Action video game playing is associated with improved visual sensitivity, but not alterations in visual sensory memory.
Action video game playing has been experimentally linked to a number of perceptual and cognitive improvements. These benefits are captured through a wide range of psychometric tasks and have led to the proposition that action video game experience may promote the ability to extract statistical evidence from sensory stimuli. Such an advantage could arise from a number of possible mechanisms: improvements in visual sensitivity, enhancements in the capacity or duration for which information is retained in visual memory, or higher-level strategic use of information for decision making. The present study measured the capacity and time course of visual sensory memory using a partial report performance task as a means to distinguish between these three possible mechanisms. Sensitivity measures and parameter estimates that describe sensory memory capacity and the rate of memory decay were compared between individuals who reported high evels and low levels of action video game experience. Our results revealed a uniform increase in partial report accuracy at all stimulus-to-cue delays for action video game players but no difference in the rate or time course of the memory decay. The present findings suggest that action video game playing may be related to enhancements in the initial sensitivity to visual stimuli, but not to a greater retention of information in iconic memory buffers.


Animal models of meningiomas.
Meningiomas are frequent intracranial and intraspinal tumors. They are tumors of the elderly, and meningioma growth at certain localizations, as well as recurrent tumors or primary aggressive biology may pose a therapeutic challenge. To understand the growth characteristics of meningiomas, animal models can provide insights both from a biological and therapeutical point of view. Using genetically-engineered mouse models (GEMM), it has been proven that alterations of the neurofibromatosis type 2 (NF2) gene are key steps for benign meningioma development. Aggressive meningiomas can be induced by simultaneous activation of Nf2 and the PDGF (platelet-derived growth factor)/-PDGF-Receptor (R) system, or inactivation of Tp53 and cdkn2ab in mice. However, mechanisms acting in NF2 wild-type meningiomas are poorly understood so far, because appropriate models are lacking. Xenograft models have been used either by implantation of primary cultures derived from human meningiomas, or immortalized human cell lines, respectively. While the value of primary cells is limited due to low rate of overall tumor growth and slow proliferation, xenograft approaches have been shown to be helpful for the evaluation of potential medical treatment options. Future studies must incorporate new molecular meningioma tumor drivers, as well as potential treatment options based on recurrent genetic alterations into the generation of meningioma models.


Selection of Non-Mycotoxigenic Inulinase Producers in the Group of Black Aspergilli for Use in Food Processing.
Inulinases are used for fructooligosaccharide production and they are of interest for both scientific community and industry. Black aspergilli represent a diverse group of species that has use for enzyme production, in particular some species are known as potent inulinase producers. Finding new potential producers from the environment is as important as improving the production with known strains. Safe use of enzymes produced by aspergilli in food industry is placed ahead of their benefit for inulinase production. Here we show a specific approach to finding/screening of newly isolated fungal inulinase producers that combines a newly developed screening method and an equally important assessment of the toxigenic potential of the fungus. In this study 39 black aspergilli collected from different substrates in Serbia were identified and assessed for inulinase production. The most common species were Aspergillus tubingensis (51.2%), followed by A. niger (23.1%), A. welwitschiae (23.1%) and A. uvarum (2.6%). The isolates for inulinase production were selected using a cheap and easy, fast and non-hazardous alternative inulinase screening test developed in this work. Enzymatic activity of selected inulinase-producing strains was confirmed spectrophotometrically. Since some A. niger and A. welwitschiae strains are able to produce mycotoxins ochratoxin A (OTA) and fumonisins (FB), the toxigenic potential of selected inulinase producers was assessed analytically and genetically. Fungal enzyme producer can be considered safe for use in food industry only after comparing the results of both approaches for investigating toxic potential, the direct presence of mycotoxins in the enzyme preparation (analytically) and the presence of mycotoxin gene clusters (genetically). In some strains the absence of OTA and FB production capability was molecularly confirmed by the absence of complete or critical parts of biosynthetic gene clusters, respectively. The two best inulinase producers and mycotoxin non-producers (without mycotoxin production capability as additional safety) were selected as potential candidates for further development of enzyme production. The presented innovative approach for the selection of potential fungal enzyme producer shows that only non-toxigenic fungi could be considered as useful in food industry. Although this study was done on local isolates, the approach is applicable globally.


A 7.81 W 355 nm ultraviolet picosecond laser using La2CaB10O19 as a nonlinear optical crystal.
We demonstrate high-power 355 nm ultraviolet (UV) picosecond (ps) laser using a type I phase-matching nonlinear optical crystal of La(2)CaB(10)O(19) (LCB), which possesses the characteristic of non-hygroscopicity. The high-power third harmonic generation was successfully achieved from two types of 1064 nm ps fundamental lasers. The maximum output power of 7.81 W of 355 nm UV laser was obtained with a pump of 35.2 W 1064 nm ps laser (80 MHz repetition rate, 10 ps pulse width) with optical conversion efficiency of 22.2%. The experimental results show that the LCB crystal is a promising candidate for generating high-power UV laser.


Activity and onset of action of reboxetine and effect of combination with sertraline in an animal model of depression.
The limitations of antidepressant drugs to treat depression has warranted ongoing research to identify pharmacological agents and strategies which offer a faster onset of action and greater therapeutic efficacy. Noradrenaline and serotonin are widely reported to be involved in the mechanism of action of antidepressants and the recent development of selective reuptake inhibitors of these transmitters has provided the opportunity to determine the effects of targeting these transmitter systems, alone and in combination, in an antidepressant response. The present study investigated the effects of reboxetine, a new antidepressant that selectively inhibits noradrenaline reuptake, sertraline, a selective serotonin reuptake inhibitor and a combination treatment composed of the two drugs in the olfactory bulbectomized (OB) rat model of depression. Sub-acute (2 days) administration of reboxetine (2.5, 5, and 10 mg/kg, i.p.) to sham-operated and OB rats reduced the immobility time in the forced swim test. Repeated (14 days) reboxetine (10 mg/kg) treatment attenuated the OB-related behavioural hyperactivity in the 'open-field' test. Examination of the onset of the antidepressant effect in the 'open-field' test demonstrated that reboxetine (10 mg/kg), sertraline (5 mg/kg) and the combination reduced the behavioural hyperactivity after 14 days but not before this following 3, 7 or 10 days of treatment. Reduced 5-hydroxyindoleacetic acid (5-HIAA) concentrations in amygdaloid cortex of both sham and OB rats following sertraline and combination treatments are likely to be related to acute pharmacological effects on the reuptake of 5-hydroxytryptamine (5-HT). Attenuation of the hypothermia induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.05 mg/kg s.c.) and clonidine (0.1 mg/kg s.c.) occurred in the reboxetine and sertraline combination treated groups following both 7 and 14 days administration indicating changes to 5-HT1A receptor and alpha2-adrenoceptor sensitivity. The results indicate that changes to 8-OH-DPAT and clonidine-induced responses occur quicker with the combination treatment than with either reboxetine or sertraline treatments alone.


Distinctive Olfactory Pattern in Parkinson's Disease and Non-Neurodegenerative Causes of Hyposmia.
Olfactory dysfunction is common in Parkinson's disease (PD). The characteristics of the hyposmia in PD have not been well defined. To characterize the pattern of the olfactory deficit in PD and in other non-neurodegenerative aetiologies of hyposmia. We evaluated 36 PD patients, 20 patients with hyposmia secondary to acute respiratory infection (ARI), and 19 patients with hyposmia secondary to traumatic brain injury (TBI). For comparison purposes, we included a group of 15 controls age and sex matched with PD patients. PD patients were classified based on disease duration and severity in de novo PD, and PD with and without chronic levodopa-related complications. The Barcelona Smell Identification Test was applied to all participants. For the first cranial nerve odours, PD patients scored lower than controls on smell detection (85.28 vs. 97.67%, p = 0.006), definition (79.58 vs. 93.33%, p = 0.007), recognition (63.33 vs. 81%, p = 0.020), and forced choice (58.06 vs. 82%, p < 0.001). Compared with ARI, forced choice was significantly better in PD patients (p < 0.001), but no differences were found regarding other olfactory characteristics. TBI patients showed significantly lower scores than the other study groups in all the olfaction items. For the fifth cranial nerve odours, recognition (p = 0.003) and identification (p = 0.019) were lower in the TBI group than in the others. No differences were found among PD subgroups regarding any olfactory characteristic. A differential pattern of hyposmia was observed in PD patients compared to other non-neurodegenerative aetiologies. Further studies with larger samples should replicate our results.


Neonatal Resuscitation Practices in Turkey: A Survey of the Turkish Neonatal Society and the Union of European Neonatal and Perinatal Societies.
Optimal care in the delivery room is important to decrease neonatal morbidity and mortality. We aimed to evaluate neonatal resuscitation practices in Turkish centers. A cross-sectional survey consisted of a 91-item questionnaire focused on delivery room practices in neonatal resuscitation and was sent to 50 Turkish centers. Hospitals with <2500 and those with ≥2500 births/year were compared. In 2018, approximately 240 000 births occurred at participating hospitals with a median of 2630 births/year. Participating hospitals were able to provide nasal continuous-positiveairway-pressure/high-flow nasal cannula, mechanical ventilation, high-frequency oscillatory ventilation, inhaled nitric oxide, and therapeutic hypothermia similarly. Antenatal counseling was routinely performed on parents at 56% of all centers. A resuscitation team was present at 72% of deliveries. Umbilical cord management for both term and preterm infants was similar between centers. The rate of delayed cord clamping was approximately 60% in term and late preterm infants. Thermal management for preterm infants (<32 weeks) was similar. Hospitals had appropriate equipment with similar rates of interventions and management, except conti nuous-positive-airway-pressure and positive-end-expiratory-pressure levels (cmH2O) used in preterm infants (P = .021, and P = .032). Ethical and educational aspects were also similar. This survey provided information on neonatal resuscitation practices in a sample of hospitals from all regions of Turkey and allowed us to see weaknesses in some fields. Although adherence to the guidelines was high among centers, further implementations are required in the areas of antenatal counseling, cord management, and circulation assessment in the delivery room.


