Combined cardiological and neurological abnormalities due to filamin A gene mutation.
Cardiac defects can be the presenting symptom in patients with mutations in the X-linked gene FLNA. Dysfunction of this gene is associated with cardiac abnormalities, especially in the left ventricular outflow tract, but can also cause a congenital malformation of the cerebral cortex. We noticed that some patients diagnosed at the neurogenetics clinic had first presented to a cardiologist, suggesting that earlier recognition may be possible if the diagnosis is suspected. From the Erasmus MC cerebral malformations database 24 patients were identified with cerebral bilateral periventricular nodular heterotopia (PNH) without other cerebral cortical malformations. In six of these patients, a pathogenic mutation in FLNA was present. In five a cardiac defect was also found in the outflow tract. Four had presented to a cardiologist before the cerebral abnormalities were diagnosed. The cardiological phenotype typically consists of aortic or mitral regurgitation, coarctation of the aorta or other left-sided cardiac malformations. Most patients in this category will not have a FLNA mutation, but the presence of neurological complaints, hyperlaxity of the skin or joints and/or a family history with similar cardiac or neurological problems in a possibly X-linked pattern may alert the clinician to the possibility of a FLNA mutation.


Thrombin-induced CCAAT/enhancer-binding protein β activation and IL-8/CXCL8 expression via MEKK1, ERK, and p90 ribosomal S6 kinase 1 in lung epithelial cells.
Thrombin, a serine protease, is a well-known coagulation factor generated during vascular injury and plays an important role in lung inflammation. We previously showed that the c-Src- and Rac/PI3K/Akt-dependent NF-κB pathways are involved in thrombin-induced IL-8/CXCL8 expression in human lung epithelial cells (A549). In this study, we investigated the role of the MEK kinase (MEKK)1/ERK/p90 ribosomal S6 kinase (RSK)1-dependent C/EBPβ signaling pathway in thrombin-induced IL-8/CXCL8 expression. Thrombin-induced IL-8/CXCL8 release and IL-8/CXCL8-luciferase activity were attenuated by small interfering RNA (siRNA) of C/EBPβ and by cells transfected with the C/EBPβ site mutation of the IL-8/CXCL8 construct. Moreover, thrombin-induced κB-luciferase activity was also inhibited by C/EBPβ siRNA. The thrombin-induced increases in IL-8/CXCL8 release and IL-8/CXCL8-luciferase were also inhibited by MEKK1 siRNA, PD98059 (an MEK inhibitor), U0126 (an ERK inhibitor), and RSK1 siRNA. Treatment of cells with thrombin caused an increase in C/EBPβ phosphorylation at Thr(235), C/EBPβ-luciferase activity, recruitment of C/EBPβ to the IL-8/CXCL8 promoter, and C/EBPβ-specific DNA complex formation. Furthermore, thrombin-mediated C/EBPβ phosphorylation and C/EBPβ-luciferase activity were inhibited by MEKK1 siRNA, PD98059, and RSK1 siRNA. Stimulation of cells with thrombin resulted in an increase in RSK1 phosphorylation at Thr(359)/Ser(363), and this effect was inhibited by MEKK1 siRNA and PD98059. The thrombin-induced increase in ERK activation was inhibited by MEKK1 siRNA. These results imply that thrombin activates the MEKK1/ERK/RSK1 signaling pathway, which in turn initiates C/EBPβ activation, recruitment of C/EBPβ to the IL-8/CXCL8 promoter, and C/EBPβ-specific DNA complex formation, and ultimately induces IL-8/CXCL8 expression and release in lung epithelial cells.


The role and assembly mechanism of nucleoprotein in influenza A virus ribonucleoprotein complexes.
The nucleoprotein of negative-strand RNA viruses forms a major component of the ribonucleoprotein complex that is responsible for viral transcription and replication. However, the precise role of nucleoprotein in viral RNA transcription and replication is not clear. Here we show that nucleoprotein of influenza A virus is entirely dispensable for replication and transcription of short viral RNA-like templates in vivo, suggesting that nucleoprotein represents an elongation factor for the viral RNA polymerase. We also find that the recruitment of nucleoprotein to nascent ribonucleoprotein complexes during replication of full-length viral genes is mediated through nucleoprotein-nucleoprotein homo-oligomerization in a 'tail loop-first' orientation and is independent of RNA binding. This work demonstrates that nucleoprotein does not regulate the initiation and termination of transcription and replication by the viral polymerase in vivo, and provides new mechanistic insights into the assembly and regulation of viral ribonucleoprotein complexes.


Methicillin resistance alters the biofilm phenotype and attenuates virulence in Staphylococcus aureus device-associated infections.
Clinical isolates of Staphylococcus aureus can express biofilm phenotypes promoted by the major cell wall autolysin and the fibronectin-binding proteins or the icaADBC-encoded polysaccharide intercellular adhesin/poly-N-acetylglucosamine (PIA/PNAG). Biofilm production in methicillin-susceptible S. aureus (MSSA) strains is typically dependent on PIA/PNAG whereas methicillin-resistant isolates express an Atl/FnBP-mediated biofilm phenotype suggesting a relationship between susceptibility to β-lactam antibiotics and biofilm. By introducing the methicillin resistance gene mecA into the PNAG-producing laboratory strain 8325-4 we generated a heterogeneously resistant (HeR) strain, from which a homogeneous, high-level resistant (HoR) derivative was isolated following exposure to oxacillin. The HoR phenotype was associated with a R₆₀₂H substitution in the DHHA1 domain of GdpP, a recently identified c-di-AMP phosphodiesterase with roles in resistance/tolerance to β-lactam antibiotics and cell envelope stress. Transcription of icaADBC and PNAG production were impaired in the 8325-4 HoR derivative, which instead produced a proteinaceous biofilm that was significantly inhibited by antibodies against the mecA-encoded penicillin binding protein 2a (PBP2a). Conversely excision of the SCCmec element in the MRSA strain BH1CC resulted in oxacillin susceptibility and reduced biofilm production, both of which were complemented by mecA alone. Transcriptional activity of the accessory gene regulator locus was also repressed in the 8325-4 HoR strain, which in turn was accompanied by reduced protease production and significantly reduced virulence in a mouse model of device infection. Thus, homogeneous methicillin resistance has the potential to affect agr- and icaADBC-mediated phenotypes, including altered biofilm expression and virulence, which together are consistent with the adaptation of healthcare-associated MRSA strains to the antibiotic-rich hospital environment in which they are frequently responsible for device-related infections in immuno-compromised patients.


Characterization of NAADP-mediated calcium signaling in human spermatozoa.
Ca(2+) signaling in spermatozoa plays a crucial role during processes such as capacitation and release of the acrosome, but the underlying molecular mechanisms still remain unclear. Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent Ca(2+)-releasing second messenger in a variety of cellular processes. The presence of a NAADP synthesizing enzyme in sea urchin sperm has been previously reported, suggesting a possible role of NAADP in sperm Ca(2+) signaling. In this work we used in vitro enzyme assays to show the presence of a novel NAADP synthesizing enzyme in human sperm, and to characterize its sensitivity to Ca(2+) and pH. Ca(2+) fluorescence imaging studies demonstrated that the permeable form of NAADP (NAADP-AM) induces intracellular [Ca(2+)] increases in human sperm even in the absence of extracellular Ca(2+). Using LysoTracker, a fluorescent probe that selectively accumulates in acidic compartments, we identified two such stores in human sperm cells. Their acidic nature was further confirmed by the reduction in staining intensity observed upon inhibition of the endo-lysosomal proton pump with Bafilomycin, or after lysosomal bursting with glycyl-l-phenylalanine-2-naphthylamide. The selective fluorescent NAADP analog, Ned-19, stained the same subcellular regions as LysoTracker, suggesting that these stores are the targets of NAADP action.


The gonadotrophin-releasing hormone receptor of alpha T3-1 pituitary cells regulates cellular levels of both of the phosphoinositidase C-linked G proteins, Gq alpha and G11 alpha, equally.
The alpha T3-1 cell line, an immortalized gonadotroph cell line, expresses high levels of the gonadotrophin-releasing hormone (GnRH) receptor. Sustained exposure of these cells to the GnRH receptor agonist des-Gly10-[D-Ala6]luteinizing hormone-releasing hormone ethylamide resulted in a substantial down-regulation of cellular levels of a combination of the alpha subunits of the phospholipase C-beta 1-linked G proteins Gq and G11, as assessed by immunoblotting with an antiserum able to identify these two proteins equally. This effect was dependent upon the concentration of agonist used (EC50 = 4 nM) and on the time of the treatment (t1/2 = 6 hr) when a maximally effective concentration of agonist (1 microM) was used. Comparison of agonist regulation of inositol phosphate generation and Gq alpha/G11 alpha down-regulation demonstrated that effects on inositol phosphate production were approximately 3-fold more potent. In contrast to Gq alpha/G11 alpha, membrane-associated levels of Gs alpha and G12 alpha, the G proteins that transduce stimulatory and inhibitory regulation, respectively, of adenylyl cyclase, were not altered by agonist treatment. Analysis of mRNA by reverse transcriptase/polymerase chain reaction indicated the coexpression by alpha T3-1 cells of mRNA corresponding to both Gq alpha and G11 alpha. Immunoblotting with antisera selective for either Gq alpha or G11 alpha confirmed their coexpression. Resolution of membranes from untreated and agonist-treated alpha T3-1 cells under sodium dodecyl sulfate-polyacrylamide gel electrophoresis conditions able to separate Gq alpha from G11 alpha indicated that G11 alpha was more prevalent than Gq alpha at steady state but that agonist treatment regulated cellular levels of both of these G proteins in a nonselective manner. Sustained activation of protein kinase C with phorbol myristate acetate was unable to mimic agonist regulation of cellular Gq alpha/G11 alpha levels, as was treatment of alpha T3-1 cells with the selective protein kinase C inhibitor chelerythrine. These data suggest that the GnRH receptor is able to interact functionally with both Gq alpha and G11 alpha in alpha T3-1 cells and that sustained exposure to a GnRH receptor agonist selectively regulates the cellular levels of the G proteins that interact with the receptor.


