EGFR, p16INK4a and E-cadherin immuno-histochemistry and EGFR point mutations analyses in invasive cervical cancer specimens from Moroccan women.
The involvement of human papillomavirus in the development of cervical cancer has been firmly established. However, better management of cervical cancer rests on good diagnosis and an effective therapy. In this study we evaluated the frequency of point mutations in epidermal growth factor receptor (EGFR) for future use of tyrosine kinase inhibitors in clinical treatment and to assess the use of EGFR, p16INK4a and E-cadherin as biomarkers in cervical cancer diagnosis with immunohistochemistry. Fifty-three patient specimens of cervical cancer were analysed for HPV infection, for EGFR mutations in exons 18 through 21, and for expression of EGFR, p16INK4a and E-cadherin by immunostaining. Results showed that 79.24% of the cases (42/53) are HPV positive and the HPV types more closely associated with risk are HPV 16 and 18. In all 53 analysed specimens, any mutation affecting the EGFR kinase domain in exons 18 through 21 was observed. Expressions of EGFR, p16INK4a and E-cadherin were detected in 88,67% (47/53), 92,45% (49/53) and 79,24% (42/53) of analysed specimens respectively. Thus, EGFR, p16INK4a and E-cadherin would be excellent tools for IHC analysis during the cervical cancer development. EGFR and p16INK4a can be used for early diagnosis and E-cadherin for cancer progression and cell migration. However, treatment of cervical cancer with TKIs may not be effective and the identification of other EGFR inhibitors is needed.


Magnetic resonance imaging in patients with a pacemaker system designed for the magnetic resonance environment.
Magnetic resonance imaging (MRI) of pacemaker patients is contraindicated due to documented potential risks to the patient from hazardous interactions between the MRI and pacemaker system. The purpose of this prospective, randomized, controlled, worldwide clinical trial was to evaluate the safety and effectiveness of a pacemaker system designed for safe use in MRI for any bradycardia indicated patient. Patients (n = 464) were randomized to undergo an MRI scan between 9 and 12 weeks postimplant (MRI group, n = 258) or not to undergo MRI (control group, n = 206) after successful implantation of the specially designed dual-chamber pacemaker and leads. Patients were monitored for arrhythmias, symptoms, and pacemaker system function during 14 nonclinically indicated relevant brain and lumbar MRI sequences. Sequences were performed at 1.5 T and included scans with high radiofrequency power deposition and/or high gradient dB/dt exposure. Clinical evaluation of the pacemaker system function occurred immediately before and after MRI, 1 week and 1 month post-MRI, and at corresponding times for the control group. Primary endpoints for safety analyzed the MRI procedure complication-free rate and for effectiveness compared capture and sensing performance between MRI and control groups. No MRI-related complications occurred during or after MRI, including sustained ventricular arrhythmias, pacemaker inhibition or output failures, electrical resets, or other pacemaker malfunctions. Pacing capture threshold and sensed electrogram amplitude changes were minimal and similar between study groups. This trial documented the ability of this pacemaker system to be exposed in a controlled fashion to MRI in a 1.5 T scanner without adverse impact on patient outcomes or pacemaker system function.


Cognitive therapy for people with a schizophrenia spectrum diagnosis not taking antipsychotic medication: an exploratory trial.
Although antipsychotic medication is the first line of treatment for schizophrenia, many service users choose to refuse or discontinue their pharmacological treatment. Cognitive therapy (CT) has been shown to be effective when delivered in combination with antipsychotic medication, but has yet to be formally evaluated in its absence. This study evaluates CT for people with psychotic disorders who have not been taking antipsychotic medication for at least 6 months. Twenty participants with schizophrenia spectrum disorders received CT in an open trial. Our primary outcome was psychiatric symptoms measured using the Positive and Negative Syndromes Scale (PANSS), which was administered at baseline, 9 months (end of treatment) and 15 months (follow-up). Secondary outcomes were dimensions of hallucinations and delusions, self-rated recovery and social functioning. T tests and Wilcoxon's signed ranks tests revealed significant beneficial effects on all primary and secondary outcomes at end of treatment and follow-up, with the exception of self-rated recovery at end of treatment. Cohen's d effect sizes were moderate to large [for PANSS total, d=0.85, 95% confidence interval (CI) 0.32-1.35 at end of treatment; d=1.26, 95% CI 0.66-1.84 at follow-up]. A response rate analysis found that 35% and 50% of participants achieved at least a 50% reduction in PANSS total scores by end of therapy and follow-up respectively. No patients deteriorated significantly. This study provides preliminary evidence that CT is an acceptable and effective treatment for people with psychosis who choose not to take antipsychotic medication. An adequately powered randomized controlled trial is warranted.


β-Cell failure in type 2 diabetes: a case of asking too much of too few?
The islet in type 2 diabetes (T2DM) is characterized by a deficit in β-cells, increased β-cell apoptosis, and extracellular amyloid deposits derived from islet amyloid polypeptide (IAPP). In the absence of longitudinal studies, it is unknown if the low β-cell mass in T2DM precedes diabetes onset (is a risk factor for diabetes) or develops as a consequence of the disease process. Although insulin resistance is a risk factor for T2DM, most individuals who are insulin resistant do not develop diabetes. By inference, an increased β-cell workload results in T2DM in some but not all individuals. We propose that the extent of the β-cell mass that develops during childhood may underlie subsequent successful or failed adaptation to insulin resistance in later life. We propose that a low innate β-cell mass in the face of subsequent insulin resistance may expose β-cells to a burden of insulin and IAPP biosynthetic demand that exceeds the cellular capacity for protein folding and trafficking. If this threshold is crossed, intracellular toxic IAPP membrane permeant oligomers (cylindrins) may form, compromising β-cell function and inducing β-cell apoptosis.


Prediction of non-occurrence of syncope during a tilt-table test by early heart rate variations.
A recent study showed that, in a select patient population with no drug use and no cardiac or other illness, an increase in heart rate equal to or less than 18 beats per minute from baseline in the first 6 minutes of a tilt-table test at 60 degrees identifies patients who will not develop syncope during prolonged tilting, with specificity and positive predictive value nearing 100 percent. We retrospectively reviewed 110 consecutive tilt-table tests at an angle of 70 degrees or more, performed at our institutions between 1994 and 1999 in patients with and without cardiac disease or drug use. Excluded were 320 additional patients due to either incomplete heart rate documentation or development of syncope in the first ten minutes of tilting. The difference between maximal heart rate in the first ten minutes during tilting and the average of at least two baseline heart rate measurements was used to assess correlation with the non-occurrence of syncope during the same test. The tilt-table angle used varied from 70 degrees to 90 degrees (80 degrees in 89 percent of patients). There was a strongly significant (p < 0.0001) correlation between a sustained rise in heart rate equal to or less than 18 beats per minute in the first ten minutes of tilting and the non-occurrence of subsequent syncope during the test. The sensitivity, specificity, positive and negative predictive values were 75.7 percent, 65.0 percent, 79.1 percent and 60.47 percent, respectively. These data indicate that even in the routine setting, that is, a non-select population and at a higher tilt-table angle, an increase in heart rate equal to or less than 18 beats per minute in the first ten minutes of tilting constitutes a good predictor of a negative test. However, the specificity and positive predictive value of this criterion were not high enough to justify an early termination of the test.


Recombination in Escherichia coli and the definition of biological species.
The DNA sequence of part of the gnd (6-phosphogluconate dehydrogenase) gene was determined for eight wild strains of Escherichia coli and for Salmonella typhimurium. Since a region of the trp (tryptophan) operon and the phoA (alkaline phosphatase) gene have been sequenced from the same strains, the gene trees for these three regions were determined and compared. Gene trees are different from species or strain trees in that a gene tree is derived from a particular segment of DNA, whereas a species or strain tree should be derived from many such segments and is the tree that best represents the phylogenetic relationship of the species or strains. If there were no recombination in E. coli, the gene trees for different genes would not be statistically different from the strain tree or from each other. But, if the gene trees are significantly different, there must have been recombination. Methods are proposed that show these gene trees to be statistically different. Since the gene trees are different, we conclude that recombination is important in natural populations of E. coli. Finally, we suggest that gene trees can be used to create an operational means of defining bacterial species by using the biological species definition.


Post-translational control of transcription factors: methylation ranks highly.
Methylation of lysine and arginine residues on histones has long been known to determine both chromatin structure and gene expression. In recent years, the methylation of non-histone proteins has emerged as a prevalent modification which impacts on diverse processes such as cell cycle control, DNA repair, senescence, differentiation, apoptosis and tumourigenesis. Many of these non-histone targets represent transcription factors, cell signalling molecules and tumour suppressor proteins. Evidence now suggests that the dysregulation of methyltransferases, demethylases and reader proteins is involved in the development of many diseases, including cancer, and several of these proteins represent potential therapeutic targets for small molecule compounds, fuelling a recent surge in chemical inhibitor design. Such molecules will greatly help us to understand the role of methylation in both health and disease.


A Modular High-Throughput In Vivo Screening Platform Based on Chimeric Bacterial Receptors.
Multidrug resistance (MDR) is a globally relevant problem that requires novel approaches. Two-component systems are a promising, yet untapped target for novel antibacterials. They are prevalent in bacteria and absent in mammals, and their activity can be modulated upon perception of various stimuli. Screening pre-existing compound libraries could reveal small molecules that inhibit stimulus-perception by virulence-modulating receptors, reduce signal output from essential receptors or identify artificial stimulatory ligands for novel SHKs that are involved in virulence. Those small molecules could possess desirable therapeutic properties to combat MDR. We propose that a modular screening platform in which the periplasmic domain of the targeted receptors are fused to the cytoplasmic domain of a well-characterized receptor that governs fluorescence reporter genes could be employed to rapidly screen currently existing small molecule libraries. Here, we have examined two previously created Tar-EnvZ chimeras and a novel NarX-EnvZ chimera. We demonstrate that it is possible to couple periplasmic stimulus-perceiving domains to an invariable cytoplasmic domain that governs transcription of a dynamic fluorescent reporter system. Furthermore, we show that aromatic tuning, or repositioning the aromatic residues at the end of the second transmembrane helix (TM2), modulates baseline signal output from the tested chimeras and even restores output from a nonfunctional NarX-EnvZ chimera. Finally, we observe an inverse correlation between baseline signal output and the degree of response to cognate stimuli. In summary, we propose that the platform described here, a fluorescent Escherichia coli reporter strain with plasmid-based expression of the aromatically tuned chimeric receptors, represents a synthetic biology approach to rapidly screen pre-existing compound libraries for receptor-modulating activities.


