaired in male germ cells lacking Camk4.
Ca2+/calmodulin-dependent protein kinase IV (Camk4; also known as CaMKIV), a multifunctional serine/threonine protein kinase with limited tissue distribution, has been implicated in transcriptional regulation in lymphocytes, neurons and male germ cells. In the mouse testis, however, Camk4 is expressed in spermatids and associated with chromatin and nuclear matrix. Elongating spermatids are not transcriptionally active, raising the possibility that Camk4 has a novel function in male germ cells. To investigate the role of Camk4 in spermatogenesis, we have generated mice with a targeted deletion of the gene Camk4. Male Camk4-/- mice are infertile with impairment of spermiogenesis in late elongating spermatids. The sequential deposition of sperm basic nuclear proteins on chromatin is disrupted, with a specific loss of protamine-2 and prolonged retention of transition protein-2 (Tnp2) in step-15 spermatids. Protamine-2 is phosphorylated by Camk4 in vitro, implicating a connection between Camk4 signalling and the exchange of basic nuclear proteins in mammalian male germ cells. Defects in protamine-2 have been identified in sperm of infertile men, suggesting that our results may have clinical implications for the understanding of human male infertility.


[Pharmacoeconomic analysis of the treatment of methicillin-resistant Staphylococcus aureus with daptomycin or vancomycin].
The increased morbidity, mortality and high costs associated with bacteremia caused by methicillin-resistant Staphylococcus aureus (MRSA) is a major public health problem. Pharmacoeconomic analysis was performed to compare the efficiency of daptomycin (DAP) against vancomycin (VAN) in the treatment of this infection. Retrospective, deterministic and probabilistic cost-effectiveness analysis. The effectiveness of the treatments was estimated from the results of a randomized clinical trial, which compared DAP (6 mg / kg IV daily) and VAN (1 g IV every 12 hours), both with or without gentamicin (1 mg / kg IV every 8 hours). Resource utilization was estimated from the clinical trial of the drug datasheets and Spanish sources, the unit costs were obtained also from Spanish sources. Monte Carlo probabilistic analysis and deterministic analysis were performed. The clinical trial cure rates were higher with DAP (44.4%, 95% CI 43.5 to 45.4%) than with VAN (31.8%, 95% CI 30.9 to 32.7%) not statistically significant (p = 0.2203) but with economic impact. With DAP would occur less costs due to treatment failure (rescue antibiotics, additional tests, prolonged hospital stay and adverse reactions) than with VAN. In the base case the average cost of disease per patient was € 12,329 to € 12,696 with DAP and VAN (difference of 367 €). DAP treatment was dominant (more effective, with lower costs than VAN) both in the deterministic and probabilistic analysis. In the Monte Carlo simulation, DAP was the most cost-effective treatment in 100% of the 10,000 simulations, for a willingness to pay € 12,000 per additional cure (approximate cost of MRSA bacteraemia episode). According to this model, daptomycin is more cost-effective than vancomycin in treating MRSA bacteremia. The higher cost of acquisition of daptomycin does not imply a higher cost of treating this infection.


Interferon Gamma Induces the Increase of Cell-Surface Markers (CD80/86, CD83 and MHC-II) in Splenocytes From Atlantic Salmon.
Type II interferon gamma (IFNγ) is a pleiotropic cytokine capable of modulating the innate and adaptive immune responses which has been widely characterized in several teleost families. In fish, IFNγ stimulates the expression of cytokines and chemokines associated with the pro-inflammatory response and enhances the production of nitrogen and oxygen reactive species in phagocytic cells. This work studied the effect of IFNγ on the expression of cell-surface markers on splenocytes of Atlantic salmon (Salmo salar). In vitro results showed that subpopulations of mononuclear splenocytes cultured for 15 days were capable of increasing gene expression and protein availability of cell-surface markers such as CD80/86, CD83 and MHC II, after being stimulated with recombinant IFNγ. These results were observed for subpopulations with characteristics associated with monocytes (51%), and features that could be related to lymphocytes (46.3%). In addition, a decrease in the expression of zbtb46 was detected in IFNγ-stimulated splenocytes. Finally, the expression of IFNγ and cell-surface markers was assessed in Atlantic salmon under field conditions. In vivo results showed that the expression of ifnγ increased simultaneously with the up-regulation of cd80/86, cd83 and mhcii during a natural outbreak of Piscirickettsia salmonis. Overall, the results obtained in this study allow us to propose IFNγ as a candidate molecule to stimulate the phenotypic progression of a small population of immune cells, which will increase antigen presenting cells markers. Thereby, modulatory strategies using IFNγ may generate a robust and coordinated immune response in fish against pathogens that affect aquaculture.


Genetic GIScience: Toward a Place-Based Synthesis of the Genome, Exposome, and Behavome.
The exposome, defined as the totality of an individual's exposures over the life course, is a seminal concept in the environmental health sciences. Although inherently geographic, the exposome as yet is unfamiliar to many geographers. This article proposes a place-based synthesis, genetic geographic information science (Genetic GISc) that is founded on the exposome, genome+ and behavome. It provides an improved understanding of human health in relation to biology (the genome+), environmental exposures (the exposome), and their social, societal and behavioral determinants (the behavome). Genetic GISc poses three key needs: First, a mathematical foundation for emergent theory; Second, process-based models that bridge biological and geographic scales; Third, biologically plausible estimates of space-time disease lags. Compartmental models are a possible solution; this article develops two models using pancreatic cancer as an exemplar. The first models carcinogenesis based on the cascade of mutations and cellular changes that lead to metastatic cancer. The second models cancer stages by diagnostic criteria. These provide empirical estimates of the distribution of latencies in cellular states and disease stages, and maps of the burden of yet to be diagnosed disease. This approach links our emerging knowledge of genomics to cancer progression at the cellular level, to individuals and their cancer stage at diagnosis, to geographic distributions of cancer in extant populations. These methodological developments and exemplar provide the basis for a new synthesis in health geography: genetic geographic information science.


Betulinic acid, a natural PDE inhibitor restores hippocampal cAMP/cGMP and BDNF, improve cerebral blood flow and recover memory deficits in permanent BCCAO induced vascular dementia in rats.
Vascular dementia (VaD) is the second most common form of senile dementia, embraces memory deficits, neuroinflammation, executive function damage, mood and behavioral changes and abnormal cerebral blood flow. The purpose of the study was to explore the therapeutic potential of betulinic acid in bilateral common carotid artery occlusion (BCCAO) induced VaD in experimental rats. VaD was induced by BCCAO in rats and betulinic acid (10 and 15 mg/kg/day po) was administered 1 week after surgery. The cerebral blood pressure of the animal was recorded before and after the treatment using Laser Doppler flow meter. Object recognition task for non-spatial, Morris water maze for spatial and locomotor activity was performed to evaluate behavioral changes in rats. At the end of the study, animals were decapitated and hippocampus was separated to perform biochemical, neuroinflammatory and second messengers cAMP/cGMP analysis. Histology was done to study the brain pathophysiology. BCCAO surgery was able to significantly impaired memory in rats as observed behavioral and biochemical parameters. Moreover, BA demonstrated a neuroprotective effect in a dose-dependent manner. BA was able to re-establish cerebral blood flow, restore behavioral parameters and showed significant improvements in the as cAMP,cGMP and BDNF levels, restrain the oxidative stress and inflammatory parameters. In histopathology, betulinic acid treated groups showed a decrease in microgliosis and less pathological abnormalities comparable to diseased rat's brain. The observed effect might be attributed to the neuroprotective potential of betulinic acid and its ability to restore cognitive impairment and hippocampal neurochemistry in VaD.