A practice change model for quality improvement in primary care practice.
Faced with a rapidly changing healthcare environment, primary care practices often have to change how they practice medicine. Yet change is difficult, and the process by which practice improvement can be understood and facilitated has not been well elucidated. Therefore, we developed a model of practice change using data from a quality improvement intervention that was successful in creating a sustainable practice improvement. A multidisciplinary team evaluated data from the Study To Enhance Prevention by Understanding Practice (STEP-UP), a randomized clinical trial conducted to improve the delivery of evidence-based preventive services in 79 northeastern Ohio practices. The team conducted comparative case-study analyses of high- and low-improvement practices to identify variables that are critical to the change process and to create a conceptual model for the change. The model depicts the critical elements for understanding and guiding practice change and emphasizes the importance of these elements' evolving interrelationships. These elements are (1) motivation of key stakeholders to achieve the target for change; (2) instrumental, personal, and interactive resources for change; (3) motivators outside the practice, including the larger healthcare environment and community; and (4) opportunities for change--that is, how key stakeholders understand the change options. Change is influenced by the complex interaction of factors inside and outside the practice. Interventions that are based on understanding the four key elements and their interrelationships can yield sustainable quality improvements in primary care practice.


A common set of engulfment genes mediates removal of both apoptotic and necrotic cell corpses in C. elegans.
Similar to mammalian excitotoxic cell death, necrotic-like cell death (NCD) in Caenorhabditis elegans can be initiated by hyperactive ion channels. Here we investigate the requirements for genes that execute and regulate programmed cell death (PCD) in necrotic-like neuronal death caused by a toxic MEC-4 channel. Neither the kinetics of necrosis onset nor the total number of necrotic corpses generated is altered by any C. elegans mutation known to block PCD, which provides genetic evidence that the activating mechanisms for NCD and apoptotic cell death are distinct. In contrast, all previously reported ced genes required for phagocytotic removal of apoptotic corpses, as well as ced-12, a new engulfment gene we have identified, are required for efficient elimination of corpses generated by distinct necrosis-inducing stimuli. Our results show that a common set of genes acts to eliminate cell corpses irrespective of the mode of cell death, and provide the first identification of the C. elegans genes that are required for orderly removal of necrotic cells. As phagocytotic mechanisms seem to be conserved from nematodes to humans, our findings indicate that injured necrotic cells in higher organisms might also be eliminated before lysis through a controlled process of corpse removal, a hypothesis that has significant therapeutic implications.


Evidence for subclinical avian influenza virus infections among rural Thai villagers.
Regions of Thailand reported sporadic outbreaks of A/H5N1 highly pathogenic avian influenza (HPAI) among poultry between 2004 and 2008. Kamphaeng Phet Province, in north-central Thailand had over 50 HPAI poultry outbreaks in 2004 alone, and 1 confirmed and 2 likely other human HPAI infections between 2004 and 2006. In 2008, we enrolled a cohort of 800 rural Thai adults living in 8 sites within Kamphaeng Phet Province in a prospective study of zoonotic influenza transmission. We studied participants' sera with serologic assays against 16 avian, 2 swine, and 8 human influenza viruses. Among participants (mean age 49.6 years and 58% female) 65% reported lifetime poultry exposure of at least 30 consecutive minutes. Enrollees had elevated antibodies by microneutralization assay against 3 avian viruses: A/Hong Kong/1073/1999(H9N2), A/Thailand/676/2005(H5N1), and A/Thailand/384/2006(H5N1). Bivariate risk factor modeling demonstrated that male gender, lack of an indoor water source, and tobacco use were associated with elevated titers against avian H9N2 virus. Multivariate modeling suggested that increasing age, lack of an indoor water source, and chronic breathing problems were associated with infection with 1 or both HPAI H5N1 strains. Poultry exposure was not associated with positive serologic findings. These data suggest that people in rural central Thailand may have experienced subclinical avian influenza infections as a result of yet unidentified environmental exposures. Lack of an indoor water source may play a role in transmission.


Think globally, translate locally: what mitotic spindles and neuronal synapses have in common.
Early metazoan development is programmed by maternal mRNAs inherited by the egg at the time of fertilization. These mRNAs are not translated en masse at any one time or at any one place, but instead their expression is regulated both temporally and spatially. Recent evidence has shown that one maternal mRNA, cyclin B1, is concentrated on mitotic spindles in the early Xenopus embryo, where its translation is controlled by CPEB (cytoplasmic polyadenylation element binding protein), a sequence-specific RNA binding protein. Disruption of the spindle-associated translation of this mRNA results in a morphologically abnormal mitotic apparatus and inhibited cell division. Mammalian neurons, particularly in the synapto-dendritic compartment, also contain localized mRNAs such as that encoding alpha-CaMKII. Here, synaptic activation drives local translation, an event that is involved in synaptic plasticity and possibly long-term memory storage. Synaptic translation of alpha-CaMKII mRNA also appears to be controlled by CPEB, which is enriched in the postsynaptic density. Therefore, CPEB-controlled local translation may influence such seemingly disparate processes as the cell cycle and synaptic plasticity.


Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID-19.
The global pandemic of coronavirus disease 2019 (COVID-19) is associated with the development of acute respiratory distress syndrome (ARDS), which requires ventilation in critically ill patients. The pathophysiology of ARDS results from acute inflammation within the alveolar space and prevention of normal gas exchange. The increase in proinflammatory cytokines within the lung leads to recruitment of leukocytes, further propagating the local inflammatory response. A consistent finding in ARDS is the deposition of fibrin in the air spaces and lung parenchyma. COVID-19 patients show elevated D-dimers and fibrinogen. Fibrin deposits are found in the lungs of patients due to the dysregulation of the coagulation and fibrinolytic systems. Tissue factor (TF) is exposed on damaged alveolar endothelial cells and on the surface of leukocytes promoting fibrin deposition, while significantly elevated levels of plasminogen activator inhibitor 1 (PAI-1) from lung epithelium and endothelial cells create a hypofibrinolytic state. Prophylaxis treatment of COVID-19 patients with low molecular weight heparin (LMWH) is important to limit coagulopathy. However, to degrade pre-existing fibrin in the lung it is essential to promote local fibrinolysis. In this review, we discuss the repurposing of fibrinolytic drugs, namely tissue-type plasminogen activator (tPA), to treat COVID-19 associated ARDS. tPA is an approved intravenous thrombolytic treatment, and the nebulizer form has been shown to be effective in plastic bronchitis and is currently in Phase II clinical trial. Nebulizer plasminogen activators may provide a targeted approach in COVID-19 patients to degrade fibrin and improving oxygenation in critically ill patients.


The inequality footprints of nations: a novel approach to quantitative accounting of income inequality.
In this study we use economic input-output analysis to calculate the inequality footprint of nations. An inequality footprint shows the link that each country's domestic economic activity has to income distribution elsewhere in the world. To this end we use employment and household income accounts for 187 countries and an historical time series dating back to 1990. Our results show that in 2010, most developed countries had an inequality footprint that was higher than their within-country inequality, meaning that in order to support domestic lifestyles, these countries source imports from more unequal economies. Amongst exceptions are the United States and United Kingdom, which placed them on a par with many developing countries. Russia has a high within-country inequality nevertheless it has the lowest inequality footprint in the world, which is because of its trade connections with the Commonwealth of Independent States and Europe. Our findings show that the commodities that are inequality-intensive, such as electronic components, chemicals, fertilizers, minerals, and agricultural products often originate in developing countries characterized by high levels of inequality. Consumption of these commodities may implicate within-country inequality in both developing and developed countries.


[Investigation of gastric cancer chemotherapy in hiroshima prefecture].
The Hiroshima Oncology Group of Gastric Cancer(HOG-GC)distributed a multiple-answer questionnaire to investigate the realities of chemotherapy for gastric cancer. Seventy-six hospitals in Hiroshima were surveyed. The Japanese classification was used for the staging criteria. Forty-one hospitals, including 10 centers for cancer treatment, completed and returned the questionnaires. For stage II & III cases requiring adjuvant chemotherapy, S-1 was the most commonly used(84%)regimen. A standard starting dose was used in 79% of these cases, and S-1 was administered for one year continuously in 84% of the cases. For stage I B & II (T1), S-1 and UFT were used in 45%and 20%of the cases, respectively. In cases with non-resectable gastric cancer, S-1 plus CDDP and S-1 alone were used as a first-line therapy in 62% and 26% of the patients under 75 years age, respectively, and in 33% and 46% of the patients older than 75 years of age, respectively. In patients with ascites and peritoneal dissemination, S-1 plus CDDP, S-1, S-1 plus DTX, S-1 plus PTX, and PTX were used in 26%, 15%, 21%, 17%, and 17% of cases, respectively. Some of the patients with peritoneal dissemination underwent gastrectomy. S-1 was widely used for gastric cancer chemotherapy in Hiroshima Prefecture. Taxane-containing regimens or palliative gastrectomy were commonly used in cases with peritoneal dissemination.


Role of steroidal anti-inflammatory agent prior to intracorporeal lithotripsy under local anesthesia for ureterovesical junction calculus: A prospective randomized controlled study.
The objective of the following study is to assess the effect of steroidal anti-inflammatory agent on the outcome of ureterorenoscopic lithotripsy (URSL) for ureterovesical junction (UVJ) calculus. This was a prospective randomized controlled study conducted at the Department of Urology, Regional Institute of Medical Sciences, Imphal. One hundred and twenty-six patients requiring ureteroscopic lithotripsy for UVJ calculus were randomly assigned into two groups. The study group received tablet deflazacort 30 mg once a day for 10 days prior to the procedure, whereas the control group did not receive such treatment. Parameters with respect to the outcome of the procedure were recorded for all patients in both groups. Fisher's exact and independent t-test was used to compare the outcome between the groups where P < 0.05 was considered to be statistically significant. There was significant statistical difference (P - 0.016) on the endoscopic appearance of the region of ureteric orifice in patients receiving steroidal anti-inflammatory agent compared with control. Severe procedure related pain and mean operative time was less in the study group compared to control (P - 0.020 and 0.031, respectively). Re-treatment rates in the study group were lower than the control group (4.76% vs. 17.46%) and found to be statistically significant (P - 0.044). It is found that computed tomography (CT) appearance (r - 0.399) and stone size (r - 0.410) strongly correlate with the endoscopic findings of the region of UVJ (P - 0.001). Inflamed and or obliterated ureteric orifice is the major constraints for stone clearance at ureterovesical junction. The present study showed the administration of tablet deflazacort (a steroidal anti-inflammatory agent) significantly improves the outcome of URSL under local anesthesia. We strongly recommend its use prior to URSL for UVJ calculus, especially for stone size ≥10.24 mm and on CT evidence of prominent soft tissue swelling at the UVJ.