Logic-based models in systems biology: a predictive and parameter-free network analysis method.
Highly complex molecular networks, which play fundamental roles in almost all cellular processes, are known to be dysregulated in a number of diseases, most notably in cancer. As a consequence, there is a critical need to develop practical methodologies for constructing and analysing molecular networks at a systems level. Mathematical models built with continuous differential equations are an ideal methodology because they can provide a detailed picture of a network's dynamics. To be predictive, however, differential equation models require that numerous parameters be known a priori and this information is almost never available. An alternative dynamical approach is the use of discrete logic-based models that can provide a good approximation of the qualitative behaviour of a biochemical system without the burden of a large parameter space. Despite their advantages, there remains significant resistance to the use of logic-based models in biology. Here, we address some common concerns and provide a brief tutorial on the use of logic-based models, which we motivate with biological examples.


Gender issues from the perspective of health-care professionals in Neuro-oncology: an EANO and EORTC Brain Tumor Group survey.
Women represent an increasing proportion of the overall workforce in medicine but are underrepresented in leadership roles. To explore gender inequalities and challenges in career opportunities, a web-based survey was conducted among the membership of the European Association of Neuro-Oncology and the Brain Tumor Group of the European Organisation for Research and Treatment of Cancer. A total of 228 colleagues responded to the survey: 129 women (median age 45 years; range, 25-66 years) and 99 men (median age 48 years; range, 24-81 years); 153 participants (67%) were married and 157 participants (69%) had at least 1 child. Women less often declared being married (60% vs 77%, P = .007) or having a child (63% vs 77%, P = .024). Men more frequently had a full-time position (88% vs 75%, P = .036). Women and men both perceived an underrepresentation of women in leadership positions. Half of participants agreed that the most important challenges for women are leading a team and obtaining a faculty position. Fewer women than men would accept such a position (42% vs 56%). The main reasons were limited time for career and an inappropriate work and life balance. Women specifically cited negative discrimination, limited opportunities, and lack of self-confidence. Discrimination of women at work was perceived by 64% of women vs 47% of men (P = .003). Women are perceived as experiencing more difficulties in acquiring a leadership position. Personal preferences may account for an underrepresentation of women in leadership positions, but perceived gender inequalities extend beyond disparities of access to leadership.


Multiple-subjects connectivity-based parcellation using hierarchical Dirichlet process mixture models.
We propose a hierarchical infinite mixture model approach to address two issues in connectivity-based parcellations: (i) choosing the number of clusters, and (ii) combining data from different subjects. In a Bayesian setting, we model voxel-wise anatomical connectivity profiles as an infinite mixture of multivariate Gaussian distributions, with a Dirichlet process prior on the cluster parameters. This type of prior allows us to conveniently model the number of clusters and estimate its posterior distribution directly from the data. An important benefit of using Bayesian modelling is the extension to multiple subjects clustering via a hierarchical mixture of Dirichlet processes. Data from different subjects are used to infer on class parameters and the number of classes at individual and group level. Such a method accounts for inter-subject variability, while still benefiting from combining different subjects data to yield more robust estimates of the individual clusterings.


Restless legs syndrome in end stage renal disease patients undergoing hemodialysis.
The prevalence of Restless legs syndrome (RLS) in End Stage Renal Disease (ESRD) patients is higher than that in the general population. However, the associations of RLS within the ESRD population are inconsistent and RLS is usually neglected in dialysis centers, although it impairs the life quality among ESRD patients. We aim to investigate the prevalence of RLS in patients with ESRD undergoing maintenance hemodialysis and evaluate the risk factors of developing RLS and the effect of RLS on quality of life among ESRD patients. ESRD patients undergoing maintenance hemodialysis in Shanghai General Hospital dialysis unit from July 2016 to October 2016 were enrolled in the study. RLS was diagnosed according to the criteria of the International Restless Legs Syndrome Study Group (IRLSSG). IRLSSG Severity Scale was used to evaluate the severity of RLS. Pittsburgh Sleep Quality Index (PSQI) was used to evaluate sleep quality, and Hospital Anxiety and Depression Scale (HADS) was used to estimate anxiety and depression. Serologic and historic variables were analyzed to determine predictors of RLS in the ESRD population. A total of 137 ESRD patients were enrolled. The prevalence of RLS among the ESRD patients was 20.44%. The risk of RLS was increased significantly in females (OR = 2.729, p = 0.032) and daily alcohol drinkers (OR = 4.716, p = 0.022). RLS increased the risks of sleep disorders (25/28, 89.3% vs 73/109, 67.0%, p = 0.02) and sedative hypnotics intake (7/28, 25.0% vs 10/109, 9.2%, p = 0.047) and impaired the sleep quality (7/109 vs 11/28, p = 0.001) according to PSQI sum scores. A high RLS prevalence among the ESRD patients undergoing hemodialysis was confirmed. ESRD patients who are women and drinking alcohol have a higher risk of RLS. The sleep quality was significantly impaired and sleeping medication use was more common among the ESRD patients with RLS.


The NOTCH ligand JAGGED2 promotes pancreatic cancer metastasis independent of NOTCH signaling activation.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal disease with a high rate of metastasis. Numerous signaling events have been implicated in the molecular pathogenesis of this neoplasm. Aberrantly high expression of JAGGED2, one of the NOTCH ligands, often occurs in human PDAC. However, what role JAGGED2 plays in the disease development and whether JAGGED2 executes its function through activating NOTCH signaling remain to be determined. We report here that JAGGED2 plays a critical role in promoting PDAC metastasis in vitro and in vivo. Depletion of JAGGED2, but not its homolog JAGGED1, profoundly inhibited both migration and invasion without influencing cell proliferation. Furthermore, reconstitution of JAGGED2 expression rescued the migratory defect. Surprisingly, neither pharmacologic nor genetic inhibition of NOTCH downstream signaling resulted in obvious defect in metastasis. Instead, depletion of NOTCH1 expression per se gave rise to migratory defects similar to JAGGED2 ablation. Moreover, blockade of ligand-receptor interaction by a specific JAGGED2-Fc fusion protein dramatically inhibited PDAC cell migration, suggesting that tumor metastasis relies on physical interactions of JAGGED2-NOTCH1 but not Notch downstream signaling activation. Taken together, our data reveal a novel role of NOTCH in regulation of PDAC metastasis, and identify JAGGED2 as a critical mediator in this event. These findings also provide rationale for developing small molecules or biologic agents targeting JAGGED2 for therapeutic intervention.


Aborted sudden cardiac death as a presentation of isolated non-compaction cardiomyopathy.
Left ventricular non-compaction cardiomyopathy (LVNC) is a rare disorder characterized by a thick myocardial wall with two distinct layers consisting of compacted and noncompacted myocardium. The major clinical manifestations of LVNC have been described as heart failure, cardiac arrhythmias, and cardioembolic events. In this report we present a case of a young woman with LVNC who presented with aborted sudden cardiac death. This is the second case of LVNC reported in Puerto Rico, but the first presenting with this complication. Recent advances in the field of cardiology allow the identification and diagnosis of this disease; thus, preventive and treatment strategies could be established for this potentially life-threatening condition. LVNC has to be considered in young patients presenting with sudden cardiac death.


Back electron-hole recombination in hematite photoanodes for water splitting.
The kinetic competition between electron-hole recombination and water oxidation is a key consideration for the development of efficient photoanodes for solar driven water splitting. In this study, we employed three complementary techniques, transient absorption spectroscopy (TAS), transient photocurrent spectroscopy (TPC), and electrochemical impedance spectroscopy (EIS), to address this issue for one of the most widely studied photoanode systems: nanostructured hematite thin films. For the first time, we show a quantitative agreement between all three techniques. In particular, all three methods show the presence of a recombination process on the 10 ms to 1 s time scale, with the time scale and yield of this loss process being dependent upon applied bias. From comparison of data between these techniques, we are able to assign this recombination phase to recombination of bulk hematite electrons with long-lived holes accumulated at the semiconductor/electrolyte interface. The data from all three techniques are shown to be consistent with a simple kinetic model based on competition between this, bias dependent, recombination pathway and water oxidation by these long-lived holes. Contrary to most existing models, this simple model does not require the consideration of surface states located energetically inside the band gap. These data suggest two distinct roles for the space charge layer developed at the semiconductor/electrolyte interface under anodic bias. Under modest anodic bias (just anodic of flatband), this space charge layer enables the spatial separation of initially generated electrons and holes following photon absorption, generating relatively long-lived holes (milliseconds) at the semiconductor surface. However, under such modest bias conditions, the energetic barrier generated by the space charge layer field is insufficient to prevent the subsequent recombination of these holes with electrons in the semiconductor bulk on a time scale faster than water oxidation. Preventing this back electron-hole recombination requires the application of stronger anodic bias, and is a key reason why the onset potential for photocurrent generation in hematite photoanodes is typically ~500 mV anodic of flat band and therefore needs to be accounted for in electrode design for PEC water splitting.


The roadmap towards elimination of lymphatic filariasis by 2030: insights from quantitative and mathematical modelling.
The Global Programme to Eliminate Lymphatic Filariasis was launched in 2000 to eliminate lymphatic filariasis (LF) as a public health problem by 1) interrupting transmission through mass drug administration (MDA) and 2) offering basic care to those suffering from lymphoedema or hydrocele due to the infection. Although impressive progress has been made, the initial target year of 2020 will not be met everywhere. The World Health Organization recently proposed 2030 as the new target year for elimination of lymphatic filariasis (LF) as a public health problem. In this letter, LF modelers of the Neglected Tropical Diseases (NTDs) Modelling Consortium reflect on the proposed targets for 2030 from a quantitative perspective. While elimination as a public health problem seems technically and operationally feasible, it is uncertain whether this will eventually also lead to complete elimination of transmission. The risk of resurgence needs to be mitigated by strong surveillance after stopping interventions and sometimes perhaps additional interventions.


