The role of macrophage lineage cells in kidney graft rejection and survival.
Large numbers of macrophage lineage cells are present in transplants undergoing ischemia-reperfusion injury and rejection, and their presence correlates with a high probability of rejection. However, the extent to which monocytes and macrophages contribute to kidney graft rejection is poorly understood. The heterogeneity of the monocyte/macrophage lineage cells could be one of the reasons why these cells have been neglected up to now. Circulating monocytes can be divided into various subsets, which are able to give rise to tissue macrophages and dendritic cells. Macrophages are believed to be highly plastic cells that can respond to environmental signals by changing their phenotype and function. Macrophages have established roles in early and late kidney graft inflammation, tissue homeostasis, remodeling, and repair. In kidney transplantation, macrophages are believed to play a role in both damage and repair of the graft, depending on the type of macrophages involved, the environmental drive, and the time after transplantation. The heterogeneity and plasticity of monocytes and macrophages are obstacles to translating the functional relevance of this cell lineage to diagnostic and prognostic clinical parameters and to defining specific, macrophage-related, therapeutic targets. Recent evidence has indicated an immunomodulatory role for the so-called regulatory macrophages in induction of tolerance in kidney transplant recipients. In this article, we summarize current views on monocyte/macrophage immunobiology in kidney transplantation. Key issues for ongoing research are discussed.


Structural analysis of missense mutations in galactokinase 1 (GALK1) leading to galactosemia type-2.
Galactosemia type 2 is an autosomal recessive disorder characterized by the deficiency of galactokinase (GALK) enzyme due to missense mutations in GALK1 gene, which is associated with various manifestations such as hyper galactosemia and formation of cataracts. GALK enzyme catalyzes the adenosine triphosphate (ATP)-dependent phosphorylation of α-d-galactose to galactose-1-phosphate. We searched 4 different literature databases (Google Scholar, PubMed, PubMed Central, and Science Direct) and 3 gene-variant databases (Online Mendelian Inheritance in Man, Human Gene Mutation Database, and UniProt) to collect all the reported missense mutations associated with GALK deficiency. Our search strategy yielded 32 missense mutations. We used several computational tools (pathogenicity and stability, biophysical characterization, and physiochemical analyses) to prioritize the most significant mutations for further analyses. On the basis of the pathogenicity and stability predictions, 3 mutations (P28T, A198V, and L139P) were chosen to be tested further for physicochemical characterization, molecular docking, and simulation analyses. Molecular docking analysis revealed a decrease in interaction between the protein and ATP in all the 3 mutations, and molecular dynamic simulations of 50 ns showed a loss of stability and compactness in the mutant proteins. As the next step, comparative physicochemical changes of the native and the mutant proteins were carried out using essential dynamics. Overall, P28T and A198V were predicted to alter the structure and function of GALK protein when compared to the mutant L139P. This study demonstrates the power of computational analysis in variant classification and interpretation and provides a platform for developing targeted therapeutics.


Long-term toxicity of [(177)Lu-DOTA (0),Tyr (3)]octreotate in rats.
Studies on peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues have shown promising results with regard to tumour control. The efficacy of PRRT is limited by uptake and retention in the proximal tubules of the kidney, which might lead to radiation nephropathy. We investigated the long-term renal toxicity after different doses of [(177)Lu-DOTA(0),Tyr(3)]octreotate and the effects of dose fractionation and lysine co-injection in two tumour-bearing rat models. Significant renal toxicity was detected beyond 100 days after start of treatment as shown by elevated serum creatinine and proteinuria. Microscopically, tubules were strongly dilated with flat epithelium, containing protein cylinders. Creatinine levels rose significantly after 555 MBq [(177)Lu-DOTA(0),Tyr(3)]octreotate, but were significantly lower after 278 MBq (single injection) or two weekly doses of 278 MBq. Renal damage scores were maximal after 555 MBq and significantly lower in the 278 and 2x278 MBq groups. Three doses of 185 MBq [(177)Lu-DOTA(0),Tyr(3)]octreotate with intervals of a day, a week or a month significantly influenced serum creatinine (469+/-18, 134+/-70 and 65+/-15 micromol/l, respectively; p<0.001). Renal histological damage scores were not significantly influenced by dose fractionation. Lysine co-administration with three weekly treatments of 185 MBq significantly lowered serum creatinine and proteinuria. Injection of high doses of [(177)Lu-DOTA(0),Tyr(3)]octreotate resulted in severe renal damage in rats as indicated by proteinuria, elevated serum creatinine and histological damage. This damage was dose dependent and became overt between 100 and 200 days after treatment. Dose fractionation had significant beneficial effects on kidney function. Also, lysine co-injection successfully prevented functional damage.


Linguistic and pragmatic aspects of narration in Finnish typically developing children and children with specific language impairment.
This study investigates narratives of Finnish children with specific language impairment (SLI) from linguistic and pragmatic perspectives, in order to get a comprehensive overview of these children's narrative abilities. Nineteen children with SLI (mean age 6;1 years) and 19 typically developing age-matched children participated in the study. Their picture-elicited narrations were analysed for linguistic productivity and complexity, grammatical and referential accuracy, event content, the use of mental state expressions and narrative comprehension. Children with SLI showed difficulties in every aspect of narration in comparison to their peers. Only one measure of productivity, the number of communication units, did not reach statistical significance. Not only was linguistic structure fragile but also pragmatic aspects of storytelling (referencing, event content, mental state expressions and inferencing) were demanding for children with SLI. Results suggest that pragmatic aspects of narration should be taken into account more often when assessing narrative abilities of children with SLI.


A new model for SOS-induced mutagenesis: how RecA protein activates DNA polymerase V.
In Escherichia coli, cell survival and genomic stability after UV radiation depends on repair mechanisms induced as part of the SOS response to DNA damage. The early phase of the SOS response is mostly dominated by accurate DNA repair, while the later phase is characterized with elevated mutation levels caused by error-prone DNA replication. SOS mutagenesis is largely the result of the action of DNA polymerase V (pol V), which has the ability to insert nucleotides opposite various DNA lesions in a process termed translesion DNA synthesis (TLS). Pol V is a low-fidelity polymerase that is composed of UmuD'(2)C and is encoded by the umuDC operon. Pol V is strictly regulated in the cell so as to avoid genomic mutation overload. RecA nucleoprotein filaments (RecA*), formed by RecA binding to single-stranded DNA with ATP, are essential for pol V-catalyzed TLS both in vivo and in vitro. This review focuses on recent studies addressing the protein composition of active DNA polymerase V, and the role of RecA protein in activating this enzyme. Based on unforeseen properties of RecA*, we describe a new model for pol V-catalyzed SOS-induced mutagenesis.


Individual correlates of health service utilization and the cost of poor adjustment to chronic illness.
It was conjectured that a small group of chronically ill in tertiary ambulatory clinics consume a large amount of health resources and that, from the perspective of the patient, psychosocial rather than disease variables would most explain their health service utilization and subsequent cost. New referrals with a chronic illness (N = 215) to one of three clinics (oncology, rheumatology, and gastroenterology) consented to participate in a subsequent trial of a psychosocial intervention designed to promote their adjustment to illness and, conceivably, to reduce their health service utilization. At baseline an inventory to describe the disease, treatment, functional capacity, prognosis, and socioeconomic situation of consenting subjects was completed. In addition, subjects completed the Psychosocial Adjustment to Illness Inventory (PAIS-SR), the Family Assessment Device (FAD), the Meaning of Illness Questionnaire (MIQ), and a Health Service Utilization Inventory designed to assess direct and indirect costs of health resources. These data were entered into a concurrent analytic survey design. Participating subjects represented a more socioeconomically advantaged and better-adjusted group of chronically ill patients compared with others referred to the tertiary clinics. They were representative of all new referrals in their use of the majority of health services. However, once hospitalized, participating subjects stayed longer and used specialists less. There was no important relationship between disease severity or prognosis and any type of service utilization, including hospitalization. Because the strongest correlate of all types of health services consumed was psychosocial adjustment to illness (r = 0.28 to 0.33), patients were partitioned into one of three categories of adjustment to illness: good, fair, and poor. The total annual cost per patient was $23,883, if poorly adjusted, compared with $9,791 if well adjusted. If cash transfers (benefits paid by different types of insurance) are added, the average 1987 annual cost per poorly adjusted subject was $31,291 per patient, compared with $13,771 for a patient well adjusted to the illness. There was a statistically significant and economically important linear gradient in 1987 treatment costs per category of adjustment. The possible economic implications for psychosocial intervention are highlighted.


Modeling Surgical Technical Skill Using Expert Assessment for Automated Computer Rating.
Computer vision was used to predict expert performance ratings from surgeon hand motions for tying and suturing tasks. Existing methods, including the objective structured assessment of technical skills (OSATS), have proven reliable, but do not readily discriminate at the task level. Computer vision may be used for evaluating distinct task performance throughout an operation. Open surgeries was videoed and surgeon hands were tracked without using sensors or markers. An expert panel of 3 attending surgeons rated tying and suturing video clips on continuous scales from 0 to 10 along 3 task measures adapted from the broader OSATS: motion economy, fluidity of motion, and tissue handling. Empirical models were developed to predict the expert consensus ratings based on the hand kinematic data records. The predicted versus panel ratings for suturing had slopes from 0.73 to 1, and intercepts from 0.36 to 1.54 (Average R2 = 0.81). Predicted versus panel ratings for tying had slopes from 0.39 to 0.88, and intercepts from 0.79 to 4.36 (Average R2 = 0.57). The mean square error among predicted and expert ratings was consistently less than the mean squared difference among individual expert ratings and the eventual consensus ratings. The computer algorithm consistently predicted the panel ratings of individual tasks, and were more objective and reliable than individual assessment by surgical experts.