Origin of nucleosynthetic isotope heterogeneity in the solar protoplanetary disk.
Stable-isotope variations exist among inner solar system solids, planets, and asteroids, but their importance is not understood. We report correlated, mass-independent variations of titanium-46 and titanium-50 in bulk analyses of these materials. Because titanium-46 and titanium-50 have different nucleosynthetic origins, this correlation suggests that the presolar dust inherited from the protosolar molecular cloud was well mixed when the oldest solar system solids formed, but requires a subsequent process imparting isotopic variability at the planetary scale. We infer that thermal processing of molecular cloud material, probably associated with volatile-element depletions in the inner solar system, resulted in selective destruction of thermally unstable, isotopically anomalous presolar components, producing residual isotopic heterogeneity. This implies that terrestrial planets accreted from thermally processed solids with nonsolar isotopic compositions.


MBGD update 2013: the microbial genome database for exploring the diversity of microbial world.
The microbial genome database for comparative analysis (MBGD, available at http://mbgd.genome.ad.jp/) is a platform for microbial genome comparison based on orthology analysis. As its unique feature, MBGD allows users to conduct orthology analysis among any specified set of organisms; this flexibility allows MBGD to adapt to a variety of microbial genomic study. Reflecting the huge diversity of microbial world, the number of microbial genome projects now becomes several thousands. To efficiently explore the diversity of the entire microbial genomic data, MBGD now provides summary pages for pre-calculated ortholog tables among various taxonomic groups. For some closely related taxa, MBGD also provides the conserved synteny information (core genome alignment) pre-calculated using the CoreAligner program. In addition, efficient incremental updating procedure can create extended ortholog table by adding additional genomes to the default ortholog table generated from the representative set of genomes. Combining with the functionalities of the dynamic orthology calculation of any specified set of organisms, MBGD is an efficient and flexible tool for exploring the microbial genome diversity.


The management and prognosis of patients with hepatocellular carcinoma: what has changed in 20 years?
There has been remarkable progress in the management of hepatocellular carcinoma (HCC) during the last several decades, but its effect on the prognosis of HCC patient needs clarification. We analysed the changes that affected prognosis of HCC patients diagnosed over two different eras. A retrospective study of 1318 patients diagnosed with HCC from 1986 to 2012 was conducted. Analysis was done according to two cohorts, cohort 1 (patients diagnosed with HCC from 1986 to 1992) and cohort 2 (patients diagnosed from 2006 to 2012). Hepatitis B virus was the most common cause of liver disease for both cohorts (66.2% and 66.0%). The proportion of patients with Barcelona Clinic Liver Cancer stage 0/A was significantly lower in cohort 1 than in cohort 2 (14.4% vs. 39.5%, P < 0.001). The proportions of patients diagnosed during surveillance and general health check-up were significantly higher in cohort 2 than in cohort 1 (28.6% vs. 10.6% and 26.3% vs. 7.9%, respectively) while those diagnosed during symptomatic evaluation was significantly higher in cohort 1 than in cohort 2 (45.1 vs. 81.4%, P < 0.001). Surgical resection rate was similar between the two cohorts (26.1% vs 26%) while the transcatheter arterial chemoembolization rate which was the highest in cohort 1 (40.6%) was overtaken by radiofrequency ablation in cohort 2 (55%) at BCLC stage 0/A. Median survival duration in cohort 2 was significantly longer than cohort 1 (65.0 vs. 7.9 months, P < 0.001). Implementation of national cancer surveillance and the advancement of treatment modalities have likely led to early detection of HCC and improvements in prognosis over the last 20 years.


Microfluidic chambers using fluid walls for cell biology.
Many proofs of concept have demonstrated the potential of microfluidics in cell biology. However, the technology remains inaccessible to many biologists, as it often requires complex manufacturing facilities (such as soft lithography) and uses materials foreign to cell biology (such as polydimethylsiloxane). Here, we present a method for creating microfluidic environments by simply reshaping fluids on a substrate. For applications in cell biology, we use cell media on a virgin Petri dish overlaid with an immiscible fluorocarbon. A hydrophobic/fluorophilic stylus then reshapes the media into any pattern by creating liquid walls of fluorocarbon. Microfluidic arrangements suitable for cell culture are made in minutes using materials familiar to biologists. The versatility of the method is demonstrated by creating analogs of a common platform in cell biology, the microtiter plate. Using this vehicle, we demonstrate many manipulations required for cell culture and downstream analysis, including feeding, replating, cloning, cryopreservation, lysis plus RT-PCR, transfection plus genome editing, and fixation plus immunolabeling (when fluid walls are reconfigured during use). We also show that mammalian cells grow and respond to stimuli normally, and worm eggs develop into adults. This simple approach provides biologists with an entrée into microfluidics.


Measuring the Changes in Aggregate Cycling Patterns between 2003 and 2012 from a Space Syntax Perspective.
There has been a world-wide surge of interest in cycling over the last 10 years of which London has seen a continuous growth in cyclists and investment in infrastructure that has resulted in the introduction of the Barclays Cycle Superhighway and Barclays Cycling Hiring Scheme. Despite the investment in cycling infrastructure, there has been little understanding of cycling activity patterns in general and the effect of spatial configuration on cycling route choices. This research aims at measuring the impact of cycling infrastructure and spatial configuration on aggregate cyclist movement over two time periods. To do so, this paper presents a spatial-based cyclist movement statistical model that regress cyclist movement flows with measure of spatial configuration, safety and infrastructure and urban character attributes. Using Elephant and Castle, a Central London location, as a case study, the authors analyze cycling movement data sets from 2003 and 2012 to compare the change in cycling behaviour and the impact that the Cycling Superhighway 07, introduced in 2011, has had on cycling patterns. Findings confirm the growth of cycling in London with a 1000% increase in cyclists along some routes in comparison to a 10% increase in population at the same time. More importantly, results also suggest that higher cyclist movement were observed along routes with greater convenience and continuity-over and above route segregation from vehicular traffic. The relationship between spatial configuration and aggregate cyclists movement is consistent between 2003 and 2012 where spatial configuration have remained the same while changes were observed in both modal split and cycling infrastructure. This result is in line with previous research wherein aggregate higher cyclists movement are observed on major routes offering direct connections than less direct routes. From a spatial cognition perspective, this research enriches our understanding on how the external built environment as measured by the spatial configuration measure relates to aggregated cyclists movement overtime and in identifying key potential factors in influencing cyclist wayfinding. Further research is needed into validating the results and examining this relationship at an individual basis on route choice. These results help us better understand the trade off between cycling safety and cycling legibility which could help inform cycling route design in the future.


Polymorphism E23K (rs5219) in the KCNJ11 gene in Euro-Brazilian subjects with type 1 and 2 diabetes.
Insulin secretion is regulated by ATP-sensitive potassium channels (KATP). The potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11) gene, located on chromosome 11p15.1, encodes the subunit Kir6.2 that forms the pore region of KATP channels in pancreatic β-cells. Among the single nucleotide polymorphisms (SNPs) associated with KCNJ11, the E23K polymorphism (rs5219) promotes a substitution (G > A) of a glutamic acid residue for lysine at position 23. The E23K SNP has been associated with diabetes in several populations, although with controversial results. The aim of this study was to evaluate the association of the E23K SNP with type 1 and 2 diabetes in a case-control study approved by the Ethics Committee. We genotyped 458 Euro-Brazilian individuals, classified as healthy (control group, CTRL, N = 217), patients with type 1 diabetes mellitus (T1D, N = 102), and patients with type 2 diabetes mellitus (T2D, N = 139). Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using BanII restriction digestion. The restriction fragments were separated by polyacrylamide gel electrophoresis and visualized by ethidium bromide staining. The genotype (EE/EK/KK) frequencies (%) for the CTRL group (38.2/50.2/11.6), T1D (34.3/52.0/13.7), and T2D (38.2/48.9/12.9) were in Hardy-Weinberg equilibrium and there were no significant differences (CRTL vs T1D, P = 0.771; CRTL vs T2D, P = 0.937; T1D vs T2D, P = 0.831). The minor allele frequencies (MAF; K) for CTRL (37.0%), T1D (39.7%), and T2D (37.4%) were not different among the groups (P > 0.05). The MAF value for healthy subjects was similar to other Caucasian populations (34.5-37.5%). In summary, the E23K polymorphism (rs5219) was not associated with type 1 or 2 diabetes mellitus in the studied population.


A biomechanical model of the lumbar spine during upright isometric flexion, extension, and lateral bending.
Task-specific and subject-specific lumbar trunk muscle function, muscle geometry, and vertebral density data were collected from 16 men. A biomechanical model was used to determine muscle strength and the compressive forces acting on the lumbar spine. To develop an anatomic biomechanical model of the low back that could be used to derive task-specific muscle function parameters and to predict compressive forces acting on the low back. Several model-specific constraints were examined, including the notion of bilateral trunk muscle anatomic symmetry, the influence of muscle lines of action, and the use of density-derived vertebral strength for model validation. Clinical and basic science investigators are currently using a battery of diverse biomechanical techniques to evaluate trunk muscle strength. Noteworthy is the large variability in muscle function parameters reported for different subjects and for different tasks. This information is used to calculate forces and moments acting on the low back, but limited data exist concerning the assessment of subject-specific, multiaxis, isometric trunk muscle functions. A trunk dynamometer was used to measure maximum upright, isometric trunk moments in the sagittal (extension, flexion) and coronal (lateral flexion) planes. Task- and subject-specific trunk muscle strength or "gain" was determined from the measured trunk moments and magnetic resonance image-based muscle cross-sectional geometry. Model-predicted compressive forces obtained using muscle force and body force equilibrium equations were compared with density-derived estimates of compressive strength. Individual task-specific muscle gain values differed significantly between subjects and between each of the tasks they performed (extension > flexion > lateral flexion). Significant differences were found between left side and right side muscle areas, and the lines of action of the muscles deviated significantly from the vertical plane. Model-predicted lumbar compressive forces were 38% (lateral flexion) to 73% (extension) lower that the L3 vertebral compressive strength estimated from vertebral density. The present study suggests that biomechanical models of the low back should be based on task-specific and subject-specific muscle function and precise geometry. Vertebral strength estimates based upon vertebral density appear to be useful for validation of model force predictions.