Attrition in the RAND Health Insurance Experiment: a response to Nyman.
In a prior article in this journal, John Nyman argues that the effect on health care use and spending found in the RAND Health Insurance Experiment is an artifact of greater voluntary attrition in the cost-sharing plans relative to the free care plan. Specifically, he speculates that those in the cost-sharing plans, when faced with a hospitalization, withdrew. His argument is implausible because (1) families facing a hospitalization would be worse off financially by withdrawing; (2) a large number of observational studies find a similar effect of cost sharing on use; (3) those who left did not differ in their utilization prior to leaving; (4) if there had been no attrition and cost sharing did not reduce hospitalization rates, each adult in each family that withdrew would have had to have been hospitalized once each year for the duration of time they would otherwise have been in the experiment, an implausibly high rate; (5) there are benign explanations for the higher attrition in the cost-sharing plans. Finally, we obtained follow-up health-status data on the great majority of those who left prematurely. We found the health-status findings were insensitive to the inclusion of the attrition cases.


[Occupational injury, a public health priority].
The aim of this review is to stimulate new ideas and actions for the prevention of this important public health problem. In 2002 and 2003, respectively, the number of non-fatal occupational injuries was 971,406 and 906,638. Thus, every day in Spain there are more than 2500 non-fatal and between 2 and 3 fatal occupational injuries. Although the profile of the at-risk worker population has changed greatly over the past decade, both quantitatively and qualitatively, the risk of occupational injury still centers on blue collar workers, whether qualified or nonqualified, in the primary and secondary sectors of economic activity. The most common mechanisms of occupational injuries are overexertion for non-fatal injuries and traffic-related for fatal events. The adverse health consequences of new types of employment, which emphasize flexibility and deregulation of the labour market, are exemplified by the association between temporary employment and increased risk of occupational injury. New injury prevention programs have emerged in the last decade, but they appear to have had limited impact. Preventive activities should focus both on working conditions at the company level (micro) as well as on employment and industrial public policies (macro). Greater evaluation is needed of these latter policies.


Melanocortin 4 Receptor Pathway Dysfunction in Obesity: Patient Stratification Aimed at MC4R Agonist Treatment.
The hypothalamic melanocortin 4 receptor (MC4R) pathway serves a critical role in regulating body weight. Loss of function (LoF) mutations in the MC4R pathway, including mutations in the pro-opiomelanocortin (POMC), prohormone convertase 1 (PCSK1), leptin receptor (LEPR), or MC4R genes, have been shown to cause early-onset severe obesity. Through a comprehensive epidemiological analysis of known and predicted LoF variants in the POMC, PCSK1, and LEPR genes, we sought to estimate the number of US individuals with biallelic MC4R pathway LoF variants. We predict ~650 α-melanocyte-stimulating hormone (MSH)/POMC, 8500 PCSK1, and 3600 LEPR homozygous and compound heterozygous individuals in the United States, cumulatively enumerating >12,800 MC4R pathway-deficient obese patients. Few of these variants have been genetically diagnosed to date. These estimates increase when we include a small subset of less rare variants: β-MSH/POMC,PCSK1 N221D, and a PCSK1 LoF variant (T640A). To further define the MC4R pathway and its potential impact on obesity, we tested associations between body mass index (BMI) and LoF mutation burden in the POMC, PCSK1, and LEPR genes in various populations. We show that the cumulative allele burden in individuals with two or more LoF alleles in one or more genes in the MC4R pathway are predisposed to a higher BMI than noncarriers or heterozygous LoF carriers with a defect in only one gene. Our analysis represents a genetically rationalized study of the hypothalamic MC4R pathway aimed at genetic patient stratification to determine which obese subpopulations should be studied to elucidate MC4R agonist (e.g., setmelanotide) treatment responsiveness.


Sleep disturbance in preschool-aged hyperactive and nonhyperactive children.
In spite of inadequate laboratory demonstrations of sleep problems in children with attention deficit disorder with hyperactivity, the belief persists that such problems exist. Sleep restlessness is, in fact, one of the criteria in the Diagnostic and Statistical Manual of Mental Disorders, ed 3, definition of attention deficit disorder with hyperactivity, and sleep problems are listed on two major checklists often used for describing the symptoms of this disorder. In a series of three studies, sleep problems were investigated in preschool-aged children with attention deficit disorder relative to control children without the disorder. Results of the first two studies demonstrated clearly that parents of hyperactive children considered their children to have many more sleep problems than did parents of the control children. Parental daily documentation, which is less likely to be affected by reporting bias, was used in the third study. Although the results of the third study supported the finding of increased frequency of night wakings in these children, there was no difference in total sleep time or sleep onset latency between the two groups. Two other significant group differences (enuresis and night sweats) were primarily due to subgroups of children with attention deficit disorder and hyperactivity. The greater number of sleep wakings, which disrupt parents' sleep, may be responsible for the clinical reports that these children are poor sleepers.


Large-scale integrative network-based analysis identifies common pathways disrupted by copy number alterations across cancers.
Many large-scale studies analyzed high-throughput genomic data to identify altered pathways essential to the development and progression of specific types of cancer. However, no previous study has been extended to provide a comprehensive analysis of pathways disrupted by copy number alterations across different human cancers. Towards this goal, we propose a network-based method to integrate copy number alteration data with human protein-protein interaction networks and pathway databases to identify pathways that are commonly disrupted in many different types of cancer. We applied our approach to a data set of 2,172 cancer patients across 16 different types of cancers, and discovered a set of commonly disrupted pathways, which are likely essential for tumor formation in majority of the cancers. We also identified pathways that are only disrupted in specific cancer types, providing molecular markers for different human cancers. Analysis with independent microarray gene expression datasets confirms that the commonly disrupted pathways can be used to identify patient subgroups with significantly different survival outcomes. We also provide a network view of disrupted pathways to explain how copy number alterations affect pathways that regulate cell growth, cycle, and differentiation for tumorigenesis. In this work, we demonstrated that the network-based integrative analysis can help to identify pathways disrupted by copy number alterations across 16 types of human cancers, which are not readily identifiable by conventional overrepresentation-based and other pathway-based methods. All the results and source code are available at http://compbio.cs.umn.edu/NetPathID/.


Surface lattice resonances strongly coupled to Rhodamine 6G excitons: tuning the plasmon-exciton-polariton mass and composition.
We demonstrate the strong coupling of surface lattice resonances (SLRs)--hybridized plasmonic/photonic modes in metallic nanoparticle arrays--to excitons in Rhodamine 6G molecules. We investigate experimentally angle-dependent extinction spectra of silver nanorod arrays with different lattice constants, with and without the Rhodamine 6G molecules. The properties of the coupled modes are elucidated with simple Hamiltonian models. At low momenta, plasmon-exciton-polaritons--the mixed SLR/exciton states--behave as free-quasiparticles with an effective mass, lifetime, and composition tunable via the periodicity of the array. The results are relevant for the design of plasmonic systems aimed at reaching the quantum degeneracy threshold, wherein a single quantum state becomes macroscopically populated.


Biochemical characterization and cellular imaging of a novel, membrane permeable fluorescent cAMP analog.
A novel fluorescent cAMP analog (8-[Pharos-575]- adenosine-3', 5'-cyclic monophosphate) was characterized with respect to its spectral properties, its ability to bind to and activate three main isoenzymes of the cAMP-dependent protein kinase (PKA-Ialpha, PKA-IIalpha, PKA-IIbeta) in vitro, its stability towards phosphodiesterase and its ability to permeate into cultured eukaryotic cells using resonance energy transfer based indicators, and conventional fluorescence imaging. The Pharos fluorophore is characterized by a Stokes shift of 42 nm with an absorption maximum at 575 nm and the emission peaking at 617 nm. The quantum yield is 30%. Incubation of the compound to RIIalpha and RIIbeta subunits increases the amplitude of excitation and absorption maxima significantly; no major change was observed with RIalpha. In vitro binding of the compound to RIalpha subunit and activation of the PKA-Ialpha holoenzyme was essentially equivalent to cAMP; RII subunits bound the fluorescent analog up to ten times less efficiently, resulting in about two times reduced apparent activation constants of the holoenzymes compared to cAMP. The cellular uptake of the fluorescent analog was investigated by cAMP indicators. It was estimated that about 7 muM of the fluorescent cAMP analog is available to the indicator after one hour of incubation and that about 600 muM of the compound had to be added to intact cells to half-maximally dissociate a PKA type IIalpha sensor. The novel analog combines good membrane permeability- comparable to 8-Br-cAMP - with superior spectral properties of a modern, red-shifted fluorophore. GFP-tagged regulatory subunits of PKA and the analog co-localized. Furthermore, it is a potent, PDE-resistant activator of PKA-I and -II, suitable for in vitro applications and spatial distribution evaluations in living cells.


The potential of bio-methane as bio-fuel/bio-energy for reducing greenhouse gas emissions: a qualitative assessment for Europe in a life cycle perspective.
Anaerobic digestion is a well known process that (while still capable of showing new features) has experienced several waves of technological development. It was "born" as a wastewater treatment system, in the 1970s showed promise as an alternative energy source (in particular from animal waste), in the 1980s and later it became a standard for treating organic-matter-rich industrial wastewater, and more recently returned to the market for its energy recovery potential, making use of different biomasses, including energy crops. With the growing concern around global warming, this paper looks at the potential of anaerobic digestion in terms of reduction of greenhouse gas (GHG) emissions. The potential contribution of anaerobic digestion to GHG reduction has been computed for the 27 EU countries on the basis of their 2005 Kyoto declarations and using life cycle data. The theoretical potential contribution of anaerobic digestion to Kyoto and EU post-Kyoto targets has been calculated. Two different possible biogas applications have been considered: electricity production from manure waste, and upgraded methane production for light goods vehicles (from landfill biogas and municipal and industrial wastewater treatment sludges). The useful heat that can be produced as by-product from biogas conversion into electricity has not been taken into consideration, as its real exploitation depends on local conditions. Moreover the amount of biogas already produced via dedicated anaerobic digestion processes has also not been included in the calculations. Therefore the overall gains achievable would be even higher than those reported here. This exercise shows that biogas may considerably contribute to GHG emission reductions in particular if used as a biofuel. Results also show that its use as a biofuel may allow for true negative GHG emissions, showing a net advantage with respect to other biofuels. Considering also energy crops that will become available in the next few years as a result of Common Agricultural Policy (CAP) reform, this study shows that biogas has the potential of covering almost 50% of the 2020 biofuel target of 10% of all automotive transport fuels, without implying a change in land use. Moreover, considering the achievable GHG reductions, a very large carbon emission trading "value" could support the investment needs.However, those results were obtained through a "qualitative" assessment. In order to produce robust data for decision makers, a quantitative sustainability assessment should be carried out, integrating different methodologies within a life cycle framework. The identification of the most appropriate policy for promoting the best set of options is then discussed.