Tissue-specific restriction of cyclophilin A-independent HIV-1- and SIV-derived lentiviral vectors.
The host factor alpha isoform of the tripartite motif 5 (TRIM5alpha) restricts human immunodeficiency virus type 1 (HIV-1) infection in certain non-human primate species. Restriction of HIV-1 is enhanced by binding of the viral capsid to cyclophilin A (CypA) in target cells, although CypA is not absolutely required for restriction in rhesus macaque cells. Simian immunodeficiency virus (SIV) is not restricted by rhesus macaque TRIM5alpha and its capsid does not bind to CypA. Here, the effect of lentiviral CypA dependence on restriction in different tissues was examined by engineering an HIV-1 capsid quadruple mutant (V(86)P/H(87)Q/I(91)V/M(96)I) lentiviral vector (HIV(quad)) that is CypA-independent. Whereas HIV-1 was restricted in rhesus macaque and owl monkey epithelial cells, infection with the HIV(quad) vector was efficient at high viral concentrations. In contrast, HIV(quad) was largely restricted in primary rhesus macaque CD34(+) cells. Human epithelial and primary CD34(+) cells were permissive for HIV-1, HIV(quad) and SIV, whereas transduction of human T cells by HIV(quad) or SIV was impaired. The restrictive human cells did not express increased levels of TRIM5alpha, and restriction was not relieved by abolishing CypA, consistent with HIV(quad) and SIV being CypA-independent. Pseudotyping of lentiviral vectors with the gibbon ape leukemia virus envelope altered their sensitivity to perturbations of the virus-CypA interaction compared to pseudotyping with vesicular stomatitis virus glycoproteins, suggesting that the viral entry pathway modulates restriction. Together, these studies reveal that an HIV-1 capsid quadruple mutant can partially overcome lentiviral restriction in non-human primate epithelial cells, but not in hematopoietic cells. Similarly, human cells vary in their permissiveness for CypA-independent lentiviruses, and suggest the presence of tissue-specific factor(s) that can inhibit lentiviral transduction independently of viral interaction with TRIM5alpha and CypA.


Identification of Distinct Unmutated Chronic Lymphocytic Leukemia Subsets in Mice Based on Their T Cell Dependency.
Chronic lymphocytic leukemia (CLL) can be divided into prognostically distinct subsets with stereotyped or non-stereotyped, mutated or unmutated B cell receptors (BCRs). Individual subsets vary in antigen specificity and origin, but the impact of antigenic pressure on the CLL BCR repertoire remains unknown. Here, we employed IgH.TEμ mice that spontaneously develop CLL, expressing mostly unmutated BCRs of which ~35% harbor VH11-2/Vκ14-126 and recognize phosphatidylcholine. Proportions of VH11/Vκ14-expressing CLL were increased in the absence of functional germinal centers in IgH.TEμ mice deficient for CD40L or activation-induced cytidine deaminase. Conversely, in vivo T cell-dependent immunization decreased the proportions of VH11/Vκ14-expressing CLL. Furthermore, CLL onset was accelerated by enhanced BCR signaling in Siglec-G-/- mice or in mice expressing constitutively active Bruton's tyrosine kinase. Transcriptional profiling revealed that VH11 and non-VH11 CLL differed in the upregulation of specific pathways implicated in cell signaling and metabolism. Interestingly, principal component analyses using the 148 differentially expressed genes revealed that VH11 and non-VH11 CLL clustered with BCR-stimulated and anti-CD40-stimulated B cells, respectively. We identified an expression signature consisting of 13 genes that were differentially expressed in a larger panel of T cell-dependent non-VH11 CLL compared with T cell-independent VH11/Vκ14 or mutated IgH.TEμ CLL. Parallel differences in the expression of these 13 signature genes were observed between heterogeneous and stereotypic human unmutated CLL. Our findings provide evidence for two distinct unmutated CLL subsets with a specific transcriptional signature: one is T cell-independent and B-1 cell-derived while the other arises upon antigen stimulation in the context of T-cell help.


Congenital cytomegalovirus infection.
Clinical details of 50 infants with congenital cytomegalovirus infection identified in a prospective study are reported. The mean birthweight, gestational age, and head circumference of children with congenital cytomegalovirus infection were not significantly different from those of controls. Three (6%) had symptoms at birth--two neurological and one pneumonitis. In the first four months of life transient hepatosplenomegaly occurred in two infected children and six suffered interstitial pneumonitis. Three congenitally infected children have major neurological handicaps including spastic quadriplegia, microcephaly, and psychomotor delay, and five (10%), including the one with quadriplegia, have sensorineural deafness which is bilateral in three (6%). Estimates based on these findings suggest that the impact of congenital cytomegalovirus infection is comparable to that of congenital rubella in the era before vaccination. Of the 42 children where the nature of maternal infection was classifiable, congenital infection followed primary maternal infection in 32 (76%) and recurrent infection in 10 (24%). Neurological defects followed exposure to primary maternal infection in all three trimesters of pregnancy and also recurrent maternal infection.


Endotoxin-induced monocytic microparticles have contrasting effects on endothelial inflammatory responses.
Septic shock is a severe disease state characterised by the body's life threatening response to infection. Complex interactions between endothelial cells and circulating monocytes are responsible for microvasculature dysfunction contributing to the pathogenesis of this syndrome. Here, we intended to determine whether microparticles derived from activated monocytes contribute towards inflammatory processes and notably vascular permeability. We found that endotoxin stimulation of human monocytes enhances the release of microparticles of varying phenotypes and mRNA contents. Elevated numbers of LPS-induced monocytic microparticles (mMP) expressed CD54 and contained higher levels of transcripts for pro-inflammatory cytokines such as TNF, IL-6 and IL-8. Using a prothrombin time assay, a greater reduction in plasma coagulation time was observed with LPS-induced mMP than with non-stimulated mMP. Co-incubation of mMP with the human brain endothelial cell line hCMEC/D3 triggered their time-dependent uptake and significantly enhanced endothelial microparticle release. Unexpectedly, mMP also modified signalling pathways by diminishing pSrc (tyr416) expression and promoted endothelial monolayer tightness, as demonstrated by endothelial impedance and permeability assays. Altogether, these data strongly suggest that LPS-induced mMP have contrasting effects on the intercellular communication network and display a dual potential: enhanced pro-inflammatory and procoagulant properties, together with protective function of the endothelium.


Association of poultry farms with housefly and morbidity: a comparative study from raipur rani, haryana.
Large poultry belt is located in the residential areas of rural Haryana in North India. Housefly problem has become a big nuisance in this area. Policy makers require evidence of the association of poultry farming with houseflies and its possible impact on the health of the population. Across-sectional two-group comparison study was conducted. Six villages within 3 km and another six villages beyond 5 km from any poultry farms were selected as the study and the control villages, respectively. We measured indoor and outdoor housefly density and family morbidity in the last 1 month and observed the poultry hygiene and manure management practices. The mean fly density was 1737 (95% CI 697-2778) houseflies in study villages compared to 100 (95% CI 2-197) houseflies in the control area. The mean all-cause morbidity was also significantly higher in study village families compared to control village families. Poultry farm hygiene and use of insecticides and growth regulators were inadequate. Poultry farms are associated strongly with high fly density and high infectious morbidity in this area.Monitoring and regulation for poultry manure management practices and insecticide use practices need to be strengthened.


Quercetin, a natural dietary flavonoid, acts as a chemopreventive agent against prostate cancer in an in vivo model by inhibiting the EGFR signaling pathway.
Prostate cancer incidence and mortality rates have increased over the past years. The purpose of the present study was to examine the molecular mechanism underlying the chemopreventive effects of quercetin on prostate cancer in an in vivo model. Sprague-Dawley male rats were divided into four groups, Group I: vehicle control (propylene glycol), Group II: chemically induced cancer model (MNU + T); Group III: chemically induced cancer model + quercetin (200 mg per kg b.w.); Group IV: quercetin (200 mg per kg b.w.). Serum levels of quercetin were assessed by high performance liquid chromatography (HPLC). EGFR, PI3K/Akt protein levels were significantly increased in chemically induced cancer rats, which were brought back to normalcy in both DLP & VP (dorsolateral prostate & ventral prostate) by quercetin supplementation. Also, the protein expression levels of proliferating cell nuclear antigen (PCNA), N-cadherin, vimentin, and cyclin D1 exhibited a significant increase in both DLP & VP of chemically induced cancer rats. However, simultaneous quercetin supplementation significantly decreased PCNA, N-cadherin, vimentin, and cyclin D1 protein levels compared to chemically induced cancer rats. The E-cadherin expression was decreased in chemically induced cancer animals. Simultaneous quercetin supplementation prevented it. Real time PCR was used to study the mRNA expression of snail, slug and twist. Quercetin significantly decreased snail, slug, and twist mRNA levels in chemically induced cancer rats. To conclude from the present study, quercetin was effective in preventing prostate cancer progression by inhibiting the EGFR signaling pathway and by regulating cell adhesion molecules in Sprague Dawley rats.


Combinations of techniques that effectively change health behavior: evidence from Meta-CART analysis.
Many health-promoting interventions combine multiple behavior change techniques (BCTs) to maximize effectiveness. Although, in theory, BCTs can amplify each other, the available meta-analyses have not been able to identify specific combinations of techniques that provide synergistic effects. This study overcomes some of the shortcomings in the current methodology by applying classification and regression trees (CART) to meta-analytic data in a special way, referred to as Meta-CART. The aim was to identify particular combinations of BCTs that explain intervention success. A reanalysis of data from Michie, Abraham, Whittington, McAteer, and Gupta (2009) was performed. These data included effect sizes from 122 interventions targeted at physical activity and healthy eating, and the coding of the interventions into 26 BCTs. A CART analysis was performed using the BCTs as predictors and treatment success (i.e., effect size) as outcome. A subgroup meta-analysis using a mixed effects model was performed to compare the treatment effect in the subgroups found by CART. Meta-CART identified the following most effective combinations: Provide information about behavior-health link with Prompt intention formation (mean effect size ḡ = 0.46), and Provide information about behavior-health link with Provide information on consequences and Use of follow-up prompts (ḡ = 0.44). Least effective interventions were those using Provide feedback on performance without using Provide instruction (ḡ = 0.05). Specific combinations of BCTs increase the likelihood of achieving change in health behavior, whereas other combinations decrease this likelihood. Meta-CART successfully identified these combinations and thus provides a viable methodology in the context of meta-analysis.