Comparison of the Bacterial Gut Microbiome of North American Triatoma spp. With and Without Trypanosoma cruzi.
Chagas disease, caused by the hemoflagellate protist Trypanosoma cruzi, affects nearly 6 million people worldwide, mainly in Latin America. Hematophagous triatomine insects ("kissing bugs") are the primary vectors of T. cruzi throughout the Americas and feed on a variety of animals, including humans. Control of triatomines is central to the control of T. cruzi infection. Recent advances in mitigation of other insect-borne diseases via the manipulation of insect-associated bacteria as a way to halt or slow disease transmission has opened questions to the applicability of these methods to Chagas disease vectors. Few studies have examined the hindgut microbiome of triatomines found in North America. In the current study, two species of triatomines were collected across Texas, United States, screened for the presence of T. cruzi, and analyzed for the bacterial composition of their hindguts using a 16S rRNA gene-fragment metabarcoding approach. We compared diversity of microbial community profiles across 74 triatomine insects to address the hypothesis that the richness and abundance of bacterial groups differ by T. cruzi infection and strain type, blood meal engorgement status, insect species, sex, and collection location. The gut microbial community of individual triatomines was characterized by low intraindividual taxonomic diversity and high interindividual variation that was weakly predicted by triatomine species, and was not predicted by triatomine sex, collection location, T. cruzi infection status, or blood meal score. However, we did find bacterial groups enriched in T. cruzi-positive individuals, including Enterobacterales, and Petrimonas. Additionally, we detected Salmonella enterica subspecies diarizonae in three triatomine individuals; this species is commonly associated with reptiles and domesticated animals and is a pathogen of humans. These data suggest that Triatoma spp. in Texas have variable patterns of colonized and transient bacteria, and may aid in development of novel means to interfere with transmission of the Chagas disease parasite T. cruzi. Deeper understanding of the effects of parasite infection on diverse insect vector microbiomes may highlight disease transmission risk and facilitate discovery of possible intervention strategies for biological control of this emerging vector-borne disease of global health significance.


Whole genome comparison of a large collection of mycobacteriophages reveals a continuum of phage genetic diversity.
The bacteriophage population is large, dynamic, ancient, and genetically diverse. Limited genomic information shows that phage genomes are mosaic, and the genetic architecture of phage populations remains ill-defined. To understand the population structure of phages infecting a single host strain, we isolated, sequenced, and compared 627 phages of Mycobacterium smegmatis. Their genetic diversity is considerable, and there are 28 distinct genomic types (clusters) with related nucleotide sequences. However, amino acid sequence comparisons show pervasive genomic mosaicism, and quantification of inter-cluster and intra-cluster relatedness reveals a continuum of genetic diversity, albeit with uneven representation of different phages. Furthermore, rarefaction analysis shows that the mycobacteriophage population is not closed, and there is a constant influx of genes from other sources. Phage isolation and analysis was performed by a large consortium of academic institutions, illustrating the substantial benefits of a disseminated, structured program involving large numbers of freshman undergraduates in scientific discovery.


Estimation of the spontaneous mutation rate per nucleotide site in a Drosophila melanogaster full-sib family.
We employed deep genome sequencing of two parents and 12 of their offspring to estimate the mutation rate per site per generation in a full-sib family of Drosophila melanogaster recently sampled from a natural population. Sites that were homozygous for the same allele in the parents and heterozygous in one or more offspring were categorized as candidate mutations and subjected to detailed analysis. In 1.23 × 10(9) callable sites from 12 individuals, we confirmed six single nucleotide mutations. We estimated the false negative rate in the experiment by generating synthetic mutations using the empirical distributions of numbers of nonreference bases at heterozygous sites in the offspring. The proportion of synthetic mutations at callable sites that we failed to detect was <1%, implying that the false negative rate was extremely low. Our estimate of the point mutation rate is 2.8 × 10(-9) (95% confidence interval = 1.0 × 10(-9) - 6.1 × 10(-9)) per site per generation, which is at the low end of the range of previous estimates, and suggests an effective population size for the species of ∼1.4 × 10(6). At one site, point mutations were present in two individuals, indicating that there had been a premeiotic mutation cluster, although surprisingly one individual had a G→A transition and the other a G→T transversion, possibly associated with error-prone mismatch repair. We also detected three short deletion mutations and no insertions, giving a deletion mutation rate of 1.2 × 10(-9) (95% confidence interval = 0.7 × 10(-9) - 11 × 10(-9)).


Global health, global surgery and mass casualties: II. Mass casualty centre resources, equipment and implementation.
Trauma/stroke centres optimise acute 24/7/365 surgical/critical care in high-income countries (HICs). Concepts from low-income and middle-income countries (LMICs) offer additional cost-effective healthcare strategies for limited-resource settings when combined with the trauma/stroke centre concept. Mass casualty centres (MCCs) integrate resources for both routine and emergency care-from prevention to acute care to rehabilitation. Integration of the various healthcare systems-governmental, non-governmental and military-is key to avoid both duplication and gaps. With input from LMIC and HIC personnel of various backgrounds-trauma and subspecialty surgery, nursing, information technology and telemedicine, and healthcare administration-creative solutions to the challenges of expanding care (both daily and disaster) are developed. MCCs are evolving initially in Chile and Pakistan. Technologies for cost-effective healthcare in LMICs include smartphone apps (enhance prehospital care) to electronic data collection and analysis (quality improvement) to telemedicine and drones/robots (support of remote regions and resource optimisation during both daily care and disasters) to resilient, mobile medical/surgical facilities (eg, battery-operated CT scanners). The co-ordination of personnel (within LMICs, and between LMICs and HICs) and the integration of cost-effective advanced technology are features of MCCs. Providing quality, cost-effective care 24/7/365 to the 5 billion who lack it presently makes MCCs an appealing means to achieve the healthcare-related United Nations Sustainable Development Goals for 2030.


Histone modifications underlie monocyte dysregulation in patients with systemic sclerosis, underlining the treatment potential of epigenetic targeting.
Systemic sclerosis (SSc) is a severe autoimmune disease, in which the pathogenesis is dependent on both genetic and epigenetic factors. Altered gene expression in SSc monocytes, particularly of interferon (IFN)-responsive genes, suggests their involvement in SSc development. We investigated the correlation between epigenetic histone marks and gene expression in SSc monocytes. Chromatin immunoprecipitation followed by sequencing (ChIPseq) for histone marks H3K4me3 and H3K27ac was performed on monocytes of nine healthy controls and 14 patients with SSc. RNA sequencing was performed in parallel to identify aberrantly expressed genes and their correlation with the levels of H3K4me3 and H3K27ac located nearby their transcription start sites. ChIP-qPCR assays were used to verify the role of bromodomain proteins, H3K27ac and STATs on IFN-responsive gene expression. 1046 and 534 genomic loci showed aberrant H3K4me3 and H3K27ac marks, respectively, in SSc monocytes. The expression of 381 genes was directly and significantly proportional to the levels of such chromatin marks present near their transcription start site. Genes correlated to altered histone marks were enriched for immune, IFN and antiviral pathways and presented with recurrent binding sites for IRF and STAT transcription factors at their promoters. IFNα induced the binding of STAT1 and STAT2 at the promoter of two of these genes, while blocking acetylation readers using the bromodomain BET family inhibitor JQ1 suppressed their expression. SSc monocytes have altered chromatin marks correlating with their IFN signature. Enzymes modulating these reversible marks may provide interesting therapeutic targets to restore monocyte homeostasis to treat or even prevent SSc.


HDAC inhibitor confers radiosensitivity to prostate stem-like cells.
Radiotherapy can be an effective treatment for prostate cancer, but radiorecurrent tumours do develop. Considering prostate cancer heterogeneity, we hypothesised that primitive stem-like cells may constitute the radiation-resistant fraction. Primary cultures were derived from patients undergoing resection for prostate cancer or benign prostatic hyperplasia. After short-term culture, three populations of cells were sorted, reflecting the prostate epithelial hierarchy, namely stem-like cells (SCs, α2β1integrin(hi)/CD133(+)), transit-amplifying (TA, α2β1integrin(hi)/CD133(-)) and committed basal (CB, α2β1integrin(lo)) cells. Radiosensitivity was measured by colony-forming efficiency (CFE) and DNA damage by comet assay and DNA damage foci quantification. Immunofluorescence and flow cytometry were used to measure heterochromatin. The HDAC (histone deacetylase) inhibitor Trichostatin A was used as a radiosensitiser. Stem-like cells had increased CFE post irradiation compared with the more differentiated cells (TA and CB). The SC population sustained fewer lethal double-strand breaks than either TA or CB cells, which correlated with SCs being less proliferative and having increased levels of heterochromatin. Finally, treatment with an HDAC inhibitor sensitised the SCs to radiation. Prostate SCs are more radioresistant than more differentiated cell populations. We suggest that the primitive cells survive radiation therapy and that pre-treatment with HDAC inhibitors may sensitise this resistant fraction.


The successful concurrent use of two long-acting depot antipsychotics in a patient with treatment-resistant schizophrenia and history of serious violence: a case report.
This case report describes a forensic psychiatric patient presenting with treatment-resistant schizophrenia and serious interpersonal violence complicated by poor adherence to oral medication who was treated successfully with two concurrent long-acting depot antipsychotics. Treatment response was measured for a 6-month period at 6-weekly intervals, post-initiation using the Positive and Negative Symptoms of Schizophrenia with Excited Component score (PANSS-EC), Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression Scale (CGI). At 6 months, the presentation was found to have markedly improved. The overall PANSS-EC score was reduced by 43.9%, with reductions in Positive Symptom and Excited Component subscales most evident. BPRS Score was reduced from 81 at baseline to 47 at 18 weeks. There was improvement in the patient's level of cooperativeness, aggression and engagement in ward therapeutic activities. Although concurrent use of two depot antipsychotics requires further exploration, there is potential benefit for patient groups presenting with treatment-resistant schizophrenia and poor compliance. Due to risk of serious adverse effects which are difficult to reverse with long-acting formulations, we recommend this option be reserved for this complex patient population and exclusively in care settings allowing close physical health monitoring.


