The neurotrophic receptor Ntrk2 directs lymphoid tissue neovascularization during Leishmania donovani infection.
The neurotrophic tyrosine kinase receptor type 2 (Ntrk2, also known as TrkB) and its ligands brain derived neurotrophic factor (Bdnf), neurotrophin-4 (NT-4/5), and neurotrophin-3 (NT-3) are known primarily for their multiple effects on neuronal differentiation and survival. Here, we provide evidence that Ntrk2 plays a role in the pathologic remodeling of the spleen that accompanies chronic infection. We show that in Leishmania donovani-infected mice, Ntrk2 is aberrantly expressed on splenic endothelial cells and that new maturing blood vessels within the white pulp are intimately associated with F4/80(hi)CD11b(lo)CD11c(+) macrophages that express Bdnf and NT-4/5 and have pro-angiogenic potential in vitro. Furthermore, administration of the small molecule Ntrk2 antagonist ANA-12 to infected mice significantly inhibited white pulp neovascularization but had no effect on red pulp vascular remodeling. We believe this to be the first evidence of the Ntrk2/neurotrophin pathway driving pathogen-induced vascular remodeling in lymphoid tissue. These studies highlight the therapeutic potential of modulating this pathway to inhibit pathological angiogenesis.


Group II introns in eubacteria and archaea: ORF-less introns and new varieties.
Group II introns are a major class of ribozymes found in bacteria, mitochondria, and plastids. Many introns contain reverse transcriptase open reading frames (ORFs) that confer mobility to the introns and allow them to persist as selfish DNAs. Here, we report an updated compilation of group II introns in Eubacteria and Archaea comprising 234 introns. One new phylogenetic class is identified, as well as several specialized lineages. In addition, we undertake a detailed search for ORF-less group II introns in bacterial genomes in order to find undiscovered introns that either entirely lack an ORF or encode a novel ORF. Unlike organellar group II introns, we find only a handful of ORF-less introns in bacteria, suggesting that if a substantial number exist, they must be divergent from known introns. Together, these results highlight the retroelement character of bacterial group II introns, and suggest that their long-term survival is dependent upon retromobility.


Probing conserved amino acids in phospholipase D (Brassica oleracea var. capitata) for their importance in hydrolysis and transphosphatidylation activity.
In addition to hydrolysis of glycerophospholipids, phospholipases D (PLDs) catalyze the head group exchange. The molecular basis of this transphosphatidylation potential, which strongly varies for PLDs from different sources, is unknown hitherto. Recently, the genes of two PLD isoenzymes from white cabbage have been sequenced and expressed in Escherchia coli, yielding the basis for mutational studies. In the present paper, three sequence characteristics of the isoenzyme (PLD2) that corresponds to the often used enzyme isolated from cabbage leaves have been probed for their importance in hydrolysis as well as transphosphatidylation activities: (i) the two HKD motifs, (ii) the C terminus and (iii) the eight cysteine residues. All these regions or amino acids are highly conserved in alpha-type plant PLDs. Based on multiple alignments, predictions of secondary structure and comparisons of hydrophobicity profiles, 35 enzyme variants were created and assayed. All positions tested proved to be very sensitive towards amino acid exchanges with respect to hydrolytic activity in the absence of glycerol as well as to the ratio of hydrolytic and transphosphatidylation activities in the presence of glycerol. A significant increase of total activity and transphosphatidylation activity could be obtained by the substitutions C310S and C625S.


Incidental discovery of high systemic lupus erythematosus disease activity associated with cytomegalovirus viral activity.
We try to find the association of cytomegalovirus (CMV) infection and anti-beta2 glycoprotein 1 autoantibodies (anti-beta2 GP1), a key antibody in antiphospholipid syndrome (APS), among systemic lupus erythematosus (SLE) and cerebral vascular accident (CVA) patients. This retrospective study enrolled serum samples obtained from 87 SLE and 97 CVA patients who have been checked for the existence of anti-beta2 GP1. First, the prevalence rate of anti-CMV IgG and IgM in patients with and without anti-beta2 GP1 were compared. Second, the prevalence of anti-CMV IgG and IgM were compared between SLE and CVA patients. Last, this study analyzed the clinical characteristics and disease activity in SLE patients with positive anti-CMV IgM and IgG. No difference existed in the prevalence rate of anti-CMV IgG and IgM between positive or negative anti-beta2 GP1 serum samples in both SLE and CVA patients. However, the prevalence of anti-CMV IgM was significantly higher in the SLE group than in the CVA group. Severity of clinical features and SLEDAI scores were considerably higher in patients with positive anti-CMV IgM than in SLE patients with negative anti-CMV IgM. Very impressively, all IgM-positive SLE samples (9/9) carrying highest levels of anti-CMV IgG, indicated reactivation of the latent CMV infection. Hence, it suggests that CMV reactivation might contribute toward the disease flare in some SLE patients. In future, a prospective and longitudinal study is stongly indicated.


Normal human immunoglobulin G4 is bispecific: it has two different antigen-combining sites.
Unlike other immunoglobulin G (IgG) subclasses, IgG4 antibodies in plasma have been reported to be functionally monovalent. In this paper we show that the apparent monovalency of circulating IgG4 is caused by asymmetry of plasma IgG4. A large fraction of plasma IgG4 molecules have two different antigen-binding sites, resulting in bispecificity. Sera from patients with IgG4 antibodies to both house dust mite and grass pollen induced cross-linking of Sepharose-bound grass pollen antigen to radiolabelled house dust mite allergen Der p I. This bispecific binding activity was not observed in sera with IgG4 antibodies to either grass pollen or house dust mite exclusively. Depletion of IgG4 antibodies resulted in disappearance of the bispecific activity. By size exclusion chromatography we excluded the possibility that bispecific activity was caused by aggregation of IgG4 antibodies. These results indicate that circulating (polyclonal) IgG4 antibodies have two different antigen-binding sites and therefore are functionally monovalent antibodies.


Inhibition of shivering in man by thermal stimulation of the facial area.
The contribution of the facial thermoreceptors to thermoregulatory shivering was studied. Seven subjects were exposed to -3 degrees C ambient air for 1 h. Radiant heat was applied to the facial area during 30 s periods at 10 min intervals and the effects on the integrated electromyographic activity (IEMG) in the brachial biceps, trapezius and femoral rectus muscles, and on the heart rate (HR) were studied. During cold-air exposure mean skin temperature as measured at four sites decreased by 15.5 +/- 0.6 degrees C (mean +/- SE) while rectal temperature remained virtually unchanged. During the radiant heat exposures IEMG activity decreased by 18.9 +/- 2.3%; HR decreased by 11 +/- 1 beats min-1. The changes in IEMG occurred within or slightly below the range of maximum cold receptor sensitivity (20-30 degrees C) and coincided with the maximum rate of change in chin temperature. The observed inhibition of shivering IEMG during locally applied facial heat stimulation suggest that the trigeminal region contributes an important input to the overall thermoregulatory responses.


Exclusive Breast Feeding and Its Associated Factors Among Mothers of <12 Months Old Child in Harar Town, Eastern Ethiopia: A Cross-Sectional Study.
Exclusive breast-feeding is the practice of feeding breast milk during the first 6 months and no other liquids and solid foods except medications. Despite its demonstrated benefits, exclusive breast-feeding practice in many countries including Ethiopia is lower than the international recommendation. However, studies about exclusive breast-feeding in the study area are limited. Therefore, this study aimed to fill this gap. Community-based cross-sectional study was employed. A cluster sampling method was used to select 577 women who had a child aged <12 months. Data were collected using a pretested interviewer-administered questionnaire. Epi-Data version 3.1 and SPSS version 21 were used for data entry and analysis. Bivariate and multivariate logistic regressions were used to analyze the association between the dependent and independent variables. A total of 577 study participants have participated in the study which gives 97.8% response. Exclusive breast-feeding practice among the mothers was 45.8%. Women in the age group of 26-40 were 2 times more likely to breast-feed than women in the age group of 18-25 at (AOR = 1.980 [95% CI = 1.098, 3.570]). Women who have information about exclusive breast-feeding were two times more likely to breast feed than those who have no information at (AOR = 1.952 [95% CI = 1.130, 3.373]). Those women who initiated breast-feeding early were 12 times more likely to breastfeed than those women who did not initiate early at (AOR = 12.336 [95% CI = 1.331, 14.316]). The overall exclusive breast-feeding practice among the women was found to be less. Age, information on breast-feeding and early initiation of breast-feeding were found as important predictors of exclusive breast-feeding. Improving access to information on recommended infant feeding is vital, and encouraging exclusive breast-feeding among mothers through proper counseling and mother-friendly work environment is advisable.


Characteristics of clinical laboratory technician students and effects on program outcome.
To characterize student attrition in CLT education programs and relate program outcome (graduate, voluntary withdrawal, or academic dismissal) to student characteristics in three clusters of variables: academic, background and demographic characteristics, and environmental factors. Longitudinal, prospective study using a written survey and follow-up data collection. Not applicable. 1527 students from 61 CLT academic-based educational programs located across the U.S. Not applicable. Participants completed a forced-choice written survey eliciting demographic and background information and measuring variables related to their involvement with the academic program and environmental factors external to the college. Program outcome groups: graduates, voluntary withdrawals, and academic dismissals were compared on each variable. Graduates of CLT programs differ significantly from both academic dismissals and voluntary withdrawals on variables from all three variable clusters. Student characteristics exhibited early in CLT programs may help identify those students who are at risk of academic failure or voluntary withdrawal. Knowledge of factors associated with lack of CLT program persistence may help educators design successful intervention programs to enhance retention.