Percutaneous coronary intervention outcomes in patients with rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis.
Patients with autoimmune rheumatic disease (AIRD) are at an increased risk of coronary artery disease. The present study sought to examine the prevalence and outcomes of AIRD patients undergoing percutaneous coronary intervention (PCI) from a national perspective. All PCI-related hospitalizations recorded in the US National Inpatient Sample (2004-2014) were included, stratified into four groups: no AIRD, RA, SLE and SSc. We examined the prevalence of AIRD subtypes and assessed their association with in-hospital adverse events using multivariable logistic regression [odds ratios (OR) (95% CI)]. Patients with AIRD represented 1.4% (n = 90 469) of PCI hospitalizations. The prevalence of RA increased from 0.8% in 2004 to 1.4% in 2014, but other AIRD subtypes remained stable. In multivariable analysis, the adjusted odds ratio (aOR) of in-hospital complications [aOR any complication 1.13 (95% CI 1.01, 1.26), all-cause mortality 1.32 (1.03, 1.71), bleeding 1.50 (1.30, 1.74), stroke 1.36 (1.14, 1.62)] were significantly higher in patients with SSc compared with those without AIRD. There was no difference in complications between the SLE and RA groups and those without AIRD, except higher odds of bleeding in SLE patients [aOR 1.19 (95% CI 1.09, 1.29)] and reduced odds of all-cause mortality in RA patients [aOR 0.79 (95% CI 0.70, 0.88)]. In a nationwide cohort of US hospitalizations, we demonstrate increased rates of all adverse clinical outcomes following PCI in people with SSc and increased bleeding in SLE. Management of such patients should involve a multiteam approach with rheumatologists.


Comparison of review articles published in peer-reviewed and throwaway journals.
To compare the quality, presentation, readability, and clinical relevance of review articles published in peer-reviewed and "throwaway" journals. We reviewed articles that focused on the diagnosis or treatment of a medical condition published between January 1 and December 31, 1998, in the 5 leading peer-reviewed general medical journals and high-circulation throwaway journals. Reviewers independently assessed the methodologic and reporting quality, and evaluated each article's presentation and readability. Clinical relevance was evaluated independently by 6 physicians. Of the 394 articles in our sample, 16 (4.1%) were peer-reviewed systematic reviews, 135 (34.3%) were peer-reviewed nonsystematic reviews, and 243 (61.7%) were nonsystematic reviews published in throwaway journals. The mean (SD) quality scores were highest for peer-reviewed articles (0.94 [0.09] for systematic reviews and 0.30 [0.19] for nonsystematic reviews) compared with throwaway journal articles (0.23 [0.03], F(2,391) = 280.8, P<.001). Throwaway journal articles used more tables (P =.02), figures (P =.01), photographs (P<.001), color (P<.001), and larger font sizes (P<.001) compared with peer-reviewed articles. Readability scores were more often in the college or higher range for peer-reviewed journals compared with the throwaway journal articles (104 [77.0%] vs 156 [64.2%]; P =.01). Peer-reviewed article titles were judged less relevant to clinical practice than throwaway journal article titles (P<.001). Although lower in methodologic and reporting quality, review articles published in throwaway journals have characteristics that appeal to physician readers.


Choosing an epidemiological model structure for the economic evaluation of non-communicable disease public health interventions.
Non-communicable diseases are the leading global causes of mortality and morbidity. Growing pressures on health services and on social care have led to increasing calls for a greater emphasis to be placed on prevention. In order for decisionmakers to make informed judgements about how to best spend finite public health resources, they must be able to quantify the anticipated costs, benefits, and opportunity costs of each prevention option available. This review presents a taxonomy of epidemiological model structures and applies it to the economic evaluation of public health interventions for non-communicable diseases. Through a novel discussion of the pros and cons of model structures and examples of their application to public health interventions, it suggests that individual-level models may be better than population-level models for estimating the effects of population heterogeneity. Furthermore, model structures allowing for interactions between populations, their environment, and time are often better suited to complex multifaceted interventions. Other influences on the choice of model structure include time and available resources, and the availability and relevance of previously developed models. This review will help guide modelers in the emerging field of public health economic modeling of non-communicable diseases.


Cardiac magnetic resonance imaging characteristics of isolated left ventricular noncompaction in a Chinese adult Han population.
To analyze cardiac magnetic resonance imaging (CMR) characteristics in patients with isolated left ventricular noncompaction (IVNC) and assess its value in the diagnosis of IVNC in a Chinese adult Han population. We collected a consecutive series of 30 patients with IVNC from January 1, 2007, to December 31, 2008. During the same period, we prospectively included patients drawn from groups given a potential differential diagnosis for IVNC. All magnetic resonance images were analyzed using 17-segment model. Left ventricular ejection fraction was significantly lower for patients with DCM (16.2 ± 5.2%, P < 0.001) and higher in AR (47.6 ± 16.2%, P = 0.009), AS (54.6 ± 21.1%, P = 0.001) and HHD (62.4 ± 6.8%, P < 0.001) compared with IVNC (33.0 ± 14.1%). The two-layered structure was most frequently seen at the apical segments, followed by the mid-cavity and basal segments in patients with INVC. The anterior and lateral walls were more commonly involved in patients with IVNC. The number of noncompacted segments and end-diastolic ratio of non-compacted to compacted myocardium (NC/C ratio) was greater in patients with IVNC than in other five groups. The end-diastolic NC/C ratio of >2.5 had 96.4% sensitivity and 97.4% specificity for identifying patients with IVNC. CMR provides an accurate and reliable evaluation of the localization and extent of noncompacted myocardium at end-diastole. The end-diastolic NC/C ratio of >2.5 had high diagnostic accuracy for IVNC in a Chinese adult Han population.


Choice-correlated activity fluctuations underlie learning of neuronal category representation.
The ability to categorize stimuli into discrete behaviourally relevant groups is an essential cognitive function. To elucidate the neural mechanisms underlying categorization, we constructed a cortical circuit model that is capable of learning a motion categorization task through reward-dependent plasticity. Here we show that stable category representations develop in neurons intermediate to sensory and decision layers if they exhibit choice-correlated activity fluctuations (choice probability). In the model, choice probability and task-specific interneuronal correlations emerge from plasticity of top-down projections from decision neurons. Specific model predictions are confirmed by analysis of single-neuron activity from the monkey parietal cortex, which reveals a mixture of directional and categorical tuning, and a positive correlation between category selectivity and choice probability. Beyond demonstrating a circuit mechanism for categorization, the present work suggests a key role of plastic top-down feedback in simultaneously shaping both neural tuning and correlated neural variability.


Infection-related and -unrelated malignancies, HIV and the aging population.
HIV-positive people have increased risk of infection-related malignancies (IRMs) and infection-unrelated malignancies (IURMs). The aim of the study was to determine the impact of aging on future IRM and IURM incidence. People enrolled in EuroSIDA and followed from the latest of the first visit or 1 January 2001 until the last visit or death were included in the study. Poisson regression was used to investigate the impact of aging on the incidence of IRMs and IURMs, adjusting for demographic, clinical and laboratory confounders. Linear exponential smoothing models forecasted future incidence. A total of 15 648 people contributed 95 033 person-years of follow-up, of whom 610 developed 643 malignancies [IRMs: 388 (60%); IURMs: 255 (40%)]. After adjustment, a higher IRM incidence was associated with a lower CD4 count [adjusted incidence rate ratio (aIRR) CD4 count < 200 cells/μL: 3.77; 95% confidence interval (CI) 2.59, 5.51; compared with ≥ 500 cells/μL], independent of age, while a CD4 count < 200 cells/μL was associated with IURMs in people aged < 50 years only (aIRR: 2.51; 95% CI 1.40-4.54). Smoking was associated with IURMs (aIRR: 1.75; 95% CI 1.23, 2.49) compared with never smokers in people aged ≥ 50 years only, and not with IRMs. The incidences of both IURMs and IRMs increased with older age. It was projected that the incidence of IRMs would decrease by 29% over a 5-year period from 3.1 (95% CI 1.5-5.9) per 1000 person-years in 2011, whereas the IURM incidence would increase by 44% from 4.1 (95% CI 2.2-7.2) per 1000 person-years over the same period. Demographic and HIV-related risk factors for IURMs (aging and smoking) and IRMs (immunodeficiency and ongoing viral replication) differ markedly and the contribution from IURMs relative to IRMs will continue to increase as a result of aging of the HIV-infected population, high smoking and lung cancer prevalence and a low prevalence of untreated HIV infection. These findings suggest the need for targeted preventive measures and evaluation of the cost-benefit of screening for IURMs in HIV-infected populations.


Basic newborn resuscitation guidelines for healthcare providers in Maragua District Hospital: a best practice implementation project.
The overall aim of this project was to assess compliance with evidence-based criteria regarding newborn resuscitation among healthcare workers in the maternity units in Maragua District Hospital (a busy district hospital in Kenya). Globally, the majority of deaths under five years are attributable to neonatal causes. Perinatal asphyxia accounts for a significant portion of these deaths, especially in developing countries. These deaths are largely preventable, and interventions geared towards assisting newborns to initiate their first breath within the first minute of life have markedly reduced mortality. This implementation project was conducted in the maternity units of a busy district hospital. Evidence-based audit criteria were developed on the basis of an evidence summary developed by the Joanna Briggs Institute (JBI). Using the JBI Practical Application of Clinical Evidence System software (JBI PACES), a baseline audit was conducted including a sample size of 55 healthcare providers and 300 patient case notes followed by an identification of potential barriers and strategies to overcome them. A follow-up audit including a sample size of 55 healthcare providers was conducted by using the same audit criteria. Improvements in practice were demonstrated in all criteria. The baseline audit demonstrated that three of the five audit criteria were found to be less than 50%, indicating moderate compliance with current evidence with regards to newborn resuscitation. Following implementation of the strategies, which included a six-week education and demonstrative skills training, and updating of the protocols and equipment, there was a significant improvement in all the criteria audited, with the first four criteria achieving 100% compliance, and the fifth criteria achieving 90% compliance. On completion of the project, the participants demonstrated an increase in knowledge and skills on newborn resuscitation, which led to a significant reduction in admission of newborns with birth asphyxia to the newborn unit.