Low-dose chemotherapy of desmoid tumors.
Eight patients with desmoid tumors, symptomatic, and none a candidate for conservative surgery, were treated with weekly vinblastine, maximum dose 10 mg/week, and methotrexate, maximum dose 50 mg/week. Symptomatic relief was obtained in all patients. Using Eastern Cooperative Oncology Group (ECOG) criteria, two patients had a complete remission, one of which has lasted for 30 months, four patients have had partial remissions, one patient has had a mixed response, and one patient who has been treated for only 4 weeks, a minimal response. Toxicity has been minor and transient. Chemotherapy appears to be an acceptable alternative to radical surgery in selected patients with desmoid tumors.


Microfluidic high-throughput RT-qPCR measurements of the immune response of primary bovine mammary epithelial cells cultured from milk to mastitis pathogens.
Bovine mastitis, the inflammation of the udder, is a major problem for the dairy industry and for the welfare of the animals. To better understand this disease, and to implement two special techniques for studying mammary gland immunity in vitro, we measured the innate immune response of primary bovine mammary epithelial cells (pbMEC) from six Brown Swiss cows after stimulation with the heat-inactivated mastitis pathogens, Escherichia coli 1303 and Staphylococcus aureus 1027. The cells were extracted and cultivated from milk instead of udder tissue, which is usually done. The advantages of this technique are non-invasiveness and less contamination by fibroblasts. For the first time, pbMEC gene expression (GE) was measured with a microfluidic high-throughput real-time reverse transcription-quantitative PCR platform, the BioMark HD™ system from Fluidigm. In addition to the physiological analysis, the precision and suitability of this method was evaluated in a large data set. The mean coefficient of variance (± s.e.) between repeated chips was 4.3 ± 0.4% for highly expressed and 3.3 ± 0.4% for lowly expressed genes. Quantitative PCR (qPCR) replicate deviations were smaller than the cell culture replicate deviations, indicating that biological and cell culture differences could be distinguished from the background noise. Twenty-two genes (complement system, chemokines, inflammatory cytokines, antimicrobial peptides, acute phase response and toll-like receptor signalling) were differentially expressed (P < 0.05) with E. coli. The most upregulated gene was the acute phase protein serum amyloid A3 with 618-time fold. S. aureus slightly induced CCL5, IL10, TLR4 and S100A12 expression and failed to elicit a distinct overall innate immune response. We showed that, with this milk-derived pbMEC culture and the high-throughput qPCR technique, it is possible to obtain similar results in pbMEC expression as with conventional PCR and with satisfactory precision so that it can be applied in future GE studies in pbMEC.


Cardiovascular Applications of Hyperpolarized MRI.
Many applications of MRI are limited by an inherently low sensitivity. Previous attempts to overcome this insensitivity have focused on the use of MRI systems with stronger magnetic fields. However, the gains that can be achieved in this way are relatively small and increasing the magnetic field invariably leads to greater technical challenges. More recently, the development of a range of techniques, which can be gathered under the umbrella term of "hyperpolarization," has offered potential solutions to the low sensitivity. Hyperpolarization techniques have been demonstrated to temporarily increase the signal available in an MRI experiment by as much as 100,000-fold. This article outlines the main hyperpolarization techniques that have been proposed and explains how they can increase MRI signals. With particular emphasis on the emerging technique of dynamic nuclear polarization, the existing preclinical cardiovascular applications are reviewed and the potential for clinical translation is discussed.


Factors associated with the transition to oral feeding in infants fed by nasogastric tubes.
Following a review of 100 infants fed by nasogastric tubes, medical factors associated with the length of transition to complete oral feeding were identified through correlational and multiple regression analyses. Six of the 100 infants had an extremely lengthy transition or never progressed to oral feeding; the remaining 94 infants progressed to oral feeding within 2 to 58 days. The total number of medical complications correlated significantly and positively with the length of transition. Digestive, respiratory, and cardiac complications were all significant predictors of the length of transition to oral feeding. The results of this study may assist occupational therapists in earlier identification of and intervention for infants fed by nasogastric tubes who are at risk for later oral feeding problems and a longer transition from nasogastric tube to oral feeding.


Grid technology in tissue-based diagnosis: fundamentals and potential developments.
Tissue-based diagnosis still remains the most reliable and specific diagnostic medical procedure. It is involved in all technological developments in medicine and biology and incorporates tools of quite different applications. These range from molecular genetics to image acquisition and recognition algorithms (for image analysis), or from tissue culture to electronic communication services. Grid technology seems to possess all features to efficiently target specific constellations of an individual patient in order to obtain a detailed and accurate diagnosis in providing all relevant information and references. Grid technology can be briefly explained by so-called nodes that are linked together and share certain communication rules in using open standards. The number of nodes can vary as well as their functionality, depending on the needs of a specific user at a given point in time. In the beginning of grid technology, the nodes were used as supercomputers in combining and enhancing the computation power. At present, at least five different Grid functions can be distinguished, that comprise 1) computation services, 2) data services, 3) application services, 4) information services, and 5) knowledge services. The general structures and functions of a Grid are described, and their potential implementation into virtual tissue-based diagnosis is analyzed. As a result Grid technology offers a new dimension to access distributed information and knowledge and to improving the quality in tissue-based diagnosis and therefore improving the medical quality.


Energy transfer in lanthanide upconversion studies for extended optical applications.
Lanthanide pairs, which can upconvert low energy photons into higher energy photons, are promising for efficient upconversion emission. A typical system with Yb(3+) as a sensitizer can convert short NIR into visible/ultraviolet light via energy transfer between lanthanide ions. Such upconverting nanocrystals doped with lanthanide ions have found significant potential in bioimaging, photochemical reactions and energy conversion. This review presents a fundamental understanding of energy transfer in lanthanide-supported photon upconversion. We introduce the emerging progress in excitation selection based on the energy transfer within lanthanide ions or activation from antennae, with an outlook in the development and applications of the lanthanide upconversion emissions.


Use of autologous bone graft in anterior cervical decompression: morbidity & quality of life analysis.
Autologous iliac crest graft has long been the gold standard graft material used in cervical fusion. However its harvest has significant associated morbidity, including protracted postoperative pain scores at the harvest site. Thus its continued practice warrants scrutiny, particularly now that alternatives are available. Our aims were to assess incidence and nature of complications associated with iliac crest harvest when performed in the setting of Anterior Cervical Decompression (ACD). Also, to perform a comparative analysis of patient satisfaction and quality of life scores after ACD surgeries, when performed with and without iliac graft harvest. All patients who underwent consecutive ACD procedures, with and without the use of autologous iliac crest graft, over a 48 month period were included (n = 53). Patients were assessed clinically at a minimum of 12 months postoperatively and administered 2 validated quality of life questionnaires: the SF-36 and Cervical Spine Outcomes Questionnaires (Response rate 96%). Primary composite endpoints included incidence of bone graft donor site morbidity, pain scores, operative duration, and quality of life scores. Patients who underwent iliac graft harvest experienced significant peri-operative donor site specific morbidity, including a high incidence of pain at the iliac crest (90%), iliac wound infection (7%), a jejunal perforation, and longer operative duration (285 minutes vs. 238 minutes, p = 0.026). Longer term follow-up demonstrated protracted postoperative pain at the harvest site and significantly lower mental health scores on both quality of life instruments, for those patients who underwent autologous graft harvest ACD with iliac crest graft harvest is associated with significant iliac crest donor site morbidity and lower quality of life at greater than 12 months post operatively. This is now avoidable by using alternatives to autologous bone without compromising clinical or technical outcome.


White matter disease and sleep-disordered breathing after acute stroke.
To assess sleep-disordered breathing (SDB) in patients with acute stroke and its relationship to prestroke cerebrovascular disease, particularly leukoariosis. The authors studied SDB and CT evidence of prestroke cerebrovascular disease, nonacute brain infarction, and white matter disease (WMD) in 78 previously independent patients with acute stroke. Subjects underwent respiratory sleep studies to determine the Apnea-Hypopnea Index (AHI) and Desaturation Index (DI) 7 to 14 days following stroke. CT scans were evaluated for severity of acute prestroke cerebrovascular disease and WMD severity. Prestroke cerebrovascular disease was present in 49 (63%) patients and was associated with worse SDB (mean AHI 35 vs 23, p < 0.01; mean DI 28 vs 18, p < 0.05), particularly in men (mean AHI 43 vs 27, p < 0.01). WMD severity correlated with AHI (r = 0.26, p < 0.05) and age (r = 0.56, p < 0.01). WMD severity in frontal and basal ganglia areas showed the strongest association. On multivariate analysis, WMD severity correlated independently with AHI (R(2) = 0.07, p < 0.05). The presence of prestroke cerebrovascular disease and severity of WMD are associated with worse SDB. These findings suggest that either white matter is particularly vulnerable to the hypoxia and blood pressure variability associated with SDB or that WMD is a major factor exacerbating SDB following stroke.


The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy?
The use of bioidentical hormones, including progesterone, estradiol, and estriol, in hormone replacement therapy (HRT) has sparked intense debate. Of special concern is their relative safety compared with traditional synthetic and animal-derived versions, such as conjugated equine estrogens (CEE), medroxyprogesterone acetate (MPA), and other synthetic progestins. Proponents for bioidentical hormones claim that they are safer than comparable synthetic and nonhuman versions of HRT. Yet according to the US Food and Drug Administration and The Endocrine Society, there is little or no evidence to support claims that bioidentical hormones are safer or more effective. This paper aimed to evaluate the evidence comparing bioidentical hormones, including progesterone, estradiol, and estriol, with the commonly used nonbioidentical versions of HRT for clinical efficacy, physiologic actions on breast tissue, and risks for breast cancer and cardiovascular disease. Published papers were identified from PubMed/MEDLINE, Google Scholar, and Cochrane databases, which included keywords associated with bioidentical hormones, synthetic hormones, and HRT. Papers that compared the effects of bioidentical and synthetic hormones, including clinical outcomes and in vitro results, were selected. Patients report greater satisfaction with HRTs that contain progesterone compared with those that contain a synthetic progestin. Bioidentical hormones have some distinctly different, potentially opposite, physiological effects compared with their synthetic counterparts, which have different chemical structures. Both physiological and clinical data have indicated that progesterone is associated with a diminished risk for breast cancer, compared with the increased risk associated with synthetic progestins. Estriol has some unique physiological effects, which differentiate it from estradiol, estrone, and CEE. Estriol would be expected to carry less risk for breast cancer, although no randomized controlled trials have been documented. Synthetic progestins have a variety of negative cardiovascular effects, which may be avoided with progesterone. Physiological data and clinical outcomes demonstrate that bioidentical hormones are associated with lower risks, including the risk of breast cancer and cardiovascular disease, and are more efficacious than their synthetic and animal-derived counterparts. Until evidence is found to the contrary, bioidentical hormones remain the preferred method of HRT. Further randomized controlled trials are needed to delineate these differences more clearly.