Insulin Resistance Improves More in Women than In Men in Association with a Weight Loss Intervention.
Fasting glucose and homeostatic model assessment-insulin resistance (HOMA-IR) are important measures of the risk for metabolic syndrome and diabetes. Weight loss interventions are considered part of the first line of therapy for those who develop disease states associated with insulin resistance, such as pre-diabetes, diabetes, or metabolic syndrome. Sex differences in insulin resistance have been extensively reported, but sex differences in the ability to improve insulin sensitivity are not well-established. This study sought to identify factors that predict change in HOMA-IR in response to weight loss. Non-diabetic subjects who were overweight/obese (n=100) were randomly assigned to a walnut-enriched reduced-energy diet or a standard reduced-energy-density diet in a 6-month weight loss intervention. There were no significant differences in weight change, glucose, insulin, or HOMA-IR between the two diet groups. These subjects were combined into a single cohort and analyzed with multivariate analysis. The combined groups lost an average of 8.7 kg (p<0.0001), decreased serum glucose by an average 0.2 mmol/L (p<0.001), and decreased HOMA-IR by an average of 1.4 (p<0.0001). Change in HOMA-IR (R2=0.69) was positively associated with weight change (p<0.0001) and male sex (p<0.01), and negatively associated with baseline HOMA-IR (p<0.0001). Findings from this study suggest that men may have a more difficult time improving insulin sensitivity as compared with women with an equivalent weight loss and baseline HOMA-IR. One hypothesis to explain the differences across sexes may be due to sex differences in visceral adipose fat (VAT). This may mean that insulin resistant men require more aggressive intervention than women to prevent progression to metabolic syndrome or diabetes.


Prognostication of patients with clear cell renal cell carcinomas based on quantification of DNA methylation levels of CpG island methylator phenotype marker genes.
The CpG island methylator phenotype (CIMP) of clear cell renal cell carcinomas (ccRCCs) is characterized by accumulation of DNA methylation at CpG islands and poorer patient outcome. The aim of this study was to establish criteria for prognostication of patients with ccRCCs using the ccRCC-specific CIMP marker genes. DNA methylation levels at 299 CpG sites in the 14 CIMP marker genes were evaluated quantitatively in tissue specimens of 88 CIMP-negative and 14 CIMP-positive ccRCCs in a learning cohort using the MassARRAY system. An additional 100 ccRCCs were also analyzed as a validation cohort. Receiver operating characteristic curve analysis showed that area under the curve values for the 23 CpG units including the 32 CpG sites in the 7 CIMP-marker genes, i.e. FAM150A, ZNF540, ZNF671, ZNF154, PRAC, TRH and SLC13A5, for discrimination of CIMP-positive from CIMP-negative ccRCCs were larger than 0.95. Criteria combining the 23 CpG units discriminated CIMP-positive from CIMP-negative ccRCCs with 100% sensitivity and specificity in the learning cohort. Cancer-free and overall survival rates of patients with CIMP-positive ccRCCs diagnosed using the criteria combining the 23 CpG units in a validation cohort were significantly lower than those of patients with CIMP-negative ccRCCs (P = 1.41 × 10-5 and 2.43 × 10-13, respectively). Patients with CIMP-positive ccRCCs in the validation cohort had a higher likelihood of disease-related death (hazard ratio, 75.8; 95% confidence interval, 7.81 to 735; P = 1.89 × 10-4) than those with CIMP-negative ccRCCs. The established criteria are able to reproducibly diagnose CIMP-positive ccRCCs and may be useful for personalized medicine for patients with ccRCCs.


System xc⁻ cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS.
System x(c)(-) is an amino acid antiporter that typically mediates the exchange of extracellular l-cystine and intracellular L-glutamate across the cellular plasma membrane. Studied in a variety of cell types, the import of L-cystine through this transporter is critical to glutathione production and oxidative protection. The exchange-mediated export of L-glutamate takes on added significance within the CNS, as it represents a non-vesicular route of release through which this excitatory neurotransmitter can participate in either neuronal signalling or excitotoxic pathology. When both the import of L-cystine and the export of L-glutamate are taken into consideration, system x(c)(-) has now been linked to a wide range of CNS functions, including oxidative protection, the operation of the blood-brain barrier, neurotransmitter release, synaptic organization, viral pathology, drug addiction, chemosensitivity and chemoresistance, and brain tumour growth. The ability to selectively manipulate system x(c)(-), delineate its function, probe its structure and evaluate it as a therapeutic target is closely linked to understanding its pharmacology and the subsequent development of selective inhibitors and substrates. Towards that goal, this review will examine the current status of our understanding of system x(c)(-) pharmacology and the structure-activity relationships that have guided the development of an initial pharmacophore model, including the presence of lipophilic domains adjacent to the substrate binding site. A special emphasis is placed on the roles of system x(c)(-) within the CNS, as it is these actions that are among the most exciting as potential long-range therapeutic targets.


Infant Videofluoroscopic Swallow Study Testing, Swallowing Interventions, and Future Acute Respiratory Illness.
Tube feedings are commonly prescribed to infants with swallowing abnormalities detected by videofluoroscopic swallow study (VFSS), but there are no studies demonstrating efficacy of these interventions to reduce risk of acute respiratory illness (ARI). We sought to measure the association between swallowing interventions and future ARI, among VFSS-tested infants. Retrospective cohort of all infants (<12 months) tested with VFSS at a children's hospital between January 1, 2010, and January 1, 2012. Hospital ARI encounters (emergency, observation, or inpatient status) in a 22-hospital integrated health care delivery system, between the first VFSS and age 3 years, were measured. VFSS results were grouped by normal, intermediate, and oropharyngeal aspiration (OPA), with OPA further subdivided by silent versus cough and thin versus thick liquid OPA. Cox regression modeled the association between swallowing interventions (thickened or nasal tube feedings) and ARI, accounting for changes in swallowing and interventions over time. 576 infants were tested with a VFSS in their first year of life, receiving a total of 1051 VFSSs in their first 3 years of life. More than 60% of infants received a measured feeding intervention. With the exception of infants with silent OPA who received thickened feedings, neither thickening nor nasal tube feedings, compared with no intervention, were associated with a decreased risk of subsequent ARI. Swallowing interventions and repeated testing are common among VFSS-tested infants. However, the importance of diagnosing and intervening on VFSS-detected swallowing abnormalities for the majority of tested infants remains unclear.


Integrated analyses resolve conflicts over squamate reptile phylogeny and reveal unexpected placements for fossil taxa.
Squamate reptiles (lizards and snakes) are a pivotal group whose relationships have become increasingly controversial. Squamates include >9000 species, making them the second largest group of terrestrial vertebrates. They are important medicinally and as model systems for ecological and evolutionary research. However, studies of squamate biology are hindered by uncertainty over their relationships, and some consider squamate phylogeny unresolved, given recent conflicts between molecular and morphological results. To resolve these conflicts, we expand existing morphological and molecular datasets for squamates (691 morphological characters and 46 genes, for 161 living and 49 fossil taxa, including a new set of 81 morphological characters and adding two genes from published studies) and perform integrated analyses. Our results resolve higher-level relationships as indicated by molecular analyses, and reveal hidden morphological support for the molecular hypothesis (but not vice-versa). Furthermore, we find that integrating molecular, morphological, and paleontological data leads to surprising placements for two major fossil clades (Mosasauria and Polyglyphanodontia). These results further demonstrate the importance of combining fossil and molecular information, and the potential problems of estimating the placement of fossil taxa from morphological data alone. Thus, our results caution against estimating fossil relationships without considering relevant molecular data, and against placing fossils into molecular trees (e.g. for dating analyses) without considering the possible impact of molecular data on their placement.


Primary bladder adenocarcinoma versus metastatic colorectal adenocarcinoma: a persisting diagnostic challenge.
This study attempted to distinguish primary bladder adenocarcinoma (PBA) from metastatic colonic adenocarcinomas (MCA), which is a difficult diagnostic and clinical problem. Twenty-four cases of bladder adenocarcinomas (12 primary & 12 metastatic colorectal) were included in the study with urothelial carcinoma (UC) and colonic adenocarcinoma (CA) as controls. A panel of immunohistochemical (IHC) stains along with fluorescence in-situ hybridization (FISH), using the UroVysion probe set, was performed. The majority of the PBAs presented with advanced disease. Enteric histologic subtype was the most common morphological variant. Strong nuclear with cytoplasmic-membranous staining of β-catenin was seen in 75% of MCA and only 16.7% PBA (<10% staining cells). Although abnormal nuclear staining with E-cadherin was seen in both PBA and MCA, it was more frequent in former. CK-7, CK-20, villin and CDX-2 stains were not helpful in distinguishing the two entities. FISH did not reveal any unique differences in chromosomal abnormality between the two groups. Although there was a statistically significant difference in β-catenin and E-cadherin staining between two groups, we did not find any IHC or FISH marker that was specific for PBA. Distinction between PBA and MCA remains a diagnostic problem and clinical correlation is vital before rendering a diagnosis. The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1393156268152357.


Worldwide Case Reports Using the iTClamp for External Hemorrhage Control.
Historically, hemorrhage control strategies consisted of manual pressure, pressure dressings, gauze with or without hemostatic ingredients for wound packing, or the use of tourniquets. The iTClamp is a relatively new alternative to stop external bleeding. An anonymous survey was used to evaluate the outcomes of the iTClamp in worldwide cases of external bleeding. A total of 245 evaluable applications were reported. The iTClamp stopped the bleeding in 81% (n = 198) of the cases. Inadequate bleeding control was documented in 8% (n = 20) and in the remaining 11% (n = 27), bleeding control was not reported. The top three anatomic body regions for iTClamp application were the scalp, 37% (n = 91); arm, 20% (n = 49); and leg, 19% (n = 46). In 26% of the reported cases (direct pressure [23% (n = 63)] and tourniquets [3% (n = 8]), other techniques were abandoned in favor of the iTClamp. Conversely, the iTClamp was abandoned in favor of direct pressure 11 times (4.4%) and abandoned in favor of a tourniquet three times (1%). The iTClamp appears to be a fast and reliable device to stop external bleeding. Because of its function and possible applications, it has potential to lessen the gap between and add to the present selection of devices for treatment of external bleeding.