Integrated evaluation of the performance of a more than seven year old permeable reactive barrier at a site contaminated with chlorinated aliphatic hydrocarbons (CAHs).
An important issue of concern for permeable reactive iron barriers is the long-term efficiency of the barriers due to the long operational periods required. Mineral precipitation resulting from the anaerobic corrosion of the iron filings and bacteria present in the barrier may play an important role in the long-term performance. An integrated study was performed on the Vapokon permeable reactive barrier (PRB) in Denmark by groundwater and iron core sample characterization. The detailed field groundwater sampling carried out from more than 75 well screens up and downstream the barrier showed a very efficient removal (>99%) for the most important CAHs (PCE, TCE and 1,1,1-TCA). However, significant formation of cis-DCE within the PRB resulted in an overall insufficient efficiency for cis-DCE removal. The detailed analysis of the upstream groundwater revealed a very heterogeneous spatial distribution of contaminant loading into the PRB, which resulted in that only about a quarter of the barrier system is treating significant loads of CAHs. Laboratory batch experiments using contaminated groundwater from the site and iron material from the core samples revealed that the aged iron material performed equally well as virgin granular iron of the same type based on determined degradation rates despite that parts of the cored iron material were covered by mineral precipitates (especially iron sulfides, carbonate green rust and aragonite). The PCR analysis performed on the iron core samples indicated the presence of a microbial consortium in the barrier. A wide range of species were identified including sulfate and iron reducing bacteria, together with Dehalococcoides and Desulfuromonas species indicating microbial reductive dehalogenation potential. The microbes had a profound effect on the performance of the barrier, as indicated by significant degradation of dichloromethane (which is typically unaffected by zero valent iron) within the barrier.


Cytomegalovirus destruction of focal adhesions revealed in a high-throughput Western blot analysis of cellular protein expression.
Human cytomegalovirus (HCMV) systematically manages the expression of cellular functions, rather than exerting the global shutoff of host cell protein synthesis commonly observed with other herpesviruses during the lytic cycle. While microarray technology has provided remarkable insights into viral control of the cellular transcriptome, HCMV is known to encode multiple mechanisms for posttranscriptional and post-translation regulation of cellular gene expression. High-throughput Western blotting (BD Biosciences Powerblot technology) with 1,009 characterized antibodies was therefore used to analyze and compare the effects of infection with attenuated high-passage strain AD169 and virulent low-passage strain Toledo at 72 hpi across gels run in triplicate for each sample. Six hundred ninety-four proteins gave a positive signal in the screen, of which 68 from strain AD169 and 71 from strain Toledo were defined as being either positively or negatively regulated by infection with the highest level of confidence (BD parameters). In follow-up analyses, a subset of proteins was selected on the basis of the magnitude of the observed effect or their potential to contribute to defense against immune recognition. In analyses performed at 24, 72, and 144 hpi, connexin 43 was efficiently downregulated during HCMV infection, implying a breakdown of intercellular communication. Mitosis-associated protein Eg-5 was found to be differentially upregulated in the AD169 and Toledo strains of HCMV. Focal adhesions link the actin cytoskeleton to the extracellular matrix and have key roles in initiating signaling pathways and substrate adhesion and regulating cell migration. HCMV suppressed expression of the focal-adhesion-associated proteins Hic-5, paxillin, and alpha-actinin. Focal adhesions were clearly disrupted in HCMV-infected fibroblasts, with their associated intracellular and extracellular proteins being dispersed. Powerblot shows potential for rapid screening of the cellular proteome during HCMV infection.


Selective serotonin reuptake inhibitor poisoning: An evidence-based consensus guideline for out-of-hospital management.
A review of US poison center data for 2004 showed over 48,000 exposures to selective serotonin reuptake inhibitors (SSRIs). A guideline that determines the conditions for emergency department referral and prehospital care could potentially optimize patient outcome, avoid unnecessary emergency department visits, reduce health care costs, and reduce life disruption for patients and caregivers. An evidence-based expert consensus process was used to create the guideline. Relevant articles were abstracted by a trained physician researcher. The first draft of the guideline was created by the lead author. The entire panel discussed and refined the guideline before distribution to secondary reviewers for comment. The panel then made changes based on the secondary review comments. The objective of this guideline is to assist poison center personnel in the appropriate out-of-hospital triage and initial management of patients with a suspected ingestion of an SSRI by 1) describing the process by which an ingestion of an SSRI might be managed, 2) identifying the key decision elements in managing cases of SSRI ingestion, 3) providing clear and practical recommendations that reflect the current state of knowledge, and 4) identifying needs for research. This guideline applies to ingestion of immediate-release forms of SSRIs alone. Co-ingestion of additional substances might require different referral and management recommendations depending on their combined toxicities. This guideline is based on an assessment of current scientific and clinical information. The expert consensus panel recognizes that specific patient care decisions may be at variance with this guideline and are the prerogative of the patient and the health professionals providing care, considering all of the circumstances involved. This guideline does not substitute for clinical judgment. Recommendations are in chronological order of likely clinical use. The grade of recommendation is in parentheses. 1) All patients with suicidal intent, intentional abuse, or in cases in which a malicious intent is suspected (e.g., child abuse or neglect) should be referred to an emergency department. This activity should be guided by local poison center procedures. In general, this should occur regardless of the dose reported (Grade D). 2) Any patient already experiencing any symptoms other than mild effects (mild effects include vomiting, somnolence [lightly sedated and arousable with speaking voice or light touch], mydriasis, or diaphoresis) should be transported to an emergency department. Transportation via ambulance should be considered based on the condition of the patient and the length of time it will take the patient to arrive at the emergency department (Grade D). 3) Asymptomatic patients or those with mild effects (defined above) following isolated unintentional acute SSRI ingestions of up to five times an initial adult therapeutic dose (i.e., citalopram 100 mg, escitalopram 50 mg, fluoxetine 100 mg, fluvoxamine 250 mg, paroxetine 100 mg, sertraline 250 mg) can be observed at home with instructions to call the poison center back if symptoms develop. For patients already on an SSRI, those with ingestion of up to five times their own single therapeutic dose can be observed at home with instructions to call the poison center back if symptoms develop (Grade D). 4) The poison center should consider making follow-up calls during the first 8 hours after ingestion, following its normal procedure. Consideration should be given to the time of day when home observation will take place. Observation during normal sleep hours might not reliably identify the onset of toxicity. Depending on local poison center policy, patients could be referred to an emergency department if the observation would take place during normal sleeping hours of the patient or caretaker (Grade D). 5) Do not induce emesis (Grade C). 6) The use of oral activated charcoal can be considered since the likelihood of SSRI-induced loss of consciousness or seizures is small. However, there are no data to suggest a specific clinical benefit. The routine use of out-of-hospital oral activated charcoal in patients with unintentional SSRI overdose cannot be advocated at this time (Grade C). 7) Use intravenous benzodiazepines for seizures and benzodiazepines and external cooling measures for hyperthermia (>104 degrees F [>40 degrees C]) for SSRI-induced serotonin syndrome. This should be done in consultation with and authorized by EMS medical direction, by a written treatment protocol or policy, or with direct medical oversight (Grade C).


N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine.
Cyclin-dependent kinases (CDKs) and their regulators show frequent abnormalities in tumors. Ten low molecular weight pharmacologic inhibitors of CDKs are currently in clinical trials against various cancers, including the 2,6,9-trisubstituted purine (R)-roscovitine (CYC202/Seliciclib). We here report the characterization of N-&-N1, a bioisoster of roscovitine displaying improved antitumoral properties. N-&-N1 shows exquisite selectivity for CDKs, with 2- to 3-fold enhanced potency compared with (R)-roscovitine. Inhibition of retinoblastoma protein phosphorylation and RNA polymerase II Ser2 phosphorylation in neuroblastoma SH-SY5Y cells exposed to N-&-N1 indicates that N-&-N1 is able to inhibit CDKs in a cellular context. N-&-N1 also down-regulates the expression of RNA polymerase. Cocrystal structures of N-&-N1 and (R)-roscovitine in complex with CDK2/cyclin A reveal that both inhibitors adopt similar binding modes. A competitive assay shows that, compared with (R)-roscovitine, N-&-N1 has reduced affinity for Erk2 and pyridoxal kinase. N-&-N1 triggers cell death in a panel of diverse cell lines. Cell death is accompanied by events characteristic of apoptosis: cytochrome c release, activation of effector caspases, and poly(ADP-ribose) polymerase cleavage. Induction of p53 and p21CIP1 and down-regulation of the Mcl-1 antiapoptotic factor were also observed. Studies in mice show that N-&-N1 has pharmacokinetics properties similar to those of (R)-roscovitine. Altogether, these results show that analogues of (R)-roscovitine can be designed with improved antitumor potential.


Intracellular forms of pox viruses as shown by the electron microscope (Vaccinia, Ectromelia, Molluscum Contagiosum).
The intracellular development of three pox viruses has been studied with the electron microscope using thin sections of infected tissue. Cells infected with vaccinia, ectromelia, and molluscum contagiosum viruses all form developmental bodies preliminary to the production of mature virus. Developmental bodies, believed to be virus precursors, are round to oval, slightly larger than mature virus particles, less dense to electrons, and have a more varied morphology. It is suggested as a working hypothesis that the process of maturation of a virus particle takes place as follows. In the earliest form the developmental bodies appear as hollow spheres, imbedded in a very dense cytoplasmic mass constituting an inclusion body, or in a less dense matrix near the nucleus in cells without typical inclusion bodies. The spheres become filled with a homogeneous material of low electron density. A small, dense granule appears in each developmental body and grows in size at the expense of the low density material. Following growth of the granule, particles are found with the dimensions of mature virus and having complex internal structure resembling bars or dumbells. Mature virus is ovoid and very dense to electrons. An "empty" interior may be found within its thick walls.


Ecology and geography of human monkeypox case occurrences across Africa.
As ecologic niche modeling (ENM) evolves as a tool in spatial epidemiology and public health, selection of the most appropriate and informative environmental data sets becomes increasingly important. Here, we build on a previous ENM analysis of the potential distribution of human monkeypox in Africa by refining georeferencing criteria and using more-diverse environmental data to identify environmental parameters contributing to monkeypox distributional ecology. Significant environmental variables include annual precipitation, several temperature-related variables, primary productivity, evapotranspiration, soil moisture, and pH. The potential distribution identified with this set of variables was broader than that identified in previous analyses but does not include areas recently found to hold monkeypox in southern Sudan. Our results emphasize the importance of selecting the most appropriate and informative environmental data sets for ENM analyses in pathogen transmission mapping.


alpha-Glycerylphosphorylcholine administration increases the GH responses to GHRH of young and elderly subjects.
Growth hormone (GH) secretion is decreased during aging in humans and in rodents. This decrease may be due to increased hypothalamic somatostatin release, which is inhibited by cholinergic agonists, or to decreased secretion of GHRH. Alpha-glyceryl-phosphorylcholine (alpha-GFC) is a putative acetylcholine precursor used in the treatment of cognitive disorders in the elderly. In order to learn what effect alpha-GFC had on GH secretion, GH-release hormone (GHRH) was given to young and old human volunteers, with or without the addition of alpha-GFC. GH secretion was greater in the younger subjects than in the old individuals, and both groups had a greater GH response to the GHRH+alpha-GFC than to GHRH alone. The potentiating effect of alpha-GFC on GH secretion was more pronounced in the elderly subjects. These findings confirm the observation that aged individuals respond less well to GHRH than younger subjects, and provides further evidence that increased cholinergic tone enhances GH release.