Sense of happiness in Polish patients with multiple sclerosis.
Happiness is crucial to patient well-being and their acceptance of their disease. The aim of this study was to assess the sense of happiness in persons with multiple sclerosis (PwMS), compare it to the level of happiness in patients with other neurological conditions, and determine which factors affect the sense of happiness in PwMS. Five hundred and eighty-nine PwMS and 145 control subjects (post-stroke patients with chronic pain syndromes and neuropathies) were included in the study. Due to the differences between the groups in terms of demographic variables, an adjusted group of PwMS (n = 145) was selected from the entire group of PwMS. All patients were assessed using the Oxford Happiness Questionnaire (OHQ), the Satisfaction with Life Scale (SLS), and the Family APGAR Questionnaire. Based on regression analysis, the study examined which variables affected the level of happiness in the groups. Analysis of the OHQ scores showed that PwMS had a lower sense of happiness compared to the control group in the overall score [113.21 (25-42) vs. 119.88 (25-49), respectively; p = 0.031] and the subscales (OHQ subscale 1 - 54.52 vs. 57.84, respectively; p = 0.027; subscale 2 - 35.61 vs. 37.67; respectively; p = 0.044). Based on linear regression analysis, life satisfaction (β = 0.40; p < 0.001), positive orientation (β = 0.32; p < 0.001), and primary education (β = 0.08; p = 0.009) were the most significant predictors of a higher level of happiness in PwMS. Similar results were found in the control group. The sense of happiness in PwMS was lower than in patients with other conditions. The most important factors influencing happiness included life satisfaction and positive orientation. Influencing these predictors should be the aim of psychological interventions, especially in patients with a reduced sense of happiness.


Neuronal turnover in the Xenopus laevis olfactory epithelium during metamorphosis.
Metamorphic changes in the amphibian olfactory system present many interesting questions concerning the competing possibilities of neuronal respecification versus replacement. For example, are olfactory neurons retained during this transition with their presumed sensitivity to waterborne versus airborne stimuli respecified, or are olfactory neurons completely replaced? We address this question using the African clawed frog (Xenopus laevis) as a model. The water-sensing nose (principal cavity; PC) of larval X. laevis is respecified into an air-sensing cavity in adults, with changes in odorant receptor gene expression, ultrastructure, and site of innervation of the receptor neurons. The vomeronasal organ (VNO) does not appear to change function, structure, or innervation during metamorphosis. We labeled PC and VNO olfactory receptor neurons with injections of retrogradely transported fluorescent microspheres into the main and accessory olfactory bulbs. Injections were performed in larvae, and animals were allowed to survive through metamorphosis. After metamorphosis, few labeled cells were observed in the PC, whereas the VNO and the olfactory bulbs remained heavily labeled. Animals that were killed before metamorphosis always had extensive label in the PC epithelium regardless of how long the beads were present. This suggests that changes in the PC olfactory epithelium that are seen during metamorphosis are due primarily to turnover of the neurons in this epithelium rather than to respecification of existing neurons. These results also are discussed in terms of natural turnover time of olfactory receptor neurons.


Preselection of retrovirally transduced bone marrow avoids subsequent stem cell gene silencing and age-dependent extinction of expression of human beta-globin in engrafted mice.
Transcriptional silencing of genes transferred into hematopoietic stem cells poses one of the most significant challenges to the success of gene therapy. If the transferred gene is not completely silenced, a progressive decline in gene expression as the mice age often is encountered. These phenomena were observed to various degrees in mouse transplant experiments using retroviral vectors containing a human beta-globin gene, even when cis-linked to locus control region derivatives. Here, we have investigated whether ex vivo preselection of retrovirally transduced stem cells on the basis of expression of the green fluorescent protein driven by the CpG island phosphoglycerate kinase promoter can ensure subsequent long-term expression of a cis-linked beta-globin gene in the erythroid lineage of transplanted mice. We observed that 100% of mice (n = 7) engrafted with preselected cells concurrently expressed human beta-globin and the green fluorescent protein in 20-95% of their RBC for up to 9.5 mo posttransplantation, the longest time point assessed. This expression pattern was successfully transferred to secondary transplant recipients. In the presence of beta-locus control region hypersensitive site 2 alone, human beta-globin mRNA expression levels ranged from 0.15% to 20% with human beta-globin chains detected by HPLC. Neither the proportion of positive blood cells nor the average expression levels declined with time in transplanted recipients. Although suboptimal expression levels and heterocellular position effects persisted, in vivo stem cell gene silencing and age-dependent extinction of expression were avoided. These findings support the further investigation of this type of vector for the gene therapy of human hemoglobinopathies.


The effect of portal hypertension on transforming growth factor-alpha and epidermal growth factor receptor in the gastric mucosa of rats.
The aim of this study was to evaluate the expression of transforming growth factor-alpha (TGF-alpha) and epidermal growth factor receptor (EGFR) immunohistochemically in gastric mucosa of portal hypertensive (PHT) and sham-operated rats. PHT was induced experimentally by partial ligation of the portal vein (PVL) in 12 male Wistar rats; another group of 12 rats (control) received sham operations. The severity of macroscopic gastric mucosal lesions and immunoreactivity of TGF-alpha and EGFR were evaluated 14 days following the above procedure. The damage to gross gastric mucosa was found to be significantly greater in the PVL group than the control group (p<0.01). Additionally, the TGF-alpha and EGFR immunoreactivities were significantly more intense in the PVL groups compared to the control (P<0.05). The TGF-alpha and EGFR immunoreactive cells were more prominent around injured mucosa. From these findings, we suggest that locally produced TGF-alpha and EGFR may play an important role in the gastric mucosal repair following PHT to rats.


Induction of S-phase entry by E2F transcription factors depends on their nuclear localization.
The E2F transcription factors are essential for regulating the correct timing of activation of several genes whose products are implicated in cell proliferation and DNA replication. The E2Fs are targets for negative regulation by the retinoblastoma protein family, which includes pRB, p107, and p130, and they are in a pathway that is frequently found altered in human cancers. There are five members of the E2F family, and they can be divided into two functional subgroups. Whereas, upon overexpression, E2F-1, -2, and -3 induce S phase in quiescent fibroblasts and override G1 arrests mediated by the p16INK4A tumor suppressor protein or neutralizing antibodies to cyclin D1, E2F-4 and -5 do not. Using E2F-1 and E2F-4 as representatives of the two subgroups, we showed here, by constructing a set of chimeric proteins, that the amino terminus of E2F-1 is sufficient to confer S-phase-inducing potential as well as the ability to efficiently transactivate an E2F-responsive promoter to E2F-4. We found that the E2F-1 amino terminus directs chimeric proteins to the nucleus. Surprisingly, a short nuclear localization signal derived from simian virus 40 large T antigen could perfectly substitute for the presence of the E2F-1 amino terminus in these assays. Thus, nuclearly localized E2F-4, when overexpressed, displayed biological activities similar to those of E2F-1. Furthermore, we showed that nuclear localization of endogenous E2F-4 is cell cycle regulated, with E2F-4 being nuclear in the G0 and early G1 phases and mainly cytoplasmic after the pRB family members have become phosphorylated. We propose a novel mechanism for the regulation of E2F-dependent transcription in which E2F-4 regulates transcription only from G0 until mid- to late G1 phase whereas E2F-1 is active in late G1 and S phases, until it is inactivated by cyclin A-dependent kinase in late S phase.


Therapeutic hypothermia in severe hypoxic-ischemic encephalopathy: a cost-effectiveness analysis.
The incidence of hypoxic-ischemic encephalopathy (HIE) is 0.5 per 1,000 live births. Current standard treatment is therapeutic hypothermia (cooling) begun within 6 hours of life. In infants with severe HIE, this results in fewer deaths; however, more infants survive with major neurodevelopmental disability. We sought to determine whether cooling is cost-effective compared to no cooling in cases of severe HIE, and to compare it to the cost-effectiveness of cooling in cases of moderate HIE. A decision analytic model using TreeAge Pro (2020) software was designed comparing cooling to no cooling in a cohort of 5,800 term neonates with HIE. Model inputs were derived from the literature. Utilities were applied to life expectancy to generate quality-adjusted life years (QALYs). All costs and QALYs were discounted at an annual rate of 3%. The strategy was considered cost-effective if the incremental cost-effectiveness ratio (ICER) was below the willingness-to-pay threshold of $100,000 per QALY. Sensitivity analyses were conducted to assess the robustness of the results. Cooling for the management of severe HIE resulted in increased costs and increased QALYs, with an ICER of 6,864. In our theoretical cohort, cooling resulted in 835 fewer neonatal deaths, but 52 additional cases of severe neurological disability with cooling due to increased survival. When varying the probability of a healthy child with cooling in univariate sensitivity analysis, cooling was found to be the cost-effective strategy across all ranges and the dominant (lower costs, higher QALYs) strategy above 68% (baseline estimate: 63%). Multivariate sensitivity analysis found cooling was the cost-effective strategy 99.7% of the time. Cooling is the cost-effective intervention with improved outcomes for neonates with severe perinatal hypoxic-ischemic encephalopathy over a wide range of assumptions. Despite the increased cost, more neonates survive morbidity free when compared with no cooling.


Concurrent use of methotrexate and celecoxib increases risk of silent liver fibrosis in rheumatoid arthritis patients with subclinical reduced kidney function.
We evaluated the effects of concurrent use of methotrexate and celecoxib on silent liver and kidney damages in rheumatoid arthritis (RA) patients. We enrolled 92 RA patients with normal laboratory results related to liver and kidney functions, who had received methotrexate and celecoxib concurrently over 6 months. Liver stiffness measurement (LSM) using transient elastography and ultrasonography were performed along with blood and urine tests. Estimated glomerular filtration rate (eGFR) was calculated by both the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD) equations. Initial eGFR represented kidney function at the time of the initiation of celecoxib. The cutoff for abnormal LSM values was adopted as 5.3 kPa. The optimal cutoff of each eGFR for abnormal LSM values was also calculated. The median age of patients was 55 years old (74 women). The median LSM was 4.4 kPa and the median eGFRs and median initial eGFRs ranged from 89 to 99 mL/min/1.73 m(2). The cumulative doses of methotrexate and celecoxib and their concurrent administration duration did not affect LSM values and eGFRs. Both eGFRs were significantly associated with LSM values. Patients with initial eGFR(CKD-EPI), initial eGFR(MDRD), and eGFR(CKD-EPI) below each optimal cutoff had significantly high risks for silent liver fibrosis (RR 9.4, 10.3, and 4.4, p < 0.001, respectively). Both initial eGFRs (CKD-EPI and MDRD) and eGFR (CKD-EPI) were significant predictors for the development of silent liver fibrosis in RA patients who had received methotrexate and celecoxib concurrently for at least 6 months.