Act your (old) age: prescriptive, ageist biases over succession, consumption, and identity.
Perspectives on ageism have focused on descriptive stereotypes concerning what older people allegedly are. By contrast, we introduce prescriptive stereotypes that attempt to control how older people should be: encouraging active Succession of envied resources, preventing passive Consumption of shared resources, and avoidance of symbolic, ingroup identity resources. Six studies test these domains, utilizing vignette experiments and simulated behavioral interactions. Across studies, younger (compared with middle-aged and older) raters most resented elder violators of prescriptive stereotypes. Moreover, these younger participants were most polarized toward older targets (compared with middle-aged and younger analogues)--rewarding elders most for prescription adherences and punishing them most for violations. Taken together, these findings offer a novel approach to ageist prescriptions, which disproportionately target older people, are most endorsed by younger people, and suggest how elders shift from receiving the default prejudice of pity to either prescriptive resentment or reward.


Enhanced in vitro activation of immunocompetent cells in healthy individuals being subcutaneously 'vaccinated' with placebo (physiological saline).
The effect of subcutaneous injection of physiological saline (given as 'placebo' in a randomized double-blinded placebo-controlled study) on immunocompetent cells from healthy individuals was analyzed. In two studies in 1998/1999 and 2002, 16 and 13 healthy individuals, respectively, were injected subcutaneously with 1 ml physiological saline twice a week for up to 12 weeks. Lymphocytes were isolated before and during exposure and incubated with recall antigens (purified protein derivative [PPD], tetanus toxoid [TT], bacillus Calmette-Guerin [BCG]). The production of T-helper type 1-, type 2-, and macrophage/monocyte-related cytokines was analyzed by ELISA. There was a significant increase of the recall-antigen-induced production of IFNgamma, IL-5, IL-13, TNFalpha, and GM-CSF in both groups during the observation period. Subcutaneous injection of placebo, therefore, enhances immunoreactivity. Psychological aspects, activation of the autonomous nerve system or local activation of mast cells or dendritic cells may be responsible for this phenomenon.


Is the distal hyperplastic polyp a marker for proximal neoplasia?
The current literature is unclear about the association between distal hyperplastic polyps and synchronous neoplasia (adenomatous polyps and cancer) in the proximal colon. To estimate the prevalence of proximal neoplasia associated with distal hyperplastic polyps. Database searches (medline and embase from 1966 to 2001) and manual search of the bibliographies of included and excluded studies, case reports, editorials, review articles, and textbooks of Gastroenterology. Studies describing the prevalence of proximal neoplasia in persons with distal hyperplastic polyps. Demographics, clinical variables, study design, and prevalence of proximal neoplasia associated with various distal colorectal findings. Of 18 included studies, 12 involved asymptomatic individuals in which the pooled absolute risk of any proximal neoplasia associated with distal hyperplastic polyps was 25% (95% confidence interval [95% CI], 21% to 29%). In 4 studies where colonoscopy was performed irrespective of distal findings, the absolute risk was 21% (95% CI, 14% to 28%). The relative risk of finding any proximal neoplasia in persons with distal hyperplastic polyps was 1.3 (95% CI, 0.9 to 1.8) compared to those with no distal polyps. Among 6 studies of patients with symptoms or risk factors for neoplasia, the absolute risk of proximal neoplasia was 35% (95% CI, 32% to 39%) in persons with distal hyperplastic polyps. In 2 studies of screening colonoscopy, advanced proximal neoplasia (cancer, or a polyp with villous histology or severe dysplasia, or a tubular adenoma >/=1 cm) was present in 4% to 5% of persons with distal hyperplastic polyps, which was 1.5 to 2.6 times greater than in those with no distal polyps. In asymptomatic persons, a distal hyperplastic polyp is associated with a 21% to 25% risk for any proximal neoplasia and a 4% to 5% risk of advanced proximal neoplasia, and may justify examination of the proximal colon. Further study is needed to determine the risk of advanced proximal neoplasia associated with size and number of distal hyperplastic polyps.


The influence of antihypertensive therapy on cerebral autoregulation in aged hypertensive rats.
Cerebrovascular responses to hemorrhage induced hypotension were tested in aged (24 month) spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) after ten weeks of antihypertensive drug or sham treatment. Antihypertensive drug treatment consisted of 1 mg/kg/day minoxidil, 4 mg/kg/day hydralazine and 4 mg/kg/day propranolol given in the drinking water. Antihypertensive therapy produced a 30% decrease in systolic blood pressure in aged SHR to levels not significantly different from sham treated WKY. Cerebral blood flow (CBF), measured under control conditions using ketamine anesthesia, was not significantly different between sham and drug treated SHR and WKY. Cerebral oxygen metabolic rate (CMRO2) was significantly decreased in drug treated SHR and WKY compared to sham treated rats. Lowering blood pressure to a level between 80 and 95 torr produced no significant change in CBF or CMRO2 in sham or drug treated WKY or antihypertensive treated SHR, but a produced a significant decrease it both CBF and CMRO2 in sham treated SHR. Decreasing mean blood pressure to 50-60 torr produced a significant decrease in CBF but not CMRO2 in both WKY treatment groups and in hypertensive treated SHR, but again in sham treated SHR both CBF ana CMRO2 were significantly decreased. These results indicate that aged hypertensive rats are unable to maintain CBF or CMRO2 under even moderate hypotensive test conditions, and that cerebral autoregulation can be improved with antihypertensive therapy.


Drug-induced thrombotic thrombocytopenic purpura: A systematic review and review of European and North American pharmacovigilance data.
Many medications have been reported to be associated with thrombotic thrombocytopenic purpura (TTP) through pharmacovigilance data and published case reports. Whilst there are existing data available regarding drug-induced thrombotic microangiopathy, there is no available synthesis of evidence to assess drug-induced TTP (DI-TTP). Despite this lack of evidence, patients with TTP are often advised against using many medications due to the theoretical risk of DI-TTP. This systematic review evaluated the evidence for an association of medications reported as potential triggers for TTP. Of 5098 records available 261 articles were assessed further for eligibility. Fifty-seven reports, totalling 90 patients, were included in the final analysis. There were no cases where the level of association was rated as definite or probable, demonstrating a lack of evidence of any drug causing DI-TTP. This paucity of evidence was also demonstrated in the pharmacovigilance data, where 613 drugs were reported as potential causes of TTP without assessment of the strength of association. This systematic review demonstrates the need for standardised reporting of potential drugs causing TTP. Many reports omit basic information and, therefore, hinder the chance of finding a causative link if one exists.


Immunometabolic factors in adolescent chronic disease are associated with Th1 skewing of invariant Natural Killer T cells.
Invariant Natural Killer T (iNKT) cells respond to the ligation of lipid antigen-CD1d complexes via their T-cell receptor and are implicated in various immunometabolic diseases. We considered that immunometabolic factors might affect iNKT cell function. To this end, we investigated iNKT cell phenotype and function in a cohort of adolescents with chronic disease and immunometabolic abnormalities. We analyzed peripheral blood iNKT cells of adolescents with cystic fibrosis (CF, n = 24), corrected coarctation of the aorta (CoA, n = 25), juvenile idiopathic arthritis (JIA, n = 20), obesity (OB, n = 20), and corrected atrial septal defect (ASD, n = 25) as controls. To study transcriptional differences, we performed RNA sequencing on a subset of obese patients and controls. Finally, we performed standardized co-culture experiments using patient plasma, to investigate the effect of plasma factors on iNKT cell function. We found comparable iNKT cell numbers across patient groups, except for reduced iNKT cell numbers in JIA patients. Upon ex-vivo activation, we observed enhanced IFN-γ/IL-4 cytokine ratios in iNKT cells of obese adolescents versus controls. The Th1-skewed iNKT cell cytokine profile of obese adolescents was not explained by a distinct transcriptional profile of the iNKT cells. Co-culture experiments with patient plasma revealed that across all patient groups, obesity-associated plasma factors including LDL-cholesterol, leptin, and fatty-acid binding protein 4 (FABP4) coincided with higher IFN-γ production, whereas high HDL-cholesterol and insulin sensitivity (QUICKI) coincided with higher IL-4 production. LDL and HDL supplementation in co-culture studies confirmed the effects of lipoproteins on iNKT cell cytokine production. These results suggest that circulating immunometabolic factors such as lipoproteins may be involved in Th1 skewing of the iNKT cell cytokine response in immunometabolic disease.


Improving the lens design and performance of a contemporary electromagnetic shock wave lithotripter.
The efficiency of shock wave lithotripsy (SWL), a noninvasive first-line therapy for millions of nephrolithiasis patients, has not improved substantially in the past two decades, especially in regard to stone clearance. Here, we report a new acoustic lens design for a contemporary electromagnetic (EM) shock wave lithotripter, based on recently acquired knowledge of the key lithotripter field characteristics that correlate with efficient and safe SWL. The new lens design addresses concomitantly three fundamental drawbacks in EM lithotripters, namely, narrow focal width, nonidealized pulse profile, and significant misalignment in acoustic focus and cavitation activities with the target stone at high output settings. Key design features and performance of the new lens were evaluated using model calculations and experimental measurements against the original lens under comparable acoustic pulse energy (E+) of 40 mJ. The -6-dB focal width of the new lens was enhanced from 7.4 to 11 mm at this energy level, and peak pressure (41 MPa) and maximum cavitation activity were both realigned to be within 5 mm of the lithotripter focus. Stone comminution produced by the new lens was either statistically improved or similar to that of the original lens under various in vitro test conditions and was significantly improved in vivo in a swine model (89% vs. 54%, P = 0.01), and tissue injury was minimal using a clinical treatment protocol. The general principle and associated techniques described in this work can be applied to design improvement of all EM lithotripters.


Orchestration of dynamic copper navigation - new and missing pieces.
A general principle in all cells in the body is that an essential metal - here copper - is taken up at the plasma membrane, directed through cellular compartments for use in specific enzymes and pathways, stored in specific scavenging molecules if in surplus, and finally expelled from the cells. Here we attempt to provide a critical view on key concepts involved in copper transfer across membranes and through compartments in the human body. The focus of this review is on the influence of bioinorganic and thermodynamic rules on the flow in cellular copper networks. Transition of copper from one oxidation state to another will often lead to errant electrons that are highly reactive and prone to form radicals and reactive oxygen or nitrogen species (ROS and RNS). Strict control of potentially toxic oxidative species is an important part of understanding the edge of human copper metabolism. The present review critically covers translocation across simple and complex membranes as well as extracellular and intracellular copper routing. We discuss in depth four tissues with polarized cell barriers - the gut, liver, kidneys, and brain - to illustrate the similarities and differences in transcellular transfer. Copper chaperoning, buffering and binding dynamics to guide the metal to different sites are also covered, while individual molecular interaction kinetics are not detailed. Sorting and targeting mechanisms and principles crucial for correct localisation will also be touched upon.