A Comprehensive Computer-Aided Polyp Detection System for Colonoscopy Videos.
Computer-aided detection (CAD) can help colonoscopists reduce their polyp miss-rate, but existing CAD systems are handicapped by using either shape, texture, or temporal information for detecting polyps, achieving limited sensitivity and specificity. To overcome this limitation, our key contribution of this paper is to fuse all possible polyp features by exploiting the strengths of each feature while minimizing its weaknesses. Our new CAD system has two stages, where the first stage builds on the robustness of shape features to reliably generate a set of candidates with a high sensitivity, while the second stage utilizes the high discriminative power of the computationally expensive features to effectively reduce false positives. Specifically, we employ a unique edge classifier and an original voting scheme to capture geometric features of polyps in context and then harness the power of convolutional neural networks in a novel score fusion approach to extract and combine shape, color, texture, and temporal information of the candidates. Our experimental results based on FROC curves and a new analysis of polyp detection latency demonstrate a superiority over the state-of-the-art where our system yields a lower polyp detection latency and achieves a significantly higher sensitivity while generating dramatically fewer false positives. This performance improvement is attributed to our reliable candidate generation and effective false positive reduction methods.


Chemical activation of the mechanotransduction channel Piezo1.
Piezo ion channels are activated by various types of mechanical stimuli and function as biological pressure sensors in both vertebrates and invertebrates. To date, mechanical stimuli are the only means to activate Piezo ion channels and whether other modes of activation exist is not known. In this study, we screened ~3.25 million compounds using a cell-based fluorescence assay and identified a synthetic small molecule we termed Yoda1 that acts as an agonist for both human and mouse Piezo1. Functional studies in cells revealed that Yoda1 affects the sensitivity and the inactivation kinetics of mechanically induced responses. Characterization of Yoda1 in artificial droplet lipid bilayers showed that Yoda1 activates purified Piezo1 channels in the absence of other cellular components. Our studies demonstrate that Piezo1 is amenable to chemical activation and raise the possibility that endogenous Piezo1 agonists might exist. Yoda1 will serve as a key tool compound to study Piezo1 regulation and function.


Type 2 diabetes mellitus and skeletal muscle metabolic function.
Type 2 diabetic patients are characterized by a decreased fat oxidative capacity and high levels of circulating free fatty acids (FFAs). The latter is known to cause insulin resistance, in particularly in skeletal muscle, by reducing insulin stimulated glucose uptake, most likely via accumulation of lipid inside the muscle cell. A reduced skeletal muscle oxidative capacity can exaggerate this. Furthermore, type 2 diabetes is associated with impaired metabolic flexibility, i.e. an impaired switching from fatty acid to glucose oxidation in response to insulin. Thus, a reduced fat oxidative capacity and metabolic inflexibility are important components of skeletal muscle insulin resistance. The cause of these derangements in skeletal muscle of type 2 diabetic patients remains to be elucidated. An impaired mitochondrial function is a likely candidate. Evidence from both in vivo and ex vivo studies supports the idea that an impaired skeletal muscle mitochondrial function is related to the development of insulin resistance and type 2 diabetes mellitus. A decreased mitochondrial oxidative capacity in skeletal muscle was revealed in diabetic patients, using in vivo 31-Phosphorus Magnetic Resonance Spectroscopy (31P-MRS). However, quantification of mitochondrial function using ex vivo high-resolution respirometry revealed opposite results. Future (human) studies should challenge this concept of impaired mitochondrial function underlying metabolic defects and prove if mitochondria are truly functional impaired in insulin resistance, or low in number, and whether it represents the primary starting point of pathogenesis of insulin resistance, or is just an other feature of the insulin resistant state.


Transglutaminase is essential for IgA nephropathy development acting through IgA receptors.
IgA nephropathy (IgAN) is a common cause of renal failure worldwide. Treatment is limited because of a complex pathogenesis, including unknown factors favoring IgA1 deposition in the glomerular mesangium. IgA receptor abnormalities are implicated, including circulating IgA-soluble CD89 (sCD89) complexes and overexpression of the mesangial IgA1 receptor, TfR1 (transferrin receptor 1). Herein, we show that although mice expressing both human IgA1 and CD89 displayed circulating and mesangial deposits of IgA1-sCD89 complexes resulting in kidney inflammation, hematuria, and proteinuria, mice expressing IgA1 only displayed endocapillary IgA1 deposition but neither mesangial injury nor kidney dysfunction. sCD89 injection into IgA1-expressing mouse recipients induced mesangial IgA1 deposits. sCD89 was also detected in patient and mouse mesangium. IgA1 deposition involved a direct binding of sCD89 to mesangial TfR1 resulting in TfR1 up-regulation. sCD89-TfR1 interaction induced mesangial surface expression of TGase2 (transglutaminase 2), which in turn up-regulated TfR1 expression. In the absence of TGase2, IgA1-sCD89 deposits were dramatically impaired. These data reveal a cooperation between IgA1, sCD89, TfR1, and TGase2 on mesangial cells needed for disease development. They demonstrate that TGase2 is responsible for a pathogenic amplification loop facilitating IgA1-sCD89 deposition and mesangial cell activation, thus identifying TGase2 as a target for therapeutic intervention in this disease.


Mining gene-centric relationships from literature: the roles of gene mutation and gene expression in supporting drug discovery.
Identifying drug target candidates is an important task for early development throughout the drug discovery process. This process is supported by the development of new high-throughput technologies that enable better understanding of disease mechanism. It becomes critical to facilitate effective analysis of the large amount of biological data. However, with much of the biological knowledge represented in the literature in the form of natural text, analysis and interpretation of high-throughput data has not reached its potential effectiveness. In this paper, we describe our solution in employing text mining as a technique in finding scientific information for target and biomarker discovery from the biomedical literature. Our approach utilises natural language processing techniques to capture linguistic patterns for the extraction of biological knowledge from text. Additionally, we discuss how the extracted knowledge is used for the analysis of biological data such as next-generation sequencing and gene expression data.


Concurrent white matter bundles and grey matter networks using independent component analysis.
Developments in non-invasive diffusion MRI tractography techniques have permitted the investigation of both the anatomy of white matter pathways connecting grey matter regions and their structural integrity. In parallel, there has been an expansion in automated techniques aimed at parcellating grey matter into distinct regions based on functional imaging. Here we apply independent component analysis to whole-brain tractography data to automatically extract brain networks based on their associated white matter pathways. This method decomposes the tractography data into components that consist of paired grey matter 'nodes' and white matter 'edges', and automatically separates major white matter bundles, including known cortico-cortical and cortico-subcortical tracts. We show how this framework can be used to investigate individual variations in brain networks (in terms of both nodes and edges) as well as their associations with individual differences in behaviour and anatomy. Finally, we investigate correspondences between tractography-based brain components and several canonical resting-state networks derived from functional MRI.


National Survey Of The Aetiological Assessment Service Of Permanent Childhood Hearing Loss In Ireland
Aim The Universal Neonatal Hearing Screening Programme (UNHS) was implemented nationally in 2014. All infants identified with permanent childhood hearing loss (PCHL) should have a paediatric assessment performed. This survey aimed to assess available paediatric services and to inform service development. Methods All paediatricians involved in assessment of infants with PCHL were identified. A questionnaire was developed using the BAAP standards. Results were collated on excel. Results Thirty-three paediatricians assess children with PCHL, only 18% (6/33) had received specific training. Waiting time for assessment was beyond the recommended timeframe in the majority of cases (mean 14.4 weeks, range 2-52). Timely access to services such as MRI, genetics and ophthalmology was limited. Conclusion The survey highlights significant deficits in the paediatric component of the UNHS. A model of regionalisation with recommendations to improve the paediatric skill set, resources and supporting services is suggested.


Learning the law: practical proposals for UK medical education.
Ongoing serious breaches in medical professionalism might be avoided if UK doctors rethink their approach to law. UK medical education has a role in creating a climate of change by re-examining how law is taught to medical students. Adopting a more insightful approach in the UK to the impact of The Human Rights Act and learning to manipulate legal concepts, such as conflict of interest, need to be taught to medical students now if UK doctors are to manage complex decision-making in the NHS of the future. The literature is reviewed from a unique personal perspective of a doctor and lawyer, and practical proposals for developing medical education in law in the UK are suggested.


Roles of phosphate and fibroblast growth factor 23 in cardiovascular disease.
Disturbances in phosphate homeostasis are common in patients with chronic kidney disease. As kidney function declines, circulating concentrations of phosphate and the phosphate-regulatory hormone, fibroblast growth factor (FGF)-23, rise progressively. Higher serum levels of phosphate and FGF-23 are associated with an increased risk of adverse outcomes, including all-cause mortality and cardiovascular events. The associations between higher FGF-23 levels and adverse cardiovascular outcomes are generally independent of serum phosphate levels, and might be strongest for congestive heart failure. Higher serum phosphate levels are also modestly associated with an increased risk of cardiovascular events even after accounting for FGF-23 levels. This observation suggests that FGF-23 and phosphate might promote distinct mechanisms of cardiovascular toxicity. Indeed, animal models implicate high serum phosphate as a mechanism of vascular calcification and endothelial dysfunction, whereas high levels of FGF-23 are implicated in left ventricular hypertrophy. These seemingly distinct, but perhaps additive, adverse effects of phosphate on the vasculature and FGF-23 on the heart suggest that future population-level and individual-level interventions will need to simultaneously target these molecules to reduce the risk of associated cardiovascular events.