The prevalence of chronic pain in United States adults: results of an Internet-based survey.
A cross-sectional, Internet-based survey was conducted in a nationally representative sample of United States (US) adults to estimate the point prevalence of chronic pain and to describe sociodemographic correlates and characteristics of chronic pain. The survey was distributed to 35,718 members (aged 18 years and older) of a Web-enabled panel that is representative of the US population, and 27,035 individuals responded. Crude and weighted prevalence estimates were calculated and stratified by age, sex, and type of chronic pain. The weighted point-prevalence of chronic pain (defined as chronic, recurrent, or long-lasting pain lasting for at least 6 months) was 30.7% (95% CI, 29.8-31.7). Prevalence was higher for females (34.3%) than males (26.7%) and increased with age. The weighted prevalence of primary chronic lower back pain was 8.1% and primary osteoarthritis pain was 3.9%. Half of respondents with chronic pain experienced daily pain, and average (past 3 months) pain intensity was severe (≥ 7 on a scale ranging from 0 to 10) for 32%. Multiple logistic regression analysis identified low household income and unemployment as significant socioeconomic correlates of chronic pain. Chronic pain is prevalent among US adults and is related to indicators of poorer socioeconomic status. The results of this cross-sectional Internet-based survey suggest a considerable burden of chronic pain in US adults. Chronic pain, experienced by about a third of the population, was correlated with indicators of poorer socioeconomic status. Primary chronic pain was most commonly attributed to lower back pain, followed by osteoarthritis pain.


Generalized Ligamentous Laxity Is an Independent Predictor of Poor Outcomes After the Modified Broström Procedure for Chronic Lateral Ankle Instability.
The modified Broström procedure for chronic lateral ankle instability (CLAI) has presented outstanding clinical results. However, after the procedure, some patients with generalized ligamentous laxity have experienced a recurrence of ankle instability. To understand the effect of generalized ligamentous laxity on prognosis and risk of recurrence in a cohort of patients with CLAI after the modified Broström procedure. Cohort study; Level of evidence, 3. A total of 199 ankles from 188 patients underwent the modified Broström procedure for CLAI with a mean follow-up of 60.1 months (range, 48-108 months). Generalized ligamentous laxity was assessed in all patients. The Karlsson-Peterson ankle score (Karlsson score), talar tilt angle, and anterior displacement of the talus were used to evaluate clinical and radiological outcomes. Risk factors associated with clinical outcomes were evaluated using bivariate analysis and logistic regression analysis. Survival outcomes were compared using Kaplan-Meier analysis. Generalized ligamentous laxity was evident in 42 cases (21.1%). The average Karlsson score improved from 54.6 ± 7.1 preoperatively to 87.9 ± 7.2 at last follow-up (P < .001). The presence of generalized ligamentous laxity was significantly associated with poor clinical and radiological outcomes. The rates of clinical failure were 10.8% and 45.2% in the nonlaxity group and the laxity group, respectively (P < .001). According to bivariate analysis, generalized ligamentous laxity, syndesmosis widening, osteochondral lesion of the talus, high preoperative talar tilt angle (>15°), and high preoperative anterior displacement of the talus (>10 mm) were significantly associated with clinical failure. Multivariate logistic regression analysis revealed that generalized ligamentous laxity was the most important independent predictor of clinical failure after the modified Broström procedure. The cumulative success rates for the nonlaxity group were significantly superior to those for the laxity group in Kaplan-Meier curves (P < .001). Generalized ligamentous laxity is an independent predictor of poor outcomes and a risk factor of recurrent instability following the modified Broström procedure for CLAI.


Temporal and spatial influences incur reconfiguration of Arctic heathland soil bacterial community structure.
Microbial responses to Arctic climate change could radically alter the stability of major stores of soil carbon. However, the sensitivity of plot-scale experiments simulating climate change effects on Arctic heathland soils to potential confounding effects of spatial and temporal changes in soil microbial communities is unknown. Here, the variation in heathland soil bacterial communities at two survey sites in Sweden between spring and summer 2013 and at scales between 0-1 m and, 1-100 m and between sites (> 100 m) were investigated in parallel using 16S rRNA gene T-RFLP and amplicon sequencing. T-RFLP did not reveal spatial structuring of communities at scales < 100 m in any site or season. However, temporal changes were striking. Amplicon sequencing corroborated shifts from r- to K-selected taxon-dominated communities, influencing in silico predictions of functional potential. Network analyses reveal temporal keystone taxa, with a spring betaproteobacterial sub-network centred upon a Burkholderia operational taxonomic unit (OTU) and a reconfiguration to a summer sub-network centred upon an alphaproteobacterial OTU. Although spatial structuring effects may not confound comparison between plot-scale treatments, temporal change is a significant influence. Moreover, the prominence of two temporally exclusive keystone taxa suggests that the stability of Arctic heathland soil bacterial communities could be disproportionally influenced by seasonal perturbations affecting individual taxa.


The protective effects of shikonin on hepatic ischemia/reperfusion injury are mediated by the activation of the PI3K/Akt pathway.
Hepatic ischemia/reperfusion (I/R) injury, which can result in severe liver injury and dysfunction, occurs in a variety of conditions such as liver transplantation, shock, and trauma. Cell death in hepatic I/R injury has been linked to apoptosis and autophagy. Shikonin plays a significant protective role in ischemia/reperfusion injury. The purpose of the present study was to investigate the protective effect of shikonin on hepatic I/R injury and explore the underlying mechanism. Mice were subjected to segmental (70%) hepatic warm ischemia to induce hepatic I/R injury. Two doses of shikonin (7.5 and 12.5 mg/kg) were administered 2 h before surgery. Balb/c mice were randomly divided into four groups: normal control, I/R, and shikonin preconditioning at two doses (7.5 and 12.5 mg/kg). The serum and liver tissues were collected at three time points (3, 6, and 24 h). Shikonin significantly reduced serum AST and ALT levels and improved pathological features. Shikonin affected the expression of Bcl-2, Bax, caspase 3, caspase 9, Beclin-1, and LC3, and upregulated PI3K and p-Akt compared with the levels in the I/R group. Shikonin attenuated hepatic I/R injury by inhibiting apoptosis and autophagy through a mechanism involving the activation of PI3K/Akt signaling.


No neuropathologic evidence for an increased frequency of Alzheimer's disease among elderly schizophrenics.
There is currently controversy as to the frequency of Alzheimer's disease (AD) in elderly persons with schizophrenia. Several studies have reported an increased frequency of AD in elderly schizophrenics, whereas others have found no increase. This issue is important because it has been hypothesized that medications used to treat schizophrenia may exacerbate AD histopathology. We examined autopsy cases from a state psychiatric hospital and a Veterans Affairs medical center. Charts were reviewed on 166 subjects to determine if the history warranted a DSM-IV diagnosis of schizophrenia. All subjects had complete gross and microscopic neuropathologic evaluations, which were reviewed for evidence of Alzheimer's disease. Retrospective chart review identified 51 subjects over the age of 55 who met DSM-IV criteria for schizophrenia (mean age = 71.7 years, SD = 8.6, range 56-95 years). Of these 51, only I met neuropathologic criteria for AD, a frequency of 2%. The frequency of subjects meeting neuropathologic criteria for Alzheimer's disease in our sample of schizophrenics was equal to or less than that found in the general population. Because institutionalized populations may contain an excess of elderly schizophrenic patients with severe behavioral pathologies, which may in turn reflect the presence of neurodegenerative processes such as Alzheimer's disease, our results may actually overestimate the frequency of Alzheimer's in the entire schizophrenic population. The frequency of Alzheimer's disease in the elderly with schizophrenia may be less than that in the general population.


Differences in Muscle Quantity and Quality by HIV Serostatus and Sex.
People with HIV (PWH) experience greater declines in both muscle function and muscle mass with aging. Whether changes in muscle quality and quantity with aging differ between men and women with HIV and the implications on muscle function are not established. In coordinated substudies of the Multicenter AIDS Cohort Study and Women's Interagency HIV Study, participants completed physical function and falls assessments; total trunk/thigh density, inversely related to fatty infiltration, and area were quantified from computed tomography (CT) scans. Generalized linear models were used to explore variables affecting density/area, and associations between area/density and physical function and falls. CT scans were available on 387 men (198 PWH) and 184 women (118 PWH). HIV serostatus was associated with greater lateralis, paraspinal, and hamstring area, but lower psoas area and density. Older age and female sex were associated with smaller trunk muscle area and lower density. Both lower muscle area and muscle density were associated with several measures of impaired physical function. The odds of falling were lower with greater hamstring density, but not associated with other measurers of muscle area or density. In summary, older adults with HIV appear to have smaller and less dense (fattier) psoas, a key component in truncal stability and hip flexion that could have implications on physical function. The longitudinal associations of muscle area and density with physical function require careful investigation, with a particular focus on characteristics and interventions that can preserve muscle area, density, and function over time.


n-3 PUFAs in cancer, surgery, and critical care: a systematic review on clinical effects, incorporation, and washout of oral or enteral compared with parenteral supplementation.
n-3 (omega-3) Fatty acids (FAs) may have beneficial effects in patients with cancer or in patients who undergo surgery or critical care. Our aim was to systematically review the effects of oral or enteral and parenteral n-3 FA supplementation on clinical outcomes and to describe the incorporation of n-3 FAs into phospholipids of plasma, blood cells, and mucosal tissue and the subsequent washout in these patients. We investigated the supplementation of n-3 FAs in these patients by using a systematic literature review. In cancer, the oral or enteral supplementation of n-3 FAs contributed to the maintenance of body weight and quality of life but not to survival. We did not find any studies on parenteral supplementation of n-3 FAs in cancer. In surgical oncology, we did not find any studies on enteral supplementation of n-3 FAs. However, postoperative parenteral supplementation in surgical oncology may reduce the length of a hospital stay. For general surgery, we did not find any studies on enteral supplementation of n-3 FAs, and evidence on parenteral supplementation was insufficient. In critical care, enteral supplementation of n-3 FAs had beneficial effects on clinical outcomes; evidence on parenteral supplementation in critical care was inconsistent. The incorporation of n-3 FAs in plasma and blood cells was slower with enteral supplementation (4-7 d) than with parenteral supplementation (1-3 d). The washout was 5-7 d. This review shows the beneficial effects of n-3 FA supplementation in cancer, surgical oncology, and critical care patients. Supplementation in these specific patient populations could be considered with the route of administration taken into account.