Clinical impact of closure of the mucosal defect after duodenal endoscopic submucosal dissection.
Delayed adverse events (bleeding or perforation) are major concerns associated with duodenal endoscopic submucosal dissection (ESD). The aim of this study was to assess the efficacy of prophylactic closure of the mucosal defect after duodenal ESD. This is a retrospective study from a university hospital. One hundred sixty-eight patients (173 lesions) who underwent duodenal ESD between July 2010 and June 2017 were included in this study. The study participants were divided into 3 subgroups according to the degree of closure: complete group, incomplete group, and unclosed group. The proportion of delayed adverse events, maximum serum level of C-reactive protein (CRP), and total length of hospital stay were compared among these subgroups. Moreover, a multivariate logistic regression model was constructed to identify the risk factors for delayed adverse events. The proportion of delayed adverse events in the complete group, incomplete group, and unclosed group were 1.7%, 25%, and 15.6%, respectively. The difference between the complete group and the other groups was significant (P < .01). The maximum serum CRP level was much lower (1.51 ± 2.18 mg/dL vs 6.28 ± 10.0 mg/dL, P < .01), and the length of hospital stay was significantly shorter in the complete group than in the incomplete/unclosed group (median [range] 5 [5-14] days vs 8 [4-59] days, P < .01). Multivariate analysis revealed that complete closure had a significant decrease in delayed adverse events (odds ratio [OR], 0.055; 95% confidence interval [CI], 0.01-0.29; P < .01), and a lesion located distal from the descending part showed a statistical tendency to an increase in delayed adverse events (OR, 4.48; 95% CI, 0.85-23.6; P = .08). The present study revealed that complete closure of the mucosal defect after duodenal ESD significantly decreased the number of delayed adverse events and improved other outcomes.


Phylogenetic relationships among the true porpoises (Cetacea:Phocoenidae).
Portions of the cytochrome b gene and control region of the mitochondrial DNA molecule were sequenced to investigate systematic relationships among the six extant species of true porpoises, (Cetacea: Phocoenidae). Phylogenetic analyses of mitochondrial cytochrome b sequences support a close relationship between Burmeister's porpoise, Phocoena spinipinnis, and the vaquita, Phocoena sinus, and the association of these two species with the spectacled porpoise, Australophocaena dioptrica. The latter result is not in concordance with a recent morphological reclassification which groups A. dioptrica with Dall's porpoise, Phocoenoides dalli, in the subfamily Phocoenoidinae. The molecular analysis found no support for this grouping. A. dioptrica was originally described as a member of the genus Phocoena, and our results support returning it to that genus at this time. Finally, the data suggest that the tropical species Neophocaena phocaenoides, the finless porpoise, may represent the most basal member of the family. The control region sequences corroborated the relationships among the closely related taxa P. sinus, P. spinipinnis, and A. dioptrica, but were unable to resolve the deeper branches of the tree, probably as a result of a high level of saturation of these sequences.


A critical review of internet information about depression.
The source and quality of information about depression available on the Internet were examined. Online searches using the phrase "depression and treatment" were conducted on ten major Internet search engines. The first 20 sites generated by each engine were examined. The Web sites and the individual Web pages they contained were categorized by source, target audience, and affiliation with either a for-profit or a not-for-profit organization. Each site was rated by whether it mentioned the nine symptoms and five major criteria of a major depressive episode and whether it made any of three basic treatment recommendations. Ratings were compared to determine whether treatment differences between the sites could be attributed to the site's source. The search generated a total of 178 active sites. Overall, the quality of information was poor. Only half of the sites mentioned any DSM-IV diagnostic symptom or criteria in their descriptions of depression, and only a quarter listed 11 to 14 symptoms or criteria. Almost half of the sites made no mention of medications, psychotherapy, or professional consultation as suggested treatments for depression. Almost two-thirds of the pages were found on for-profit sites. Documents from these sites scored lower on diagnostic accuracy and treatment recommendations than those from not-for-profit sites. The quality of information on the Internet produced by the search was quite low. For-profit Web sites appeared much more frequently than not-for-profit sites among the first 20 sites generated by each search engine, and they contained poorer information.


Compliant eating of maternally prompted food predicts increased body mass index z-score gain in girls: results from a population-based sample.
Poorer "division of responsibility" (DoR) feeding, characterized by high parental control and reduced child food choice, may promote pediatric obesity, although population-based prospective data are lacking. We tested whether poorer DoR feeding predicts childhood overweight/obesity onset and BMI z-score gain, over 10 years in the National Longitudinal Study of Youth. We studied 302 girls and 316 boys, with mean ages 52.24 and 52.35 months, respectively, in 1986, who were followed for 10 years. We excluded children who were initially overweight/obese. Mothers completed three DoR feeding questions in 1986: (1) child eating compliance of prompted foods; (2) child eating compliance of initially refused foods; and (3) mother-allotted child food choice. Child BMI (kg/m(2)) was calculated from measured weights and heights in 1986, 1988, 1992, 1994, and 1996. Daughters who complied with maternal food prompts [odds ratio (OR), 2.01] and those who obeyed maternal prompts to consume initially rejected foods (OR, 2.29) "most of the time" were significantly more likely than daughters who complied less frequently to become overweight/obese after 8 years. Also, more frequent eating compliance (p<0.001) and more frequent compliance of initially rejected foods (p=0.003) predicted greater BMI z-score gain in girls. These associations were not found for boys. Maternal obesity consistently predicted overweight/obesity risk in girls (ORs, 2.48-8.63) and boys (ORs, 2.27- 4.03). Teaching parents to avoid coercive feeding practices, while encouraging child self-selection of healthier foods, may help their daughters to achieve better energy balance.


Identification of procyanidins in cocoa (Theobroma cacao) and chocolate using high-performance liquid chromatography/mass spectrometry.
Monomeric and oligomeric procyanidins present in cocoa and chocolate were separated and identified using a modified normal-phase high-performance liquid chromatography (HPLC) method coupled with on-line mass spectrometry (MS) analysis using an atmospheric pressure ionization electrospray chamber. The chromatographic separation was achieved using a silica stationary phase in combination with a gradient ascending in polarity. This qualitative report confirms the presence of a complex series of procyanidins in raw cocoa and certain chocolates using HPLC/MS techniques. Although both cocoa and chocolate contained monomeric and oligomeric procyanidin units 2-10, only use of negative mode provided MS data for the higher oligomers (i.e., >pentamer). Application of this method for qualitative analysis of proanthocyanidins in other food products and confirmation of this method as a reliable quantitative tool for determining levels of procyanidins in cocoa, chocolate, and other food products are currently being investigated.


Effectiveness and harms of recombinant human bone morphogenetic protein-2 in spine fusion: a systematic review and meta-analysis.
Recombinant human bone morphogenetic protein-2 (rhBMP-2) is used as a bone graft substitute in spinal fusion, which unites (fuses) bones in the spine. The accuracy and completeness of journal publications of industry-sponsored trials on the effectiveness and harms of rhBMP-2 has been called into question. To independently assess the effectiveness and harms of rhBMP-2 in spinal fusion and reporting bias in industry-sponsored journal publications. Individual-patient data (IPD) from 17 industry-sponsored studies; related internal documents; and searches of MEDLINE (1996 to August 2012), other databases, and reference lists. Randomized, controlled trials (RCTs) and cohort studies of rhBMP-2 versus any control and uncontrolled studies of harms. Effectiveness outcomes in IPD were recalculated using consistent definitions. Study characteristics and results were abstracted by 1 investigator and confirmed by another. Two investigators independently assessed quality using predefined criteria. Thirteen RCTs and 31 cohort studies were included. For lumbar spine fusion, rhBMP-2 and iliac crest bone graft were similar in overall success, fusion, and other effectiveness measures and in risk for any adverse event, although rates were high across interventions (77% to 93% at 24 months from surgery). For anterior lumbar interbody fusion, rhBMP-2 was associated with nonsignificantly increased risk for retrograde ejaculation and urogenital problems. For anterior cervical spine fusion, rhBMP-2 was associated with increased risk for wound complications and dysphagia. At 24 months, the cancer risk was increased with rhBMP-2 (risk ratio, 3.45 [95% CI, 1.98 to 6.00]), but event rates were low and cancer was heterogeneous. Early journal publications misrepresented the effectiveness and harms through selective reporting, duplicate publication, and underreporting. Outcome assessment was not blinded, and ascertainment of harms in trials was poor. No trials were truly independent of industry sponsorship. In spinal fusion, rhBMP-2 has no proven clinical advantage over bone graft and may be associated with important harms, making it difficult to identify clear indications for rhBMP-2. Earlier disclosure of all relevant data would have better informed clinicians and the public than the initial published trial reports did. Yale University and Medtronic.


Lysosomal and proteasomal degradation play distinct roles in the life cycle of Cx43 in gap junctional intercellular communication-deficient and -competent breast tumor cells.
The present study was designed to determine the specific roles played by lysosomes and proteasomes in the degradation of Cx43 in both gap junctional intercellular communication-deficient MDA-MB-231 and -competent BICR-M1Rk cells. In MDA-MB-231 cells, immunolocalization and brefeldin A protein transport blocking studies revealed that there was a propensity for newly synthesized Cx43 to be transported to lysosomes. On the other hand, light and electron microscopic analysis of BICR-M1Rk cells showed that Cx43 gap junctions were prevalent with a subpopulation of intracellular Cx43 localized to lysosomes. In both cell types, Western blots revealed a notable increase in total cellular Cx43 in response to lysosome inhibitors. Interestingly, lactacystin inhibition of proteosomal degradation in MDA-MB-231 cells resulted in a marked increase in phosphorylated Cx43 at the expense of non-phosphorylated Cx43, and this change corresponded with an increase in "oversized" gap junction plaques. In BICR-M1Rk cells, lactacystin treatment partially prevented the BFA-induced loss of gap junctions. Together, our data suggests that lysosomes play a key role in not only degrading internalized gap junction in BICR-M1Rk cells but also in degrading Cx43 delivered from early secretory compartments to lysosomes in MDA-MB-231 cells. Overall proteasomal degradation regulates the stability of phosphorylated Cx43 and appears to promote the internalization of Cx43 from the cell surface.