[Esophageal achalasia of unknown etiology in children].
To report a case of a 9-year-old female presented with esophageal achalasia and approached with surgery. The authors discuss the treatment and make a literature review on the topic. Childhood esophageal achalasia is an unusual disease, often with unknown etiology. The main symptoms are esophageal vomits, dysphagia and weight loss. The diagnosis can be made by esophagogram and endoscopy, but the main examination is the esophageal manometry. Even though the surgical approach is a well-established therapy, some alternative treatments have been used, such as the endoscopy balloon dilatation and the use of botulinum toxin. Esophageal achalasia is a rare disease in childhood, with unknown etiology. The presentation may be confused with gastroeshophageal reflux, sometimes causing a diagnosis delay. The surgical approach, as well as an antireflux procedure, is the treatment of choice.


Neuroendocrine Regulation of Male Sexual Behavior.
The major brain areas that control males' sexual motivation and performance include the amygdala, the bed nucleus of the stria terminalis (BNST), the medial preoptic area (MPOA), and paraventricular nucleus (PVN) of the hypothalamus, as well as the mesolimbic dopamine (DA) system. The MPOA, PVN, and brain stem and spinal nuclei control the genital reflexes. Sensory and motor aspects are integrated and elicited by the amygdala, BNST, MPOA, PVN, and the mesolimbic and nigrostriatal DA tracts, which are integral for other social behaviors, as well. Developmental hormonal effects organize the network to elicit specific behaviors, which are activated by those hormones in adolescence and adulthood. Steroid hormones primarily work through slow genomic mechanisms that increase enzymes, receptors, or structural proteins, although they may also activate membrane receptors for rapid effects. © 2019 American Physiological Society. Compr Physiol 9:1383-1410, 2019.


Shear stress-dependent platelet function after LDL cholesterol apheresis.
Platelets play a crucial role in the pathogenesis of acute coronary syndrome (ACS). Thrombus formation with subsequent arterial occlusion is a major determinant in ACS and stroke. Platelets also essentially contribute to the development and progression of atherosclerotic lesions. The aim of the present study was to investigate the effects lipid lowering by LDL apheresis on platelet function in patients with coronary artery disease. In six patients with angiographically proven coronary artery disease, venous blood samples were obtained before and after LDL cholesterol apheresis. Citrated whole blood (200 microl) was circulated in polystyrene wells at a shear rate of 1875 s(-1) for 2 min with a rotating teflon cone. Shear-stress dependent platelet adhesion was measured before and after apheresis. After apheresis, there were significant reductions in LDL (-58%) and HDL (-17%) cholesterol, triglycerides (-43%), fibrinogen (-52%), lipoprotein (a) (-57%) and CRP (-57%) levels. LDL apheresis significantly reduced shear-stress dependent platelet adhesion. Bolus administration of heparin significantly prolonged activated clotting time, but had no significant effect on platelet adhesion or aggregates. In patients with coronary artery disease, shear-stress dependent platelet adhesion is reduced by a single LDL apheresis. In addition to its cholesterol-lowering effect, LDL apheresis reduces circulating levels of fibrinogen and C-reactive protein.


U.S. elementary and secondary schools: equalizing opportunity or replicating the status quo?
Although education pays off handsomely in the United States, children from low-income families attain less education than children from more advantaged families. In this article, Cecilia Elena Rouse and Lisa Barrow investigate why family background is so strongly linked to education. The authors show that family socioeconomic status affects such educational outcomes as test scores, grade retention, and high school graduation, and that educational attainment strongly affects adult earnings. They then go on to ask why children from more advantaged families get more or better schooling than those from less advantaged families. For low-income students, greater psychological costs, the cost of forgone income (continuing in school instead of getting a job), and borrowing costs all help to explain why these students attain less education than more privileged children. And these income-related differences in costs may themselves be driven by differences in access to quality schools. As a result, U.S. public schools tend to reinforce the transmission of low socioeconomic status from parents to children. Policy interventions aimed at improving school quality for children from disadvantaged families thus have the potential to increase social mobility. Despite the considerable political attention paid to increasing school accountability, as in the No Child Left Behind Act, along with charter schools and vouchers to help the children of poor families attend private school, to date the best evidence suggests that such programs will improve student achievement only modestly. Based on the best research evidence, smaller class sizes seem to be one promising avenue for improving school quality for disadvantaged students. High teacher quality is also likely to be important. However, advantaged families, by spending more money on education outside school, can and will partly undo policy attempts to equalize school quality for poor and nonpoor children.


A high-spin square-planar Fe(ii) complex stabilized by a trianionic pincer-type ligand and conclusive evidence for retention of geometry and spin state in solution.
Square-planar high-spin Fe(ii) molecular compounds are rare and the only three non-macrocyclic or sterically-driven examples reported share a common FeO4 core. Using an easily modifiable pincer-type ligand, the successful synthesis of the first compound of this type that breaks the FeO4 motif was achieved. In addition, we present the first evidence that geometry and spin state persist in solution. Extensive characterization includes the first high-field EPR and variable field/temperature Mössbauer spectra for this class of compounds. Analysis of the spectroscopic data indicates this complex exhibits a large and positive zero-field splitting tensor. Furthermore, the unusually small ΔEQ value determined for this compound is rationalized on the basis of DFT calculations.


Differential labeling with orotic acid and uridine in compensatroy renal hypertrophy.
Using [5-3H]orotic acid and [5-3H]uridine as precursors, we compared the efficiency of labeling and the localization of labeled RNA during compensatory hypertrophy of the mouse kidney. [5-3H]orotic acid in tubules labeled RNA 15 times more intensely that [5-3H]uridine, presumably because of greater incorporation of orotic acid into tubular cells. Of the orotic acid label, 97% was in tubular cells, mostly in the proximal tubules. Only about 80% of the uridine label was in the tubules; the ratio in proximal tubules compared with that in distal tubules was 2:1. No changes in distribution within the nephron were produced during compensatory hypertrophy. [5-3H]uridine should be used as the precursor of generalized labeling is desired, but [5-3H5orotic acid is the better precursor of RNA for many studies of compensatory hypertrophy since it is more efficient and concentrates in the segments of greatest biologic activity.


Dual-modality fluorescence and full-field optical coherence microscopy for biomedical imaging applications.
Full-field optical coherence microscopy (FFOCM) is a high-resolution interferometric technique that is particularly attractive for biomedical imaging. Here we show that combining it with structured illumination fluorescence microscopy on one platform can increase its versatility since it enables co-localized registration of optically sectioned reflectance and fluorescence images. To demonstrate the potential of this dual modality, a fixed and labeled mouse retina was imaged. Results showed that both techniques can provide complementary information and therefore the system could potentially be useful for biomedical imaging applications.


Internal State: Dynamic, Interconnected Communication Loops Distributed Across Body, Brain, and Time.
Internal state profoundly alters perception and behavior. For example, a starved fly may approach and consume foods that it would otherwise find undesirable. A socially engaged newt may remain engaged in the presence of a predator, whereas a solitary newt would otherwise attempt to escape. Yet, the definition of internal state is fluid and ill-defined. As an interdisciplinary group of scholars spanning five career stages (from undergraduate to full professor) and six academic institutions, we came together in an attempt to provide an operational definition of internal state that could be useful in understanding the behavior and the function of nervous systems, at timescales relevant to the individual. In this perspective, we propose to define internal state through an integrative framework centered on dynamic and interconnected communication loops within and between the body and the brain. This framework is informed by a synthesis of historical and contemporary paradigms used by neurobiologists, ethologists, physiologists, and endocrinologists. We view internal state as composed of both spatially distributed networks (body-brain communication loops), and temporally distributed mechanisms that weave together neural circuits, physiology, and behavior. Given the wide spatial and temporal scales at which internal state operates-and therefore the broad range of scales at which it could be defined-we choose to anchor our definition in the body. Here we focus on studies that highlight body-to-brain signaling; body represented in endocrine signaling, and brain represented in sensory signaling. This integrative framework of internal state potentially unites the disparate paradigms often used by scientists grappling with body-brain interactions. We invite others to join us as we examine approaches and question assumptions to study the underlying mechanisms and temporal dynamics of internal state.


Structure-property relationship for two-photon absorbing multiporphyrins: supramolecular assembly of highly-conjugated multiporphyrinic ladders and prisms.
Two-photon absorption (TPA) phenomena of a series of single-strand as well as supramolecular self-assembled ladders and prisms of highly conjugated ethyne bridged multiporphyrin dimer, trimer, and star shaped pentamer have been investigated. The ligand mediated self-assembled supramolecular structures were characterized by UV-visible spectroscopy and small- and wide-angle X-ray scattering (SAXS/WAXS) analysis. The TPA cross section values of multiporphyrins increase nonlinearly from approximately 100 to approximately 18000 GM with an increased number of porphyrin units and elongated pi-conjugation length by virtue of charge transfer and excited-state cumulenic configurations. The observed opposite TPA behavior between their supramolecular ladder and prism configurations necessitates the importance of interstrand interactions between the multiporphyrinic units and the overall shape of the assembly. Furthermore, the diminished TPA cross section of the pentamer, despite the increased pi-conjugation resulting from duplex formation suggests that destabilizing the essential functional configurations at the cost of elongation of pi-delocalization pathway must cause unfavorable effects. We have also shown that one- and two-photon allowed energy-levels of linear multiporphyrins are nearly isoenergetic and the latter transition originates exclusively from the extent of pi-delocalization within the molecule. The identical TPA maximum position of the trimer and pentamer indicates that the TPA of the pentamer arises only from its basic trimer unit in spite of its extended two-dimensional pi-conjugation pathway involving five porphyrinic units.