Care transitions service: a pharmacy-driven program for medication reconciliation through the continuum of care.
A quality-improvement program at University of New Mexico Hospital (UNMH) encompassing admission, discharge, and postdischarge medication reconciliation activities is described, with a report on initial assessments of the program's impact on rates of medication-related problems (MRPs). Pharmacists conducted a five-month evaluation of the UNMH Care Transitions Service (CTS), which serves inpatients admitted to the hospital's family medicine service, providing medication reconciliation and targeted MRP interventions. Selected patients who received CTS services from November 2012 through March 2013 (n = 191) were included in the analysis. The study endpoints were the rates and types of MRPs identified, the most commonly implicated medication classes, and predictors of MRPs. Postdischarge MRP rates during a two-month trial of CTS services at a UNMH outpatient clinic were also evaluated. During the five-month evaluation of inpatient CTS services, a total of 1140 MRPs were identified (an average of 6 per patient), about 70% of which were resolved independently of provider review using pharmacy-driven protocols. During the two-month pilot test of CTS outpatient services (n = 16), a total of 28 MRPs were identified; in over 80% of cases, there was a decline in the number of MRPs from the admission to the postdischarge medication reconciliation. MRPs were identified through the continuum of care. The majority of MRPs identified in both the inpatient and outpatient settings involved patient variables and patient nonadherence. Seventy percent of inpatient MRPs were resolved independently by the CTS team under pharmacy-driven protocols.


Effect of Non-Surgical Periodontal Therapy on the Serum Sialic Acid Levels in Diabetic Patients with Periodontitis.
Sialic acid (SA), a family of acetylated derivatives of neuraminic acid, an acute phase reactant by itself. It usually occurs as a terminal component at the non-reducing end of carbohydrate chains of glycoproteins and glycolipids. SA participates in multiple physiological functions, such as cell-to-cell interactions, cell migration and proliferation. Diabetes mellitus (DM) is a chronic metabolic disorder characterized by rise in blood glucose level. Periodontitis is a chronic inflammatory disease of the periodontal tissue, leading to destruction of bone surrounding the tooth and ultimately tooth loss. There is a two way relationship between diabetes mellitus and periodontitis. Periodontitis is the sixth complication of diabetes along with retinopathy, nephropathy, neuropathy, macrovascular disease, and altered wound healing. Inflammatory mediators like interleukin-6 and tumor necrosis factor-alpha produced during periodontal inflammation can interfere with the actions of insulin receptors and worsen the glycemic control of diabetic patients. Periodontitis is a major cause of tooth loss, affecting over 300 million people and bacteria associated with periodontitis are also linked with systemic problems like endocarditis, atherosclerosis. Recent work has highlighted a major role for the host sugar sialic acid in the biofilm physiology and host-pathogen interactions of T. forsithya, a key periodontal pathogen. There exists a need for a biomarker, for early detection of disease evolution and more robust therapy efficacy measurements. Serum sialic acids were estimated in Indian population by diphenylamine method and Thiobarbituric acid method. The average values were 68 ± 2.6 mg percent by DPA method and 56 ± 5 mg percent by TBA (thiobarbituric acid assay) method. Age and sex showed no influence on serum sialic acid level. Objectives of the present study was to compare (TSSA) level in healthy subjects, subjects with (CMP) with and without (NIDDM) and its effect on non-surgical periodontal therapy. In the present study, the participants were divided into three groups: Group A, B and C. Group A consists of systemically healthy subjects, Group B consists of subjects with (CMP) while Group C consists of subjects with (CMP) with (NIDDM) and results of this study indicated that, at baseline, there were significant differences between Group A, B and Group C with respect to all the clinical parameters, including (GI), (OHI-S), (PPD), (CAL), (TSSA) and (HbA1c) levels. Thus (TSSA) level could be considered as novel biomarker in the progression of periodontal disease and diabetic status. Periodontitis could be considered as a potential, modifiable, and independent risk factor for the development of diabetes. Early detection of elevated (TSSA) level may help in interpreting the progression of periodontitis, risk of development of diabetes mellitus in future and also to prevent complications.


[The effect of microinjections of vasopressin into the inhibitory centers of the brain stem on rat behavior].
Microinjection of the arginin-vasopressin into the medial parabrachial nucleus, n. cuneiformis, raphe median nucleus and raphe magnus nucleus suppressed spontaneous locomotor activity and orienting response to electrical stimulation of hypothalamus in rats. Microinjections of 5,6-dihydroxytriptamine in n. raphe magnus blocked the inhibition of behaviour elicited by vasopressin.


Statistically based splicing detection reveals neural enrichment and tissue-specific induction of circular RNA during human fetal development.
The pervasive expression of circular RNA is a recently discovered feature of gene expression in highly diverged eukaryotes, but the functions of most circular RNAs are still unknown. Computational methods to discover and quantify circular RNA are essential. Moreover, discovering biological contexts where circular RNAs are regulated will shed light on potential functional roles they may play. We present a new algorithm that increases the sensitivity and specificity of circular RNA detection by discovering and quantifying circular and linear RNA splicing events at both annotated and un-annotated exon boundaries, including intergenic regions of the genome, with high statistical confidence. Unlike approaches that rely on read count and exon homology to determine confidence in prediction of circular RNA expression, our algorithm uses a statistical approach. Using our algorithm, we unveiled striking induction of general and tissue-specific circular RNAs, including in the heart and lung, during human fetal development. We discover regions of the human fetal brain, such as the frontal cortex, with marked enrichment for genes where circular RNA isoforms are dominant. The vast majority of circular RNA production occurs at major spliceosome splice sites; however, we find the first examples of developmentally induced circular RNAs processed by the minor spliceosome, and an enriched propensity of minor spliceosome donors to splice into circular RNA at un-annotated, rather than annotated, exons. Together, these results suggest a potentially significant role for circular RNA in human development.


Measuring energy, macro and micronutrient intake in UK children and adolescents: a comparison of validated dietary assessment tools.
Measuring dietary intake in children and adolescents can be challenging due to misreporting, difficulties in establishing portion size and reliance on recording dietary data via proxy reporters. The aim of this review was to present results from a recent systematic review of reviews reporting and comparing validated dietary assessment tools used in younger populations in the UK. Validation data for dietary assessment tools used in younger populations (≤18 years) were extracted and summarised using results from a systematic review of reviews of validated dietary assessment tools. Mean differences and Bland-Altman limits of agreement (LOA) between the test and reference tool were extracted or calculated and compared for energy, macronutrients and micronutrients. Seventeen studies which reported validation of 14 dietary assessment tools (DATs) were identified with relevant nutrition information. The most commonly validated nutrients were energy, carbohydrate, protein, fat, calcium, iron, folate and vitamin C. There were no validated DATs reporting assessment of zinc, iodine or selenium intake. The most frequently used reference method was the weighed food diary, followed by doubly labelled water and 24 h recall. Summary plots were created to facilitate comparison between tools. On average, the test tools reported higher mean intakes than the reference methods with some studies consistently reporting wide LOA. Out of the 14 DATs, absolute values for LOA and mean difference were obtained for 11 DATs for EI. From the 24 validation results assessing EI, 16 (67%) reported higher mean intakes than the reference. Of the seven (29%) validation studies using doubly labelled water (DLW) as the reference, results for the test DATs were not substantially better or worse than those using other reference measures. Further information on the studies from this review is available on the www.nutritools.org website. Validated dietary assessment tools for use with children and adolescents in the UK have been identified and compared. Whilst tools are generally validated for macronutrient intakes, micronutrients are poorly evaluated. Validation studies that include estimates of zinc, selenium, dietary fibre, sugars and sodium are needed.


Diagnostic and clinical values of non-cardiac ultrasound in COPD: A systematic review.
Clinical and research utility of non-cardiac ultrasound (US) in chronic obstructive pulmonary disease (COPD) has been widely investigated. However, there is no systematic review assessing the clinical values of non-cardiac US techniques in COPD. We systematically searched electronic databases from inception to 24 June 2020. Two independent reviewers in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines extracted data. A narrative synthesis of the results was conducted considering non-cardiac US techniques that looked for diaphragm, muscles and bones in patients with COPD. In total, 2573 abstracts were screened, and 94 full-text papers were reviewed. A total of 54 studies met the inclusion criteria. Thirty-five studies assessed the diaphragm, while 19 studies evaluated different muscles, including limb muscles and pulmonary lesions in COPD using US. Of the 54 included studies, 30% (16/54) evaluated the changes in either limb muscles or diaphragmatic features before and after physical interventions; 67% (36/54) assessed the correlations between sonographic features and COPD severity. Indeed, 14/15 and 9/13 studies reported a significant reduction in diaphragm excursion and thickness in COPD compared with healthy subjects, respectively; this was correlated significantly with the severity and prognosis of COPD. Three studies reported links between diaphragm length and COPD, where lower diaphragm length correlated with poorer prognosis and outcomes. Quadriceps (rectus femoris), ankle dorsiflexor (tibialis anterior) and vastus lateralis were the most common muscles in COPD assessed by US. More than 70% (12/17) of the studies reported a significant reduction in the cross-sectional area (CSA) of the rectus femoris, rectus femoris and vastus lateralis thickness in COPD compared with healthy subjects. Quadriceps CSA and thickness correlated positively with COPD prognosis, in which patients with reduced quadriceps CSA and thickness have higher risk of exacerbation, readmission and death. US measurements of diaphragm excursion and thickness, as well as lower limb muscles strength, size and thickness, may provide a safe, portable and effective alternative to radiation-based techniques in diagnosis and prognosis as well as tracking improvement postintervention in patients with COPD.


Expression and post-transcriptional regulation of ornithine decarboxylase during early Xenopus development.
In this paper we show that large changes in ornithine decarboxylase (ODC) activity occurred during early Xenopus development. Following fertilization, this enzyme activity rises with a quantitatively correlated accumulation of putrescine and spermidine. This increase in ODC activity was associated with an increased translation of the maternal ODC mRNA, which was stable in the embryo and whose polyadenylation increased slightly between fertilization and the mid-blastula transition (MBT). ODC activity was stable in cycloheximide-treated embryos, indicating that before the MBT this enzyme was not degraded. After the MBT, ODC activity fell, but no decrease in this mRNA was observed. In gastrulae, ODC mRNA was both increased in amount and polyadenylated. The reduced ODC activity at this stage of development was not associated with a fall in ribosome loading of the mRNA. Treatment of post-MBT embryos with cycloheximide lead to an accentuation of the normally observed decrease in ODC activity. Expression of Xenopus ODC in mutant ODC-deficient Chinese hamster ovary cells (C 55.7 cells) showed that the Xenopus enzyme was rapidly degraded and can be regulated post-translationally by polyamines, indicating that the post-MBT fall in ODC activity could be caused by a change in protein turnover or by polyamine-mediated regulation.