Increasing physical activity among young children from disadvantaged communities: study protocol of a group randomised controlled effectiveness trial.
Participation in regular physical activity (PA) during the early years helps children achieve healthy body weight and can substantially improve motor development, bone health, psychosocial health and cognitive development. Despite common assumptions that young children are naturally active, evidence shows that they are insufficiently active for health and developmental benefits. Exploring strategies to increase physical activity in young children is a public health and research priority. Jump Start is a multi-component, multi-setting PA and gross motor skill intervention for young children aged 3-5 years in disadvantaged areas of New South Wales, Australia. The intervention will be evaluated using a two-arm, parallel group, randomised cluster trial. The Jump Start protocol was based on Social Cognitive Theory and includes five components: a structured gross motor skill lesson (Jump In); unstructured outdoor PA and gross motor skill time (Jump Out); energy breaks (Jump Up); activities connecting movement to learning experiences (Jump Through); and a home-based family component to promote PA and gross motor skill (Jump Home). Early childhood education and care centres will be demographically matched and randomised to Jump Start (intervention) or usual practice (comparison) group. The intervention group receive Jump Start professional development, program resources, monthly newsletters and ongoing intervention support. Outcomes include change in total PA (accelerometers) within centre hours, gross motor skill development (Test of Gross Motor Development-2), weight status (body mass index), bone strength (Sunlight MiniOmni Ultrasound Bone Sonometer), self-regulation (Heads-Toes-Knees-Shoulders, executive function tasks, and proxy-report Temperament and Approaches to learning scales), and educator and parent self-efficacy. Extensive quantitative and qualitative process evaluation and a cost-effectiveness evaluation will be conducted. The Jump Start intervention is a unique program to address low levels of PA and gross motor skill proficiency, and support healthy lifestyle behaviours among young children in disadvantaged communities. If shown to be efficacious, the Jump Start approach can be expected to have implications for early childhood education and care policies and practices, and ultimately a positive effect on the health and development across the life course. Australian and New Zealand Clinical Trials Registry No: ACTRN12614000597695 , first received: June 5, 2014.


How Playfulness Motivates - Putative Looping Effects of Autonomy and Surprise Revealed by Micro-Phenomenological Investigations.
Play and playfulness have repeatedly been suggested to promote learning and performance, also in environments traditionally not connotated with play. However, finding empirical evidence for these claims has been aggravated by the lack of a definition of play and playfulness fitting to this description. This paper proposes to consider playfulness as an attitude, mode or mental stance, that can be modulated independent of the activity pursued and of the general character of the person. It furthermore introduces the micro-phenomenological method to assess the process and outcome of such modulation. To explore this, we devised a simple building task in a controlled within-subject design, interviewing each participant on how they accomplished the task when asked to perform it so that it either felt playful or not playful. The outcomes of this data driven approach supported this notion of playfulness as a stance, and allowed for specific hypotheses about the temporal course and mechanisms of becoming playful. They suggest that an experience of autonomy and self-expression may be key to the success of the modulation. They furthermore indicate that the resulting playful state may allow for an exploratory engagement with materials that can lead to surprising results. Such unexpected results seem to enhance participants' feeling of competence which, in turn, may increase the motivation for the task. We discuss these results within the framework of Deci and Ryan's motivational theory and in relation to current research on gamification and learning.


Modeling of pathological traits in Alzheimer's disease based on systemic extracellular signaling proteome.
The study of chronic brain diseases including Alzheimer's disease in patients is typically limited to brain imaging or psychometric testing. Given the epidemic rise and insufficient knowledge about pathological pathways in sporadic Alzheimer's disease, new tools are required to identify the molecular changes underlying this disease. We hypothesize that levels of specific secreted cellular signaling proteins in cerebrospinal fluid or plasma correlate with pathological changes in the Alzheimer's disease brain and can thus be used to discover signaling pathways altered in the disease. Here we measured 91 proteins of this subset of the cellular communication proteome in plasma or cerebrospinal fluid in patients with Alzheimer's disease and cognitively normal controls to mathematically model disease-specific molecular traits. We found small numbers of signaling proteins that were able to model key pathological markers of Alzheimer's disease, including levels of cerebrospinal fluid β-amyloid and tau, and classify disease in independent samples. Several of these factors had previously been implicated in Alzheimer's disease supporting the validity of our approach. Our study also points to proteins which were previously unknown to be associated with Alzheimer's disease thereby implicating novel signaling pathways in this disorder.


T2D and Depression Risk Gene Proteasome Modulator 9 is Linked to Insomnia.
Insomnia increases type-2 diabetes (T2D) risk. The 12q24 locus is linked to T2D, depression, bipolar disorder and anxiety. At the 12q24 locus, the Proteasome-Modulator 9 (PSMD9) single nucleotide polymorphisms (SNPs) rs74421874 [intervening sequence (IVS) 3+nt460-G>A], rs3825172 (IVS3+nt437-C>T) and rs14259 (E197G-A>G) are linked to: T2D, depression, anxiety, maturity-onset-diabetes-of the young 3/MODY3, obesity, waist circumference, hypertension, hypercholesterolemia, T2D-macrovascular disease, T2D-microvascular disease, T2D-neuropathy, T2D-carpal-tunnel syndrome, T2D-nephropathy, T2D-retinopathy and non-diabetic retinopathy. PSMD9 SNP rs1043307/rs14259 (E197G-A>G) plays a role in anti-depressant therapy response, depression and schizophrenia. We aimed at determining PSMD9 rs74421874/rs3825172/rs14259 SNPs potential linkage to primary insomnia and sleep hours in T2D families. We recruited 200 Italian T2D families phenotyping them for primary insomnia and sleep hours per night. PSMD9-T2D-risk SNPs rs74421874/rs3825172 and rs1043307/rs14259 were tested for linkage with insomnia and sleep hours. Non-parametric-linkage analysis, linkage-disequilibrium-model analysis, single-SNP analysis, cluster-based-parametric analysis, quantitative-trait and variant-component analysis were performed using Merlin software. To validate data, 1000 replicates were executed for the significant non-parametric data. PSMD9 rs74421874 (IVS3+nt460-G>A), rs3825172 (IVS3+nt437-C>T) and rs1043307/rs14259 (E197G-A>G) SNPs are linked to insomnia in our Italian families.


Analytic height correlation function of rough surfaces derived from light scattering.
We derive an analytic expression for the height correlation function of a homogeneous, isotropic rough surface based on the inverse wave scattering method of Kirchhoff theory. The expression directly relates the height correlation function to diffuse scattered intensity along a linear path at fixed polar angle. We test the solution by measuring the angular distribution of light scattered from rough silicon surfaces and comparing extracted height correlation functions to those derived from atomic force microscopy (AFM). The results agree closely with AFM over a wider range of roughness parameters than previous formulations of the inverse scattering problem, while relying less on large-angle scatter data. Our expression thus provides an accurate analytical equation for the height correlation function of a wide range of surfaces based on measurements using a simple, fast experimental procedure.


Comparative characterization of mAb producing hapten-specific hybridoma cells by flow cytometric analysis and ELISA.
A novel method that optimizes the screening for antibody-secreting hapten-specific hybridoma cells by using flow cytometry is described. Cell clones specific for five different haptens were analyzed. We selectively double stained and analyzed fixed hybridoma cells with fluorophore-labeled haptens to demonstrate the target-selectivity, and with a fluorophore-labeled anti-mouse IgG antibody to characterize the level of surface expression of membrane-bound IgGs. ELISA measurements with the supernatants of the individual hybridoma clones revealed that antibodies from those cells, which showed the highest fluorescence intensities in the flow cytometric analysis, also displayed the highest affinities for the target antigens. The fluorescence intensity of antibody-producing cells corresponded well with the produced antibodies' affinities toward their respective antigens. Immunohistochemical staining verified the successful double labeling of the cells. Our method makes it possible to perform a high-throughput screening for hybridoma cells, which have both an adequate IgG production rate and a high target affinity.


Human adult stem cells derived from adipose tissue and bone marrow attenuate enteric neuropathy in the guinea-pig model of acute colitis.
Mesenchymal stem cells (MSCs) have been identified as a viable treatment for inflammatory bowel disease (IBD). MSCs derived from bone marrow (BM-MSCs) have predominated in experimental models whereas the majority of clinical trials have used MSCs derived from adipose tissue (AT-MSCs), thus there is little consensus on the optimal tissue source. The therapeutic efficacies of these MSCs are yet to be compared in context of the underlying dysfunction of the enteric nervous system innervating the gastrointestinal tract concomitant with IBD. This study aims to characterise the in vitro properties of MSCs and compare their in vivo therapeutic potential for the treatment of enteric neuropathy associated with intestinal inflammation. BM-MSCs and AT-MSCs were validated and characterised in vitro. In in vivo experiments, guinea-pigs received either 2,4,6-trinitrobenzene-sulfonate acid (TNBS) for the induction of colitis or sham treatment by enema. MSCs were administered at a dose of 1x10(6) cells via enema 3 hours after the induction of colitis. Colon tissues were collected 24 and 72 hours after TNBS administration to assess the level of inflammation and damage to the ENS. MSC migration to the myenteric plexus in vivo was elucidated by immunohistochemistry and in vitro using a modified Boyden chamber assay. Cells exhibited multipotency and a typical surface immunophenotype for validation as bona fide MSCs. In vitro characterisation revealed distinct differences in growth kinetics, clonogenicity and cell morphology between MSC types. In vivo, BM-MSCs were comparatively more effective than AT-MSCs in attenuating leukocyte infiltration and neuronal loss in the myenteric plexus. MSCs from both sources equally ameliorated body weight loss, gross morphological damage to the colon, changes in the neurochemical coding of neuronal subpopulations and the reduction in density of extrinsic and intrinsic nerve fibres innervating the colon. MSCs from both sources migrated to the myenteric plexus in in vivo colitis and in an in vitro assay. These data from in vitro experiments suggest that AT-MSCs are ideal for cellular expansion. However, BM-MSCs were more therapeutic in the treatment of enteric neuropathy and plexitis. These characteristics should be considered when deciding on the MSC tissue source.