Automated Determination of As(III) in Waters with an Electrochemical Sensor Integrated into a Modular Microfluidic System.
The presence of high levels of arsenic in waters poses a threat to the human health in many countries all over the world. Effective surveillance programs of water quality require the implementation of in-field tests to assess early the presence of this metal ion and other contaminants. To date, there exist few market-available analytical approaches that suffer from important limitations related to cost, in addition to complex reactions, very long analysis times, and/or high limits of detection. This work describes a robust electrochemical sensor integrated into a modular microfluidic system that shows a clear potential to be deployed for the on-site monitoring of inorganic As(III) species. Flexible and transparent microfluidic modules are fabricated by rapid prototyping techniques and include different microfluidic components among them, flow cells where electrochemical sensors can be easily and reversibly inserted. The electrochemical sensor comprises a gold nanoparticle (AuNP)-modified gold thin-film electrode that is readily applied to the sensitive detection of As(III) by anodic stripping linear sweep voltammetry. The microfluidic system enables the automatic sensor calibration, sample uptake, and preconditioning as well as As(III) detection. The system response to As(III) is linear in a concentration range of 1-150 μg L-1, with a detection limit of 0.42 μg L-1, which is well below the threshold value of 10 μg L-1 set by the World Health Organization. Analysis of tap water and two water samples from two Argentinean aquifers, spiked with different As(III) concentrations, demonstrates the excellent performance of the system.


Biofunctional metal-phenolic films from dietary flavonoids.
We assembled dietary, bioactive flavonoids into a metal coordinated network to form thin, surface-bound films and hollow capsules, overcoming the poor water solubility of free flavonoids. Films formed from quercetin, myricetin, luteolin and fisetin show radical scavenging activity, a renowned feature of their parent flavonoids, and can be reused over multiple cycles. These films are expected to have potential applications in the pharmaceutical and food industries.


Interaction of self-guided beams of different frequencies.
We show that a self-guided beam in a nonlinear planar film can be split, switched, or deflected in a controlled manner by use of another self-guided beam of a different frequency. The new phenomena are power dependent and are potentially attractive for all-optical photonic device applications.


Levels of lipoprotein and homocysteine in non-obese and obese patients with polycystic ovary syndrome.
This study was designed to examine the relationship between homocysteine (Hcy), lipoprotein levels and insulin resistance in obese and non-obese patients with polycystic ovary syndrome (PCOS). Eighty-five patients (38 obese, 47 non-obese) with PCOS and 50 healthy subjects (25 obese, 25 non-obese) were included in the study. PCOS was defined according to the Homburg criterion. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone sulfate (DHEA-S), insulin, 17-hydroxyprogesterone, free testosterone, androstenedione, vitamin B12 and folate were measured. Also, serum concentrations of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), lipoprotein (a) (Lp(a)), apoprotein B (Apo B) and apoprotein A (Apo A) were determined. Plasma Hcy levels were measured. Insulin resistance was evaluated by homeostasis model assessment (HOMA). Plasma Hcy levels were significantly higher in women with PCOS than in healthy women. HOMA-R (insulin resistance) was significantly higher in women with PCOS compared with healthy women. Serum fasting TC, LDL-C, TG, Apo B, vitamin B12 and folate levels were similar between PCOS and control groups. Lp(a) levels were higher in PCOS patients than in control subjects, whereas HDL-C and Apo A levels were lower. Compared with obese PCOS subjects, non-obese PCOS subjects had low HOMA-R, TC, LDL-C, TG, Apo B, Lp(a) and androgen levels. Plasma Hcy levels, serum HDL-C and Apo A levels were similar between obese and non-obese women with PCOS. Levels of HDL-C and Apo A were lower in both obese and non-obese PCOS patients than in obese and non-obese control subjects, whereas Lp(a) levels were higher. No correlation was observed between plasma Hcy, body mass index, HOMA-R, serum androgen levels, TC, LDL-C, HDL-C, Apo A, Apo B and Lp(a) levels. These results showed that elevated insulin resistance and plasma Hcy levels, and changes in serum lipid profile, which are possible risk factors for cardiovascular disorders, play important roles in the development of cardiovascular disease in both obese and non-obese patients with PCOS.


Opposing effects of glucagon and triiodothyronine on the hepatic levels of messenger ribonucleic acid S14 and the dependence of such effects on circadian factors.
We have studied the effect of glucagon on the expression of a triiodothyronine (T3) and carbohydrate-inducible mRNA sequence (mRNA-S14) in rat liver that undergoes a threefold diurnal variation (peak, 2200 h; nadir, 0800 h). Glucagon injection into euthyroid rats (25 micrograms/100 g body wt i.p., three doses at 15-min intervals) during the nocturnal plateau of mRNA-S14 caused a monoexponential disappearance of this sequence (t1/2, 90 min) accompanied by a 90% reduction in the transcriptional rate in a nuclear run-off assay, indicative of a near total reduction of synthesis. This effect was markedly attenuated in rats treated with T3 (200 micrograms/100 g body wt i.p.) 24 h before glucagon injection. When T3 was given 15 min after glucagon, the glucagon-initiated decline in mRNA-S14 was reversed within 90 min, suggesting a rapid interaction between the two hormones in the evening. Curiously, administration of T3 alone at this hour did not affect a significant increase in mRNA-S14. At 0800 h, however, T3 caused the expected brisk induction of this sequence, whereas glucagon was without effect. In essence, glucagon affected mRNA-S14 synthesis only in the evening, while T3 increased levels of this sequence above the baseline only in the morning. T3, however, reversed the effect of prior glucagon injection at night. The observed alterations in hormonal responsivity could underly the diurnal variation of mRNA-S14 expression. Moreover, the data suggest the hypothesis that T3 may act on S14 gene expression by antagonizing factors that inhibit its transcription.


Case management for the treatment of patients with major depression in general practices--rationale, design and conduct of a cluster randomized controlled trial--PRoMPT (PRimary care Monitoring for depressive Patient's Trial) [ISRCTN66386086]--study protocol.
Depression is a disorder with high prevalence in primary health care and a significant burden of illness. The delivery of health care for depression, as well as other chronic illnesses, has been criticized for several reasons and new strategies to address the needs of these illnesses have been advocated. Case management is a patient-centered approach which has shown efficacy in the treatment of depression in highly organized Health Maintenance Organization (HMO) settings and which might also be effective in other, less structured settings. PRoMPT (PRimary care Monitoring for depressive Patients Trial) is a cluster randomised controlled trial with General Practice (GP) as the unit of randomisation. The aim of the study is to evaluate a GP applied case-management for patients with major depressive disorder. 70 GPs were randomised either to intervention group or to control group with the control group delivering usual care. Each GP will include 10 patients suffering from major depressive disorder according to the DSM-IV criteria. The intervention group will receive treatment based on standardized guidelines and monthly telephone monitoring from a trained practice nurse. The nurse investigates the patient's status concerning the MDD criteria, his adherence to GPs prescriptions, possible side effects of medication, and treatment goal attainment. The control group receives usual care--including recommended guidelines. Main outcome measure is the cumulative score of the section depressive disorders (PHQ-9) from the German version of the Prime MD Patient Health Questionnaire (PHQ-D). Secondary outcome measures are the Beck-Depression-Inventory, self-reported adherence (adapted from Moriskey) and the SF-36. In addition, data are collected about patients' satisfaction (EUROPEP-tool), medication, health care utilization, comorbidity, suicide attempts and days out of work. The study comprises three assessment times: baseline (T0) , follow-up after 6 months (T1) and follow-up after 12 months (T2). Depression is now recognized as a disorder with a high prevalence in primary care but with insufficient treatment response. Case management seems to be a promising intervention which has the potential to bridge the gap of the usually time-limited and fragmented provision of care. Case management has been proven to be effective in several studies but its application in the private general medical practice setting remains unclear.


Protective immunity induced in Aotus monkeys by a recombinant SERA protein of Plasmodium falciparum: further studies using SERA 1 and MF75.2 adjuvant.
We describe the third of three vaccination trials of Panamanian Aotus monkeys with a recombinant blood-stage antigen derived from the malaria parasite Plasmodium falciparum. Immunization was performed with an N-terminal region of the SERA antigen (serine repeat antigen protein), SERA 1, that contains a 262-amino-acid fragment including amino acids 24 to 285 of the 989-amino-acid SERA protein. Vaccinations were carried out with the recombinant protein mixed with either Freund's, MF75.2, or MF59.2 adjuvant. A control group that did not receive SERA 1 but only MF75.2 adjuvant was included. Monkeys vaccinated with the antigen MF59.2 mixture produced low anti-SERA 1 titers and were not protected. Monkeys vaccinated with antigen and Freund's adjuvant had, in general, a higher average anti-SERA 1 titer (107,278) than did monkeys immunized with SERA 1 and MF75.2 (40, 143), yet monkeys in both groups were well protected. Monkeys that received only MF75.2 developed neither detectable anti-SERA 1 nor anti-P. falciparum antibodies prior to or 10 days after parasite challenge, yet were apparently protected against infection. Monkeys vaccinated with either SERA 1 and Freund's, SERA 1 and MF75.2, or MF75.2 alone and that had been challenged but did not develop a countable parasitemia were treated with a curative dose of mefloquine 100 days after parasite challenge and then rechallenged 40 days later. None of the five rechallenged monkeys that had originally received SERA 1 and Freund's developed a countable parasitemia. Only one of five rechallenged monkeys that originally received SERA 1 and MF75.2 developed a high countable parasitemia, while two animals developed a barely countable parasitemia. Four of the rechallenged monkeys that had originally received only MF75.2 developed a moderate to high countable parasitemia. The results indicate that vaccination with SERA 1 and either Freund's or MF75.2 adjuvant provides protection and vaccination with MF75.2 alone can provide a temporary protection unrelated to the induction of anti-SERA 1 or antimalarial antibodies.


Clostridium difficile infection and inflammatory bowel disease.
Over the past 15 years, Clostridium difficile infection (CDI) in patients with inflammatory bowel disease (IBD) has increased both in incidence and severity. Traditional risk factors for CDI are similar in IBD and non-IBD populations, but there is a significant proportion of IBD patients which have distinctive characteristics. Patients with ulcerative colitis (UC) are more susceptible to CDI and have more severe outcomes than those with Crohn's disease (CD). CDI may be difficult to distinguish from an IBD flare due to similar clinical presentation, and therefore screening for CDI is recommended at every flare in such patients. Several studies showed worse clinical outcomes in IBD patients with CDI, including longer hospital stay, higher colectomy and mortality rates than in those without CDI. Vancomycin and metronidazole appear to have similar efficacy in patients with moderate disease, but vancomycin is preferred in severe disease. Measures must be taken to prevent the spread of infection. Clinicians should have a high index of suspicion for CDI when evaluating a patient with IBD flare, as rapid detection and prompt treatment of infection improve outcomes. This review summarizes the available literature on epidemiology, risk factors, clinical aspects, diagnostic methods, treatment, outcome, and prevention of CDI in IBD patients.