Association of 8p23 deletions with poor survival in head and neck cancer.
Allelic loss at 8p23 occurs frequently in head and neck squamous cell carcinoma. The objective of this study was to determine the prognostic importance of 8p23 loss. We tested 51 primary tumors and 19 lymph node metastases for loss of heterozygosity with 7 microsatellite polymorphisms at 8p23 and correlated the results with disease-free interval and disease-specific survival. The Kaplan-Meier analysis demonstrated statistically significant association of 8p23 allelic loss with both shorter disease-free interval and disease-specific survival. For the pN stage, the log-rank test indicated significance in correlation with the disease-free interval, whereas the pT stage showed a significant correlation with disease-specific survival. Multivariate analysis identified loss of heterozygosity at 8p23 as independent prognostic marker for disease-free interval. Our data suggest that 8p23 allelic loss is associated with poor prognosis in head and neck squamous cell carcinoma and could be useful refining diagnosis of these tumors.


Epigenomic Analysis of Sézary Syndrome Defines Patterns of Aberrant DNA Methylation and Identifies Diagnostic Markers.
Sézary syndrome (Sz) is a malignancy of skin-homing CD4(+) memory T cells that is clinically characterized by erythroderma, lymphadenopathy, and blood involvement. Distinction of Sz from erythroderma secondary to inflammatory skin diseases (erythrodermic inflammatory dermatosis [EID]) is often challenging. Recent studies identified recurrent mutations in epigenetic enzymes involved in DNA modification in Sz. Here we defined the DNA methylomes of purified CD4(+) T cells from patients with Sz, EID, and healthy control subjects. Sz showed extensive global DNA methylation alterations, with 7.8% of 473,921 interrogated autosomal CpG sites showing hypomethylation and 3.2% hypermethylation. Promoter CpG islands were markedly enriched for hypermethylation. The 126 genes with recurrent promoter hypermethylation in Sz included multiple candidate tumor suppressors that showed transcriptional repression, implicating aberrant methylation in the pathogenesis of Sz. Validation in an independent sample set showed promoter hypermethylation of CMTM2, C2orf40, G0S2, HSPB6, PROM1, and PAM in 94-100% of Sz samples but not in EID samples. Notably, promoter hypermethylation of a single gene, the chemokine-like factor CMTM2, was sufficient to accurately distinguish Sz from EID in all cases. This study shows that Sz is characterized by widespread yet distinct DNA methylation alterations, which can be used clinically as epigenetic diagnostic markers.


Proton-Coupled Oligopeptide Transport (Slc15) in the Brain: Past and Future Research.
This mini-review describes the role of the solute carrier (SLC)15 family of proton-coupled oligopeptide transporters (POTs) and particularly Pept2 (Slc15A2) and PhT1 (Slc15A4) in the brain. That family transports endogenous di- and tripeptides and peptidomimetics but also a number of drugs. The review focuses on the pioneering work of David E. Smith in the field in identifying the impact of PepT2 at the choroid plexus (the blood-CSF barrier) as well as PepT2 and PhT1 in brain parenchymal cells. It also discusses recent findings and future directions in relation to brain POTs including cellular and subcellular localization, regulatory pathways, transporter structure, species differences and disease states.


Group cohesiveness in children free-play activity: A social network analysis.
Despite the ethnic diversity and presence of Amerindian communities in all Brazilian states, the indigenous population suffers from a long process of invisibility and stereotyping. Aiming to increase interethnic associations, together with Mbya-Guarani leaders we promoted interventions in which indigenous and non-indigenous children shared free playtime. We hypothesised that free play activity would stimulate group cohesiveness, mitigating ethnic group avoidance in children's playgroups. Twenty-one Mbya-Guarani and 61 non-indigenous children participated in two "Encounters for Play." We recorded children's social interactions during the free playtimes. We selected the first and last 10 minutes of each encounter and performed scans every 30s registering spatial proximity (children who were up to 1 m of each other) and play. Then, we applied Social Network Analysis to explore the children's association pattern at the beginning and end of playtime in each encounter. Our results show free play activity was effective in stimulating group cohesiveness. Children' proximity association pattern and playgroup configuration changed between clips, and there was a significant correlation between both categories' associations. We conclude that the encounters have potential applicability as an intervention to mitigate ethnic group avoidance in children.


Scalable Anatomically-Tunable Fully In-Ear Dry-Electrode Array for User-Generic Unobtrusive Electrophysiology.
Traditional scalp EEG instrumentation is bulky and arduous to set up, requiring wires that constrain the subject's movement, conductive wet gels that dry over time which limits long-term recording, and/or is socially stigmatized. Therefore, there is growing research in in-ear EEG to increase user wearability, ease of use, and concealability. However, the fabrication of in-ear EEG sensors utilizes complex equipment and materials to capture the intricate geometry of the ear and to fabricate custom earpieces and electrodes. This work aims to lower the barrier of entry by decreasing the fabrication complexity by using PCB components with versatile, user-generic designs. Measured results on the assembled earpiece demonstrate that it viably captures eye blinks, jaw clench, auditory steady-state response (ASSR), and alpha modulation. Additionally, electrochemical impedance spectroscopy (EIS) experiments show reliable electrode-skin contact with impedance comparable to conventional dry-electrode designs at substantially greater channel density.


Histology-based Classification Predicts Pattern of Recurrence and Improves Risk Stratification in Primary Retroperitoneal Sarcoma.
To determine the prognostic significance of histologic type/subtype in a large series of patients with primary resected retroperitoneal sarcoma. The histologic diversity and rarity of retroperitoneal sarcoma has hampered the ability to predict patient outcome. From a single-institution, prospective database, 675 patients treated surgically for primary, nonmetastatic retroperitoneal sarcoma during 1982 to 2010 were identified and histologic type/subtype was reviewed. Clinicopathologic variables were analyzed for association with disease-specific death (DSD), local recurrence (LR), and distant recurrence (DR). Median follow-up for survivors was 7.5 years. The predominant histologies were well-differentiated liposarcoma, dedifferentiated liposarcoma, and leiomyosarcoma. Five-year cumulative incidence of DSD was 31%, and factors independently associated with DSD were R2 resection, resection of 3 or more contiguous organs, and histologic type. Five-year cumulative incidence for LR was 39% and for DR was 24%. R1 resection, age, tumor size, and histologic type were independently associated with LR; size, resection of 3 or more organs, and histologic type were independently associated with DR. Liposarcoma and leiomyosarcoma were associated with late recurrence and DSD (as long as 15 years from diagnosis). For solitary fibrous tumor, LR was uncommon (<10%), but early distant recurrence was common (36% at 5 years). Nomograms were developed to predict DSD, LR, and DR. Histologic type/subtype is the most important independent predictor of DSD, LR, and DR in primary retroperitoneal sarcoma. Histology predicts the pattern and incidence of LR and DR and will aid in more accurate patient counseling and selection of patients for adjuvant therapy trials.


Group precipitation and age hardening of nanostructured Fe-based alloys with ultra-high strengths.
The precipitation of nanoparticles plays a key role in determining the properties of many structural materials, and the understanding of their formation and stabilization mechanisms has been a long standing interest in the material field. However, the critical issues involving the group precipitation of various nanoparticles and their cooperative hardening mechanism remain elusive in the newly discovered Fe-based alloys with nanostructures. Here we quantitatively elucidate the nucleation mechanism, evolution kinetics and hardening effects of the group-precipitated nanoparticles in the Fe-Cu-Ni-Al-based alloys by atom probe tomography together with both first-principles and thermodynamic calculations. Our results provide the compelling evidence for two interesting but complex group precipitation pathways of nanoparticles, i.e., the Cu-rich and NiAl-based precipitations. The co-existence of the two precipitation pathways plays a key role in age hardening kinetics and ultimately enhances the hardening response, as compared to the single particle type of strengthening, therefore providing an effective new approach for strengthening materials for structural applications.


Paucity of high-quality studies reporting on salt and health outcomes from the science of salt: A regularly updated systematic review of salt and health outcomes (April 2017 to March 2018).
The purpose of this review is to identify, summarize, and critically appraise studies on dietary salt and health outcomes that were published from April 2017 to March 2018. The search strategy was adapted from a previous systematic review on dietary salt and health. Identified studies were screened based on a priori defined criteria to identify publications eligible for detailed critical appraisals. Overall, 6747 citations were identified by the search strategy, and 42 health outcome studies were identified. Three of the 42 studies met the criteria for methodological quality and health outcomes and underwent detailed critical appraisals and commentary. In addition, a systematic review and meta-analysis was critically appraised, although it did not strictly meet our methodological criteria. All four of the studies critically appraised found that sodium reduction improved blood pressure, especially in individuals with hypertension. In addition, sodium reduction reduced albuminuria in patients with stage 1-3 chronic kidney disease. Examination of the time course of blood pressure responses to sodium reduction revealed lowering sodium in the context of an average American diet may not produce maximal blood pressure reductions within a 4-week intervention period. This review provides further evidence of the benefit of sodium reduction for blood pressure lowering and gives insights into the subgroups of the population that may derive the greatest benefit from sodium reduction and the time course required to see benefit. Only three high-quality studies were identified during this 12-month review period, highlighting the critical need for more well-conducted rigorous studies in this area.


[Critical periods in the development of spurs in light of the theory of phylembryogenesis].
Two critical periods have been established in the development of spurs representing a derivative of the corneous squama. During the first period the exposure to x-rays results in the development of the corneous squama instead of the spur, and the same exposure during the second critical period completely suppresses the development of the spur. These periods seem to correspond to the truning-points in the chain of morphogenetical processes of the spur formation associated with phylembryogeneses. Department of Embryology, Institute of Experimental Medicine, USSR Acad. Med. Sci., Leningrad.


Neurodevelopment. Parasympathetic neurons originate from nerve-associated peripheral glial progenitors.
The peripheral autonomic nervous system reaches far throughout the body and includes neurons of diverse functions, such as sympathetic and parasympathetic. We show that the parasympathetic system in mice--including trunk ganglia and the cranial ciliary, pterygopalatine, lingual, submandibular, and otic ganglia--arise from glial cells in nerves, not neural crest cells. The parasympathetic fate is induced in nerve-associated Schwann cell precursors at distal peripheral sites. We used multicolor Cre-reporter lineage tracing to show that most of these neurons arise from bi-potent progenitors that generate both glia and neurons. This nerve origin places cellular elements for generating parasympathetic neurons in diverse tissues and organs, which may enable wiring of the developing parasympathetic nervous system.