The HDAC inhibitor, MPT0E028, enhances erlotinib-induced cell death in EGFR-TKI-resistant NSCLC cells.
Epidermal growth factor receptor (EGFR), which promotes cell survival and division, is found at abnormally high levels on the surface of many cancer cell types, including many cases of non-small cell lung cancer. Erlotinib (Tarceva), an oral small-molecule tyrosine kinase inhibitor, is a so-called targeted drug that inhibits the tyrosine kinase domain of EGFR, and thus targets cancer cells with some specificity while doing less damage to normal cells. However, erlotinib resistance can occur, reducing the efficacy of this treatment. To develop more effective therapeutic interventions by overcoming this resistance problem, we combined the histone deacetylase inhibitor, MPT0E028, with erlotinib in an effort to increase their antitumor effects in erlotinib-resistant lung adenocarcinoma cells. This combined treatment yielded significant growth inhibition, induced the expression of apoptotic proteins (PARP, γH2AX, and caspase-3), increased the levels of acetylated histone H3, and showed synergistic effects in vitro and in vivo. These effects were independent of the mutation status of the genes encoding EGFR or K-Ras. MPT0E028 synergistically blocked key regulators of the EGFR/HER2 signaling pathways, attenuating multiple compensatory pathways (e.g., AKT, extracellular signal-regulated kinase, and c-MET). Our results indicate that this combination therapy might be a promising strategy for facilitating the effects of erlotinib monotherapy by activating various networks. Taken together, our data provide compelling evidence that MPT0E028 has the potential to improve the treatment of heterogeneous and drug-resistant tumors that cannot be controlled with single-target agents.


Attenuation of myocardial injury by HMGB1 blockade during ischemia/reperfusion is toll-like receptor 2-dependent.
Genetic or pharmacological ablation of toll-like receptor 2 (TLR2) protects against myocardial ischemia/reperfusion injury (MI/R). However, the endogenous ligand responsible for TLR2 activation has not yet been detected. The objective of this study was to identify HMGB1 as an activator of TLR2 signalling during MI/R. C57BL/6 wild-type (WT) or TLR2(-/-)-mice were injected with vehicle, HMGB1, or HMGB1 BoxA one hour before myocardial ischemia (30 min) and reperfusion (24 hrs). Infarct size, cardiac troponin T, leukocyte infiltration, HMGB1 release, TLR4-, TLR9-, and RAGE-expression were quantified. HMGB1 plasma levels were measured in patients undergoing coronary artery bypass graft (CABG) surgery. HMGB1 antagonist BoxA reduced cardiomyocyte necrosis during MI/R in WT mice, accompanied by reduced leukocyte infiltration. Injection of HMGB1 did, however, not increase infarct size in WT animals. In TLR2(-/-)-hearts, neither BoxA nor HMGB1 affected infarct size. No differences in RAGE and TLR9 expression could be detected, while TLR2(-/-)-mice display increased TLR4 and HMGB1 expression. Plasma levels of HMGB1 were increased MI/R in TLR2(-/-)-mice after CABG surgery in patients carrying a TLR2 polymorphism (Arg753Gln). We here provide evidence that absence of TLR2 signalling abrogates infarct-sparing effects of HMGB1 blockade.


Association of a leukemic stem cell gene expression signature with clinical outcomes in acute myeloid leukemia.
In many cancers, specific subpopulations of cells appear to be uniquely capable of initiating and maintaining tumors. The strongest support for this cancer stem cell model comes from transplantation assays in immunodeficient mice, which indicate that human acute myeloid leukemia (AML) is driven by self-renewing leukemic stem cells (LSCs). This model has significant implications for the development of novel therapies, but its clinical relevance has yet to be determined. To identify an LSC gene expression signature and test its association with clinical outcomes in AML. Retrospective study of global gene expression (microarray) profiles of LSC-enriched subpopulations from primary AML and normal patient samples, which were obtained at a US medical center between April 2005 and July 2007, and validation data sets of global transcriptional profiles of AML tumors from 4 independent cohorts (n = 1047). Identification of genes discriminating LSC-enriched populations from other subpopulations in AML tumors; and association of LSC-specific genes with overall, event-free, and relapse-free survival and with therapeutic response. Expression levels of 52 genes distinguished LSC-enriched populations from other subpopulations in cell-sorted AML samples. An LSC score summarizing expression of these genes in bulk primary AML tumor samples was associated with clinical outcomes in the 4 independent patient cohorts. High LSC scores were associated with worse overall, event-free, and relapse-free survival among patients with either normal karyotypes or chromosomal abnormalities. For the largest cohort of patients with normal karyotypes (n = 163), the LSC score was significantly associated with overall survival as a continuous variable (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.08-1.22; log-likelihood P <.001). The absolute risk of death by 3 years was 57% (95% CI, 43%-67%) for the low LSC score group compared with 78% (95% CI, 66%-86%) for the high LSC score group (HR, 1.9 [95% CI, 1.3-2.7]; log-rank P = .002). In another cohort with available data on event-free survival for 70 patients with normal karyotypes, the risk of an event by 3 years was 48% (95% CI, 27%-63%) in the low LSC score group vs 81% (95% CI, 60%-91%) in the high LSC score group (HR, 2.4 [95% CI, 1.3-4.5]; log-rank P = .006). In multivariate Cox regression including age, mutations in FLT3 and NPM1, and cytogenetic abnormalities, the HRs for LSC score in the 3 cohorts with data on all variables were 1.07 (95% CI, 1.01-1.13; P = .02), 1.10 (95% CI, 1.03-1.17; P = .005), and 1.17 (95% CI, 1.05-1.30; P = .005). High expression of an LSC gene signature is independently associated with adverse outcomes in patients with AML.


Identification of the sex-determining region of the Ceratitis capitata Y chromosome by deletion mapping.
In the medfly Ceratitis capitata, the Y chromosome is responsible for determining the male sex. We have mapped the region containing the relevant factor through the analysis of Y-autosome translocations using fluorescence in situ hybridization with two different probes. One probe, the clone pY114, contains repetitive, Y-specific DNA sequences from C. capitata, while the second clone, pDh2-H8, consists of ribosomal DNA sequences from Drosophila hydei. Clone pY114 labeled most of the long arm and pDh2-H8 hybridizes to the short arm and the centromeric region of the long arm. In 12 of the analyzed 19 Y-autosome translocation strains, adjacent-1 segregation products survive to the late pupal or even adult stage and can, therefore, be sexed. This was correlated with the length of the Y fragment still present in these aberrant individuals and allowed us to map the male-determining factor to a region of the long arm representing approximately 15% of the entire Y chromosome. No additional factors, affecting for example fertility, were detected outside the male-determining region.


Catastrophic shifts and lethal thresholds in a propagating front model of unstable tumor progression.
Unstable dynamics characterizes the evolution of most solid tumors. Because of an increased failure of maintaining genome integrity, a cumulative increase in the levels of gene mutation and loss is observed. Previous work suggests that instability thresholds to cancer progression exist, defining phase transition phenomena separating tumor-winning scenarios from tumor extinction or coexistence phases. Here we present an integral equation approach to the quasispecies dynamics of unstable cancer. The model exhibits two main phases, characterized by either the success or failure of cancer tissue. Moreover, the model predicts that tumor failure can be due to either a reduced selective advantage over healthy cells or excessive instability. We also derive an approximate, analytical solution that predicts the front speed of aggressive tumor populations on the instability space.


Maternal mortality at federal medical centre yola, adamawa state: a five-year review.
The North Eastern region of Nigeria has one of the highest maternal mortality ratios (MMRs) in the world, and most of these deaths are preventable. Culture, religion and customs that prevent access to care contribute immensely to these deaths. To review and document the MMR. This was a retrospective study of all maternal deaths recorded at the Federal Medical Centre Yola (FMCY). The case notes of all cases of maternal deaths from January 2007 to December 2011 were retrieved and relevant data obtained and analyzed. The age, parity, literacy level, booking status, causes of maternal deaths, were analysed. Data were presented in tables and percentages, using SPSS version 16(Chicago, USA 2006). There were 54 maternal deaths among the 8497 deliveries, giving an overall MMR of 636 per 100,000 deliveries. Thirty three folders (33) folders were retrieved and 28 had complete information for analysis. The mean (SD) age and parity were 28.2 (6.2) and 3.4 (2.0), respectively. Most deaths (9/28; 32.1%) were in the age group of 20-24 years. Multiparae (14/28; 50%) constituted the largest parity group. Majority (16/28; 57.1) were non-literates, 16/28 (57.1%) were of Hausa/Fulani extraction and 12/28 (42.9%) were unbooked. The leading causes of maternal mortality were preeclampsia/eclampsia (9/28; 32.1%), obstetric hemorrhage (8/28; 28.6%) and severe anemia (3/28; 10.7%). All those who died of preeclampsia/eclampsia were Hausa/Fulani. Most (14/28; 50%) deaths occurred within 24 h of admission. Majority of the deaths were Muslims (χ(2) = 15.108, P = <0.001). Ethnicity had no significant influence on maternal death (χ(2) = 15.550, P = 0.21). In conclusion, the MMR in FMCY is higher than the national average. The fact that most deaths occurred within 24 h of admission suggests that many of the patients delayed reaching the referring center for a variety of reasons. Preventive measures should focus on this delay, which is usually beyond the reach of the hospital. Measures to reduce preventable hospital deaths should also be put in place.


Studying complexity in health services research: desperately seeking an overdue paradigm shift.
Complexity is much talked about but sub-optimally studied in health services research. Although the significance of the complex system as an analytic lens is increasingly recognised, many researchers are still using methods that assume a closed system in which predictive studies in general, and controlled experiments in particular, are possible and preferred. We argue that in open systems characterised by dynamically changing inter-relationships and tensions, conventional research designs predicated on linearity and predictability must be augmented by the study of how we can best deal with uncertainty, unpredictability and emergent causality. Accordingly, the study of complexity in health services and systems requires new standards of research quality, namely (for example) rich theorising, generative learning, and pragmatic adaptation to changing contexts. This framing of complexity-informed health services research provides a backdrop for a new collection of empirical studies. Each of the initial five papers in this collection illustrates, in different ways, the value of theoretically grounded, methodologically pluralistic, flexible and adaptive study designs. We propose an agenda for future research and invite researchers to contribute to this on-going series.