Stability of the maternal gut microbiota during late pregnancy and early lactation.
Scarce research has been performed to assess whether the human maternal gut microbiota undergoes changes during the perinatal period. Therefore, in the present study, gut microbiota composition of seven healthy mothers(to-be) was assessed at different time points during the perinatal period (i.e. weeks 3-7 prepartum and days 3-6, 9-14, and 25-30 postpartum) using quantitative polymerase chain reaction (qPCR) and pyrosequencing, and was complemented by short-chain fatty acids (SCFA) and calprotectin quantification using high-performance liquid chromatography and enzyme-linked immunosorbent assay, respectively. qPCR revealed the predominance of members of the Firmicutes, Bacteroides, and Bifidobacterium without detectable changes over the perinatal period. Pyrosequencing supported these data in terms of microbiota stability for any population at any taxonomic level, although ratios of members of the Actinobacteria and Bacteroidetes differed between the two methods. However, the number of operational taxonomic units observed by pyrosequencing was subjected to fluctuations and the relative abundance of Streptococcus decreased numerically postpartum (P = 0.11), which may indicate that aberrancies in subdominant populations occur perinatally. Furthermore, total fecal SCFA concentrations, particularly the branched-chain fatty acids isobutyrate and isovalerate, were higher than for non-pregnant subjects throughout the perinatal period. This suggests metabolic changes and increased energy extraction via proteolytic, in addition to saccharolytic fermentation, accompanied by low-grade inflammation based on fecal calprotectin levels. Our data show that the maternal gut microbiota remained stable over the perinatal period despite altered metabolic activity and low-grade inflammation; however, it remains to be confirmed whether changes preceded earlier during pregnancy and succeeded later postpartum.


Non-conscious recognition of affect in the absence of striate cortex.
Functional neuroimaging experiments have shown that recognition of emotional expressions does not depend on awareness of visual stimuli and that unseen fear stimuli can activate the amygdala via a colliculopulvinar pathway. Perception of emotional expressions in the absence of awareness in normal subjects has some similarities with the unconscious recognition of visual stimuli which is well documented in patients with striate cortex lesions (blindsight). Presumably in these patients residual vision engages alternative extra-striate routes such as the superior colliculus and pulvinar. Against this background, we conjectured that a blindsight subject (GY) might recognize facial expressions presented in his blind field. The present study now provides direct evidence for this claim.


Modulation of disulfide dual ENKephalinase inhibitors (DENKIs) activity by a transient N-protection for pain alleviation by oral route.
The endogenous opioid system, essentially constituted by two opioid receptors which are stimulated by the natural internal effectors enkephalins (Met-enkephalin and Leu-enkephalin), is present at the different sites (peripheral, spinal, central) of the control of pain. We have demonstrated that the protection of the enkephalin inactivation by the two metallopeptidases (neprilysin and neutral aminopeptidase) increases their local concentration selectively induced by pain stimuli triggering analgesic responses. With the aim of increasing the orally antinociceptive responses of the previously described disulfide DENKIs ( [Formula: see text] CH(R1)CH2-S-S-CH2-C(R2R3)CONHCH(R4)COOR5), we designed new pro-drugs, in the same chemical series, with a transient protection of the free amino group by an acyloxyalkyl carbamate, giving rise to ((CH3)2CHCO2CH(CH3)OCONHCH(R1)CH2-S-S-CH2-C(R2R3)CONHCH(R4)COOR5) pro-drugs 2a-2g. These compounds were easily prepared from their parent analogs, with a good yield. They were tested per os and shown to be highly efficient in peripherally-controlled inflammatory and neuropathic pain with long lasting effects but completely inactive in the acute centrally-controlled hot plate test, a model of pain by excess of nociception. This demonstrates that DENKIs are able to relieve pain at its source thanks to the increase of enkephalin levels.


GPLOM: the generalized plot matrix for visualizing multidimensional multivariate data.
Scatterplot matrices (SPLOMs), parallel coordinates, and glyphs can all be used to visualize the multiple continuous variables (i.e., dependent variables or measures) in multidimensional multivariate data. However, these techniques are not well suited to visualizing many categorical variables (i.e., independent variables or dimensions). To visualize multiple categorical variables, 'hierarchical axes' that 'stack dimensions' have been used in systems like Polaris and Tableau. However, this approach does not scale well beyond a small number of categorical variables. Emerson et al. [8] extend the matrix paradigm of the SPLOM to simultaneously visualize several categorical and continuous variables, displaying many kinds of charts in the matrix depending on the kinds of variables involved. We propose a variant of their technique, called the Generalized Plot Matrix (GPLOM). The GPLOM restricts Emerson et al.'s technique to only three kinds of charts (scatterplots for pairs of continuous variables, heatmaps for pairs of categorical variables, and barcharts for pairings of categorical and continuous variable), in an effort to make it easier to understand. At the same time, the GPLOM extends Emerson et al.'s work by demonstrating interactive techniques suited to the matrix of charts. We discuss the visual design and interactive features of our GPLOM prototype, including a textual search feature allowing users to quickly locate values or variables by name. We also present a user study that compared performance with Tableau and our GPLOM prototype, that found that GPLOM is significantly faster in certain cases, and not significantly slower in other cases.


The blood vascular wreath of rat ovarian follicle, with special reference to its changes in ovulation and luteinization: a scanning electron microscopic study of corrosion casts.
Blood vascular casts of rat ovaries were prepared by injection of a low viscosity methacrylate medium, and observed by scanning electron microscopy. The proper vascular pattern of the rat ovarian follicle starts as a basket-like wreath of fine capillaries around the primary follicle. As the follicle grows larger, the wreath becomes more developed. The fully developed wreath around the Graafian follicle consists of sinusoidal capillaries. In ovulation, the apical area of the wreath is opened and the basal area of the wreath is elevated. After ovulation, the wreath shrinks and its opened area is closed, with markedly dilated vessels directly continuous with the arterial capillaries. The wreath then transforms, by intense new formation of capillaries, into a conglomerated sinusoidal capillary plexus with an avascular area within it. The avascular area soon disappears by continued intense formation of capillaries, in the plexus, and a complete and dense vascular network of the corpus luteum is formed. The capillaries of the fully developed corpus luteum are small in caliber and not sinusoidal in nature. Discontinuities of the capillaries and a flattening of the efferent branches are the initial signs of the degeneration of the corpus luteum. The small markedly degenerated corpus luteum contains only scattered thready capillaries. The corpus albicans contains few blood vessels.


Predictors of reversibility of pulmonary hypertension in cardiac transplant recipients in the first postoperative year.
Pulmonary hypertension remains a risk factor for early postoperative mortality in heart transplantation and may reduce the long-term benefits of the procedure. This study was undertaken to assess the value of baseline hemodynamic studies with nitroprusside used to predict the degree of postoperative reversibility of pulmonary hypertension in cardiac transplant recipients and to identify clinical risk factors for fixed pulmonary hypertension. Hemodynamic data from 55 consecutive patients who underwent orthotopic cardiac transplantation from June 1988 through September 1993 were analyzed. The effects of nitroprusside and transplantation on pulmonary artery pressure, cardiac output, and pulmonary vascular resistance were compared. Multiple regression analysis was used to identify the predictors of reversibility of pulmonary hypertension. Nitroprusside reduced pulmonary vascular resistance by increasing cardiac output and, to a lesser extent, by reducing the transpulmonary gradient. Pulmonary hypertension was less reversible in patients with ischemic heart disease (versus dilated cardiomyopathy) and in former smokers (versus nonsmokers). Patients with nonischemic heart failure and no smoking history had significantly lower posttransplant pulmonary vascular resistance (1.24 +/- 0.45 Wood units) than ischemic patients (who were all former smokers; 2.20 +/- 1.01 wood units) or nonischemic former smokers (1.72 +/- 0.70 Wood units). The correlation of pulmonary vascular resistance during nitroprusside challenge with posttransplant pulmonary vascular resistance was better than that of baseline pulmonary vascular resistance with posttransplant pulmonary vascular resistance. Nitroprusside testing improves the prediction of late posttransplant pulmonary vascular resistance; hence, it provides data that may be relevant to both early operative risk and later long-term effectiveness of cardiac transplantation. The finding of increased risk of fixed pulmonary hypertension associated with ischemic heart disease and smoking suggests that underlying atherosclerotic vascular disease may contribute to the irreversibility of pulmonary vascular resistance.


Risk of convulsive epilepsy following acute seizures in Kenyan children.
The prevalence of epilepsy is high in Africa, and people with epilepsy often have a history of acute seizures. We determined whether acute seizures are associated with risk for epilepsy in rural Africa, where both conditions are common and may have shared risk factors. A total of 16,438 children (2,991 with acute seizures and 13,447 without seizures) admitted to Kilifi County Hospital from 2002 to 2008 were followed up with epidemiological surveys conducted in 2003 and 2008 to assess the prevalence of epilepsy and the associated risk factors. Cox proportional hazards regression models were used to identify the risk factors. Prevalence ratios were computed using log binomial regression models. The prevalence of epilepsy was higher in admissions with acute seizures (5.0% [95% confidence interval (CI), 4.3-5.9%]) than in those without seizures (0.7% [95% CI, 0.5-0.8%]), p < 0.0001). Acute seizures were associated with epilepsy after accounting for potential confounders in a Cox regression model (hazard ratio [HR] = 1.53 [95% CI, 1.10-2.14]). Prevalence was greater in complex acute seizures (5.9%; prevalence ratio [PR] = 1.58 [95% CI, 1.13-2.20]) or status epilepticus (7.5%; PR = 1.96 [95% CI, 1.32-2.91]) than in simple acute seizures (3.7%). Factors independently associated with epilepsy following acute seizures in Cox regression models were perinatal complications (HR = 3.60 [95% CI, 1.89-6.87]), cerebral palsy (HR = 1491.51 [95% CI, 144.30-15,416.21]), duration of follow-up (HR = 1.21 [95% CI, 1.09-1.35]), and malnutrition (relative risk [RR] = 0.24 [95% CI, 0.08-0.69]). Acute seizures in children are associated with subsequent risk for epilepsy that is greater than in the general population. The burden of epilepsy may be reduced by control of causes of acute seizures.