Accuracy of procalcitonin for sepsis diagnosis in critically ill patients: systematic review and meta-analysis.
Procalcitonin is widely reported as a useful biochemical marker to differentiate sepsis from other non-infectious causes of systemic inflammatory response syndrome. In this systematic review, we estimated the diagnostic accuracy of procalcitonin in sepsis diagnosis in critically ill patients. 18 studies were included in the review. Overall, the diagnostic performance of procalcitonin was low, with mean values of both sensitivity and specificity being 71% (95% CI 67-76) and an area under the summary receiver operator characteristic curve of 0.78 (95% CI 0.73-0.83). Studies were grouped into phase 2 studies (n=14) and phase 3 studies (n=4) by use of Sackett and Haynes' classification. Phase 2 studies had a low pooled diagnostic odds ratio of 7.79 (95% CI 5.86-10.35). Phase 3 studies showed significant heterogeneity because of variability in sample size (meta-regression coefficient -0.592, p=0.017), with diagnostic performance upwardly biased in smaller studies, but moving towards a null effect in larger studies. Procalcitonin cannot reliably differentiate sepsis from other non-infectious causes of systemic inflammatory response syndrome in critically ill adult patients. The findings from this study do not lend support to the widespread use of the procalcitonin test in critical care settings.


The genetic architecture of susceptibility to parasites.
The antagonistic co-evolution of hosts and their parasites is considered to be a potential driving force in maintaining host genetic variation including sexual reproduction and recombination. The examination of this hypothesis calls for information about the genetic basis of host-parasite interactions - such as how many genes are involved, how big an effect these genes have and whether there is epistasis between loci. We here examine the genetic architecture of quantitative resistance in animal and plant hosts by concatenating published studies that have identified quantitative trait loci (QTL) for host resistance in animals and plants. Collectively, these studies show that host resistance is affected by few loci. We particularly show that additional epistatic interactions, especially between loci on different chromosomes, explain a majority of the effects. Furthermore, we find that when experiments are repeated using different host or parasite genotypes under otherwise identical conditions, the underlying genetic architecture of host resistance can vary dramatically - that is, involves different QTLs and epistatic interactions. QTLs and epistatic loci vary much less when host and parasite types remain the same but experiments are repeated in different environments. This pattern of variability of the genetic architecture is predicted by strong interactions between genotypes and corroborates the prevalence of varying host-parasite combinations over varying environmental conditions. Moreover, epistasis is a major determinant of phenotypic variance for host resistance. Because epistasis seems to occur predominantly between, rather than within, chromosomes, segregation and chromosome number rather than recombination via cross-over should be the major elements affecting adaptive change in host resistance.


Perceptions of effective clinical teaching behaviours in a hospital-based nurse training programme.
Clinical teaching behaviour is a critical determinant for quality clinical learning experiences of student nurses. It is believed that a better understanding of the perceptions of clinical teaching behaviours between student nurses and nurse educators will enhance clinical teaching. This study examined the perceptions of effective clinical teaching behaviours of nurse educators by student nurses (n = 81) and nurse educators (n = 10) in a hospital-based 3-year general nurse training programme in Hong Kong. Knox & Mogan's Nursing Clinical Teacher Effectiveness Inventory (NCTEI) (1985) was adopted. The respondents were asked to rate the importance of each discrete behaviour on a seven-point scale. It was found that there was greater agreement in the 10 most important behaviours than the 10 least important behaviours among the four groups: students, junior students, senior students and nurse educators. No statistically significant difference could be identified in the perceptions between the nurse educators and students as well as between the junior and senior students regarding the five behavioural categories. The nature and the student status of the nursing programme was accountable for most of the discrepancies between the findings of this study and those of past studies.


[Psychological factors and life change events in bipolar patients].
This article purpose is to discuss the major hypotheses concerning the relationship of personality to bipolar disorders. The data are reported and commented. Life events are introduced to confirm the influence of psychological factors in the course of these disorders, supposed to be endogenous. The status of bipolar disorder is discussed. The unitary model of major affective disorders could allow to answer the questions raised by the data.


Climate driven release of carbon and mercury from permafrost mires increases mercury loading to sub-arctic lakes.
In sub-arctic and arctic regions mercury is an element of concern for both wildlife and humans. Over thousands of years large amounts of atmospherically deposited mercury, both from natural and anthropogenic sources, have been sequestered together with carbon in northern peatlands. Many of these peatlands are currently underlain by permafrost, which controls mire stability and hydrology. With the ongoing climate change there is concern that permafrost thawing will turn large areas of these northern peatlands from carbon/mercury-sinks into much wetter carbon/mercury-sources. Here we can show that such a change in mire structure in the sub-arctic Stordalen mire in northern Sweden actually is responsible for an increased export of mercury to the adjacent lake Inre Harrsjön. We also show that sediment mercury accumulation rates during a warm period in the pre-industrial past were higher than in the 1970s when atmospheric input peaked, indicating that in areas with permafrost, climate can have an effect on mercury loading to lakes as large as anthropogenic emissions. Thawing of permafrost and the subsequent export of carbon is a widespread phenomenon, and the projection is that it will increase even more in the near future. Together with our observations from Stordalen, this makes northern peatlands into a substantial source of mercury, at risk of being released into sensitive arctic freshwater and marine systems.


Ad libitum consumption of protein- or peptide-sucrose solutions stimulates egg formation by prolonging the vitellogenic phase of oogenesis in anautogenous mosquitoes.
Anautogenous mosquitoes commonly consume nectars and other solutions containing sugar but are thought to only produce eggs in discrete gonadotrophic cycles after blood-feeding on a vertebrate host. However, some anautogenous species are known to produce eggs if amino acids in the form of protein are added to a sugar solution. Unclear is how different sources of amino acids in sugar solutions affect the processes that regulate egg formation and whether responses vary among species. In this study, we addressed these questions by focusing on Aedes aegypti and conducting some comparative assays with Aedes albopictus, Anopheles gambiae, Anopheles stephensi and Culex quinquefasciatus. Adult female mosquitoes were fed sugar solutions containing amino acids, peptides or protein. Markers for activation of a gonadotrophic cycle including yolk deposition into oocytes, oviposition, ovary ecdysteroidogenesis, expression of juvenile hormone and 20-hydroxyecdysone-responsive genes, and adult blood-feeding behavior were then measured. The five anautogenous species we studied produced eggs when fed two proteins (bovine serum albumin, hemoglobin) or a mixture of peptides (tryptone) in 10% sucrose but deposited only small amounts of yolk into oocytes when fed amino acids in 10% sucrose. Focusing on Ae. aegypti, cultures were maintained for multiple generations by feeding adult females protein- or tryptone-sugar meals. Ad libitum access to protein- or tryptone-sugar solutions protracted production of ecdysteroids by the ovaries, vitellogenin by the fat body and protease activity by the midgut albeit at levels that were lower than in blood-fed females. Females also exhibited semi-continual oogenesis and repressed host-seeking behavior. Several anautogenous mosquitoes produce eggs when provided ad libitum access to protein- or peptide-sugar meals, but several aspects of oogenesis also differ from females that blood-feed.


Molecular mechanism of a novel CD59-binding peptide sp22 induced tumor cells apoptosis.
Some short peptides discovered by phage display are found to be able to inhibit cancer growth and induce cancer cell apoptosis. In this study, a novel cancer-targeting short peptide which was composed of 22 amino acids (ACHWPWCHGWHSACDLPMHPMC, abbreviated as sp22) and specifically bound to human CD59 was screened from a M13 phage display library so as to counteract tumor immune escape activity. The mechanism of exogenous sp22 peptide in inducing apoptosis of MCF-7 cells was investigated. The results suggested that sp22 could lower CD59 expression level, downregulate Bcl-2 expression, activate Fas and caspase-3, and finally increase apoptotic cell numbers of MCF-7 cells. However, sp22 had no obvious influence on normal human embryonic lung cells. In addition, the effects of endogenous sp22 gene on CD59 expression and NKM cell apoptosis were explored using the recombinant plasmid sp22-PIRES. It showed that sp22 gene was efficiently expressed in transfected NKM cells. Compared with normal NKM cells, NKM cells transfected with sp22 displayed reduced mRNA and protein expression levels of CD59, increased sensitivity to complement-mediated cytolysis, decreased cell survival ratio, changes of the expression of apoptosis associated proteins, increased number of apoptotic cells and the appearance of apoptotic morphology. The results suggested that sp22 protein could bind to CD59 and inhibit the expression of CD59. The cytolytic activity of complement on tumor cells strengthened and apoptosis signal was stepwise transferred which might be a potential way to kill tumor cells.


Using Near Infrared Spectroscopy for Tissue Oxygenation Monitoring During Procedural Sedation: The Occurrence of Peripheral Tissue Oxygenation Changes With Respiratory Depression and Supportive Airway Measures.
The objective was to assess whether respiratory depression and supportive airway measures occurring during procedural sedation are associated with changes in peripheral tissue oxygen saturation (StO2 ). This was a prospective observational study of adult patients undergoing procedural sedation in the emergency department (ED). Patients undergoing sedation with propofol, 1:1 propofol and ketamine, and 4:1 propofol and ketamine were included. Clinical interventions, sedative medication doses, vital signs, end-tidal capnography (ETCO2 ), pulse oximetry (SpO2 ), and peripheral tissue oxygen saturation (StO2 ) were recorded. Respiratory depression was defined as the occurrence of a recorded SpO2 < 92%, an increase in ETCO2 > 10 mm Hg from baseline, or loss of capnography waveform. Supportive airway measures documented during the procedure included bag-valve mask ventilation, airway repositioning maneuvers, increase in supplemental oxygen, and stimulation to induce respiration. Relative changes in StO2 between baseline and nadir were compared among patients who met respiratory depression criteria or required a supportive airway measure and those who did not. Ninety-three patients were enrolled. Thirty-two patients (34.4%) met criteria for respiratory depression, and 31 (33.3%) required intervention in the form of a supportive airway measure. The median percent change in StO2 from procedure baseline to nadir in patients meeting criteria for respiratory depression was 13.6%, compared to 4.2% in those who did not. The change in StO2 in patients who required a supportive airway measure was 12.5% versus 5.4% in those who did not. Patients with respiratory depression and the use of supportive airway measures had greater changes in StO2 during procedural sedation than in patients who did not. Peripheral tissue oxygen saturation monitoring may be a useful tool for assessing respiratory adverse events in patients undergoing procedural sedation in the ED.