Discordant reporting of nonmedical opioid use in a nationally representative sample of US high school seniors.
Nonmedical opioid use has become a major public health concern due to increases in treatment admissions, overdoses, and deaths. Use has also been linked to heroin initiation. Reliable data on nonmedical opioid use are needed to continue to inform prevention. To determine the prevalence and correlates of discordant self-report of nonmedical use of opioids in a national sample. Utilizing a nationally representative sample of 31,149 American high school seniors in the Monitoring the Future study (2009-2013), discordant responses between self-reported 12-month nonmedical opioid use and self-reported 12-month nonmedical Vicodin and OxyContin use (reporting Vicodin/OxyContin use, but not reporting "opioid" use) were assessed. We also used multivariable logistic regression to determine the characteristics of students who were most likely to provide a discordant response. 37.1% of those reporting nonmedical Vicodin use and 28.2% of those reporting nonmedical OxyContin use did not report overall nonmedical opioid use. Prevalence of nonmedical opioid use (8.3%) would increase when factoring in Vicodin, OxyContin, or both, by 2.8%, 1.3%, and 3.3%, respectively. Females were more likely to provide a discordant response to Vicodin and highly religious students were more likely to provide a discordant response regarding OxyContin use. Those who reported cocaine or nonmedical tranquilizer use were at consistently low odds for discordant responses. Nonmedical amphetamine users were at low odds for providing a discordant Vicodin response. Prevalence of nonmedical opioid use may be underreported on some surveys, particularly among specific subpopulations. Further research on the effect of question order and skip-patterns (e.g., "gate" questions) is needed. Reliable data on nonmedical opioid use are needed to continue to accurately inform prevention.


Golimumab for rheumatoid arthritis: a systematic review.
To perform a Cochrane systematic review of benefit (American College of Rheumatology 50% improvement criteria; ACR50) and safety (adverse events and withdrawals) of golimumab in patients with rheumatoid arthritis (RA). We searched the Cochrane Central Register of Controlled Trials (CENTRAL), OVID Medline, CINAHL, Embase, Science Citation Index (Web of Science), and Current Controlled Trials databases for randomized or controlled clinical trials of golimumab compared to placebo or disease-modifying antirheumatic drug in adults with RA. Two authors independently selected appropriate studies and abstracted study characteristics and safety and efficacy data and performed risk-of-bias assessment. We calculated mean differences for continuous measures, and relative risks for categorical measures. Four randomized controlled trials with 1231 golimumab-treated and 483 placebo-treated patients were included. Of these, 436 were treated with golimumab at 50 mg every 4 weeks [a dosage approved by the US Food and Drug Administration (FDA)]. At an average of 4-6 months, compared to patients treated with placebo and methotrexate (MTX), patients treated with the FDA-approved dosage of golimumab and MTX were 2.6 times more likely to reach ACR50 (p = 0.005, 95% CI 1.3, 4.9; absolute percentage, 38% vs 15%) and 0.5 times as likely to have overall withdrawals (p = 0.005, 95% CI 0.3, 0.8; absolute percentage, 5% vs 10%). Golimumab-treated patients were significantly more likely than those taking placebo to achieve remission (22% vs 4%; p < 0.00001), and to have improvement in functional ability on the Health Assessment questionnaire [0.2 points lower (p < 0.00001, 95% CI 0.25, 0.15); absolute risk difference, -20% (95% CI -25% to -15%); relative percentage difference, -11% (95% CI -14% to -8.3%)]. The studies were too small and short to be powered sufficiently for safety outcomes, but no substantive statistically significant differences were noted between golimumab and placebo regarding adverse events, serious adverse events, infections, serious infections, lung infections, tuberculosis, cancer, withdrawals due to adverse events, and withdrawals due to inefficacy and deaths. At the approved dosage, in patients with active RA taking background MTX, golimumab is significantly more beneficial than placebo. The short-term safety profile is reasonable. Longterm surveillance studies are needed for safety assessment.


Bigger is not always better: when brains get smaller.
Many studies assume that an increase in brain size is beneficial. However, the costs of producing and maintaining a brain are high, and we argue that brain size should be secondarily reduced by natural selection whenever the costs outweigh the benefits. Our results confirm this by showing that brain size is subject to bidirectional selection. Relative to the ancestral state, brain size in bats has been reduced in fast flyers, while it has increased in manoeuvrable flyers adapted to flight in complex habitats. This study emphasizes that brain reduction and enlargement are equally important, and they should both be considered when investigating brain size evolution.


Red Light Combined with Blue Light Irradiation Regulates Proliferation and Apoptosis in Skin Keratinocytes in Combination with Low Concentrations of Curcumin.
Curcumin is a widely known natural phytochemical from plant Curcuma longa. In recent years, curcumin has received increasing attention because of its capability to induce apoptosis and inhibit cell proliferation as well as its anti-inflammatory properties in different cancer cells. However, the therapeutic benefits of curcumin are severely hampered due to its particularly low absorption via trans-dermal or oral bioavailability. Phototherapy with visible light is gaining more and more support in dermatological therapy. Red light is part of the visible light spectrum, which is able to deeply penetrate the skin to about 6 mm, and directly affect the fibroblast of the skin dermis. Blue light is UV-free irradiation which is fit for treating chronic inflammation diseases. In this study, we show that curcumin at low concentrations (1.25-3.12 μM) has a strong anti-proliferative effect on TNF-α-induced psoriasis-like inflammation when applied in combination with light-emitting-diode devices. The treatment was especially effective when LED blue light at 405 nm was combined with red light at 630 or 660 nm, which markedly amplified the anti-proliferative and apoptosis-inducing effects of curcumin. The experimental results demonstrated that this treatment reduced the viability of human skin keratinocytes, decreased cell proliferation, induced apoptosis, inhibited NF-κB activity and activated caspase-8 and caspase-9 while preserving the cell membrane integrity. Moreover, the combined treatment also down-regulated the phosphorylation level of Akt and ERK. Taken together, our results indicated that the combination of curcumin with LED blue light united red light irradiation can attain a higher efficiency of regulating proliferation and apoptosis in skin keratinocytes.


Analgesic Choice in Management of Rib Fractures: Paravertebral Block or Epidural Analgesia?
Rib fractures are commonly encountered in the setting of trauma. The aim of this study was to assess the association between the clinical outcome of rib fracture and epidural analgesia (EA) versus paravertebral block (PVB) using the National Trauma Data Bank (NTDB). Using the 2011 and 2012 versions of the NTDB, we retrieved completed records for all patients above 18 years of age who were admitted with rib fractures. Primary outcome was in-hospital mortality. Secondary outcomes were length of stay (LOS), intensive care unit (ICU) admission, ICU LOS, mechanical ventilation, duration of mechanical ventilation, development of pneumonia, and development of any other complication. Clinical outcomes were first compared between propensity score-matched EA and PVB patients. Then, EA and PVB patients were combined into the procedure group and the outcomes were compared with propensity score-matched patients that received neither intervention (no-procedure group). A total of 194,766 patients were included in the study with 1073 patients having EA, 1110 patients having PVB, and 192,583 patients having neither procedure. After propensity score matching, comparison of primary and secondary outcomes between EA and PVB patients showed no difference. Comparison of propensity score-matched procedure and no-procedure patients showed prolonged LOS and more frequent ICU admissions in patients receiving a procedure (both P < .0001), yet having no procedure was associated with a significantly increased odds of mortality (odds ratio: 2.25; 95% confidence interval, 1.14-3.84; P = .002). Using the NTDB, EA and PVB were not found to be significantly different in management of rib fractures. There was an association between use of a block and improved outcome, but this could be explained by selection of healthier patients to receive a block. Prospective study of this association is recommended.


Raman spectroscopic analysis of the molecular composition of oral cavity squamous cell carcinoma and healthy tongue tissue.
A Raman tissue spectrum is a quantitative representation of the overall molecular composition of that tissue. Raman spectra are often used as tissue fingerprints without further interpretation of the specific information that they contain about the tissue's molecular composition. In this study, we analyzed the differences in molecular composition between oral cavity squamous cell carcinoma (OCSCC) and healthy tissue structures in tongue, based on their Raman spectra. A total of 1087 histopathologically annotated spectra (142 OCSCC, 202 surface squamous epithelium, 61 muscle, 65 adipose tissue, 581 connective tissue, 26 gland, and 10 nerve) were obtained from Raman maps of 44 tongue samples from 21 patients. A characteristic, average spectrum of each tissue structure was fitted with a set of 55 pure-compound reference spectra, to define the best library of fit-spectra. Reference spectra represented proteins, lipids, nucleic acids, carbohydrates, amino acids and other miscellaneous molecules. A non-negative least-squares algorithm was used for fitting. Individual spectra per histopathological annotation were then fitted with this selected library in order to determine the molecular composition per tissue structure. The spectral contribution per chemical class was calculated. The results show that all characteristic tissue-type spectra could be fitted with a low residual of <4.82%. The content of carbohydrates, proteins and amino acids was the strongest discriminator between OCSCC and healthy tissue. The combination of carbohydrates, proteins and amino acids was used for a classification model of 'tumor' versus 'healthy tissue'. Validation of this model on an independent dataset showed a specificity of 93% at a sensitivity of 100%.


Age-dependent Pavlovian biases influence motor decision-making.
Motor decision-making is an essential component of everyday life which requires weighing potential rewards and punishments against the probability of successfully executing an action. To achieve this, humans rely on two key mechanisms; a flexible, instrumental, value-dependent process and a hardwired, Pavlovian, value-independent process. In economic decision-making, age-related decline in risk taking is explained by reduced Pavlovian biases that promote action toward reward. Although healthy ageing has also been associated with decreased risk-taking in motor decision-making, it is currently unknown whether this is a result of changes in Pavlovian biases, instrumental processes or a combination of both. Using a newly established approach-avoidance computational model together with a novel app-based motor decision-making task, we measured sensitivity to reward and punishment when participants (n = 26,532) made a 'go/no-go' motor gamble based on their perceived ability to execute a complex action. We show that motor decision-making can be better explained by a model with both instrumental and Pavlovian parameters, and reveal age-related changes across punishment- and reward-based instrumental and Pavlovian processes. However, the most striking effect of ageing was a decrease in Pavlovian attraction towards rewards, which was associated with a reduction in optimality of choice behaviour. In a subset of participants who also played an independent economic decision-making task (n = 17,220), we found similar decision-making tendencies for motor and economic domains across a majority of age groups. Pavlovian biases, therefore, play an important role in not only explaining motor decision-making behaviour but also the changes which occur through normal ageing. This provides a deeper understanding of the mechanisms which shape motor decision-making across the lifespan.