Cockayne's syndrome: correlation of clinical features with cellular sensitivity of RNA synthesis to UV irradiation.
Cockayne's syndrome (CS) is a rare autosomal recessive disorder with dwarfism, mental retardation, and otherwise clinically heterogeneous features. In cultured CS fibroblasts, the failure of RNA synthesis to recover to normal rates after UV-C irradiation provides a useful and relatively simple diagnostic test. We have measured post-UV-C RNA synthesis in 52 patients for whom a clinical diagnosis of CS was considered a possibility. Twenty-nine patients showed the defect characteristic of CS cells, and 23 had a normal response. We have attempted to correlate the cellular diagnosis with the different clinical features of the disorder. Clinical details of the patients were obtained from referring clinicians in the form of a questionnaire. Our results show that, apart from the cardinal features of dwarfism and mental retardation, sun sensitivity correlated best with a positive cellular diagnosis. Pigmentary retinopathy, gait defects, and dental caries were also good positive indicators, although several patients with a positive cellular diagnosis did not have these features.


A review of the knowledge base on healthy worksite culture.
To identify the need for worksite cultures of health, the organizational factors that support worksite cultures of health, the tools that have been used to measure worksite cultures of health, and the research needs related to healthy worksite culture. A cross-sectional survey involving a sample of 500 companies representing a broad spectrum of industries and business sectors. A literature review was conducted. Similar to a culture of safety that encourages safer behaviors and enables a safer workplace, a culture of health provides a supportive work leadership with a favorable work environment and health-related policies that promote employee health and result in substantial decrease in employee health risks and medical costs. Worksite policies and environments supporting a culture of health are important to helping employees adopt and maintain healthy behaviors.


Assessing the Feasibility and Effectiveness of an App in Improving Knowledge on Oral Cancer-an Interventional Study.
Although current oral health care initiatives have proved to be quite successful, a great number of individuals are unaware of how their choice of daily activities compromises their oral health. That is why newer technologies like WhatsApp can definitely serve as a platform to communicate dental advice, thereby strengthening the bridge between health and technology. The objective of the study was to assess the effectiveness of WhatsApp as a tool for providing health education on tobacco and oral cancer as compared to the conventional health education via PowerPoint. The study was a cluster randomized controlled trial, single-center study. The students of 18-24 years of age with WhatsApp application active in their mobile phones were included. Four classes with 182 students were randomly divided into intervention and control groups. Control group received health education on oral cancer using a PowerPoint presentation weekly, for a total of 4 weeks. Intervention group received health education through WhatsApp messaging thrice a week for 4 weeks. Pre- and post-health education knowledge scores were assessed using a questionnaire and compared using unpaired and paired two-sample t tests. Statistically significant increase in knowledge scores was seen in both groups, with highly significant improvement in the intervention group (p value = 0.00). Intergroup comparison showed no significant difference in knowledge scores at baseline, but a significant difference in post intervention knowledge scores (t = -15.05 p<0.001) WhatsApp can be a more effective tool for providing dental education on tobacco and oral cancer as compared to conventional audio-visual aids.


[Diagnostic accuracy of 201T1 SPECT.MRI in brain diseases and inter-reader variance of diagnostic performance].
Fifteen-four studies of 201T1 brain tumor SPECT were independently interpreted by 9 nuclear medicine physicians with and without reference magnetic resonance images in 2 separate sessions to define an effect of referring images, and inter-observer variations. The physicians were requested to detect foci of abnormal deposits, and to discriminate whether they were malignant or not according to 5-grade scaling of subjective diagnostic confidence. Receiver-operating characteristics (ROC) analysis was performed. Mean sensitivity for presence of lesions (SEP), and sensitivity and specificity for malignancy of 201T1 SPECT were 84, and 53 and 55%, which were changed to 94, and 74 and 55% after referring to the MR images. The SFP was significantly improved (p < 0.05), but sensitivity and specificity for malignancy, assessed by areas under the ROC curves, were not significantly improved. Inter-observer variation of the SFP was significantly reduced with addition of the referring MR images. Cerebral lobar localization of lesions by SPECT showed great inter-observer variations (true localization ranged from 30 to 68.4%). It is concluded that 201T1 brain tumor SPECT has moderate sensitivity and specificity for malignancy, which is not improved by addition of anatomical reference images, that additional MR images reduce inter-observer variation of confidence on lesion presence, and that SPECT localization of lesions has great inter-observer variations.


Left atrial and right atrial deformation in patients with coronary artery disease: a velocity vector imaging-based study.
Impaired left ventricular (LV) function has been shown by strain rate (SR) imaging in patients with coronary artery disease (CAD). Our aim was to investigate global and regional, systolic and diastolic left atrial (LA) and right atrial (RA) longitudinal deformation in CAD using velocity vector imaging. Echocardiographic and velocity vector imaging studies were performed in 20 patients with mild CAD, 40 patients with severe CAD and 25 controls. Maximal atrial volume, peak atrial longitudinal strain (ε(s)) and SR during LV systole (SRs), SR during early LV filling (SRe) and late LV filling (SRa) were measured. Longitudinal strain during atrial contraction (ε(a)) was obtained at the onset of P-wave on electrocardiography, and ε(a)/ε(s) was calculated. Longitudinal peak ε(s) and SRs of LA showed decreased trend among CAD patients. The global and lateral LA SRe were prominently lower, while RA ε(a), SRa and ε(a)/ε(s) were prominently higher in 2 CAD groups than control group (P value <0.05). As compared with controls and patients with other single-vessel disease, LA SRa and ε(a)/ε(s) ratio were significantly increased among patients with exclusively left anterior descending coronary artery (LAD) stenosis (SRa 1.14±0.38 s(-1), 1.10±0.41 s(-1), 1.45±0.46 s(-1), P value<0.05; ε(a)/ε(s) 0.44±0.11, 0.44±0.20, 0.57±0.12, P value<0.01). Apparently decreased SRe of LA and increased ε(a), SRa and ε(a)/ε(s) of RA were found in CAD patients with preserved LVEF and E/E' in gray zone. SRa and ε(a)/ε(s) of LA were found to significantly increase in those with LAD stenosis.


Effects of horizontal displacement and inter-character spacing on transposed-character effects in same-different matching.
In two same-different matching experiments we investigated whether transposed-character effects can be modulated by the horizontal displacement or inter-character spacing of target stimuli (strings of 6 consonants, digits, or symbols). Reference and target stimuli could be identical or differed either by transposing or substituting two characters. Transposition costs (greater difficulty in detecting a difference with transpositions compared with substitutions) were greater for letter stimuli compared to both digit and symbol stimuli in both experiments. In Experiment 1, half of the targets were displayed at the center of the screen and the other half were shifted by two character-positions to the left or to the right, whereas the reference was always presented at the center of the screen. Target displacement made the task harder and caused an increase in transposition costs whatever the type of stimulus. In Experiment 2, all stimuli were presented at the center of the screen and the inter-character spacing of target stimuli was increased by one character space on half of the trials. Increased spacing made the task harder and paradoxically caused an increase in transposition costs, but only significantly so for letter stimuli, and only in the discriminability (d') measure. These results suggest that target location and inter-character spacing manipulations caused an increase in positional uncertainty during the processing of location-specific complex features prior to activation of a location-invariant representation of character-in-string order. The hypothesized existence of a letter-specific order encoding mechanism accounts for the greater transposition costs seen with letter stimuli, as well as the greater modulation of these effects by an increase in inter-character spacing seen in discriminability (d').


Characterization of the type a flagellin gene from Pseudomonas aeruginosa PAK.
Flagella in procaryotes are complex structures requiring the coordinate expression of over 50 genes, including flagellin, the major repeating structural protein. We have previously shown that a functional RpoN gene product is required for expression of flagellin in Pseudomonas aeruginosa PAK (P. A. Totten and S. Lory, J. Bacteriol. 172:389-396, 1990) and have now cloned, sequenced, and determined the transcriptional start site of the structural gene for this flagellin. The clones containing this gene produced a protein that reacted on Western immunoblots with polyclonal and four different monoclonal antibodies to purified flagella. However, this flagellin protein in Escherichia coli was slightly smaller (41 kDa) than flagellin protein produced in P. aeruginosa PAK (45 kDa), indicating degradation in E. coli or modification in P. aeruginosa. Comparison of the deduced amino acid sequence of this gene with the amino acid sequences of other flagellins revealed a conservation in the N- and C-terminal domains, suggesting conservation of secretion or assembly signals between these organisms. The sequence 5' of the structural gene contained potential RpoN-specific promoters as well as a promoter sequence recognized by RpoF (sigma 28), the alternative sigma factor required for expression of flagellin genes in E. coli (and Bacillus subtilis). Deletion analysis of the promoter region as well as transcriptional start site mapping implicated the RpoF, and not the RpoN, consensus sequences as the functional promoter for the flagellin gene. Models for the involvement of both RpoN and RpoF in the expression of flagellin in P. aeruginosa are presented.