Executive control in frontal lesion aphasia: Does verbal load matter?
Executive control impairments in aphasia resulting from frontal lesions are expected, given that integrity of frontal regions is critical to executive control task performance. Yet the consistency of executive control impairments in aphasia is poorly understood. This is due to previous studies using only a brief set of measures or failing to account for the high language processing demands of many executive control tasks. This study investigated performance across a series of specific and broad executive control task, whilst comparing differences between low or high verbal task versions. Ten participants with aphasia secondary to left inferior frontal lesions and fifteen age matched controls completed a battery of verbal and low verbal executive control tasks tapping into the three core domains of inhibiting, switching, and updating of working memory. For both controls and participants with aphasia, there was no consistent influence of verbal load on either reaction time or accuracy performance. When compared to controls, participants with aphasia demonstrate a general slowing of responses across all reaction time tasks, and are less accurate on switching and updating tasks. These findings do suggest that language processing is not essential for executive control task performance, given that verbal load does not matter. Furthermore, tasks which involve holding multiple sources of information in mind, such as during switching or updating, are particularly vulnerable in aphasia.


Type I and III IFNs Produced by Plasmacytoid Dendritic Cells in Response to a Member of the Flaviviridae Suppress Cellular Immune Responses.
The pestivirus noncytopathic bovine viral diarrhea virus (BVDV) can suppress IFN production in the majority of cell types in vitro. However, IFN is detectable in serum during acute infection in vivo for ∼5-7 d, which correlates with a period of leucopoenia and immunosuppression. In this study, we demonstrate that a highly enriched population of bovine plasmacytoid dendritic cells (DCs) produced IFN in response to BVDV in vitro. We further show that the majority of the IFN produced in response to infection both in vitro and in vivo is type III IFN and acid labile. Further, we show IL-28B (IFN-λ3) mRNA is induced in this cell population in vitro. Supernatant from plasmacytoid DCs harvested postinfection with BVDV or recombinant bovine IFN-α or human IL-28B significantly reduced CD4(+) T cell proliferation induced by tubercle bacillus Ag 85-stimulated monocyte-derived DCs. Furthermore, these IFNs induced IFN-stimulated gene expression predominantly in monocyte-derived DCs. IFN-treated immature DCs derived from murine bone marrow also had a reduced capacity to stimulate T cell proliferative responses to tubercle bacillus Ag 85. Immature DCs derived from either source had a reduced capacity for Ag uptake following IFN treatment that is dose dependent. Immunosuppression is a feature of a number of pestivirus infections; our studies suggest type III IFN production plays a key role in the pathogenesis of this family of viruses. Overall, in a natural host, we have demonstrated a link between the induction of type I and III IFN after acute viral infection and transient immunosuppression.


Acid-base physiology over tidal periods in the mussel Mytilus edulis: size and temperature are more influential than seawater pH.
Ocean acidification (OA) studies to date have typically used stable open-ocean pH and CO2 values to predict the physiological responses of intertidal species to future climate scenarios, with few studies accounting for natural fluctuations of abiotic conditions or the alternating periods of emersion and immersion routinely experienced during tidal cycles. Here, we determine seawater carbonate chemistry and the corresponding in situ haemolymph acid-base responses over real time for two populations of mussel ( Mytilus edulis) during tidal cycles, demonstrating that intertidal mussels experience daily acidosis during emersion. Using these field data to parameterize experimental work we demonstrate that air temperature and mussel size strongly influence this acidosis, with larger mussels at higher temperatures experiencing greater acidosis. There was a small interactive effect of prior immersion in OA conditions (pHNBS 7.7/pCO2 930 µatm) such that the haemolymph pH measured at the start of emersion was lower in large mussels exposed to OA. Critically, the acidosis induced in mussels during emersion in situ was greater (ΔpH approximately 0.8 units) than that induced by experimental OA (ΔpH approximately 0.1 units). Understanding how environmental fluctuations influence physiology under current scenarios is critical to our ability to predict the responses of key marine biota to future environmental changes.


Advancing the right to health through global organizations: The potential role of a Framework Convention on Global Health.
Organizations, partnerships, and alliances form the building blocks of global governance. Global health organizations thus have the potential to play a formative role in determining the extent to which people are able to realize their right to health. This article examines how major global health organizations, such as WHO, the Global Fund to Fight AIDS, TB and Malaria, UNAIDS, and GAVI approach human rights concerns, including equality, accountability, and inclusive participation. We argue that organizational support for the right to health must transition from ad hoc and partial to permanent and comprehensive. Drawing on the literature and our knowledge of global health organizations, we offer good practices that point to ways in which such agencies can advance the right to health, covering nine areas: 1) participation and representation in governance processes; 2) leadership and organizational ethos; 3) internal policies; 4) norm-setting and promotion; 5) organizational leadership through advocacy and communication; 6) monitoring and accountability; 7) capacity building; 8) funding policies; and 9) partnerships and engagement. In each of these areas, we offer elements of a proposed Framework Convention on Global Health (FCGH), which would commit state parties to support these standards through their board membership and other interactions with these agencies. We also explain how the FCGH could incorporate these organizations into its overall financing framework, initiate a new forum where they collaborate with each other, as well as organizations in other regimes, to advance the right to health, and ensure sufficient funding for right to health capacity building. We urge major global health organizations to follow the leadership of the UN Secretary-General and UNAIDS to champion the FCGH. It is only through a rights-based approach, enshrined in a new Convention, that we can expect to achieve health for all in our lifetimes.


ETSR-YOLO: An improved multi-scale traffic sign detection algorithm based on YOLOv5.
In the application of driverless technology, current traffic sign recognition methods are susceptible to the influence of ambient light interference, target size changes and complex backgrounds, resulting in reduced recognition accuracy. To address these challenges, this study introduces an optimisation algorithm called ETSR-YOLO, which is based on the YOLOv5s algorithm. First, this study improves the path aggregation network (PANet) of YOLOv5s to enhance multi-scale feature fusion by generating an additional high-resolution feature layer to improve the recognition of YOLOv5s for small-sized objects. Second, the study introduces two improved C3 modules that aim to suppress background noise interference and enhance the feature extraction capabilities of the network. Finally, the study uses the Wise-IoU (WIoU) function in the post-processing stage to improve the learning ability and robustness of the algorithm to different samples. The experimental results show that ETSR-YOLO improves email@example.com by 6.6% on the Tsinghua-Tencent 100K (TT100K) dataset and by 1.9% on the CSUST Chinese Traffic Sign Detection Benchmark 2021 (CCTSDB2021) dataset. In the experiments conducted on the embedded computing platform, ETSR-YOLO demonstrates a short average inference time, thereby affirming its capability to deliver dependable traffic sign detection for intelligent vehicles operating in real-world traffic scenes. The source code and test results of the models used in this study are available at https://github.com/cbrook16/ETSR-YOLO.


Neuroprotection afforded by antagonists of endothelin-1 receptors in experimental stroke.
Endothelin-1 (ET-1) is involved on the development of cerebral edema in acute ischemic stroke. As edema is a therapeutic target in cerebral ischemia, our aim was to study the effect of antagonists for ET-1 receptors (Clazosentan® and BQ-788, specific antagonists for receptors A and B, respectively) on the development of edema, infarct volume and sensorial-motor deficits in rats subjected to ischemia by occlusion of the middle cerebral artery (MCAO). We used Wistar rats (280-320 g) submitted to ischemia by intraluminal transient (90 min) MCAO. After ischemia, rats were randomized into 4 groups (n = 6) treated with; 1) control group (saline), 2) Clazosentan® group (10 mg/kg iv), 3) BQ-788 group (3 mg/kg iv), and 4) combined treatment (Clazosentan® 10 mg/kg plus BQ-788 3 mg/kg iv). We observed that rats treated with Clazosentan® showed a reduction of edema, measured by MRI, at 72 h (hours) and at day 7 (both p < 0.0001), and a decrease in the serum levels of ET-1 at 72 h (p < 0.0001) and at day 7 (p = 0.009). The combined treatment also induced a reduction of edema at 24 h (p = 0.004), 72 h (p < 0.0001) and at day 7 (p < 0.0001), a reduction on infarct volume, measured by MRI, at 24 and 72 h, and at day 7 (all p < 0.01), and a better sensorimotor recovery at 24 and 72 h, and at day 7 (all p < 0.01). Moreover, Clazosentan® induced a decrease in AQP4 expression, while BQ-788 induced an increase in AQP9 expression. These results suggest that antagonists for ET-1 receptors may be a good therapeutic target for cerebral ischemia.