Reproductive indices in natural nests of giant Amazon river turtles Podocnemis expansa (Schweigger, 1812) (Testudines, Podocnemididae) in the Environmental Protection Area Meanders of the Araguaia River.
A count was made of unhatched eggs and hatchling live and dead Podocnemis expansa turtles in 327 natural nests located on the beaches of the Environmental Protection Area (EPA) Meanders of the Araguaia River, to determine the percentage of hatching (94.63%), non-hatching (5.37%), survival (94.24%) and hatchling mortality (5.76%), and the average percentage of dead hatchlings during the 15 days in the nursery (0.97%). The mean number of hatchlings per nest was determined from the sum of the number of live and dead hatchlings divided by the total number of nests, while the mean number of eggs per nest was determined from the sum of live and dead hatchlings and unhatched eggs divided by the number of nests. These calculations yielded the following mean values: live hatchlings (88.98 ± 23.94), dead hatchlings (0.37 ± 0.93), unhatched eggs (5.07 ± 9.57), and total number of eggs (94.42 ± 21.30). The reproductive efficiency of the wild population of P. expansa can be affected by many environmental factors such as temperature, humidity and rainfall. In addition, man-made factors like the presence of chemicals in the water and the potential for infectious disease also have significant impact. The reproductive indices data obtained from this study are indispensable for future investigations of hatching anomalies.


Dental artifacts in the head and neck region: implications for Dixon-based attenuation correction in PET/MR.
In the absence of CT or traditional transmission sources in combined clinical positron emission tomography/magnetic resonance (PET/MR) systems, MR images are used for MR-based attenuation correction (MR-AC). The susceptibility effects due to metal implants challenge MR-AC in the neck region of patients with dental implants. The purpose of this study was to assess the frequency and magnitude of subsequent PET image distortions following MR-AC. A total of 148 PET/MR patients with clear visual signal voids on the attenuation map in the dental region were included in this study. Patients were injected with [(18)F]-FDG, [(11)C]-PiB, [(18)F]-FET, or [(64)Cu]-DOTATATE. The PET/MR data were acquired over a single-bed position of 25.8 cm covering the head and neck. MR-AC was based on either standard MR-ACDIXON or MR-ACINPAINTED where the susceptibility-induced signal voids were substituted with soft tissue information. Our inpainting algorithm delineates the outer contour of signal voids breaching the anatomical volume using the non-attenuation-corrected PET image and classifies the inner air regions based on an aligned template of likely dental artifact areas. The reconstructed PET images were evaluated visually and quantitatively using regions of interests in reference regions. The volume of the artifacts and the computed relative differences in mean and max standardized uptake value (SUV) between the two PET images are reported. The MR-based volume of the susceptibility-induced signal voids on the MR-AC attenuation maps was between 1.6 and 520.8 mL. The corresponding/resulting bias of the reconstructed tracer distribution was localized mainly in the area of the signal void. The mean and maximum SUVs averaged across all patients increased after inpainting by 52% (± 11%) and 28% (± 11%), respectively, in the corrected region. SUV underestimation decreased with the distance to the signal void and correlated with the volume of the susceptibility artifact on the MR-AC attenuation map. Metallic dental work may cause severe MR signal voids. The resulting PET/MR artifacts may exceed the actual volume of the dental fillings. The subsequent bias in PET is severe in regions in and near the signal voids and may affect the conspicuity of lesions in the mandibular region.


CpG- and LPS-activated MAPK signaling in in vitro cultured salmon (Salmo salar) mononuclear phagocytes.
The Mitogen-activated protein kinases (MAPK) are involved in transmitting intracellular signals downstream of diverse cell surface receptors and mediate the response to ligands such as growth factors, hormones and cytokines. In addition, MAPK are critically involved in the innate immune response to pathogen-derived substances, commonly referred to as pathogen-associated molecular patterns (PAMPs), such as bacterial lipopolysaccharide (LPS) and bacterial DNA rich in CpG dinucleotides. Currently, a great deal of knowledge is available about the involvement of MAPK in the innate immune response to PAMPs in mammals; however, little is known about the role of the different MAPK classes in the immune response to PAMPs in lower vertebrates. In the current study, p38 phosphorylation was induced by CpG oligonucleotides (ODNs) and LPS in primary salmon mononuclear phagocytes. Pre-treatment of the cells with a p38 inhibitor (SB203580) blocked the PAMP-induced p38 activity and suppressed the upregulation of most of the CpG- and LPS-induced transcripts highlighting the role of this kinase in the salmon innate immune response to PAMPs. In contrast to p38, the phosphorylation of extracellular signal-regulated kinase (ERK), a MAPK involved primarily in response to mitogens, was high in resting cells and, surprisingly, incubation with both CpG and control ODNs downregulated the phospho-ERK levels independently of p38 activation. The basal phospho-ERK level and the CpG-inducible p38 phosphorylation were greatly influenced by the length of in vitro incubation. The basal phospho-ERK level increased gradually throughout a 5-day culture period and was PI3K-dependent as demonstrated by its sensitivity to Wortmannin suggesting it is influenced by growth factors. Overall these data indicate that both basal and PAMP-induced activity of MAPKs might be greatly influenced by the differentiation status of salmon mononuclear phagocytes.


The relevance of hearing a crack in ankle injuries.
To examine the predictive value of a crack noise or sensation in the history of injury in the diagnosis of ankle fracture. A short questionnaire was filled in on 464 patients with isolated ankle injuries attending the accident and emergency department in a three month period from July to September. These patients were seen in the usual way in the department and the need for x ray assessed according to clinical judgement and existing departmental guidelines. Cases which subsequently proved to be other than ankle injuries, for example, fractured calcaneus, were excluded from the study. A positive history of hearing or feeling a crack did not indicate the need for an x ray or increase the possibility of a fracture; indeed the history of a crack made the presence of a fracture less likely. The clinical diagnosis of absence of fracture without radiological examination may require careful explanation to the patient. Hearing a crack in the ankle does not suggest a fracture.


New insights in the dihydroxybenzenes-driven Fenton reaction: electrochemical study of interaction between dihydroxybenzenes and Fe(III).
It has been reported that the dihydroxybenzene (DHB) driven Fenton reaction is more efficient to degrade recalcitrant substrates than the simple Fenton reaction. The enhanced reactivity of the DHB driven Fenton reaction is not clear, but it could be explained by the formation of oxidant species different from the ones formed by classical Fenton reaction or by the shift of the redox potential of the complex formed by DHB and Fe(III). The redox reaction between Fe(III) and the DHBs 1,2-dihydroxybenzene (catechol, CAT), 2,3-dihydroxybenzoic acid (2,3-DHBA), 3,4-dihydroxybenzoic acid (3,4-DHBA), and 1,2-dihydroxy-3,5-benzenedisulfonate (TIRON) was studied by cyclic voltammetry to better understand the enhanced reactivity of the DHB driven Fenton reaction. It was determined that the amount of Fe(II) produced by the redox reaction between Fe(III) and DHBs was insufficient to explain the enhanced reactivity. Cyclic voltammograms (CV) of the DHBs/Fe(III) systems show a quasi-reversible or irreversible behavior and also shifting and splitting the anodic peaks. This effect can be related to DHBs oxidation by Fe(III), but not to a real interaction.


Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells.
Information on design principles governing transcriptome changes upon transition from safe to hazardous drug concentrations or from tolerated to cytotoxic drug levels are important for the application of toxicogenomics data in developmental toxicology. Here, we tested the effect of eight concentrations of valproic acid (VPA; 25-1000 μM) in an assay that recapitulates the development of human embryonic stem cells to neuroectoderm. Cells were exposed to the drug during the entire differentiation process, and the number of differentially regulated genes increased continuously over the concentration range from zero to about 3000. We identified overrepresented transcription factor binding sites (TFBS) as well as superordinate cell biological processes, and we developed a gene ontology (GO) activation profiler, as well as a two-dimensional teratogenicity index. Analysis of the transcriptome data set by the above biostatistical and systems biology approaches yielded the following insights: (i) tolerated (≤25 μM), deregulated/teratogenic (150-550 μM), and cytotoxic (≥800 μM) concentrations could be differentiated. (ii) Biological signatures related to the mode of action of VPA, such as protein acetylation, developmental changes, and cell migration, emerged from the teratogenic concentrations range. (iii) Cytotoxicity was not accompanied by signatures of newly emerging canonical cell death/stress indicators, but by catabolism and decreased expression of cell cycle associated genes. (iv) Most, but not all of the GO groups and TFBS seen at the highest concentrations were already overrepresented at 350-450 μM. (v) The teratogenicity index reflected this behavior, and thus differed strongly from cytotoxicity. Our findings suggest the use of the highest noncytotoxic drug concentration for gene array toxicogenomics studies, as higher concentrations possibly yield wrong information on the mode of action, and lower drug levels result in decreased gene expression changes and thus a reduced power of the study.


Formation of self-trapping waveguides in bulk PMMA media doped with Phenanthrenequinone.
Experimental and theoretical investigations of light self-trapping waveguides in a bulk polymeric medium based on polymethylmethacrylate (PMMA) with photosensitive phenanthrenequinone (PQ)-molecules are examined. Self-channeling was generated for the first time in this nonlinear bulk PQ-PMMA media with a thickness up to several millimeters and 0.1 mol. % PQ-concentration. The experimental formation of volume waveguide structures with a length of 2 - 3 cm at different laser wavelengths (405 nm, 488 nm, and 514.5 nm) was demonstrated. The calculations based on a model for the laser beam propagation in the bulk PQ-PMMA medium with competitive nonlinearities are in a good agreement with the experiments.


A novel minicollagen gene links cnidarians and myxozoans.
Myxozoans are enigmatic endoparasitic organisms sharing morphological features with bilateria, protists and cnidarians. This, coupled with their highly divergent gene sequences, has greatly obscured their phylogenetic affinities. Here we report the sequencing and characterization of a minicollagen homologue (designated Tb-Ncol-1) in the myxozoan Tetracapsuloides bryosalmonae. Minicollagens are phylum-specific genes encoding cnidarian nematocyst proteins. Sequence analysis revealed a cysteine-rich domain (CRD) architecture and genomic organization similar to group 1 minicollagens. Homology modelling predicted similar three-dimensional structures to Hydra CRDs despite deviations from the canonical pattern of group 1 minicollagens. The discovery of this minicollagen gene strongly supports myxozoans as cnidarians that have radiated as endoparasites of freshwater, marine and terrestrial hosts. It also reveals novel protein sequence variation of relevance to understanding the evolution of nematocyst complexity, and indicates a molecular/morphological link between myxozoan polar capsules and cnidarian nematocysts. Our study is the first to illustrate the power of using genes related to a taxon-specific novelty for phylogenetic inference within the Metazoa, and it exemplifies how the evolutionary relationships of other metazoans characterized by extreme sequence divergence could be similarly resolved.