Proteomic analysis of dunning prostate cancer cell lines with variable metastatic potential using SELDI-TOF.
Surface enhanced laser desorption and ionization-time-of-flight (SELDI-TOF) is an evolving proteomic technology for improving biomarker discovery that allows for rapid and sensitive analysis of complex protein mixtures generated from body fluids, cells, and/or tissues. SELDI--based profiling identifies unique, differentially expressed proteins relating to specific cancer-related disease states. We utilized SELDI-TOF following pre-processing with molecular separation and chemical fractionation of cell membrane extracts from three Dunning rat prostate cancer cell lines of varying metastatic potential to search novel proteins that are differentially expressed. Dunning rat cell sublines of variable (%) metastatic potential; G (0%), AT-1 (20%), and Mat-Ly-Lu (100%) were cultured in two different laboratories. Cell lysis was performed in a homogenation buffer (320 mM sucrose/50 mM Tris/0.5 mM PSMF) using Dounce homogenation. After centrifugation, the membrane pellet was washed 2x and then solublized in 2% CHAPS/8 M urea. This sample was further processed using positive pressure molecular ultrafiltration at 30 kDa or precipitation with 50% ammonium sulfate. Next, each sample was applied to an IMAC3-Ni ProteinChip (Ciphergen Biosystems, Freemont, CA) and analyzed using Ciphergen's Protein Biology System with protein peak analysis software. SELDI-TOF analysis differentiated the three Dunning rat cell sublines based upon protein concentration normalized profiles between 5,000 and 20,000 Da. The preparations from the three cells lines showed clear differences when the extracts from the metastatic sublines (AT-1 and MLL) were compared to the benign subline (G) for proteins with molecular weights of 9 kDa (decrease), 12 kDa (significant decrease), 14 kDa (decrease), and 17 kDa (significant gain). After pre-processing extracts with ammonium sulfate and molecular ultrafiltration, the molecular profile changes from one subline to the next became more apparent. Our results were reproducible using multiple runs including from Dunning cells cultured in a separate laboratory, and using different lots of SELDI ProteinChips. The application of SELDI-TOF to a series of Dunning rat prostate cancer cell lines illustrated apparent changes in protein profiles among the three cell lines with known differences in metastatic biologic activity. SELDI-TOF identified four reproducible changes in protein expression in the AT1 and MLL metastatic cell sublines. Three of the expression changes were manifested as decreases, but one protein (17 kDa) was over-expressed in the AT1 and MLL cell lines. Emphasis will be placed on the isolation, purification, and characterization of the 17 kDa over-expressed protein and its potential role in PCa metastasis.


Population history of the Red Sea--genetic exchanges between the Arabian Peninsula and East Africa signaled in the mitochondrial DNA HV1 haplogroup.
Archaeological studies have revealed cultural connections between the two sides of the Red Sea dating to prehistory. The issue has still not been properly addressed, however, by archaeogenetics. We focus our attention here on the mitochondrial haplogroup HV1 that is present in both the Arabian Peninsula and East Africa. The internal variation of 38 complete mitochondrial DNA sequences (20 of them presented here for the first time) affiliated into this haplogroup testify to its emergence during the late glacial maximum, most probably in the Near East, with subsequent dispersion via population expansions when climatic conditions improved. Detailed phylogeography of HV1 sequences shows that more recent demographic upheavals likely contributed to their spread from West Arabia to East Africa, a finding concordant with archaeological records suggesting intensive maritime trade in the Red Sea from the sixth millennium BC onwards. Closer genetic exchanges are apparent between the Horn of Africa and Yemen, while Egyptian HV1 haplotypes seem to be more similar to the Near Eastern ones.


Retrospective analysis of multiplex polymerase chain reaction-based molecular diagnostics (SES) in 70 patients with suspected central nervous system infections: A single-center study.
Central nervous system (CNS) infections present a grave health care challenge due to high morbidity and mortality. Clinical findings and conventional laboratory assessments are not sufficiently distinct for specific etiologic diagnosis. Identification of pathogens is a key to appropriate therapy. In this retrospective observational study, we evaluated the efficacy and clinical utility of syndrome evaluation system (SES) for diagnosing clinically suspected CNS infections. This retrospective analysis included inpatients in our tertiary level neurointensive care unit (NICU) and ward from February 2010 to December 2013. Cerebrospinal fluid (CSF) samples of 70 patients, clinically suspected of having CNS infections, were subjected to routine laboratory tests, culture, imaging, and SES. We analyzed the efficacy of SES in the diagnosis of CNS infections and its utility in therapeutic decision-making. SES had a clinical sensitivity of 57.4% and clinical specificity of 95.6%. Streptococcus pneumoniae and Pseudomonas aeruginosa were the top two bacterial pathogens, whereas Herpes simplex virus (HSV) was the most common viral pathogen. Polymicrobial infections were detected in 32.14% of SES-positive cases. SES elicited a change in the management in 30% of the patients from initial empiric therapy. At discharge, 51 patients recovered fully while 11 patients had partial recovery. Three-month follow-up showed only six patients to have neurological deficits. In a tertiary care center, etiological microbial diagnosis is central to appropriate therapy and outcomes. Sensitive and accurate multiplex molecular diagnostics play a critical role in not only identifying the causative pathogen but also in helping clinicians to institute appropriate therapy, reduce overuse of antimicrobials, and ensure superior clinical outcomes.


What are the determinants of food security among regional and remote Western Australian children?
To explore how determinants of food security affect children in regional and remote Western Australia (WA), across food availability, access and utilisation dimensions. The Determinants of Food Security framework guided the thematic analysis (using NVivo 10) of semi-structured interviews with 20 key informants. Food availability factors included availability, price, promotion, quality, location of outlets and variety. Food access factors included social support, financial resources, transport to food outlets, distance to food outlets and mobility. Food utilisation factors included nutrition knowledge and skills, children's food preferences, storage facilities, preparation and cooking facilities and time to purchase food. Key food availability recommendations include increasing local food supply options. Food access recommendations include ensuring equitable formal social support and empowering informal support options. Food utilisation recommendations include prioritising food literacy programs focusing on quick, healthy food preparation and budgeting skills. Implications for public health: Policymakers should invest in local food supply options, equitable social support services and experiential food literacy programs. Practitioners should focus child/parent programs on improving attitude, knowledge and skills.


Calcidiol and PTH levels in women attending an osteoporosis program.
We performed a retrospective study of 237 patients attending a specialty osteoporosis practice. Secondary causes for reduced bone mineral density (BMD) were evaluated in 196 postmenopausal women and 41 premenopausal women; mean age was 56 +/- 13.8 years (mean +/- SD). BMD was measured by dual-energy X-ray absorptiometry (DXA) (QDR 1000W/2000 Hologic). Levels of intact parathyroid hormone (iPTH), calcidiol [25(OH)D], thyroid-stimulating hormone, and 24-hour urinary calcium were measured, and serum and urine protein (SPEP and UPEP) electrophoresis were performed. Overall, 16% of our patients had 25(OH)D levels <15 ng/ml, the lowest acceptable vitamin D level without a concomitant rise in iPTH levels. Among the osteoporotic patients (T score <-2.5 SD), 17% had 25(OH)D levels <15 ng/ml and 7% <10 ng/ml. Among the osteopenic patients (-2.5 < T < -1.0 SD), 11% had 25(OH)D levels <15 ng/ml. Seventeen percent of patients with Z score </=-1.0 SD (low range normal value) had 25(OH)D levels <15 ng/ml. Low 25(OH)D levels were inversely related to high iPTH values (r = 0.30, P < 0.0001). Hypercalciuria was present in 15% of our patients, elevations of PTH levels (>65 pg/ml, upper normal limit of assay) were present in 11.5%, and hyperthyroidism in 4%. A 25(OH)D level of <25 ng/ml in women (n = 86) with no known secondary causes of low BMD was associated with an iPTH level above 49 pg/ml. The measurement of 25(OH)D levels is recommended in the evaluation of secondary causes for reduced BMD. Supplementation with vitamin D appears needed to keep 25(OH)D above 25 ng/ml, the level required to prevent increments in iPTH levels.


Effects of age and gender on the relationship between anxiety and coronary artery disease.
This study investigated the relationship between anxiety and coronary artery disease (CAD). State (S-ANX) and trait (T-ANX) anxiety were assessed with the State-Trait Personality Inventory (STPI), which was administered to 373 patients (230 males, 143 females) 12 to 18 hr prior to their undergoing coronary arteriography. Females were significantly higher than males in both T-ANX (p less than 0.05) and S-ANX (p less than 0.01). Younger patients of both sexes were significantly higher in S-ANX (p less than 0.001), but no relationship was found between T-ANX and age. Patients with CAD did not differ in S-ANX from those without CAD. T-ANX scores of female patients were unrelated to MI or CAD. Male patients with chest pain only (CPO) were higher in T-ANX than males with prior myocardial infarction or chest pain plus CAD (p less than 0.01). Although this difference was not significant for older males (p less than 0.31), younger CPO males were significantly higher in T-ANX than the other clinical groups (p less than 0.05). These results were interpreted as indicating that high T-ANX is not associated with CAD, but is a risk factor for angiography, especially for younger males.