Impact of a multicomponent hand hygiene-related intervention on the infectious risk in nursing homes: A cluster randomized trial.
The aim of this study was to assess the impact of a multifaceted hand hygiene (HH) program on the infectious risk in nursing homes (NHs). This was a 2-arm cluster randomized trial; French NHs were allocated randomly to the intervention (13 NHs) or control (13 NHs) groups. The intervention consisted of implementing a bundle of HH-related measures over 1 year, including increased availability of alcohol-based handrub, HH promotion, staff education, and local work groups. The primary end point was the incidence rate of acute respiratory infections and gastroenteritis reported in the context of clustered cases episodes. Secondary end points were mortality, hospitalization, and antibiotic prescription rates. Baseline characteristics did not differ between groups. The overall handrub consumption was higher in the intervention group over the 1-year intervention period. Because of underreporting, data on the primary end points were of insufficient quality for analysis. Hospitalizations did not differ between the 2 groups. However, the intervention group showed significantly lower mortality (2.10 vs 2.65 per 100 residents per month, respectively; P = .003) and antibiotic prescriptions (5.0 vs 5.8 defined daily doses per 100 resident days, respectively; P < .001). These results were confirmed by the longitudinal multivariate analysis adjusted for NH and resident characteristics and for seasonality (mortality rate ratio, 0.76). A multifaceted HH intervention may have a short-term impact on mortality in NHs. Nevertheless, other strategies may remain necessary to reduce morbidity.


Development of a transferable reactive force field for cobalt.
ReaxFF provides a method to describe bond-breaking and bond-forming events that can be applied to large-scale molecular dynamics simulations. This article describes the development of a ReaxFF potential for cobalt. This potential is transferable to a wide variety of cobalt systems, including various crystal structures, surfaces, clusters, and defects. The potential parameters were obtained from an extensive set of ab initio calculations. We have tested these parameters against additional DFT calculations not included in the fitting data set and found that ReaxFF provides similar or superior agreement with the DFT results compared to accepted embedded atom method descriptions for Co. We validated this potential by performing large-scale molecular dynamics simulations to predict the melting point, diffusion coefficients for the liquid as a function of temperature, and vacancy-mediated diffusion coefficients in the solid as a function of temperature and vacancy concentration. Results are compared with other theoretical methods and experiments where available. Since the ReaxFF method allows straightforward extensions to alloys and heterogeneous materials, including first-row elements, the ReaxFF parameters described here provide a foundation for the simulation of a wide range of Co-containing materials.


Myocardial hypertrophy is improved with berberine treatment via long non-coding RNA MIAT-mediated autophagy.
This study aimed to evaluate berberine (BBR) effects on myocardial hypertrophy (MH) and associated mechanisms. BBR effects on MH were evaluated in rats with constriction of abdominal aorta (CAA). qRT-PCR assay was used to measure MH-related genes, long non-coding RNAs (lncRNAs) and autophagy-related genes expressions. Western blot was performed to detect autophagy markers expression. Filamentous actin and phalloidin expressions were detected using immunofluorescence assay. BBR significantly attenuated CAA-induced MH and cardiomyocyte enlargement. CAA upregulated β myosin heavy chain and atrial natriuretic peptide expressions in heart tissues, which was attenuated by BBR. BBR suppressed myocardial infarction associated transcript (MIAT) expression in rats with CAA. p62 mRNA expression was upregulated and beclin1 and autophagy related 5 were downregulated in CAA versus control groups. The effects were abolished by BBR. In vitro studies showed that BBR ameliorated angiotensin II-induced MH and attenuated Ang II-induced MIAT expression in H9C2 cells. Expressions of phosphorylated mTOR, phosphorylated AMPK and LC3 were upregulated in H9C2 cells after Ang II stimulation, and the effects were abolished by BBR. BBR exerted beneficial effects on MH induced by CCA, and the mechanisms were associated with decreased MIAT expression and enhanced autophagy.


The population risks of dietary salt excess are exaggerated.
Policy positions on salt consumption (based largely on the association of sodium and blood pressure [BP]) has remained unchanged since the 1970s, until recently. However, this is beginning to change as new evidence emerges. The evidence supports a strong association of sodium with BP and cardiovascular disease events in hypertensive individuals, the elderly, and those who consume > 6 g/d of sodium. However, there is no association of sodium with clinical events at 3 to 6 g/day and a paradoxical higher rate of events at < 3 g/day. Therefore, until new evidence emerges, the optimal range of sodium consumption should be considered to be between 3 and 6 g/d. Population-wide sodium reduction is not justified in countries such as Canada.


The thylakoid delta pH-dependent pathway machinery facilitates RR-independent N-tail protein integration.
The thylakoidal DeltapH-dependent and bacterial twin arginine transport systems are structurally and functionally related protein export machineries. These recently discovered systems have been shown to transport folded proteins but are not known to assemble integral membrane proteins. We determined the translocation pathway of a thylakoidal FtsH homologue, plastid fusion/protein translocation factor, which is synthesized with a chloroplast-targeting peptide, a hydrophobic signal peptide, and a hydrophobic membrane anchor. The twin arginine motif in its signal peptide and its sole integration requirement of a DeltapH suggested that plastid fusion/protein translocation factor employs the DeltapH pathway. Surprisingly, changing the twin arginine to twin lysine or deleting the signal peptide did not abrogate integration capability or characteristics. Nevertheless, three criteria argue that all three forms require the DeltapH pathway for integration. First, integration was competed by an authentic DeltapH pathway precursor. Second, antibodies to DeltapH pathway component Hcf106 specifically inhibited integration. Finally, chloroplasts from the hcf106 null mutant were unable to integrate Pftf into their thylakoids. Thus, DeltapH pathway machinery facilitates both signal peptide-directed and N-tail-mediated membrane integration and does not strictly require the twin arginine motif.


A comparative study on the effect of promoting the osteogenic function of osteoblasts using isoflavones from Radix Astragalus.
Radix Astragalus has been shown to exert beneficial effects regarding the prevention postmenopausal osteoporosis. However, its mechanism of action remains to be investigated. Calycosin, formononetin, and calycosin-7-O-β-d-glucoside are the main isoflavone constituents of Astragalus. In this study, the abilities of these 3 compounds to promote osteogenic function of osteoblasts were compared, and the structure-activity relationships of these osteotrophic isoflavones were determined. Calycosin exhibited a greater effect than formononetin and calycosin-7-O-β-d-glucoside regarding improvements in osteogenic function of osteoblasts, as demonstrated by cell proliferation, alkaline phosphatase activity, collagen I and osteocalcin secretion, and the number and area of mineralized bone nodules. This suggests that calycosin may be better than formononetin and calycosin-7-O-β-d-glucoside at preserving bone mass. In addition, calycosin, formononetin, and calycosin-7-O-β-d-glucoside stimulate the expression of bone morphogenetic protein 2 and runt-related transcription factor 2 proteins, which indicates that all 3 agents may promote the osteogenesis of osteoblasts via regulation of bone morphogenetic protein 2 expression. In conclusion, calycosin may be the best candidate, with higher osteogenic activity than formononetin and calycosin-7-O-β-d-glucoside. The higher osteogenic activity of calycosin could be attributable to the superiority of its chemical structure (a hydroxyl group at position C3 of Ring B and no glucosyl group).


[Comparative analysis of the maternal motivation expression in WAG/Rij and Wistar rats in the place preference and open field tests].
Maternal behavior in females of WAG/Rij and Wistar rats was compared in the place preference test from 2 to 8 days after delivery, as well as in the open field test from 4 to 6 days after delivery. In females of WAG/Rij rats compared with females of Wistar rats weaker expression of maternal motivation has been revealed in both tests: they spend less time in the compartment associated with pups. Moreover, in females of WAG/Rij rats, number of approaches to pups, number of pup-carryings and time spent with pups (time of contacts) were less than in females of Wistar rats. Reduced maternal motivation in females of WAG/Rij rats in the place preference test persisted in repeated testing, while in the open field test it was detected only in the first testing, indicating higher reliability of the place preference test for revealing inter-strain differences in the expression of maternal motivation. It is supposed that weaker expression of maternal behavior and preference is due to hypo-function of the mesolimbic dopaminergic bran system in WAG/Rij rats as a genetic model of depression associated with absence epilepsy.


[Inhibitors of PCSK9].
Observational data show a consistent association between elevated low density lipoproteins (LDL-C) and cardiovascular disease (CVD). Reduction of LDL-C reduces the risk of CVD as has been shown by many trials. Statins are currently the most effective drugs for lowering LDL-C, but can present side effects which might limit the prescribed dosage and prevent patients from reaching the recommended LDL levels. Although treated with statins important residual cardiovascular event risk remains in patients in primary and secondary prevention for CVD. The discovery of protein convertase subtilisin kexin 9 antibodies is a very promising new hypolipidemic treatment and the aim of this review is to explain their mechanism of action and to discuss safety and efficacy results of some phase III studies.


[Role of primary care in the frequent attendance to the emergency service of a county hospital].
To know the sociodemographic variables influence on a county hospital emergency department attendance, spontaneous consults reasons and to analyze the derivations made from primary care. Descriptive, crossover. All who attended the emergency department in this period, excluded the pediatrics population, moved patients and occasional emergencies (n = 755). We collected sociodemographic characteristics, emergency justification, way of access (spontaneous or referred), spontaneous visits reasons and doctor from whom refers. Average age: 52 +/- 23. Mostly males. An 83% belongs to non-productive sectors. An 51.1% came without P10 alleging symptoms which suggested seriousness or because they considered that there are more means in a hospital. Emergencies referred from primary care, specially those referred by their family doctor were admitted in a bigger proportion and were more justified than the spontaneous ones. Self decision attendance decreases from the closest health basic area to the furthest, difference which is not observed in referred patients. The emergency user in a hospital is a male, middle-aged, non-productive laboraly. Most patients referred from primary care (specialty those by the family doctor) are justified and produce incomes. Distance inversely influences spontaneous attendance, but does not influence patients referred from primary care.