Influenza Vaccine Requirements in United States Child Care Centers.
Influenza vaccine is the most effective means to prevent influenza for the high-risk population of child care attendees. This national survey assessed child care center directors' reports of seasonal influenza vaccine requirements for children and adult caregivers. This was a 2016 telephone-based survey of child care center directors randomly selected from a national database of licensed United States child care centers and queried about influenza vaccine requirements. Conceptually related items were grouped into 4 indexes: general infection control, use of health consultants, quality of child care, and pandemic influenza preparedness. These indexes, along with other center and director characteristics, were used to predict director-reported influenza vaccine requirements. Of 518 child care center directors, only 24.5% and 13.1% reported an influenza vaccine requirement for children and adult caregivers, respectively. Center and director characteristics and the indexes were not associated with a director-reported influenza vaccine requirement. After adjusting for covariates, only having a state influenza vaccine law for children and an adult influenza vaccine requirement predicted having a child influenza vaccine requirement. Only having a child influenza vaccine requirement predicted having an adult vaccine requirement. Director-reported influenza vaccine requirements for children and adult caregivers were influenced primarily by state influenza vaccine laws. Given the high risk of children in child care and low director-reported influenza vaccine requirements, more states should pass laws requiring influenza vaccine for children and adult caregivers at child care programs.


Changes to the ACGME Common Program Requirements and Their Potential Impact on Emergency Medicine Core Faculty Protected Time.
The Accreditation Council for Graduate Medical Education (ACGME), which regulates residency and fellowship training in the United States, recently revised the minimum standards for all training programs. These standards are codified and published as the Common Program Requirements. Recent specific revisions, particularly removing the requirement ensuring protected time for core faculty, are poised to have a substantial impact on emergency medicine training programs. A group of representatives and relevant stakeholders from national emergency medicine (EM) organizations was convened to assess the potential effects of these changes on core faculty and the training of emergency physicians. We reviewed the literature and results of surveys conducted by EM organizations to examine the role of core faculty protected time. Faculty nonclinical activities contribute greatly to the academic missions of EM training programs. Protected time and reduced clinical hours allow core faculty to engage in education and research, which are two of the three core pillars of academic EM. Loss of core faculty protected time is expected to have detrimental impacts on training programs and on EM generally. We provide consensus recommendations regarding EM core faculty clinical work hour limitations to maintain protected time for educational activities and scholarship and preserve the quality of academic EM.


Spinal sensory projection neuron responses to spinal cord stimulation are mediated by circuits beyond gate control.
Spinal cord stimulation (SCS) is a therapy used to treat intractable pain with a putative mechanism of action based on the Gate Control Theory. We hypothesized that sensory projection neuron responses to SCS would follow a single stereotyped response curve as a function of SCS frequency, as predicted by the Gate Control circuit. We recorded the responses of antidromically identified sensory projection neurons in the lumbar spinal cord during 1- to 150-Hz SCS in both healthy rats and neuropathic rats following chronic constriction injury (CCI). The relationship between SCS frequency and projection neuron activity predicted by the Gate Control circuit accounted for a subset of neuronal responses to SCS but could not account for the full range of observed responses. Heterogeneous responses were classifiable into three additional groups and were reproduced using computational models of spinal microcircuits representing other interactions between nociceptive and nonnociceptive sensory inputs. Intrathecal administration of bicuculline, a GABAA receptor antagonist, increased spontaneous and evoked activity in projection neurons, enhanced excitatory responses to SCS, and reduced inhibitory responses to SCS, suggesting that GABAA neurotransmission plays a broad role in regulating projection neuron activity. These in vivo and computational results challenge the Gate Control Theory as the only mechanism underlying SCS and refine our understanding of the effects of SCS on spinal sensory neurons within the framework of contemporary understanding of dorsal horn circuitry.


How much do focal infarcts distort white matter lesions and global cerebral atrophy measures?.
White matter lesions (WML) and brain atrophy are important biomarkers in stroke and dementia. Stroke lesions, either acute or old, symptomatic or silent, are common in older people. Such stroke lesions can have similar signals to WML and cerebrospinal fluid (CSF) on magnetic resonance (MR) images, and may be classified accidentally as WML or CSF by MR image processing algorithms, distorting WML and brain atrophy volume from the true volume. We evaluated the effect that acute or old stroke lesions at baseline, and new stroke lesions occurring during follow-up, could have on measurement of WML volume, cerebral atrophy and their longitudinal progression. We used MR imaging data from patients who had originally presented with acute lacunar or minor cortical ischaemic stroke symptoms, recruited prospectively, who were scanned at baseline and about 3 years later. We measured WML and CSF volumes (ml) semi-automatically. We manually outlined the acute index stroke lesion (ISL), any old stroke lesions present at baseline, and new lesions appearing de novo during follow-up. We compared baseline and follow-up WML volume, cerebral atrophy and their longitudinal progression excluding and including the acute ISL, old and de novo stroke lesions. A non-parametric test (Wilcoxon's signed rank test) was used to compare the effects. Among 46 patients (mean age 72 years), 33 had an ISL visible on MR imaging (median volume 2.05 ml, IQR 0.88-8.88) and 7 of the 33 had old lacunes at baseline: WML volume was 8.54 ml (IQR 5.86-15.80) excluding versus 10.98 ml (IQR 6.91-24.86) including ISL (p < 0.001). At follow-up, median 39 months later (IQR 30-45), 3 patients had a de novo stroke lesion; total stroke lesion volume had decreased in 11 and increased in 22 patients: WML volume was 12.17 ml (IQR 8.54-19.86) excluding versus 14.79 ml (IQR 10.02-38.03) including total stroke lesions (p < 0.001). Including/excluding lacunes at baseline or follow-up also made small differences. Twenty-two of the 33 patients had tissue loss due to stroke lesions between baseline and follow-up, resulting in a net median brain tissue volume loss (i.e. atrophy) during follow-up of 24.49 ml (IQR 12.87-54.01) excluding versus 24.61 ml (IQR 15.54-54.04) including tissue loss due to stroke lesions (p < 0.001). Including stroke lesions in the WML volume added substantial noise, reduced statistical power, and thus increased sample size estimated for a clinical trial. Failure to exclude even small stroke lesions distorts WML volume, cerebral atrophy and their longitudinal progression measurements. This has important implications for design and sample size calculations for observational studies and randomised trials using WML volume, WML progression or brain atrophy as outcome measures. Improved methods of discriminating between stroke lesions and WML, and between tissue loss due to stroke lesions and true brain atrophy are required.


Trends in the utilization of radiotherapy for spinal meningiomas: insights from the 2004-2015 National Cancer Database.
OBJECTIVERecent studies have reported on the utility of radiosurgery for local control and symptom relief in spinal meningioma. The authors sought to evaluate national utilization trends in radiotherapy (including radiosurgery), investigate possible factors associated with its use in patients with spinal meningioma, and its impact on survival for atypical tumors.METHODSUsing the ICD-O-3 topographical codes C70.1, C72.0, and C72.1 and histological codes 9530-9535 and 9537-9539, the authors queried the National Cancer Database for patients in whom spinal meningioma had been diagnosed between 2004 and 2015. Patients who had undergone radiation in addition to surgery and those who had received radiation as the only treatment were analyzed for factors associated with each treatment.RESULTSFrom among 10,458 patients with spinal meningioma in the database, the authors found a total of 268 patients who had received any type of radiation. The patients were divided into two main groups for the analysis of radiation alone (137 [51.1%]) and radiation plus surgery (131 [48.9%]). An age > 69 years (p < 0.001), male sex (p = 0.03), and tumor size 5 to < 6 cm (p < 0.001) were found to be associated with significantly higher odds of receiving radiation alone, whereas a Charlson-Deyo Comorbidity Index ≥ 2 (p = 0.01) was associated with significantly lower odds of receiving radiation alone. Moreover, a larger tumor size (2 to < 3 cm, p = 0.01; 3 to < 4 cm, p < 0.001; 4 to < 5 cm, p < 0.001; 5 to < 6 cm, p < 0.001; and ≥ 6 cm, p < 0.001; reference = 1 to < 2 cm), as well as borderline (p < 0.001) and malignant (p < 0.001) tumors were found to be associated with increased odds of undergoing radiation in addition to surgery. Receiving adjuvant radiation conferred a significant reduction in overall mortality among patients with borderline or malignant spinal meningiomas (HR 2.12, 95% CI 1.02-4.1, p = 0.02).CONCLUSIONSThe current analysis of cases from a national cancer database revealed a small increase in the use of radiation for the management of spinal meningioma without a significant increase in overall survival. Larger tumor size and borderline or malignant behavior were found to be associated with increased radiation use. Data in the present analysis failed to show an overall survival benefit in utilizing adjuvant radiation for atypical tumors.


Relationship between Factor V Leiden Gene Variant and Risk of Ischemic Stroke: A Case-Control Study.
Factor V Leiden is the most common genetic variation among the blood coagulation pathway which leads to prothrombotic state, therefore, is considered an important gene for understating the stroke mechanism. The aim of the present study is to determine the relationship between single nucleotide polymorphism at G1691A position of Factor V gene and risk of ischemic stroke (IS) in North Indian population. In a retrospective case-control study, 250 patients with IS and 250 age- and gender-matched controls were enrolled in the period of October 2012 to September 2014 from in- and out-patient department of Neurology, All India Institute of Medical Sciences, New Delhi, India. Deoxyribonucleic acid for each case and control was isolated from peripheral blood using phenol-chloroform extraction method. Polymerase chain reaction-restriction fragment length polymorphism method was used to determine the polymorphism. Data were analyzed using STATA Software Version 13. The mean age of IS patient was 52.8 ± 12.5 years and in control group was 50.97 ± 12.7 years. Genotypic frequency distributions were in accordance with Hardy-Weinberg equilibrium in both cases and controls. As expected hypertension, diabetes, dyslipidemia, smoking, heavy alcohol intake, family history of stroke, and poor economic status were significantly associated with the risk of IS. Multivariate analysis revealed 5.17 times higher odds for developing the risk of large vessel subtype of IS in patients carrying Factor V Leiden G1691A gene variation as compared to control subjects (OR, 5.17; 95% CI, 1.32-20.3, P = 0.01). The present study suggests that Factor V Leiden G1691A polymorphism may be significantly associated with the risk of large vessel subtype of IS. Large sample size studies using prospective cohort designs are required to corroborate the present findings.