Iodinated Echogenic Glycol Chitosan Nanoparticles for X-ray CT/US Dual Imaging of Tumor.
Development of biopolymer-based imaging agents which can access rapidly and provide detailed information about the diseases has received much attention as an alternative to conventional imaging agents. However, development of biopolymer-based nanomaterials for tumor imaging still remains challenging due to their low sensitivity and image resolution. To surmount of these limitations, multimodal imaging agents have been developed, and they were widely utilized for theranostic applications. Herein, iodine containing echogenic glycol chitosan nanoparticles are developed for x-ray computed tomography (CT) and ultrasound (US) imaging of tumor diagnosis. X-ray CT/US dual-modal imaging probe was prepared by following below two steps. First, iodine-contained diatrizoic acid (DTA) was chemically conjugated to the glycol chitosan (GC) for the CT imaging. DTA conjugated GC (GC-DTA NPs) formed stable nanoparticles with an average diameter of 315 nm. Second, perfluoropentane (PFP), a US imaging agent, was physically encapsulated into GC-DTA NPs by O/W emulsion method yielding GC-DTA-PFP nanoparticles (GC-DTA-PFP NPs). The GC-DTA-PFP NPs formed nanoparticles in physiological condition, and they presented the strong x-ray CT, and US signals in phantom test in vitro. Importantly, GC-DTA-PFP NPs were effectively accumulated on the tumor site by enhanced permeation and retention (EPR) effects. Moreover, GC-DTA-PFP NPs showed x-ray CT, and US signals in tumor tissues after intratumoral and intravenous injection, respectively. Therefore, GC-DTA-PFP NPs indicated that x-ray CT/US dual-modal imaging using iodinated echogenic nanoparticles could be provided more comprehensive and accurate diagnostic information to diagnosis of tumor.


Serial analysis of gene expression (SAGE) in the rat limbal and central corneal epithelium.
To identify genes preferentially expressed in the stem-cell-rich limbal epithelium of the rat cornea. The limbal and central corneal epithelial cells of 6-week-old rats were isolated by microdissection. Serial analysis of gene expression (SAGE) libraries were constructed and analyzed, and in situ hybridization, reverse transcription-polymerase chain reaction (RT-PCR) and cDNA cloning were conducted by conventional procedures. The rat limbal and central corneal epithelial SAGE libraries consisted of 41,894 and 40,691 tags, respectively. After annotation, this was reduced to 759 transcripts specific for the limbal library and 844 transcripts specific for the central corneal library; 2292 transcripts overlapped. Transcripts encoding proteins with metabolic functions comprised the major functional category in both libraries. In situ hybridization and/or RT-PCR results of 12 of the most abundant, highly enriched transcripts in the limbal epithelium were in general agreement with the SAGE data and showed that these proteins are also expressed in the conjunctival epithelium. Interesting limbal-enriched transcripts encode WDNM1-like protein (similar to WDNM1/Expi, a putative secreted proteinase and inhibitor of metastasis), mesothelin (a cancer marker), marapsin (a trypsin-like serine protease that may control cell growth and migration), K4 and K15 (both cytokeratins), and membrane-spanning four-domain subfamily A member 8B. WDNM1-like protein was cloned and confirmed as a member of the four-disulfide core family. The SAGE results extend the database of genes expressed in the rodent cornea and suggest an association between several genes preferentially expressed in the limbal epithelium with cellular proliferation and migration.


Efficacy and safety of liposomal anthracyclines in phase I/II clinical trials.
Preclinical studies have established the pharmacologic advantages of liposomal anthracyclines, including pharmacokinetic profiles after bolus dosing that resemble continuous infusion of conventional anthracyclines, increased drug concentrations in tumor cells compared with the surrounding tissues, and reduced toxicity relative to conventional anthracycline treatment. Based on these studies, many phase I and phase II clinical trials were conducted to assess the safety and potential activity of liposomal anthracyclines in the management of both solid and hematologic tumors. These studies provided valuable insight into the safety of pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]), nonpegylated liposomal doxorubicin (Myocet [NPLD]), and liposomal daunorubicin (DaunoXome [DNX]) over a range of doses, either as single-agent therapy or in combination with other cytotoxic agents. Other liposomal anthracyclines in development may be well tolerated but their activity remains to be elucidated by clinical trials. The available data also suggest that liposomal anthracyclines have activity not only against tumor types with known sensitivity to conventional anthracyclines, but also potentially for tumors that are typically anthracycline-resistant. Despite the availability of clinical data from a wide variety of tumor types and patient populations, further studies of liposomal anthracycline therapy are needed to fully establish their safety, efficacy, and dosing in the treatment of these patients.


Percolation on networks with conditional dependence group.
Recently, the dependence group has been proposed to study the robustness of networks with interdependent nodes. A dependence group means that a failed node in the group can lead to the failures of the whole group. Considering the situation of real networks that one failed node may not always break the functionality of a dependence group, we study a cascading failure model that a dependence group fails only when more than a fraction β of nodes of the group fail. We find that the network becomes more robust with the increasing of the parameter β. However, the type of percolation transition is always first order unless the model reduces to the classical network percolation model, which is independent of the degree distribution of the network. Furthermore, we find that a larger dependence group size does not always make the networks more fragile. We also present exact solutions to the size of the giant component and the critical point, which are in agreement with the simulations well.


Acceptance and commitment therapy: a meta-analytic review.
There are now a substantial number of controlled trials investigating the efficacy of acceptance and commitment therapy (ACT). This meta-analysis combined multiple well-controlled studies to help clarify the overall impact of ACT relative to waiting lists, psychological placebos, treatment as usual, and established therapies. A comprehensive literature search produced 18 randomized controlled trials (n = 917) that were included in the final analyses. Effect size was computed with Hedges's g which can be interpreted with Cohen's convention of small (0.2), medium (0.5), and large (0.8) effects. There was a clear overall advantage of ACT compared to control conditions (effect size = 0.42). The average ACT-treated participant was more improved than 66% of the participants in the control conditions. Analyzed separately ACT was superior to waiting lists and psychological placebos (effect size = 0.68) and treatment as usual (effect size = 0.42). However, ACT was not significantly more effective than established treatments (effect size = 0.18, p = 0.13). Also, ACT was not superior to control conditions for the distress problems (anxiety/depression: effect size = 0.03, p = 0.84). The results reveal that ACT is more effective than control conditions for several problem domains, but there is no evidence yet that ACT is more effective than established treatments.


Patients' Use and Perception of Internet-Based Orthopaedic Sports Medicine Resources.
Current research is sparse regarding how patients with orthopaedic injuries perceive and use internet-based information resources. The majority of patients use the internet to research their orthopaedic condition and are receptive to guidance from their provider. Cross-sectional study. A total of 213 patients attending a sports medicine clinic on the East Coast of the United States were asked to complete a questionnaire regarding their use of internet-based information. Data from 185 patients were available for analysis. Bivariate and multivariate statistical analyses were used to determine the significance of identified associations. Overall, 54% of patients used the internet to find information about their orthopaedic condition prior to their consultation. A higher percentage of internet users were women (P = .01), were white (P = .03), and had internet access at home (P = .02). Multivariable analysis found home internet access to be the only significant independent factor predictive of patients using internet-based information sources (P < .01). The majority of patients (61%) were neutral toward orthopaedic information found online, and only 32% of patients trusted the orthopaedic information they found online. The majority of patients (83%) reported they would be receptive to providers' guidance on which internet resources to use. Only half of patients use the internet to research their orthopaedic condition. Most patients were either neutral toward or did not trust the internet-based information that they found and may forgo internet sources altogether. To help patients avoid misleading information, sports medicine providers should understand how patients are using the internet and guide patients in selecting high-quality, peer-reviewed sources of information. Doing so allows physicians to proactively educate their patients even after the clinic visit.


Local adaptations to frost in marginal and central populations of the dominant forest tree Fagus sylvatica L. as affected by temperature and extreme drought in common garden experiments.
Local adaptations to environmental conditions are of high ecological importance as they determine distribution ranges and likely affect species responses to climate change. Increased environmental stress (warming, extreme drought) due to climate change in combination with decreased genetic mixing due to isolation may lead to stronger local adaptations of geographically marginal than central populations. We experimentally observed local adaptations of three marginal and four central populations of Fagus sylvaticaL., the dominant native forest tree, to frost over winter and in spring (late frost). We determined frost hardiness of buds and roots by the relative electrolyte leakage in two common garden experiments. The experiment at the cold site included a continuous warming treatment; the experiment at the warm site included a preceding summer drought manipulation. In both experiments, we found evidence for local adaptation to frost, with stronger signs of local adaptation in marginal populations. Winter frost killed many of the potted individuals at the cold site, with higher survival in the warming treatment and in those populations originating from colder environments. However, we found no difference in winter frost tolerance of buds among populations, implying that bud survival was not the main cue for mortality. Bud late frost tolerance in April differed between populations at the warm site, mainly because of phenological differences in bud break. Increased spring frost tolerance of plants which had experienced drought stress in the preceding summer could also be explained by shifts in phenology. Stronger local adaptations to climate in geographically marginal than central populations imply the potential for adaptation to climate at range edges. In times of climate change, however, it needs to be tested whether locally adapted populations at range margins can successfully adapt further to changing conditions.


Polynuclear platinum phosphanido/phosphinito complexes: formation of P-O and P-O-P bonds through reductive coupling processes.
A mixture of the asymmetric complexes of formula [(RF)2Pt(μ-Ph2PO)(μ-PPh2)Pt(μ-PPh2)2Pt(solv)(solv')] [(1-(solv)(solv')] (solv, solv' = acetone, H2O, CH3CN) has been prepared by reaction of [(RF)2Pt(II)(μ-PPh2)2Pt(II)(μ-PPh2)2Pt(II)(NCCH3)2] with AgClO4 in CH3CN/acetone. The lability of the Pt-solvent bonds allows the displacement of the coordinated solvent molecules by dppm or Cl(-) and the isolation of the tri- or hexanuclear phosphanido/phosphinito Pt(ii) complexes [(C6F5)2Pt(μ-PPh2)(μ-PPh2O)Pt(μ-PPh2)2Pt(dppm)] (2) or [NBu4]2[(C6F5)2Pt(μ-PPh2)(μ-PPh2O)Pt(μ-PPh2)2Pt(μ-Cl)2Pt(μ-PPh2)2Pt(μ-PPh2)(μ-PPh2O)Pt(C6F5)2] (as a mixture of the two possible isomers 4a and 4b). Complex 2 reacts with AgClO4 to form the tetranuclear derivative [(C6F5)2Pt(μ-PPh2)(μ-PPh2O)Pt(μ-PPh2)2Pt(dppm)Ag(OClO3)] (3), which displays two Pt-Ag donor-acceptor bonds. The mixture of the hexanuclear isomers 4a-4b reacts with Tl(acac) producing the acetylacetonato complex [NBu4][(C6F5)2Pt(μ-PPh2)(μ-PPh2O)Pt(μ-PPh2)2Pt(acac)] (5) which, upon reaction with HCl, yields back the mixture of 4a-4b. The reaction of 4a-4b with PPh3 produces [NBu4][(C6F5)2Pt(μ-PPh2)(μ-PPh2O)Pt(μ-PPh2)2Pt(Cl)(PPh3)] (6) as a mixture of isomers with the chloro ligand located syn (6a) or anti (6b) to the PPh2O(-) group. Either the reaction of 6 with AgClO4 or the treatment of 5 with HPPh3ClO4 results in the formation of the species [(C6F5)2Pt(II)(μ-PPh2)2Pt(I)(μ-PPh2OPPh2)Pt(I)(PPh3)] (7) (44 VEC), which can be explained as the consequence of a PPh2O/PPh2 reductive coupling and a rearrangement of ligands in the molecule generating a Pt(ii),Pt(i),Pt(i) compound. All complexes were characterised in the solid state by XRD (only one of the isomers, in the cases of 4 and 6) and in solution by NMR spectroscopy.