Conservative treatment of rotator cuff injuries.
Across all ages and activity levels, rotator cuff injuries are one of the most common causes of shoulder pain. The anatomy and biomechanics of the shoulder guide the history and physical exam toward the appropriate treatment of rotator cuff injuries. Rotator cuff tears are rare under the age of 40 unless accompanied by acute trauma. Throwing athletes are prone to rotator cuff injury from various causes of impingement (subacromial, internal, or secondary) and flexibility deficits, strength deficits, or both along the kinetic chain. Most rotator cuff injuries may be treated conservatively by using regimens of nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroid injections, and functional rehabilitation therapy. Injury prevention programs are essential for the long-term care of patients with rotator cuff disease, for primary prevention, and for prevention of recurrent injuries, unless a traumatically torn rotator cuff is present. Surgical management is reserved for refractory cases that have exhausted conservative measures.


The impact of nontechnical skills on technical performance in surgery: a systematic review.
Failures in nontechnical and teamwork skills frequently lie at the heart of harm and near-misses in the operating room (OR). The purpose of this systematic review was to assess the impact of nontechnical skills on technical performance in surgery. MEDLINE, EMBASE, PsycINFO databases were searched, and 2,041 articles were identified. After limits were applied, 341 articles were retrieved for evaluation. Of these, 28 articles were accepted for this review. Data were extracted from the articles regarding sample population, study design and setting, measures of nontechnical skills and technical performance, study findings, and limitations. Of the 28 articles that met inclusion criteria, 21 articles assessed the impact of surgeons' nontechnical skills on their technical performance. The evidence suggests that receiving feedback and effectively coping with stressful events in the OR has a beneficial impact on certain aspects of technical performance. Conversely, increased levels of fatigue are associated with detriments to surgical skill. One article assessed the impact of anesthesiologists' nontechnical skills on anesthetic technical performance, finding a strong positive correlation between the 2 skill sets. Finally, 6 articles assessed the impact of multiple nontechnical skills of the entire OR team on surgical performance. A strong relationship between teamwork failure and technical error was empirically demonstrated in these studies. Evidence suggests that certain nontechnical aspects of performance can enhance or, if lacking, contribute to deterioration of surgeons' technical performance. The precise extent of this effect remains to be elucidated.


Favorable effect of moderate dose caffeine on the skeletal system in ovariectomized rats.
Caffeine, a methylxanthine present in coffee, has been postulated to be responsible for an increased risk of osteoporosis in coffee drinkers; however, the data are inconsistent. The aim of the present study was to investigate the effects of a moderate dose of caffeine on the skeletal system of rats with normal and decreased estrogen level (developing osteoporosis due to estrogen deficiency). The experiments were carried out on mature nonovariectomized and ovariectomized Wistar rats, divided into control rats and rats receiving caffeine once daily, 20 mg/kg p.o., for 4 wk. Serum bone turnover markers, bone mass, mass of bone mineral, calcium and phosphorus content, histomorphometric parameters, and bone mechanical properties were examined. Caffeine favorably affected the skeletal system of ovariectomized rats, slightly inhibiting the development of bone changes induced by estrogen deficiency (increasing bone mineralization, and improving the strength and structure of cancellous bone). Moreover, it favorably affected mechanical properties of compact bone. There were no significant effects of caffeine in rats with normal estrogen levels. In conclusion, results of the present study indicate that low-to-moderate caffeine intake may exert some beneficial effects on the skeletal system of mature organisms.


Advancing Health Professions Education Research by Creating a Network of Networks.
Producing the best evidence to show educational outcomes, such as competency achievement and credentialing effectiveness, across the health professions education continuum will require large multisite research projects and longitudinal studies. Current limitations that must be overcome to reach this goal include the prevalence of single-institution study designs, assessments of a single curricular component, and cross-sectional study designs that provide only a snapshot in time of a program or initiative rather than a longitudinal perspective.One solution to overcoming these limitations is to develop a network of networks that collaborates, using longitudinal approaches, across health professions and regions of the United States. Currently, individual networks are advancing educational innovation toward understanding the effectiveness of educational and credentialing programs. Examples of such networks include (1) the American Medical Association's Accelerating Change in Medical Education initiative, (2) the National Center for Interprofessional Practice and Education, and (3) the Accreditation Council for Graduate Medical Education's Accreditation System. In this Invited Commentary, the authors briefly profile these existing networks, identify their progress and the challenges they have encountered, and propose a vigorous way forward toward creating a national network of networks designed to determine the effectiveness of health professions education and credentialing.


Synthetic, structural and biological studies of the ubiquitin system: chemically synthesized and native ubiquitin fold into identical three-dimensional structures.
The solid-phase chemical synthesis of ubiquitin produced a molecule with physicochemical properties similar to those of the natural protein. We have grown crystals of this synthetic ubiquitin and performed an X-ray analysis at 1.8 A resolution in order to compare the synthetic protein with the known natural structure. The crystals were isomorphous with those of the natural protein, the R-factor between them being 7.1%. Difference Fourier analysis shows that the synthetic and natural structures are indistinguishable. The co-ordinates of the natural ubiquitin (1UBQ) were used as the starting point for restrained least-squares refinement (TNT program) against the synthetic X-ray data. The refinement converged to R = 16.5% and the resulting model did not change when refined against natural ubiquitin X-ray data (R = 18.7%). From both the refinement and featureless difference Fourier synthesis, we conclude that the synthetic and natural protein structures are identical. A short discussion about the uses of proteins with 'non-standard' amino acid residues is included.


Validity of a measure of the frequency of headaches with overt neck involvement, and reliability of measurement of cervical spine anthropometric and muscle performance factors.
To test the validity of a questionnaire to measure frequency of headaches related to the neck. A secondary goal was to test the reliability of field measurement of associated cervical spine anthropometric and muscle performance factors. Intermethod and test-retest comparisons. Two municipalities in a rural area of Tasmania, Australia. One hundred subjects were selected as a representative sample of never-injured adults from a comprehensive listing of the source population, and 93 participated. Subjects distinguished headaches matching three criteria for overt neck involvement, reported past-month frequency by questionnaire, and recorded in a diary occurrences during the next month. Measurements of height, weight, neck column length and circumference, lateral flexion and extension range of movement, cervical short flexor muscle endurance, and cervical long flexor and extensor strength were taken at the start and end of the month. Headache frequency was associated with neck stiffness and neck ache. There was moderate agreement (weighted K = .66) between questionnaire and diary, but better agreement (K = .72) for subjects who maintained their usual patterns of recreational sport. For this group, the correlation with "true" frequency was r(u) = .87. The anthropometric and muscle performance factors were reliably measured (intraclass correlations .96 to 1.00, kappa .78 to .86) despite minor improvement in muscle performance on retest. The questionnaire measure has construct validity. Neck-related headaches are a temporally stable presentation in never-injured subjects who maintain customary sporting activity. Measurement error was consequential, but less so for this group than for the study subjects generally. The anthropometric and muscle performance measurements were reliable, but slight improvements on retest suggest the need for multiple measurements.