The political ecology of disaster: an analysis of factors influencing U.S. tornado fatalities and injuries, 1998-2000.
This study examines casualties from tornadoes in the United States between the years 1998 and 2000. A political model of human ecology (POET) was used to explore how the environment, technology, and social inequality influence rates of fatalities and injuries in two models. Data were drawn from four sources: John Hart's Severe Plot v2.0, National Weather Service (NWS) Warning Verification data, Storm Prediction Center (SPC) watch data, and tract-level census data. Negative binomial regression was used to analyze the causes of tornado fatalities and injuries. Independent variables (following POET) are classified in the following manner: population, organization, environment, and technology. Rural population, population density, and household size correspond to population; racial minorities and deprivation represent social organization; tornado area represents environment; and tornado watches and warnings, as well as mobile homes, correspond to technology. Findings suggest a strong relationship between the size of a tornado path and both fatalities and injuries, whereas other measures related to technology, population, and organization produce significant yet mixed results. Census tracts having larger populations of rural residents was, of the nonenvironmental factors, the most conclusive regarding its effects across the two models. The outcomes of analysis, although not entirely supportive of the model presented in this study, suggest to some degree that demographic and social factors play a role in vulnerability to tornadoes.


A Database Study of Visual Outcomes and Intraoperative Complications of Postvitrectomy Cataract Surgery.
To analyze the visual outcomes and rate of intraoperative complications of phacoemulsification surgery after prior pars plana vitrectomy (PPV). Retrospective, multicenter database study. Eyes that underwent phacoemulsification between June 2005 and March 2015 at 8 sites in the United Kingdom. Study eyes were classified as vitrectomized (prior PPV group) or nonvitrectomized (reference group) depending on the vitreous state at the time of cataract surgery. Eyes with multiple intraocular surgeries or history of ocular diseases known to cause cataract progression or increased risk of intraoperative complications during phacoemulsification were excluded. Logarithm of the minimum angle of resolution (logMAR) visual acuity (VA), rate of intraoperative complications, and time interval to cataract surgery. Eyes in the prior PPV group (n = 2221) had worse preoperative logMAR VA (0.96±0.60 vs. 0.62±0.52, P < 0.0001), were from younger patients, and had longer axial lengths than the nonvitrectomized group (n = 136 533). At all postoperative time points measured up to 24 weeks, mean vision was poorer in the prior PPV group (0.41±0.47 vs. 0.17±0.29 at 4-12 weeks, P < 0.0001) and a smaller proportion of eyes achieved postoperative VA ≤0.30 logMAR (Snellen, ≥20/40) (60.8% vs. 86.5% at 4-12 weeks, P < 0.0001). The rate of posterior capsular rupture was not different between the prior PPV (1.5%) and the nonvitrectomized (1.7%) groups, but the incidences of zonular dialysis (1.3% vs. 0.6%) and dropped nuclear fragments (0.6% vs. 0.2%) were higher in the prior PPV group (P < 0.0001). The mean time interval between PPV and cataract surgery was 399 days. We found a significant improvement in VA with postvitrectomy cataract surgery. However, compared with eyes without prior PPV, there was a worse mean postoperative vision of 0.2 logMAR units, a higher rate of zonular dialysis and dropped nuclear fragments, and a similar rate of posterior capsule rupture.


Dark anaerobic dinitrogen fixation by a photosynthetic microorganism.
Photosynthetic purple bacteria can grow with dinitrogen gas as the sole nitrogen source under anaerobic conditions with light as the energy source. The bacterium Rhodopseudomonas capsulata can fix nitrogen in darkness with alternative energy conversion systems, namely, anaerobic sugar fermentation and aerobic respiration at low oxygen tension. Although growth on dinitrogen is optimal under photosynthetic conditions, the results show that reduction of dinitrogen is not obligatorily coupled to activity of the photosynthetic apparatus.


Attentional Bias Through Oscillatory Coherence Between Excitatory Activity and Inhibitory Minima.
An implementation of attentional bias is presented for a network model that couples excitatory and inhibitory oscillatory units in a manner that is inspired by the mechanisms that generate cortical gamma oscillations. Attentional biases are implemented as oscillatory coherences between excitatory units that encode the spatial location or features of the target and the pool of inhibitory units. This form of attentional bias is motivated by neurophysiological findings that relate selective attention to spike field coherence. Including also pattern recognition mechanisms, we demonstrate how this implementation of attentional bias leads to selection of an attentional target while suppressing distracters for cases of spatial and feature-based attention. With respect to neurophysiological observations, we argue that the recently found positive correlation between high firing rates and strong gamma locking with attention (Vinck, Womelsdorf, Buffalo, Desimone, & Fries, 2013) may point to an essential mechanism of the brain's attentional selection and suppression processes.


Hypothalamic influences on cardiovascular response of beagles to dynamic exercise.
We studied nine young adult beagles at rest and during four levels of dynamic exercise before and after electrolytic lesions were made in the hypothalamus in the region of the fields of Forel. The beagles were habituated to run freely on a motor-driven treadmill and were instrumented chronically to allow repeated measurement of cardiovascular variables. Variables measured or calculated included O2 consumption, cardiac output, arteriovenous O2 difference, systemic arterial pressure, systemic vascular resistance, heart rate, and mixed venous blood lactate concentration. In addition, regional blood flow was measured with radioactive microspheres in two beagles at rest and during peak exercise (6.4 km/h, 20% grade). After prelesion treadmill studies, the beagles were anesthetized and the tips of stainless steel electrodes were placed bilaterally in the hypothalamus in locations that when stimulated (100-300 microA) evoked increases in cardiovascular and muscle motor function. Lesioning (5 mA; 15 s) abolished the responses evoked by stimulation. By contrast, the cardiovascular variables measured in the beagles at rest and during dynamic exercise were similar pre- and postlesion. Therefore, loss of hypothalamic sites that produce increases in cardiovascular and muscle motor function when stimulated electrically does not appear to comprise the cardiovascular response of awake beagles to dynamic exercise.


UK and Twenty Comparable Countries GDP-Expenditure-on-Health 1980-2013: The Historic and Continued Low Priority of UK Health-Related Expenditure.
It is well-established that for a considerable period the United Kingdom has spent proportionally less of its gross domestic product (GDP) on health-related services than almost any other comparable country. Average European spending on health (as a % of GDP) in the period 1980 to 2013 has been 19% higher than the United Kingdom, indicating that comparable countries give far greater fiscal priority to its health services, irrespective of its actual fiscal value or configuration. While the UK National Health Service (NHS) is a comparatively lean healthcare system, it is often regarded to be at a 'crisis' point on account of low levels of funding. Indeed, many state that currently the NHS has a sizeable funding gap, in part due to its recently reduced GDP devoted to health but mainly the challenges around increases in longevity, expectation and new medical costs. The right level of health funding is a political value judgement. As the data in this paper outline, if the UK 'afforded' the same proportional level of funding as the mean average European country, total expenditure would currently increase by one-fifth.


Public and policy maker support for point-of-sale tobacco policies in New York.
To compare public and policy maker support for three point-of-sale tobacco policies. Two cross-sectional surveys--one of the public from the New York Adult Tobacco Survey and one of policy makers from the Local Opinion Leader Survey; both collected and analyzed in 2011. Tobacco control programs focus on educating the public and policy makers about tobacco control policy solutions. Six hundred seventy-six county-level legislators in New York's 62 counties and New York City's five boroughs (response rate: 59%); 7439 New York residents aged 18 or older. Landline response rates: 20.2% to 22%. Cell phone response rates: 9.2% to 11.1%. Gender, age, smoking status, presence of a child aged 18 years or younger in the household, county of residence, and policy maker and public support for three potential policy solutions to point-of-sale tobacco marketing. t-tests to compare the demographic makeup for the two samples. Adjusted Wald tests to test for differences in policy support between samples. The public was significantly more supportive of point-of-sale policy solutions than were policy makers: cap on retailers (48.0% vs. 19.2%, respectively); ban on sales at pharmacies (49.1% vs. 38.8%); and ban on retailers near schools (53.3% vs. 42.5%). cross-sectional data, sociodemographic differences, and variations in item wording. Tobacco control programs need to include information about implementation, enforcement, and potential effects on multiple constituencies (including businesses) in their efforts to educate policy makers about point-of-sale policy solutions.


Knee angle-specific EMG normalization: the use of polynomial based EMG-angle relationships.
The normalization of EMG signals to those recorded during a maximal voluntary contraction provides a valid construct for comparisons of relative muscle activity. However, the length dependence of muscle activation and purported, substantial, muscle translocation and changes in muscle architecture during dynamic movements presents a need for joint angle-dependent normalization processes. The purposes of the present study were to: (1) quantify variations in muscle activity across a large ROM, (2) determine the accuracy with which fitted EMG-joint angle curves accurately characterized these variations, and (3) compare peak (EMG-P) and average (EMG-A) EMG amplitudes obtained during a countermovement leg extension when normalized to both absolute peak and joint angle-specific muscle activity. Fifteen subjects performed a large ROM (110°) isokinetic (30°s(-1)) leg extension from which EMG-joint angle relationships were derived using polynomial fitting of different complexities. Ten subjects also performed loaded countermovement leg extensions from which EMG signals were normalized using peak muscle activity and EMG-angle curves. EMG amplitude varied significantly over the ROM and the use of EMG-angle curves for signal normalization resulted in significantly greater EMG-P and EMG-A than those normalized using the absolute peak EMG. Higher-order polynomial fitting better matched the filtered EMG amplitudes. Thus, there is a strong rationale for using EMG-angle polynomial fits to normalize EMG signals for large ROM movements.


Policy Design for COVID-19: Worldwide Evidence on the Efficacies of Early Mask Mandates and Other Policy Interventions.
To understand the extent to which a policy instrument's early adoption is crucial in crisis management, we leverage unique worldwide data that record the daily evolution of policy mandate adoptions and COVID-19 infection and mortality rates. The analysis shows that the mask mandate is consistently associated with lower infection rates in the short term, and its early adoption boosts the long-term efficacy. By contrast, the other five policy instruments-domestic lockdowns, international travel bans, mass gathering bans, and restaurant and school closures-show weaker efficacy. Governments prepared for a public health crisis with stronger resilience or capacity and those with stronger collectivist cultures were quicker to adopt nationwide mask mandates. From a policy design perspective, policymakers must avoid overreacting with less effective instruments and underreacting with more effective ones during uncertain times, especially when interventions differ in efficacy and cost.