Salicylic acid treatment and expression of an RNA-dependent RNA polymerase 1 transgene inhibit lethal symptoms and meristem invasion during tobacco mosaic virus infection in Nicotiana benthamiana.
Host RNA-dependent RNA polymerases (RDRs) 1 and 6 contribute to antiviral RNA silencing in plants. RDR6 is constitutively expressed and was previously shown to limit invasion of Nicotiana benthamiana meristem tissue by potato virus X and thereby inhibit disease development. RDR1 is inducible by salicylic acid (SA) and several other phytohormones. But although it contributes to basal resistance to tobacco mosaic virus (TMV) it is dispensable for SA-induced resistance in inoculated leaves. The laboratory accession of N. benthamiana is a natural rdr1 mutant and highly susceptible to TMV. However, TMV-induced symptoms are ameliorated in transgenic plants expressing Medicago truncatula RDR1. In MtRDR1-transgenic N. benthamiana plants the spread of TMV expressing the green fluorescent protein (TMV.GFP) into upper, non-inoculated, leaves was not inhibited. However, in these plants exclusion of TMV.GFP from the apical meristem and adjacent stem tissue was greater than in control plants and this exclusion effect was enhanced by SA. TMV normally kills N. benthamiana plants but although MtRDR1-transgenic plants initially displayed virus-induced necrosis they subsequently recovered. Recovery from disease was markedly enhanced by SA treatment in MtRDR1-transgenic plants whereas in control plants SA delayed but did not prevent systemic necrosis and death. Following SA treatment of MtRDR1-transgenic plants, extractable RDR enzyme activity was increased and Western blot analysis of RDR extracts revealed a band cross-reacting with an antibody raised against MtRDR1. Expression of MtRDR1 in the transgenic N. benthamiana plants was driven by a constitutive 35S promoter derived from cauliflower mosaic virus, confirmed to be non-responsive to SA. This suggests that the effects of SA on MtRDR1 are exerted at a post-transcriptional level. MtRDR1 inhibits severe symptom development by limiting spread of virus into the growing tips of infected plants. Thus, RDR1 may act in a similar fashion to RDR6. MtRDR1 and SA acted additively to further promote recovery from disease symptoms in MtRDR1-transgenic plants. Thus it is possible that SA promotes MtRDR1 activity and/or stability through post-transcriptional effects.


Functional calcitonin gene-related peptide receptors are formed by the asymmetric assembly of a calcitonin receptor-like receptor homo-oligomer and a monomer of receptor activity-modifying protein-1.
In addition to their interactions with hetero-trimeric G proteins, seven-transmembrane domain receptors are now known to form multimeric complexes that can include receptor homo- or hetero-oligomers and/or accessory proteins that modulate their activity. The calcitonin gene-related peptide (CGRP) receptor requires the assembly of the seven-transmembrane domain calcitonin receptor-like receptor with the single-transmembrane domain receptor activity-modifying protein-1 to reach the cell surface and be active. However, the relative stoichiometric arrangement of these two proteins within a receptor complex remains unknown. Despite recent advances in the development of protein-protein interactions assays, determining the composition and stoichiometric arrangements of such signaling complexes in living cells remains a challenging task. In the present study, we combined bimolecular fluorescence complementation (BiFC) with bioluminescence resonance energy transfer (BRET) to probe the stoichiometric arrangement of the CGRP receptor complex. Together with BRET competition assays, co-immunoprecipitation experiments, and BiFC imaging, dual BRET/BiFC revealed that functional CGRP receptors result from the association of a homo-oligomer of the calcitonin receptor-like receptor with a monomer of the accessory protein receptor activity-modifying protein-1. In addition to revealing the existence of an unexpected asymmetric oligomeric organization for a G protein-coupled receptor, our study illustrates the usefulness of dual BRET/BiFC as a powerful tool for analyzing constitutive and dynamically regulated multiprotein complexes.


The effect of human bone marrow stroma-derived heparan sulfate on the ex vivo expansion of human cord blood hematopoietic stem cells.
In order to address cell dose limitations associated with the use of cord blood hematopoietic stem cell (HSC) transplantation, we explored the effect of bone marrow stroma-derived heparan sulfate (HS) on the ex vivo expansion of HSCs. Heparan sulfate was isolated and purified from the conditioned media of human bone marrow stromal cells and used for the expansion of cord blood-derived CD34(+) cells in the presence of a cocktail of cytokines. The number of myeloid lineage-committed progenitor cells was increased at low dosage of HS as illustrated by an increase in the total number of colony-forming cells (CFC) and colonies of erythroid (BFU-E) and granulocyte-macrophage (CFU-GM) precursors. Notably, the stroma-derived HS did not alter the growth of CD34(+) HSCs or negatively affect the levels of various HSC phenotypic markers after expansion. This study shows that HS secreted into solution by stromal cells has the capacity to support hematopoietic cytokines in the maintenance and expansion of HSCs. The incorporation of stroma-derived HS as a reagent may improve the efficacy of cord blood HSC transplantation by enhancing the number of committed cells and accelerating the rate of engraftment.


Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity.
Extracellular vesicle (EV)-mediated intercellular transfer of signaling proteins and nucleic acids has recently been implicated in the development of cancer and other pathological conditions; however, the mechanism of EV uptake and how this may be targeted remain as important questions. Here, we provide evidence that heparan sulfate (HS) proteoglycans (PGs; HSPGs) function as internalizing receptors of cancer cell-derived EVs with exosome-like characteristics. Internalized exosomes colocalized with cell-surface HSPGs of the syndecan and glypican type, and exosome uptake was specifically inhibited by free HS chains, whereas closely related chondroitin sulfate had no effect. By using several cell mutants, we provide genetic evidence of a receptor function of HSPG in exosome uptake, which was dependent on intact HS, specifically on the 2-O and N-sulfation groups. Further, enzymatic depletion of cell-surface HSPG or pharmacological inhibition of endogenous PG biosynthesis by xyloside significantly attenuated exosome uptake. We provide biochemical evidence that HSPGs are sorted to and associate with exosomes; however, exosome-associated HSPGs appear to have no direct role in exosome internalization. On a functional level, exosome-induced ERK1/2 signaling activation was attenuated in PG-deficient mutant cells as well as in WT cells treated with xyloside. Importantly, exosome-mediated stimulation of cancer cell migration was significantly reduced in PG-deficient mutant cells, or by treatment of WT cells with heparin or xyloside. We conclude that cancer cell-derived exosomes use HSPGs for their internalization and functional activity, which significantly extends the emerging role of HSPGs as key receptors of macromolecular cargo.


ER stress and unfolded protein response in amyotrophic lateral sclerosis.
Several theories on the pathomechanism of amyotrophic lateral sclerosis (ALS) have been proposed: misfolded protein aggregates, mitochondrial dysfunction, increased glutamate toxicity, increased oxidative stress, disturbance of intracellular trafficking, and so on. In parallel, a number of drugs that have been developed to alleviate the putative key pathomechanism of ALS have been under clinical trials. Unfortunately, however, almost all studies have finished unsuccessfully. This fact indicates that the key ALS pathomechanism still remains a tough enigma. Recent studies with autopsied ALS patients and studies using mutant SOD1 (mSOD1) transgenic mice have suggested that endoplasmic reticulum (ER) stress-related toxicity may be a relevant ALS pathomechanism. Levels of ER stress-related proteins were upregulated in motor neurons in the spinal cords of ALS patients. It was also shown that mSOD1, translocated to the ER, caused ER stress in neurons in the spinal cord of mSOD1 transgenic mice. We recently reported that the newly identified ALS-causative gene, vesicle-associated membrane protein-associated protein B (VAPB), plays a pivotal role in unfolded protein response (UPR), a physiological reaction against ER stress. The ALS-linked P56S mutation in VAPB nullifies the function of VAPB, resulting in motoneuronal vulnerability to ER stress. In this review, we summarize recent advances in research on the ALS pathomechanism especially addressing the putative involvement of ER stress and UPR dysfunction.


Hospital safety climate and safety behavior: A social exchange perspective.
Safety climate is considered beneficial to the improvement of hospital safety outcomes. Nevertheless, the relations between two of its key constituents, namely those stemming from leader-subordinate relations and coworker support for safety, are still to be fully ascertained. This article uses the theoretical lens of Social Exchange Theory to study the joint impact of leader-member exchange in the safety sphere and coworker support for safety on safety-related behavior at the hospital ward level. Social exchange constructs are further related to the existence of a shame-/blame-free environment, seen as a potential antecedent of safety behavior. A cross-sectional study including 166 inpatients in hospital wards belonging to 10 public hospitals in Italy was undertaken to test the hypotheses developed. Hypothesized relations have been analyzed through a fully mediated multilevel structural equation model. This methodology allows studying behavior at the individual level, while keeping into account the heterogeneity among hospital specialties. Results suggest that the linkage between leader support for safety and individual safety behavior is mediated by coworker support on safety issues and by the creation of a shame-free environment. These findings call for the creation of a safety climate in which managerial efforts should be directed not only to the provision of new safety resources and the enforcement of safety rules but also to the encouragement of teamwork and freedom to report errors as ways to foster the capacity of the staff to communicate, share, and learn from each other.


Impaired memory and learning abilities in patients with systemic lupus erythematosus as measured by the Rey Auditory Verbal Learning Test.
The purpose of this study was to assess and characterise verbal memory impairment in patients with systemic lupus erythematosus (SLE) by the Rey Auditory Verbal Learning Test (Rey AVLT). 40 consecutive, unselected patients with SLE were evaluated with the Rey AVLT, a clinical and research tool for the study of multiple learning and memory measures. All patients were assessed for disease activity, damage, presence of antiphospholipid antibodies and depression. Findings were compared with those of 40 healthy controls matched for age, sex and education. The study group included 40 patients with SLE (37 females, 3 males), median age 33 years (range 20-59), median disease duration 8 years (range 0.3-32). The median disease activity measured by the SLE Disease Activity Index (SLEDAI) was 4 (range 0-16). Median damage measured by the SLICC/ACR (Systemic Lupus International Collaborating Clinics/American College of Rheumatology) damage index score was 0 (range 0-4). Depression was detected in 16/40 patients. Several aspects of the memory domain, as measured by the Rey AVLT, were impaired in the SLE group, using analysis of variance with repeated measures. The learning curve of patients with SLE was significantly less steep compared with that of controls, (p = 0.036), the rate of words omitted from trial to trial was higher in the SLE group (p = 0.034) and retrieval was less efficient in SLE compared with controls (p = 0.004). The significance of these findings was maintained after omitting patients with stroke or depression. Learning ability was impaired in patients with SLE with a poor and inefficient learning strategy, as reflected by an impaired learning curve, repeated omissions and impaired retrieval. This pattern of memory deficit resembles that seen in patients with frontal lobe damage and warrants further localising brain studies.


Use of Simulation in Undergraduate and Graduate Education.
Simulation is not just technology but a teaching method used to allow students to practice in a safe environment. The focus of simulation is to improve patient safety, communication, and the ability of the student to think and act as a nurse or advanced practice nurse. As use of simulation in nursing education increases, more regulations, guidelines, and standards are being developed to assist nursing programs to obtain best outcomes. This article provides readers with an overview of simulation use in undergraduate and graduate nursing education.