Exploring the role of health literacy in the evaluation of online health information: Insights from a mixed-methods study.
To gain new insights into the relationship between health literacy and evaluation of online health information. Using a mixed-methods approach, forty-four semi-structured interviews were conducted followed by a short questionnaire on health literacy and eHealth literacy. Qualitative and quantitative data were merged to explore differences and similarities among respondents with different health literacy levels. Thematic analysis showed that most respondents did not question the quality of online health information and relied on evaluation criteria not recognized by existing web quality guidelines. Individuals with low health literacy, despite presenting higher eHealth literacy scores, appeared to use less established criteria and to rely more heavily on non-established ones compared to those with high health literacy. Disparities in evaluation ability among people with different health literacy might be related to differences in awareness of the issue and to the use of different evaluation criteria. Future research should quantitatively investigate the interplay between health literacy, use of established and non-established criteria, and ability to evaluate online health information. Communication and patient education efforts should aim to raise awareness on online health information quality and to promote use of established evaluation criteria, especially among low health literate citizens.


Embodied linearity of speed control in Drosophila melanogaster.
Fruitflies regulate flight speed by adjusting their body angle. To understand how low-level posture control serves an overall linear visual speed control strategy, we visually induced free-flight acceleration responses in a wind tunnel and measured the body kinematics using high-speed videography. Subsequently, we reverse engineered the transfer function mapping body pitch angle onto flight speed. A linear model is able to reproduce the behavioural data with good accuracy. Our results show that linearity in speed control is realized already at the level of body posture-mediated speed control and is therefore embodied at the level of the complex aerodynamic mechanisms of body and wings. Together with previous results, this study reveals the existence of a linear hierarchical control strategy, which can provide relevant control principles for biomimetic implementations, such as autonomous flying micro air vehicles.


Monitoring biological membrane-potential changes: a CI QM/MM study.
In recent decades, new less-invasive, nonlinear optical methods have been proposed and optimized for monitoring fast physiological processes in biological cells. One of these methods allows the action potential (AP) in cardiomyocytes or neurons to be monitored by means of second-harmonic generation (SHG). We now present the first, to our knowledge, simulations of the dependency of the intensity of the second harmonic (I(SHG)) on variations of the transmembrane potential (TMP) in a cardiomyocyte during an action potential (AP). For this, an amphiphilic potential-sensitive styryl dye molecule with nonlinear optical properties was embedded in a dipalmitoylphosphatidylcholine (DPPC) bilayer, replacing one of the phospholipid molecules. External electrical fields with different strengths were applied across the membrane to simulate the AP of a heart-muscle cell. We used a combined classical/quantum mechanical approach to model the structure and the spectroscopic properties of the embedded chromophore. Two 10 ns molecular dynamics (MD) simulations provided input geometries for semiempirical molecular orbital (QM/MM) single-point configuration interaction (CI) calculations, which were used to calculate the wavelengths and oscillator strengths of electronic transitions in the di-8-ANEPPS dye molecule. The results were then used in a sum-over-states treatment to calculate the second-order hyperpolarizability. The square of the hyperpolarizability scales with the intensity of the second harmonic, which is used to monitor the action potentials of cardiomyocytes experimentally. Thus, we computed changes in the intensity of the second harmonic (DeltaI(SHG)) as function of TMP changes. Our results agree well with experimental measurements.


Testicular volume of healthy term neonates: Determination of normative values among Igbo babies in South-Eastern Nigeria.
Testicular volume (TV) in neonates has some predictive values of clinical importance. Establishing the normal values of TV among term newborn males of every population is important as differences exist among different populations. Much is not known on TV among Igbo newborns. The aim of this study was to determine the normative values of TV in apparently healthy term Igbo newborn males in Enugu, South-Eastern Nigeria and its relationship with gestational age (GA), birth weight (BW), and birth length (BL). This was a hospital-based, cross-sectional and descriptive study. Eight hundred and eleven apparently healthy term Igbo male neonates within the first 3 days of life were studied. The TV was measured with Prader Orchidometer (ZKL-135-H), ESP Model. Smoothed centiles (3-97th percentile values) for TV by GA were determined. Data were analyzed using the Statistical Package for Social Sciences (SPSS) version 17.0 (Chicago). P < 0.05 were regarded as statistically significant. The mean TV was 1.74 ± 0.62 ml ranging from 1 to 3 ml. The TV increased with increasing GA (P = 0.00). Pearson's correlation test between TV and birth length (r = 0.301, P = 0.001), as well as with BW (r = 0.247, P = 0.001) were significant. A linear regression demonstrated correlation between TV and birth length (P = 0.0001, r2 = 0.091). The mean TV among male Igbo newborn is 1.74 ± 0.62 ml. Also, the first smoothed percentile values for TV by GA for Nigerian Igbo babies is created.


An atypical kinase under balancing selection confers broad-spectrum disease resistance in Arabidopsis.
The failure of gene-for-gene resistance traits to provide durable and broad-spectrum resistance in an agricultural context has led to the search for genes underlying quantitative resistance in plants. Such genes have been identified in only a few cases, all for fungal or nematode resistance, and encode diverse molecular functions. However, an understanding of the molecular mechanisms of quantitative resistance variation to other enemies and the associated evolutionary forces shaping this variation remain largely unknown. We report the identification, map-based cloning and functional validation of QRX3 (RKS1, Resistance related KinaSe 1), conferring broad-spectrum resistance to Xanthomonas campestris (Xc), a devastating worldwide bacterial vascular pathogen of crucifers. RKS1 encodes an atypical kinase that mediates a quantitative resistance mechanism in plants by restricting bacterial spread from the infection site. Nested Genome-Wide Association mapping revealed a major locus corresponding to an allelic series at RKS1 at the species level. An association between variation in resistance and RKS1 transcription was found using various transgenic lines as well as in natural accessions, suggesting that regulation of RKS1 expression is a major component of quantitative resistance to Xc. The co-existence of long lived RKS1 haplotypes in A. thaliana is shared with a variety of genes involved in pathogen recognition, suggesting common selective pressures. The identification of RKS1 constitutes a starting point for deciphering the mechanisms underlying broad spectrum quantitative disease resistance that is effective against a devastating and vascular crop pathogen. Because putative RKS1 orthologous have been found in other Brassica species, RKS1 provides an exciting opportunity for plant breeders to improve resistance to black rot in crops.


CoQ10 fails to protect brain against focal and global ischemia in rats.
Release of oxygen free radicals occurs following cerebral ischemia. Studies show that oxygen free radicals mediate ischemic brain injury. CoQ10 is a potent free radical scavenger and may offset brain injury associated with reperfusion. We tested exogeneous CoQ10 as a neuroprotectant in rats following both global and focal ischemic insults. Rats were subjected to either 4-vessel occlusion ischemia (4-VO, 10 min occlusion, 7-day survival) or middle cerebral artery occlusion (MCAO, 120 min-occlusion, 22.5 h survival). Regional cerebral blood flows (rCBF) and physiological variables such as blood pressure, pO2, pCO2, plasma glucose and hematocrit were monitored and measured in focal ischemia. The animals were randomized to receive treatments of either phosphate buffered saline (PBS) vehicle or CoQ10 following global or focal ischemia. Injection times were at the end of ischemia and 3 h later for both models of ischemia. Histological outcomes are expressed as a percentage of hippocampal CA(1) cell injury in global ischemia or percentage of cortical infarct over that of non-ischemic hemisphere in focal ischemia. In global ischemia, animals treated with PBS vehicle and CoQ10 had 86+/-5% (n=8) and 83+/-10% (n=8), respectively, of hippocampal CA(1) cell injury (P>0.05). The percentage of infarct volumes in animals following focal ischemia were 23+/-9% (control, n=10) and 25+/-9% (CoQ10, n=10). There were no temperature or physiological differences between the two treatment groups. Acute treatment with CoQ10 via intraperitoneal injection does not prevent neuronal injuries following global and focal ischemia.