A novel approach to estimate the minimally important difference for the Fatigue Impact Scale in multiple sclerosis patients.
The Fatigue Impact Scale (FIS) has been used extensively to assess the impact of fatigue on health-related quality of life (HRQOL) in multiple sclerosis (MS). The objective of this study was to estimate the minimally important difference (MID) of the FIS to facilitate the interpretation of the scale in patients with MS. Data came from a cross-sectional study of 184 patients with MS. Anchor-based estimates of the MID were evaluated using patients' ratings of their own health and a clinical rating of MS severity. Using the proportional odds model, estimates of the MID were evaluated by finding FIS score differences that corresponded to a 50% increase in the odds of poorer health. Convergence between distribution- and anchor-based estimates was assessed. Nineteen items met the selection criteria for anchors. Triangulation of the anchor- and distribution-based approaches indicated that the MID of the FIS ranged between 10 and 20 points, approximately. A common metric of meaningful difference of FIS was defined across anchors measuring a broad range of HRQOL domains. The MID estimates in the current study can be used for sample size calculation in the planning of future studies and to aid researchers and clinicians in interpreting FIS score differences in patients with MS.


Variation in the delivery of telephone advice by emergency medical services: a qualitative study in three services.
An emergency ambulance is not always the appropriate response for emergency medical service patients. Telephone advice aims to resolve low acuity calls over the phone, without sending an ambulance. In England, variation in rates of telephone advice and patient recontact between services raises concerns about inequities in care. To understand this variation, this study aimed to explore operational factors influencing the provision of telephone advice. This is a multimethod qualitative study in three emergency medical services in England with different rates of telephone advice and recontact. Non-participant observation (120 hours) involved 20 call handlers and 27 clinicians (eg, paramedics). Interviews were conducted with call handlers, clinicians and clinician managers (n=20). Services varied in their views of the role of telephone advice, selection of their workforce, tasks clinicians were expected and permitted to do, and access to non-ambulance responses. Telephone advice was viewed either as an acceptable approach to managing demand or a way of managing risk. The workforce could be selected for their expertise or their inability to work 'on-the-road'. Some services permitted proactive identification of calls for a lower priority response and provided access to a wider range of response options. The findings aligned with telephone advice rates for each service, particularly explaining why one service had lower rates. Some of the variation observed can be explained by operational differences between services and some of it by access to alternative response options in the wider urgent and emergency care system. The findings indicate scope for greater consistency in the delivery of telephone advice to ensure the widest range of options to meet the needs of different populations, regardless of geographical location.


Protective and ultra-protective ventilation: using pumpless interventional lung assist (iLA).
Acute lung failure is associated with high mortality and usually requires mechanical ventilation to ensure adequate gas exchange. However, mechanical ventilation itself can be associated with major complications and can aggravate pre-existing lung disease, thus contributing to morbidity and mortality. Extracorporeal gas exchange is increasingly used when conventional mechanical ventilation has failed. In contrast to veno-venous extracorporeal membrane oxygenation (ECMO), pumpless extracorporeal interventional lung assist (iLA) is applied via an arterio-venous bypass into which a gas exchange membrane is integrated. iLA allows for efficient carbon dioxide removal, which allows for a significant reduction in ventilator settings. iLA may be a useful tool in protective or even 'ultraprotective' ventilation, enabling the application of very low tidal volumes in patients with acute respiratory failure of different etiologies. This article reviews the current status and the potential role of interventional (pumpless) lung-assist iLA within the context of lung-protective ventilation strategies.


Topical hemostasis in laparoscopic surgery.
A major goal during any surgical intervention is minimization of blood loss, which reduces the need for blood transfusion. In open surgery, the possibility for the surgeon to use the hands directly in contact with the bleeding tissues for hemostasis, makes mechanical methods, such as compression, ligatures or sutures, important to achieve proper hemostasis. In laparoscopic surgery, where the intervention is performed by means of small incisions through which the surgeon's hand cannot directly achieve the tissues, the problem of hemostasis is critical and needs more attention. Either in open or in laparoscopic surgery, significant bleeding during surgery is controlled through vessel ligation, suturing, and electrocautery. Topical hemostatic agents are useful adjuncts to surgical hemostasis for controlling non-specific bleeding. The introduction of different devices and topical agents has made possible to perform more complex interventions also in laparoscopy. The Authors discuss about the type, the field of application, the side effects of the hemostatic devices and of the topical hemostatic agents.


Lipopolysaccharide Associates with Amyloid Plaques, Neurons and Oligodendrocytes in Alzheimer's Disease Brain: A Review.
This review proposes that lipopolysaccharide (LPS, found in the wall of all Gram-negative bacteria) could play a role in causing sporadic Alzheimer's disease (AD). This is based in part upon recent studies showing that: Gram-negative E. coli bacteria can form extracellular amyloid; bacterial-encoded 16S rRNA is present in all human brains with over 70% being Gram-negative bacteria; ultrastructural analyses have shown microbes in erythrocytes of AD patients; blood LPS levels in AD patients are 3-fold the levels in control; LPS combined with focal cerebral ischemia and hypoxia produced amyloid-like plaques and myelin injury in adult rat cortex. Moreover, Gram-negative bacterial LPS was found in aging control and AD brains, though LPS levels were much higher in AD brains. In addition, LPS co-localized with amyloid plaques, peri-vascular amyloid, neurons, and oligodendrocytes in AD brains. Based upon the postulate LPS caused oligodendrocyte injury, degraded Myelin Basic Protein (dMBP) levels were found to be much higher in AD compared to control brains. Immunofluorescence showed that the dMBP co-localized with β amyloid (Aβ) and LPS in amyloid plaques in AD brain, and dMBP and other myelin molecules were found in the walls of vesicles in periventricular White Matter (WM). These data led to the hypothesis that LPS acts on leukocyte and microglial TLR4-CD14/TLR2 receptors to produce NFkB mediated increases of cytokines which increase Aβ levels, damage oligodendrocytes and produce myelin injury found in AD brain. Since Aβ1-42 is also an agonist for TLR4 receptors, this could produce a vicious cycle that accounts for the relentless progression of AD. Thus, LPS, the TLR4 receptor complex, and Gram-negative bacteria might be treatment or prevention targets for sporadic AD.


Disseminated Strongyloides stercoralis infection in HTLV-1-associated adult T-cell leukemia/lymphoma.
A 55-year-old woman with human T-cell lymphotropic virus type-1 (HTLV-1)-associated adult T-cell leukemia (ATL) and a history of previously treated Strongyloides stercoralis infection received anti-CD52 monoclonal antibody therapy with alemtuzumab on a clinical trial. After an initial response, she developed ocular involvement by ATL. Alemtuzumab was stopped and high-dose corticosteroid therapy was started to palliate her ocular symptoms. Ten days later, the patient developed diarrhea, vomiting, fever, cough, skin rash, and a deteriorating mental status. She was diagnosed with disseminated S. stercoralis. Corticosteroids were discontinued and the patient received anthelmintic therapy with ivermectin and albendazole with complete clinical recovery.


Probing the specific ion effects of biocompatible hydrated choline ionic liquids on lactate oxidase biofunctionality in sensor applications.
This paper presents an extended study on the ion effects of a series of biocompatible hydrated choline based ionic liquids (ILs) on lactate oxidase (LOx), an important enzyme in biosensing technology for the in vitro detection of lactic acid. Secondary structural analysis revealed changes in the protein conformation in hydrated ILs, while thermal unfolding/aggregation dynamics showed different profiles in the presence or absence of ILs. Moreover, LOx thermally denaturised at 90 °C showed residual activity in the presence of chloride and dihydrogen phosphate anions. Kinetic and lifetime studies were also performed, providing a better understanding of the ion effects of ILs on the biocatalytic activity of the enzyme.


The effect of physician workload on an educational intervention to increase vitamin D screening.
Changes in physician behavior are difficult to accomplish. We hypothesized measuring physicians' vitamin D levels would increase measurement of their patients' levels. We recruited faculty via e-mail. We measured physicians' serum 25(OH)D levels and asked them to complete a questionnaire created to assess the risk of vitamin D deficiency. Physicians received their vitamin D test results by mail. We monitored physicians' vitamin D testing rate per 100 patient visits in the 12 weeks before and after receipt of their own vitamin D test result. Twenty-eight (22%) of 126 primary care physicians participated in the study; all were Caucasian and 17 (61%) were women. Gender, practic type, and year of graduation from medical school were similar in participants and non-participants. Over half of participants took a multivitamin and a third took a vitamin D supplement. Although 6 (21%) reported a recent fracture, only 1 physician carried a diagnosis of osteopenia or osteoporosis. At baseline, geriatricians ordered 14 vitamin D tests per 100 patient visits, while internists and family practitioners ordered substantially fewer tests (2 and <1 tests per 100 visits, respectively). After study participation, vitamin D testing rates increased significantly among family practitioners (rate ratio 3.27, 95% CI 1.29-8.33) and internists (rate ratio 3.19, 95% CI 1.12-9.07). Physicians with heavier clinic workloads were half as likely (rate ratio 0.50, 95% CI 0.32-0.76) as those with lighter clinic workloads to increase vitamin D testing rates. Surprisingly, physicians with hypovitaminosis D demonstrated no change in vitamin D testing rates. Physicians with low vitamin D testing rates were receptive to a personal intervention involving measurement of their own vitamin D levels. High workload appeared to attenuate this effect. These novel but preliminary observations require confirmation in future studies.


Variability in ambient noise levels and call parameters of North Atlantic right whales in three habitat areas.
The North Atlantic right whale inhabits the coastal waters off the east coasts of the United States and Canada, areas characterized by high levels of shipping and fishing activities. Acoustic communication plays an important role in the social behavior of these whales and increases in low-frequency noise may be leading to changes in their calling behavior. This study characterizes the ambient noise levels, including both natural and anthropogenic sources, and right whale upcall parameters in three right whale habitat areas. Continuous recordings were made seasonally using autonomous bottom-mounted recorders in the Bay of Fundy, Canada (2004, 2005), Cape Cod Bay, (2005, 2006), and off the coast of Georgia (2004-2005, 2006-2007). Consistent interannual trends in noise parameters were found for each habitat area, with both the band level and spectrum level measurements higher in the Bay of Fundy than in the other areas. Measured call parameters varied between habitats and between years within the same habitat area, indicating that habitat area and noise levels alone are not sufficient to predict variability in call parameters. These results suggest that right whales may be responding to the peak frequency of noise, rather than the absolute noise level in their environment.