Posterior reversible encephalopathy syndrome in an oncological normotensive patient: evidence for a pathogenic role of concomitant low magnesium serum levels and chemotherapy treatment.
Posterior reversible encephalopathy (PRES) is a rare syndrome characterized by headache, confusion, seizures, visual changes and white matter edema at radiological imaging. Its pathophysiology is not clarified and different causes, including uncontrolled hypertension, eclampsia, chemotherapy and hypomagnesemia have been suggested. A woman affected by stage IV breast cancer with lower extremity deep vein thrombosis treated with low-molecular-weight-heparin, currently in therapy with Palbociclib/Fulvestrant (antiCDK4 and 6/estrogen receptor antagonist) but previously treated with several other chemotherapy lines (including VEGF inhibitor bevacizumab), was admitted to our Internal Medicine department because of ascites and abdominal pain. She was treated with diuretics (and paracentesis). Recently (six-month earlier) a pan-encephalic radiotherapy was done because of brain and skull metastasis. Among blood tests, low serum levels of hypomagnesemia were observed. She developed PRES that rapidly progressed to lethargy, unresponsiveness till coma without changes in blood pressure. Magnetic Resonance Imaging study showed bilateral parieto-occipital edema and a thrombosis of left transverse and sigmoid sinuses. Anti-edema therapy, intravenous supplementation of magnesium and decoagulation were started, with complete and rapid recovery (within 18 hours) of clinical and radiologic changes. PRES diagnosis was based on the rapid clinical recovery after antiedema treatment and magnesium supplementation. Low magnesium level related to both diuretic and Fulvestrant/Palbociclib therapies and recent radiotherapy can represent potential mechanisms favouring PRES development. The previous bevacizumab treatment may also be involved as a PRES predisposing factor. The concomitant occurrence of cerebral thrombosis can have precipitated the clinical situation.


Comparison of Host-Seeking Behavior of the Filth Fly Pupal Parasitoids, Spalangia cameroni and Muscidifurax raptor (Hymenoptera: Pteromalidae).
The pupal parasitoids, Spalangia cameroni Perkins and Muscidifurax raptor Girault and Sanders, can be purchased for biological control of house flies Musca domestica L. and stable flies Stomoxys calcitrans (L.) (Diptera: Muscidae). Little is known about the odors involved in host-seeking behavior of these two species, so odors associated with house flies were investigated in the laboratory using a Y-tube olfactometer. Odor stimuli from house fly host puparia, larvae, pine-shavings bedding with horse manure, and developing flies in the pine-shavings-manure substrate were evaluated in bioassays using the two pteromalid species. In choice tests, naïve female S. cameroni were strongly attracted to odor from the substrate containing house fly larvae and secondarily from the uninfested substrate and substrate with puparia versus humidified and purified air. This species also selected the substrate with larvae versus the substrate with the house fly puparia or uninfested substrate. Muscidifurax raptor was attracted to odor from the substrate containing puparia, washed puparia, and substrate with puparia removed. The data suggest that coexistence between the two pteromalid parasitoids, S. cameroni and M. raptor, might be promoted by different host-seeking behavior.


A comparison of community-based care for schizophrenia in south Verona and south Manchester.
The community-oriented mental illness services providing care to defined populations in south Verona, Italy (17,628 adults) and south Manchester, England (12,021 adults) have been compared to explore relationships between service organisation and patterns of service use. The composition and function of the two services and the sociodemographic characteristics of the two centres are described and related to epidemiological data on service use in the community, out-patient clinic, day hospital and in-patient care. Treated incidence of all psychiatric diagnoses and of schizophrenia were significantly higher in south Manchester than south Verona, indicating that the referral filter between primary and secondary care is more permeable in Manchester. Patients known to the service were more likely to be admitted and to have shorter in-patient stays in south Verona, indicating that the filter between in-patient care and the community is more permeable in Verona than Manchester. The organisation of services in Verona results in a smaller load on the mental health service; the shorter hospital stays can be related to better integration between hospital and community resources. The organisation of services in Manchester provides care for a greater proportion of the population, but would be likely to require increased resources for the mental health services over time.


Effects of serotonin on platelet activation in whole blood.
Serotonin (5-hydrotryptamine, 5-HT) is a weak platelet agonist, which has not been evaluated fully with respect to platelet responses in whole blood. We thus re-evaluated platelet responses to 5-HT using three whole blood techniques: flow cytometry, impedance aggregometry and filtragometry. At concentrations up to 10(-5) mol/l, 5-HT per se failed to induce platelet aggregation in whole blood, or to increase platelet fibrinogen binding or P-selectin expression. However, 5-HT potentiated platelet responses to low concentrations of adenosine diphosphate (ADP) or thrombin dose-dependently. 5-HT (10(-7), 10(-6) and 10(-5) mol/l) increased ADP-induced platelet fibrinogen binding by 40, 59 and 79%, while P-selectin expression increased by 45, 64 and 95%, respectively (P < 0.05; n = 10). The enhancing effects of 5-HT were even more pronounced in thrombin-stimulated samples, as 5-HT at 10(-8), 10(-7), 10(-6) and 10(-5) mol/l increased fibrinogen binding by 56, 128, 212 and 260% (P < 0.05), and P-selectin expression by 31, 56, 89 and 109%, respectively (P < 0.01; n = 10). The response to 5-HT was inhibited dose-dependently by a highly selective 5-HT2A receptor antagonist (SR 46349), with almost complete inhibition at 10(-6) mol/l. Impedance aggregometry showed a significant enhancement in 5 x 10(-6) mol/l ADP-induced platelet aggregation caused by 5-HT at 8 x 10(-8) mol/l (from 7.58 +/- 2.50 omega to 9.02 +/- 2.43 omega, P < 0.02, n = 12). Similarly, filtragometry readings, i.e. the time taken for platelet aggregates to occlude a microfilter, were shortened by 27% (P < 0.05, n = 9), reflecting increased platelet aggregability. Our data suggest that 5-HT per se does not activate platelets, but dose-dependently enhances platelet activation induced by ADP and, in particular, thrombin in whole blood. Thus, the idea that 5-HT is a 'helper agonist' is supported; this effect is mediated by 5-HT2A receptors.


Surgical trends in the treatment of diseases of the lumbar spine in Utah's Medicare population, 1984 to 1990.
Chronic low back pain is a major source of disability in this country. The rate of surgical treatment for back disorders varies between small geographic areas in the northeastern United States. A statewide database was utilized to determine rate of surgery for mechanical low back problems in Utah's Medicare population from 1984 to 1990. The average surgery rate for Medicare enrollees was 274.7 per 100,000, and the Utah laminectomy and discectomy rates were at least 20% higher than the U.S. average. Back surgery rates rose by 55% over the study period, primarily because of increasing rates of surgery for spinal stenosis. There was statistically significant variation in surgery rates among regions in the state, with the highest region having a rate 50% greater than the lowest region. Rates of surgery for spinal stenosis had more variation than those for herniated disc surgery. There was no significant correlation between the number of surgeons performing back surgery and the rate of surgery. The variation and increase in back surgery rates in Utah's Medicare population are likely related to changes in the use of surgery for treatment of spinal stenosis and not to an increase in the number of back surgeons. Further investigation is needed to understand better the reasons for the observed increase in back surgery rates.


Clinical implications of molecular subtyping in bladder cancer.
The purpose of this review is to examine and evaluate similarities and differences in bladder cancer expression subtypes and to understand the clinical implications of the molecular subtyping. Four independent classification systems have been described, and there are broad similarities among the subtyping callers. Two major subtypes have been identified, that is, luminal and basal, with underlying subcategories based on various distinct characteristics. Luminal tumors generally bear a better prognosis and increased survival than basal tumors, although there is subtle variation in prognosis among the different subtypes within the luminal and basal classifications. Clinical subtyping is now commercially available, although there are limitations to its generalizability and application. Expression subtyping is a new method to personalize bladder cancer management. However, there is probably not sufficient evidence to incorporate use into current standards-of-care. Validation cohorts with clinically meaningful outcomes may further establish the clinical relevance of molecular subtyping of bladder cancer. Additionally, genetic alterations in bladder cancer may 'color' the interpretation of individual tumors beyond the expression subtype to truly personalize care for bladder cancer.


Interference in the processing of adjunct control.
Recent research on the memory operations used in language comprehension has revealed a selective profile of interference effects during memory retrieval. Dependencies such as subject-verb agreement show strong facilitatory interference effects from structurally inappropriate but feature-matching distractors, leading to illusions of grammaticality (Pearlmutter et al., 1999; Wagers et al., 2009; Dillon et al., 2013). In contrast, dependencies involving reflexive anaphors are generally immune to interference effects (Sturt, 2003; Xiang et al., 2009; Dillon et al., 2013). This contrast has led to the proposal that all anaphors that are subject to structural constraints are immune to facilitatory interference. Here we use an animacy manipulation to examine whether adjunct control dependencies, which involve an interpreted anaphoric relation between a null subject and its licensor, are also immune to facilitatory interference effects. Our results show reliable facilitatory interference in the processing of adjunct control dependencies, which challenges the generalization that anaphoric dependencies as a class are immune to such effects. To account for the contrast between adjunct control and reflexive dependencies, we suggest that variability within anaphora could reflect either an inherent primacy of animacy cues in retrieval processes, or differential degrees of match between potential licensors and the retrieval probe.