Directly written monolithic waveguide laser incorporating a distributed feedback waveguide-Bragg grating.
We report the fabrication and performance of the first C-band directly written monolithic waveguide laser (WGL). The WGL device was created in an erbium- and ytterbium-doped phosphate glass host and consisted of an optical waveguide that included a distributed feedback Bragg grating structure. The femtosecond laser direct-write technique was used to create both the waveguide and the waveguide-Bragg grating simultaneously and in a single processing step. The waveguide laser was optically pumped at approximately 980 nm and lased at 1,537 nm with a bandwidth of less than 4 pm.


Validation of the NPAQ-short - a brief questionnaire to monitor physical activity and compliance with the WHO recommendations.
Using self-reported surveys to monitor physical activity levels in the population require short items covering both time and intensity. The present study aims to 1) develop the Nordic Physical Activity Questionnaire-short from the original version of the NPAQ, 2) assess test-retest reliability and criterion validity of the NPAQ-short, and 3) test the NPAQ-short's ability to monitor compliance with the WHO recommendations on physical activity. In addition, we aimed to compare open and closed-ended answering modes for the NPAQ-short. A sample of 122 participants were included. The NPAQ-short comprised of two questions on weekly moderate-to-vigorous physical activity (MVPA) and vigorous physical activity (VPA). It was filled in twice, two weeks apart, in open- and closed-ended versions. Physical activity was measured objectively by an Actiheart accelerometer worn 24 h/day seven consecutive days. Spearman's rank correlation and Cohen's kappa were used to assess correlations between the test and retest results, and between the objective and the self-reported measures. Valid data was available for 92 participants. Test-retest reliability showed Spearman's rho = 0.82 for MVPA and 0.80 for VPA. For the open-ended questions, the correlations between self-reported and objectively measured physical activity levels were Spearman's rho = 0.33 for MVPA and rho = 0.32 for VPA. For closed-ended questions, the kappa-coefficients were 0.17 for MVPA and 0.21 for VPA. When using objective and self-reported measures to monitor WHO's physical activity recommendations, the kappa correlations were 0.42 for open-ended and 0.34 for closed-ended answering modes. The NPAQ-short was found to be sufficiently reliable and valid to monitor physical activity levels in the population when using both open and closed-ended questions. However, using open-ended questions seems to be a better answering mode for self-reported surveys monitoring WHO's physical activity recommendations.


Combined small-cell and non-small-cell lung cancer.
Nine (2%) of 429 small-cell lung cancer (SCLC) patients seen at Vanderbilt University between 1977 and 1983 had a combined subtype SCLC at diagnosis (ie, small-cell carcinoma plus squamous cell or adenocarcinoma). Staging procedures and chemotherapy treatment were uniform for all 429 patients. The diagnosis of combined histology was established via bronchoscopy (six patients), needle aspiration biopsy (one), lymph node biopsy (one), and thoracotomy (one). The clinical characteristics of the combined subtype patients were similar to patients with other subtypes of SCLC (ie, there were no differences in median age, sex, performance status, and stage of disease). However, patients with a combined subtype histology had a higher incidence of peripheral lesions on chest x-ray (56% v 14%, P less than .001) and a lower median lactate dehydrogenase (LDH) (301 IU/L v 341 IU/L, P = .0002) at diagnosis. The overall response to chemotherapy (57% v 78; P = .5) and the median survival (8 months v 10 months; P = .4) of the combined subtype patients were similar to patients with other subtypes of SCLC. Two (22%) combined histology patients survived greater than or equal to 5 years. Both had had surgical resection in addition to chemotherapy. These data suggest that the combined subtype of SCLC is clinically similar to pure SCLCs and that surgery may play a prominent role in the management of these tumors. The possibility of a combined histology tumor should be considered in patients thought to have SCLC on the basis of limited biopsy material, such as a needle aspiration or bronchial biopsy, and when the primary lesion is peripherally located on chest x-ray.


Revision of the Laonice bahusiensis complex (Annelida: Spionidae) with a description of three new species.
The morphological reexamination of specimens previously identified as Laonice bahusiensis Sderstrm, 1920 from North European and Mediterranean collections, supported by the molecular analysis of freshly collected material, enabled the recognition of four different species in the region: the genuine L. bahusiensis, L. irinae n. sp. from North European waters, and L. grimaldii n. sp. and L. mediterranea n. sp. from the Mediterranean Sea. The morphology of these species is described and illustrated, and their distributions are clarified based on old and new materials. A key for their identification is also provided. The Bayesian analysis of the COI sequences (483 bp) showed that these four species form a clade, namely the L. bahusiensis species complex, morphologically characterized by the continuous dorsal crests on postbranchiate chaetigers in the adults. The genetic p-distances between the species of the complex ranged from 13.27% to 17.99%, while the intraspecific variability ranged from 0.6% to 1.57%. Together with the sister species Laonice cirrata (Sars, 1851), the L. bahusiensis complex formed the Laonice (Laonice) clade, which is morphologically characterized by the prostomium fused with the anterior peristomial margin. However, the monophyly of the L. bahusiensis complex, as well as that of the clade Laonice (Laonice), needs to be further supported through the analysis of a greater set of genes from a larger number of species.


Mass Spectrometric Quantitation of Tubulin Acetylation from Pepsin-Digested Rat Brain Tissue Using a Novel Stable-Isotope Standard and Capture by Anti-Peptide Antibody (SISCAPA) Method.
Acetylation of α-tubulin at Lys-40 is a potential biomarker for cognitive deficits in various neurological disorders. However, this key post-translational modification (PTM) has not been previously studied with mass spectrometry, due to the inadequate distribution of tryptic cleavage sites. Following peptic digestion, a surrogate sequence containing this key PTM site was identified and was found to be stable and quantitatively reproducible. A highly sensitive and specific SISCAPA-LC-MS method for quantitating rat brain tubulin acetylation was developed, validated, and applied, and only required a small amount of tissue (2.2 mg). This workflow includes peptic digestion, stable-isotope dilution, capture with antiacetylated peptide antibody bound on protein G beads, and quantitation using LC-MS. The method allowed a lower limit of quantitation at 2.50 pmol/mg and provided a linear range of 2.50-62.50 pmol/mg. Selectivity, intra and interday precision and accuracy were also validated. This method has been successfully applied in a preclinical study of organophosphate neurotoxicity, and we found that chronic exposure to chlorpyrifos led to a significant and persistent inhibition of brain tubulin acetylation.


Proteomics of Herpes Simplex Virus Type 1 Nuclear Capsids.
Herpes simplex virus replicates in the nucleus, where new capsids are assembled. It produces procapsids devoid of nucleic acid but containing the preVP22a scaffold protein. These thermo-unstable particles then mature into A-, B- or C-nuclear icosahedral capsids, depending on their ability to shed the proteolytically processed scaffold and incorporation of the viral genome. To study how these viral capsids differ, we performed proteomics studies of highly enriched HSV-1 A-, B- and C-nuclear capsids, relying in part on a novel and powerful flow virometry approach to purify C-capsids. We found that the viral particles contained the expected capsid components and identified several tegument proteins in the C-capsid fraction (pUL21, pUL36, pUL46, pUL48, pUL49, pUL50, pUL51 and pUS10). Moreover, numerous ribosomal, hnRNPs and other host proteins, absent from the uninfected controls, were detected on the capsids with some of them seemingly specific to C-capsids (glycogen synthase, four different keratin-related proteins, fibronectin 1 and PCBP1). A subsequent proteomics analysis was performed to rule out the presence of protein complexes that may share similar density as the viral capsids but do not otherwise interact with them. Using pUL25 or VP5 mutant viruses incapable of assembling C-nuclear or all nuclear capsids, respectively, we confirmed the bulk of our initial findings. Naturally, it will next be important to address the functional relevance of these proteins.IMPORTANCE Much is known about the biology of herpesviruses. This includes their unique ability to traverse the two nuclear envelopes by sequential budding and fusion steps. For HSV-1, this implies the pUL31/pUL34 and pUL17/pUL25 complexes that may favor C-capsid egress. However, this selection process is not clear, nor are all the differences that distinguish A-, B- and C-capsids. The present study probes what proteins compose these capsids, including host proteins. This should open up new research avenues to clarify the biology of this most interesting family of viruses. It also reiterates the use of flow virometry as an innovative tool to purify viral particles.