Association of Tissue Abiraterone Levels and SLCO Genotype with Intraprostatic Steroids and Pathologic Response in Men with High-Risk Localized Prostate Cancer.
Purpose: Germline variation in solute carrier organic anion (SLCO) genes influences cellular steroid uptake and is associated with prostate cancer outcomes. We hypothesized that, due to its steroidal structure, the CYP17A inhibitor abiraterone may undergo transport by SLCO-encoded transporters and that SLCO gene variation may influence intracellular abiraterone levels and outcomes.Experimental Design: Steroid and abiraterone levels were measured in serum and tissue from 58 men with localized prostate cancer in a clinical trial of LHRH agonist plus abiraterone acetate plus prednisone for 24 weeks prior to prostatectomy. Germline DNA was genotyped for 13 SNPs in six SLCO genes.Results: Abiraterone levels spanned a broad range (serum median 28 ng/mL, 108 nmol/L; tissue median 77 ng/mL, 271 nmol/L) and were correlated (r = 0.355, P = 0.001). Levels correlated positively with steroids upstream of CYP17A (pregnenolone, progesterone), and inversely with steroids downstream of CYP17A (DHEA, AED, testosterone). Serum PSA and tumor volumes were higher in men with undetectable versus detectable tissue abiraterone at prostatectomy (median 0.10 vs. 0.03 ng/dL, P = 0.02; 1.28 vs. 0.44 cc, P = 0.09, respectively). SNPs in SLCO2B1 associated with significant differences in tissue abiraterone (rs1789693, P = 0.0008; rs12422149, P = 0.03) and higher rates of minimal residual disease (tumor volume < 0.5 cc; rs1789693, 67% vs. 27%, P = 0.009; rs1077858, 46% vs. 0%, P = 0.03). LNCaP cells expressing SLCO2B1 showed two- to fourfold higher abiraterone levels compared with vector controls (P < 0.05).Conclusions: Intraprostatic abiraterone levels and genetic variation in SLCO genes are associated with pathologic responses in high-risk localized prostate cancer. Variation in SLCO genes may serve as predictors of response to abiraterone treatment. Clin Cancer Res; 23(16); 4592-601. ©2017 AACR.


Cervical spinal cord injury without radiological abnormality in adults.
Spinal cord injury occurring without concomitant radiologically demonstrable trauma to the skeletal elements of the spinal canal rim, or compromise of the spinal canal rim without fracture, is a rare event. Though documented in children, the injury is not very well reported in adults. We present seventeen adult patients with spinal cord injury without accompanying fracture of the spinal canal rim, or vertebral dislocation, seen over seven years. None had preexisting spinal canal stenosis or cervical spondylosis. Following trauma, these patients had weakness of all four limbs. They were evaluated by MRI (CT scan in one patient), which showed hypo / isointense lesion in the cord on T1 weighted images, and hyperintensity on T2 weighted images, suggesting cord contusion or oedema. MRI was normal in two patients. With conservative management, fifteen patients showed neurological improvement, one remained quadriplegic and one died. With increasing use of MRI in the evaluation of traumatic myelopathy, such injuries will be diagnosed more often. The mechanism of injury is probably acute stretching of the cord as in flexion and torsional strain. Management is essentially conservative and prognosis is better than that seen in patients with fracture or dislocation of cervical spine.


Structural properties of spatial representations in blind people: Scanning images constructed from haptic exploration or from locomotion in a 3-D audio virtual environment.
When people scan mental images, their response times increase linearly with increases in the distance to be scanned, which is generally taken as reflecting the fact that their internal representations incorporate the metric properties of the corresponding objects. In view of this finding, we investigated the structural properties of spatial mental images created from nonvisual sources in three groups (blindfolded sighted, late blind, and congenitally blind). In Experiment 1, blindfolded sighted and late blind participants created metrically accurate spatial representations of a small-scale spatial configuration under both verbal and haptic learning conditions. In Experiment 2, late and congenitally blind participants generated accurate spatial mental images after both verbal and locomotor learning of a full-scale navigable space (created by an immersive audio virtual reality system), whereas blindfolded sighted participants were selectively impaired in their ability to generate precise spatial representations from locomotor experience. These results attest that in the context of a permanent lack of sight, encoding spatial information on the basis of the most reliable currently functional system (the sensorimotor system) is crucial for building a metrically accurate representation of a spatial environment. The results also highlight the potential of spatialized audio-rendering technology for exploring the spatial representations of visually impaired participants.


eRAM: encyclopedia of rare disease annotations for precision medicine.
Rare diseases affect over a hundred million people worldwide, most of these patients are not accurately diagnosed and effectively treated. The limited knowledge of rare diseases forms the biggest obstacle for improving their treatment. Detailed clinical phenotyping is considered as a keystone of deciphering genes and realizing the precision medicine for rare diseases. Here, we preset a standardized system for various types of rare diseases, called encyclopedia of Rare disease Annotations for Precision Medicine (eRAM). eRAM was built by text-mining nearly 10 million scientific publications and electronic medical records, and integrating various data in existing recognized databases (such as Unified Medical Language System (UMLS), Human Phenotype Ontology, Orphanet, OMIM, GWAS). eRAM systematically incorporates currently available data on clinical manifestations and molecular mechanisms of rare diseases and uncovers many novel associations among diseases. eRAM provides enriched annotations for 15 942 rare diseases, yielding 6147 human disease related phenotype terms, 31 661 mammalians phenotype terms, 10,202 symptoms from UMLS, 18 815 genes and 92 580 genotypes. eRAM can not only provide information about rare disease mechanism but also facilitate clinicians to make accurate diagnostic and therapeutic decisions towards rare diseases. eRAM can be freely accessed at http://www.unimd.org/eram/.


Abnormal sensitivity of cortisol-producing adrenocortical adenomas to serotonin: in vivo and in vitro studies.
Two patients with incidentally discovered adrenocortical adenomas underwent a series of pharmacological and physiological tests after pretreatment with dexamethasone. Illicit plasma cortisol responses to the serotonin (5-HT)4 receptor agonist cisapride were observed in the two patients. Significant increases in plasma cortisol levels were also noticed after glucagon and combined TRH/GnRH/GHRH stimulation tests in patient 1 and after administration of the lysine vasopressin precursor terlipressin in patient 2. After adrenalectomy, in vitro studies were conducted to investigate the cortisol responses of cultured tumor cells to serotonergic ligands and peptide hormones. In the two cases, 5-HT stimulated cortisol secretion from tumor cells with increased efficacy and/or potency to activate steroidogenesis by comparison with normal adrenocortical cells. The corticotropic effect of 5-HT was inhibited by the specific 5-HT4 receptor antagonist GR 113808 and more potently by methiothepin, a nonspecific serotonergic antagonist having no affinity for the 5-HT4 receptor. These results show that the hypersensitivity of the tumors to 5-HT was related to tissue expression of an ectopic serotonergic receptor in addition to the eutopic 5-HT4 receptor. In the two adenoma tissues, immunohistochemical studies revealed the presence of 5-HT-like immunoreactivity within clusters of steroidogenic cells, suggesting that 5-HT acted through an autocrine/paracrine mechanism to stimulate steroidogenesis. Glucagon and GnRH but not TRH, GHRH, and human chorionic gonadotropin stimulated cortisol secretion from tumor 1 cells. In conclusion, this study provides the first observation of adrenocortical cortisol-producing adenomas hypersensitive in vivo and in vitro to serotonergic agonists. Our results also show that cortisol-producing adenomas can express simultaneously several illegitimate receptors.


Screening of α-glucosidase inhibitory activity from some plants of Apocynaceae, Clusiaceae, Euphorbiaceae, and Rubiaceae.
Diabetes mellitus (DM) is recognized as a serious global health problem that is characterized by high blood sugar levels. Type 2 DM is more common in diabetic populations. In this type of DM, inhibition of α-glucosidase is a useful treatment to delay the absorption of glucose after meals. As a megabiodiversity country, Indonesia still has a lot of potential unexploited forests to be developed as a medicine source, including as the α-glucosidase inhibitor. In this study, we determine the α-glucosidase inhibitory activity of 80% ethanol extracts of leaves and twigs of some plants from the Apocynaceae, Clusiaceae, Euphorbiaceae, and Rubiaceae. Inhibitory activity test of the α-glucosidase was performed in vitro using spectrophotometric methods. Compared with the control acarbose (IC(50) 117.20 μg/mL), thirty-seven samples of forty-five were shown to be more potent α-glucosidase inhibitors with IC(50) values in the range 2.33-112.02 μg/mL.


[Pleural amyloidosis as a cause of excessive pleural effusions].
A 83-year-old woman known with a stable disease multiple myeloma was hospitalized frequently with dyspnoea caused by copious bilateral pleural effusions. Thoracentesis was performed repeatedly but pleural effusions returned. Extensive laboratory and radiological examinations failed to reveal the cause of the pleural effusions. Finally, after pleural biopsy the diagnosis of amyloidosis of the pleura could be made. The patient died in hospital from a stroke. Pleural amyloidosis is rarely reported and is accompanied by large uni- or bilateral pleural effusions even without amyloidosis of the heart.


Multidetector computed tomography findings of arrhythmogenic right ventricular dysplasia: a case report.
Arrhythmogenic right ventricular dysplasia (ARVD) is a heart muscle disorder characterized pathologically by fatty or fibrofatty replacement and electrical instability of the right ventricular myocardium. This cardiac entity leads to sudden cardiac death, syncope, recurrent ventricular tachycardia, and in some cases, heart failure in a younger population. Contrast angiography, echocardiography, radionuclide angiography, ultrafast computed tomography (CT), and cardiovascular magnetic resonance imaging are techniques used to diagnose functional and morphologic characteristics of the disease. CT is sensitive in detecting intramyocardial fat because of its low attenuation. Recently the advances in multislice CT (MDCT) have improved temporal resolution, which has increased effectiveness in providing morphologic and functional information. We present a case with ARVD evaluated through 16-row MDCT. Fatty infiltration was clearly demonstrated by 16-slice CT; thus, multislice CT may have a significant role in the assessment and follow-up of patients with ARVD.