Does gastroesophageal reflux contribute to the development of chronic sinusitis? A review of the evidence.
Although recent studies suggest that gastroesophageal reflux disease (GERD) may contribute to a variety of ear, nose and throat and pulmonary diseases, the cause-and-effect relationship for the vast majority remains far from proven. In this article, the evidence supporting a possible causal association between GERD and chronic sinusitis has been reviewed. The evidence would suggest that: (i) a higher prevalence of GERD and a different esophagopharyngeal distribution of the gastric refluxate occurs in patients with chronic sinusitis unresponsive to conventional medical and surgical therapy compared to the general population; (ii) a biologically plausible pathogenetic mechanism exists whereby GERD may result in chronic sinusitis; and (iii) clinical manifestations of chronic sinusitis respond variably to antireflux therapy. While these findings suggest that GERD may contribute to the pathogenesis of chronic sinusitis in some patients, it is apparent that the quality of the evidence supporting each of these three lines of evidence is low and therefore does not conclusively establish a cause-and-effect relationship. A number of unresolved issues regarding prevalence, pathophysiological mechanism, diagnosis and treatment exist that deserve further investigation in order to solidify the relationship between GERD and chronic sinusitis. In conclusion, given the possible relationship between GERD and chronic sinusitis, until more convincing data are available, it may be prudent to investigate for GERD as a potential cofactor or initiating factor in patients with chronic sinusitis when no other etiology exists, or in those whose symptoms are unresponsive to conventional therapies.


Marital biography and health at mid-life.
This article develops a series of hypotheses about the long-term effects of one's history of marriage, divorce, and widowhood on health, and it tests those hypotheses using data from the Health and Retirement Study. We examine four dimensions of health at mid-life: chronic conditions, mobility limitations, self-rated health, and depressive symptoms. We find that the experience of marital disruption damages health, with the effects still evident years later; among the currently married, those who have ever been divorced show worse health on all dimensions. Both the divorced and widowed who do not remarry show worse health than the currently married on all dimensions. Dimensions of health that seem to develop slowly, such as chronic conditions and mobility limitations, show strong effects of past marital disruption, whereas others, such as depressive symptoms, seem more sensitive to current marital status. Those who spent more years divorced or widowed show more chronic conditions and mobility limitations.


Fiber nanogratings induced by femtosecond pulse laser direct writing for in-line polarizer.
Self-organized fiber nanogratings (FNGs) induced by femtosecond pulse laser direct writing are demonstrated in optical silica fibers for the first time. Ge doping in the silica fiber core plays an important role in the formation of nanogratings. Negative changes in refractive index with sawtooth fluctuation and strong birefringence of FNGs were investigated by an optical fiber refractive index analyzer and a crossed polarization microscope, respectively. The polarization features of FNGs were characterized by the Mueller matrix analytical method and in-line polarizers based on FNGs were fabricated. FNGs are promising integrated components because of their prominent properties of polarization and salient compatibility with most fiber-optic systems.


Evaluation of potential breath biomarkers for active smoking: assessment of smoking habits.
Different compounds have been reported as biomarkers of a smoking habit, but, to date, there is no appropriate biomarker for tobacco-related exposure because the proposed chemicals seem to be nonspecific or they are only appropriate for short-term exposure. Moreover, conventional sampling methodologies require an invasive method because blood or urine samples are required. The use of a microtrap system coupled to gas chromatography-mass spectrometry analysis has been found to be very effective for the noninvasive analysis of volatile organic compounds in breath samples. The levels of benzene, 2,5-dimethylfuran, toluene, o-xylene, and m- p-xylene have been analyzed in breath samples obtained from 204 volunteers (100 smokers, 104 nonsmokers; 147 females, 57 males; ages 16 to 53 years). 2,5-Dimethylfuran was always below the limit of detection (0.005 ppbv) in the nonsmoker population and always detected in smokers independently of the smoking habits. Benzene was only an effective biomarker for medium and heavy smokers, and its level was affected by smoking habits. Regarding the levels of xylenes and toluene, they were only different in heavy smokers and after short-term exposure. The results obtained suggest that 2,5-dimethylfuran is a specific breath biomarker of smoking status independently of the smoking habits (e.g., short- and long-term exposure, light and heavy consumption), and so this compound might be useful as a biomarker of smoking exposure.


Aclacinomycin A sensitizes K562 chronic myeloid leukemia cells to imatinib through p38MAPK-mediated erythroid differentiation.
Expression of oncogenic Bcr-Abl inhibits cell differentiation of hematopoietic stem/progenitor cells in chronic myeloid leukemia (CML). Differentiation therapy is considered to be a new strategy for treating this type of leukemia. Aclacinomycin A (ACM) is an antitumor antibiotic. Previous studies have shown that ACM induced erythroid differentiation of CML cells. In this study, we investigate the effect of ACM on the sensitivity of human CML cell line K562 to Bcr-Abl specific inhibitor imatinib (STI571, Gleevec). We first determined the optimal concentration of ACM for erythroid differentiation but not growth inhibition and apoptosis in K562 cells. Then, pretreatment with this optimal concentration of ACM followed by a minimally toxic concentration of imatinib strongly induced growth inhibition and apoptosis compared to that with simultaneous co-treatment, indicating that ACM-induced erythroid differentiation sensitizes K562 cells to imatinib. Sequential treatment with ACM and imatinib induced Bcr-Abl down-regulation, cytochrome c release into the cytosol, and caspase-3 activation, as well as decreased Mcl-1 and Bcl-xL expressions, but did not affect Fas ligand/Fas death receptor and procaspase-8 expressions. ACM/imatinib sequential treatment-induced apoptosis was suppressed by a caspase-9 inhibitor and a caspase-3 inhibitor, indicating that the caspase cascade is involved in this apoptosis. Furthermore, we demonstrated that ACM induced erythroid differentiation through the p38 mitogen-activated protein kinase (MAPK) pathway. The inhibition of erythroid differentiation by p38MAPK inhibitor SB202190, p38MAPK dominant negative mutant or p38MAPK shRNA knockdown, reduced the ACM/imatinib sequential treatment-mediated growth inhibition and apoptosis. These results suggest that differentiated K562 cells induced by ACM-mediated p38MAPK pathway become more sensitive to imatinib and result in down-regulations of Bcr-Abl and anti-apoptotic proteins, growth inhibition and apoptosis. These results provided a potential management by which ACM might have a crucial impact on increasing sensitivity of CML cells to imatinib in the differentiation therapeutic approaches.


Omega-3 Fatty acids and inflammation: novel interactions reveal a new step in neutrophil recruitment.
Inflammation is a physiological response to tissue trauma or infection, but leukocytes, which are the effector cells of the inflammatory process, have powerful tissue remodelling capabilities. Thus, to ensure their precise localisation, passage of leukocytes from the blood into inflamed tissue is tightly regulated. Recruitment of blood borne neutrophils to the tissue stroma occurs during early inflammation. In this process, peptide agonists of the chemokine family are assumed to provide a chemotactic stimulus capable of supporting the migration of neutrophils across vascular endothelial cells, through the basement membrane of the vessel wall, and out into the tissue stroma. Here, we show that, although an initial chemokine stimulus is essential for the recruitment of flowing neutrophils by endothelial cells stimulated with the inflammatory cytokine tumour necrosis factor-alpha, transit of the endothelial monolayer is regulated by an additional and downstream stimulus. This signal is supplied by the metabolism of the omega-6-polyunsaturated fatty acid (n-6-PUFA), arachidonic acid, into the eicosanoid prostaglandin-D(2) (PGD(2)) by cyclooxygenase (COX) enzymes. This new step in the neutrophil recruitment process was revealed when the dietary n-3-PUFA, eicosapentaenoic acid (EPA), was utilised as an alternative substrate for COX enzymes, leading to the generation of PGD(3). This alternative series eicosanoid inhibited the migration of neutrophils across endothelial cells by antagonising the PGD(2) receptor. Here, we describe a new step in the neutrophil recruitment process that relies upon a lipid-mediated signal to regulate the migration of neutrophils across endothelial cells. PGD(2) signalling is subordinate to the chemokine-mediated activation of neutrophils, but without the sequential delivery of this signal, neutrophils fail to penetrate the endothelial cell monolayer. Importantly, the ability of the dietary n-3-PUFA, EPA, to inhibit this process not only revealed an unsuspected level of regulation in the migration of inflammatory leukocytes, it also contributes to our understanding of the interactions of this bioactive lipid with the inflammatory system. Moreover, it indicates the potential for novel therapeutics that target the inflammatory system with greater affinity and/or specificity than supplementing the diet with n-3-PUFAs.


OPTIC CHIASM WIDTH IN NORMAL-TENSION AND HIGH-TENSION GLAUCOMA.
The aim of our study was to find out whether in patients with hypertensive glaucoma (HTG) and normotensive glaucoma (NTG), there is a change in the size of the chiasm depending on the changes in the visual field. Therefore, we retrospectively measured the width of the chiasm in the patients to whom we measured the size of the corpus geniculatum laterale in 2013. The group consisted of two groups of patients. Nine with hypertensive glaucoma (HTG) and nine with normotensive glaucoma (NTG). The diagnosis was based on a complex ophthalmological examination and in NTG and electrophysiological examination. The visual field was examined by a rapid threshold program on the Medmont M700. The sum of the sensitivity from both visual fields in the range of 0-22 degrees was compared with the width of the chiasm obtained by the magnetic resonance imaging using the eight channel head coil. The measured values of all subjects were analyzed using a paired t-test and a correlation coefficient. We found a reduction in the chiasma width in both glaucoma groups. We found a statistically significant difference in the size of the chiasm (p = 0.0003) between the control group and the HTG group (p = 0.001). The narrowing of the chiasm showed a slight correlation in HTG with changes in the field of vision (r = 0.139) and in NTG a moderate correlation (r = 0.375). We found a reduction in the size of the chiasm in both HTG and NTG. The sum of sensitivities in the central parts of the visual field, however, more correlated with the reduction in the size of the chiasm in NTG. This finding shows that there are two different diagnostic groups.


Light-Emitting Nanophotonic Designs Enabled by Ultrafast Laser Processing of Halide Perovskites.
Nanophotonics based on resonant nanostructures and metasurfaces made of halide perovskites have become a prospective direction for efficient light manipulation at the subwavelength scale in advanced photonic designs. One of the main challenges in this field is the lack of large-scale low-cost technique for subwavelength perovskite structures fabrication preserving highly efficient luminescence. Here, unique properties of halide perovskites addressed to their extremely low thermal conductivity (lower than that of silica glass) and high defect tolerance to apply projection femtosecond laser lithography for nanofabrication with precise spatial control in all three dimensions preserving the material luminescence efficiency are employed. Namely, with CH3 NH3 PbI3 perovskite highly ordered nanoholes and nanostripes of width as small as 250 nm, metasurfaces with periods less than 400 nm, and nanowire lasers as thin as 500 nm, corresponding to the state-of-the-art in multistage expensive lithographical methods are created. Remarkable performance of the developed approach allows to demonstrate a number of advanced optical applications, including morphology-controlled photoluminescence yield, structural coloring, optical- information encryption, and lasing.


Maximum Likelihood based comparison of the specific growth rates for P. aeruginosa and four mutator strains.
The specific growth rate for P. aeruginosa and four mutator strains mutT, mutY, mutM and mutY-mutM is estimated by a suggested Maximum Likelihood, ML, method which takes the autocorrelation of the observation into account. For each bacteria strain, six wells of optical density, OD, measurements are used for parameter estimation. The data is log-transformed such that a linear model can be applied. The transformation changes the variance structure, and hence an OD-dependent variance is implemented in the model. The autocorrelation in the data is demonstrated, and a correlation model with an exponentially decaying function of the time between observations is suggested. A model with a full covariance structure containing OD-dependent variance and an autocorrelation structure is compared to a model with variance only and with no variance or correlation implemented. It is shown that the model that best describes data is a model taking into account the full covariance structure. An inference study is made in order to determine whether the growth rate of the five bacteria strains is the same. After applying a likelihood-ratio test to models with a full covariance structure, it is concluded that the specific growth rate is the same for all bacteria strains. This study highlights the importance of carrying out an explorative examination of residuals in order to make a correct parametrization of a model including the covariance structure. The ML method is shown to be a strong tool as it enables estimation of covariance parameters along with the other model parameters and it makes way for strong statistical tools for inference studies.


Biodegradable- Versus Durable-Polymer Drug-Eluting Stents for STEMI: Final 2-Year Outcomes of the BIOSTEMI Trial.
The aim of this study was to investigate the safety and efficacy of biodegradable-polymer sirolimus-eluting stents (BP-SES) compared with durable-polymer everolimus-eluting stents (DP-EES) in patients with ST-segment elevation myocardial infarction (STEMI). Primary percutaneous coronary intervention (PCI) is an effective treatment for patients with STEMI, and long-term outcomes are determined by the safety and efficacy profile of the newest generation drug-eluting stents. BIOSTEMI (A Comparison of an Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Stent With a Durable Polymer Everolimus-Eluting Stent for Patients With Acute ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention) was an investigator-initiated, multicenter, assessor-blind, randomized superiority trial using Bayesian methods. Patients with STEMI undergoing primary PCI within 24 h of symptom onset were randomized in a 1:1 ratio to receive BP-SES (n = 649) or DP-EES (n = 651). The primary endpoint was target lesion failure (TLF), a composite of cardiac death, target vessel myocardial reinfarction, and clinically indicated target lesion revascularization (TLR) at 2 years. Between April 2016 and March 2018, 1,300 patients were included. Baseline characteristics were comparable between the 2 treatment groups. Follow-up through 2 years was complete in 1,221 patients (94%). At 2 years, TLF occurred in 33 patients (5.1%) treated with BP-SES and in 53 patients (8.1%) treated with DP-EES (rate ratio: 0.58; 95% Bayesian credible interval: 0.40 to 0.84; posterior probability of superiority = 0.998). The difference was driven by a lower incidence of clinically indicated TLR in patients treated with BP-SES compared with DP-EES (2.5% vs. 5.1%; rate ratio: 0.52; 95% Bayesian credible interval: 0.30 to 0.87; posterior probability of superiority = 0.993). There were no significant differences in rates of cardiac death, target vessel myocardial reinfarction, and definite stent thrombosis between the 2 treatment arms. In patients with STEMI undergoing primary PCI, BP-SES were superior to DP-EES with respect to TLF at 2 years. The difference was driven by lower rates of ischemia-driven TLR. (A Comparison of an Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Stent With a Durable Polymer Everolimus-Eluting Stent for Patients With Acute ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention [BIOSTEMI]; NCT02579031).


Apoptotic colonopathy under immunosuppression: mycophenolate-related effects and beyond.
Diarrhea developing in patients under immunosuppression has a variety of underlying causes. A broad spectrum of histological findings can be found in intestinal biopsies taken for the diagnostic workup of diarrhea including a pathologically increased proportion of epithelial cell apoptosis in the colon, for which the descriptive term 'apoptotic colonopathy' was coined. In recent years, the immunosuppressive drug mycophenolate (mycophenolic acid, MPA) has been identified as a prototypical cause of apoptotic colonopathy, but other conditions may show similar or overlapping histological pictures. Cases of likely or possible MPA colonopathy (n = 18) were retrospectively identified from the archive files. Clinical information on patient history, clinical presentation and endoscopic findings were recorded. All cases were routinely processed, i.e. stained by hematoxylin and eosin (HE) stain, optionally supplemented by special histochemical and immune stains. Histopathological hallmarks of MPA treatment-related changes in the colon mucosa are reviewed with respect to the major histopathological differential diagnoses including normal and near-normal findings, infectious diseases, graft-versus-host disease and inflammatory bowel diseases. Furthermore, the challenge of multiple concomitant pathologies while on MPA treatment, in particular infectious diseases, is discussed, and some open questions concerning the effects of MPA on colon pathology are pointed out.


Identifying resident care areas for a quality improvement intervention in long-term care: a collaborative approach.
In Canada, healthcare aides (also referred to as nurse aides, personal support workers, nursing assistants) are unregulated personnel who provide 70-80% of direct care to residents living in nursing homes. Although they are an integral part of the care team their contributions to the resident care planning process are not always acknowledged in the organization. The purpose of the Safer Care for Older Persons [in residential] Environments (SCOPE) project was to evaluate the feasibility of engaging front line staff (primarily healthcare aides) to use quality improvement methods to integrate best practices into resident care. This paper describes the process used by teams participating in the SCOPE project to select clinical improvement areas. The study employed a collaborative approach to identify clinical areas and through consensus, teams selected one of three areas. To select the clinical areas we recruited two nursing homes not involved in the SCOPE project and sampled healthcare providers and decision-makers within them. A vote counting method was used to determine the top five ranked clinical areas for improvement. Responses received from stakeholder groups included gerontology experts, decision-makers, registered nurses, managers, and healthcare aides. The top ranked areas from highest to lowest were pain/discomfort management, behaviour management, depression, skin integrity, and assistance with eating. Involving staff in selecting areas that they perceive as needing improvement may facilitate staff engagement in the quality improvement process.


Chromosomal regions associated with segregation distortion of molecular markers in F2, backcross, doubled haploid, and recombinant inbred populations in rice (Oryza sativa L.).
Chromosomal regions associated with marker segregation distortion in rice were compared based on six molecular linkage maps. Mapping populations were derived from one interspecific backcross and five inter-subspecific (indica/japonica) crosses, including two F2 populations, two doubled haploid (DH) populations, and one recombinant inbred (RI) population. Mapping data for each population consisted of 129-629 markers. Segregation distortion was determined based on chi-square analysis (P < 0.01) and was observed at 6.8-31.8%, of the mapped marker loci. Marker loci associated with skewed allele frequencies were distributed on all 12 chromosomes. Distortion in eight chromosomal regions bracketed previously identified gametophyte (ga) or sterility genes (S). Distortion in three other chromosomal regions was found only in DH populations, where japonica alleles were over-represented, suggesting that loci in these regions may be associated with preferential regeneration of japonica genotypes during anther culture. Three additional clusters of skewed markers were observed in more than one population in regions where no gametophytic or sterility loci have previously been reported. A total of 17 segregation distortion loci may be postulated based on this study and their locations in the rice genome were estimated.


The complexity of bladder cancer: long noncoding RNAs are on the stage.
The mammalian genome encodes thousands of long noncoding RNAs (lncRNAs) and it is increasingly clear that lncRNAs are key regulators of cellular function and development. Gain and/or loss of function studies in cell culture indicate that lncRNAs can regulate gene transcription indirectly through the targeting and recruitment of chromatin-modifying complexes as well as directly at the transcriptional or posttranscriptional levels. LncRNA biology is attracting great attention in cancer research because dysregulated lncRNAs occur in a variety of cancers, placing lncRNAs on the stage of cancer genome research. We briefly describe the latest lncRNA biology and discuss the oncogenic lncRNAs involved in core pathways in bladder cancer and the application of lncRNAs to its diagnosis and targeted treatment. LncRNAs are becoming essential components of the gene regulatory circuitry in the complexity of bladder cancer.


Vitamin D receptor gene polymorphisms, insulin-like growth factors, and prostate cancer risk: a population-based case-control study in China.
Operating through the vitamin D receptor (VDR), vitamin D inhibits prostate cancer growth and increases insulin-like growth factor binding protein (IGFBP) expression, suggesting that the vitamin D and insulin-like growth factor (IGF) regulatory systems may operate together to affect prostate cancer. Among 191 newly diagnosed prostate cancer cases and 304 randomly selected population controls in Shanghai, China, we found no significant association between the BsmI or FokI VDR gene polymorphisms and prostate cancer risk. However, we found that among men with the ff FokI genotype, those in the highest tertile of plasma IGFBP-3 had a decreased risk versus those in the lowest tertile (odds ratio, 0.14; 95% confidence interval, 0.04-0.56; P(trend) < 0.01), whereas among men with the FF and Ff genotypes, IGFBP-3 was not associated with risk. Similarly, IGFBP-1 was inversely associated with prostate cancer risk only among men with the ff FokI genotype (odds ratio, 0.25; 95% confidence interval, 0.07-0.85; P(trend) = 0.02). No such FokI genotype-specific effects were observed for IGF-I or IGF-II. Our findings in a low-risk population suggest that the IGF and vitamin D regulatory systems may interact to affect prostate cancer risk. Larger studies are needed to confirm these findings and clarify the underlying mechanisms.


Reaching an evidence-based prognosis for personalized treatment of multiple sclerosis.
Personalized treatment is ideal for multiple sclerosis (MS) owing to the heterogeneity of clinical features, but current knowledge gaps, including validation of biomarkers and treatment algorithms, limit practical implementation. The contemporary approach to personalized MS therapy depends on evidence-based prognostication, an initial treatment choice and evaluation of early treatment responses to identify the need to switch therapy. Prognostication is directed by baseline clinical, environmental and demographic factors, MRI measures and biomarkers that correlate with long-term disability measures. The initial treatment choice should be a shared decision between the patient and physician. In addition to prognosis, this choice must account for patient-related factors, including comorbidities, pregnancy planning, preferences of the patients and their comfort with risk, and drug-related factors, including safety, cost and implications for treatment sequencing. Treatment response has traditionally been assessed on the basis of relapse rate, MRI lesions and disability progression. Larger longitudinal data sets have enabled development of composite outcome measures and more stringent standards for disease control. Biomarkers, including neurofilament light chain, have potential as early surrogate markers of prognosis and treatment response but require further validation. Overall, attainment of personalized treatment for MS is complex but will be refined as new data become available.


Identification of 12-lipoxygenase interaction with cellular proteins by yeast two-hybrid screening.
The platelet isoform of 12-lipoxygenase (12-LOX) is expressed in a variety of human tumors. 12-LOX metabolizes arachidonic acid to 12(S)-hydroxyeicosateraenoic acid (12(S)-HETE), which induces a number of cellular responses associated with tumor progression and metastasis. Little is known about 12-LOX regulation and no direct regulators of 12-LOX activity have been identified. To identify potential regulators of 12-LOX, we isolated cDNAs encoding 12-LOX interacting proteins using the yeast two-hybrid system. We screened a yeast two-hybrid interaction library from human epidermoid carcinoma A431 cells and identified four cellular proteins that interact specifically with 12-LOX. We identified type II keratin 5, lamin A, the cytoplasmic domain of integrin beta4 subunit and a phosphoprotein C8FW as 12-LOX interacting proteins. Here, we demonstrated that keratin 5, a 58 kD protein required for formation of 8 nm intermediate filaments, binds to 12-LOX in human tumor cells and may contribute to the regulated trafficking of 12-LOX. We also showed that lamin A binds 12-LOX in human tumor cells. These proteins provide the first candidate regulators of 12-LOX.