The role of meta-analysis in the evaluation of the effects of early nutrition on mental and motor development in children.
The role of early nutrition as a cost-effective measure to ensure optimal infant growth, development, and long-term health is gaining attention. In particular, the role of supplementation with nutrients such as n-3 (omega-3) fatty acids, iron, zinc, and B vitamins, which are relevant to brain structure and function, is of interest. However, for all of these nutrients, there is a lack of clarity and no consensus regarding their role in the mental and motor development of children. Systematic reviews with or without a meta-analysis are a well-established means of reviewing existing evidence and of integrating findings from various studies, including those related to infant nutrition. In this article, I provide an overview of the basic principles of systematic review and meta-analysis of randomized controlled trials (RCTs) and summarize such evidence related to the effects of early nutrition on mental and motor development. The inclusion of only RCTs in a systematic review could be considered the major strength. Randomization is the only means to control for unknown and unmeasured differences between comparison groups as well as for those that are known and measured. However, even if only RCTs are included, reviews are not free of potential biases. An understanding of the strengths and limitations of the meta-analytic approach, which I discuss in this article, is needed by everyone involved in decision making regarding interventions assessed by this approach.


Nuphar lutea Extracts Exhibit Anti-Viral Activity against the Measles Virus.
Different parts of Nuphar lutea L. (yellow water lily) have been used to treat several inflammatory and pathogen-related diseases. It has shown that Nuphar lutea extracts (NUP) are active against various pathogens including bacteria, fungi, and leishmanial parasites. In an effort to detect novel therapeutic agents against negative-stranded RNA (- RNA) viruses, we have tested the effect of a partially-purified alkaloid mixture of Nuphar lutea leaves on the measles virus (MV). The MV vaccine's Edmonston strain was used to acutely or persistently infect cells. The levels of several MV proteins were detected by a Western blot and immunocytochemistry. Viral RNAs were quantitated by qRT-PCR. Virus infectivity was monitored by infecting African green monkey kidney VERO cells' monolayers. We showed that NUP protected cells from acute infection. Decreases in the MV P-, N-, and V-proteins were observed in persistently infected cells and the amount of infective virus released was reduced as compared to untreated cells. By examining viral RNAs, we suggest that NUP acts at the post-transcriptional level. We conclude, as a proof of concept, that NUP has anti-viral therapeutic activity against the MV. Future studies will determine the mechanism of action and the effect of NUP on other related viruses.


NAD+-dependent ADP-ribosyltransferase in renal brush-border membranes.
Oxidized nicotinamide adenine dinucleotide (NAD+) in cytosol may interact with renal brush-border membranes (BBM) and inhibit BBM phosphate transport. The possible mechanism of interaction was investigated in the present study. Incubation of BBM with [adenine-3H]NAD+ led to acid-stable binding of 3H to the BBM, in contrast there was no binding of 14C when [carbonyl-14C]NAD+ was used. The data are consistent with an ADP-ribosylation mechanism involving transfer of ADP-ribose from NAD+ to BBM. This was confirmed by using [adenylate-32P]NAD+ and by the release of bound 32P in the form of 5'-[32P]AMP when the BBM were treated with snake venom phosphodiesterase. After gradient centrifugation of BBM the ADP-ribosyltransferase was recovered at the same density as known BBM enzymes, indicating that ADP-ribosyltransferase is an intrinsic BBM component and not a contaminant. These findings indicate that cytosolic NAD+ may be used for ADP-ribosylation of BBM proteins and that this may be a mechanism for regulating the BBM phosphate transport system.


Revealing noncovalent interactions.
Molecular structure does not easily identify the intricate noncovalent interactions that govern many areas of biology and chemistry, including design of new materials and drugs. We develop an approach to detect noncovalent interactions in real space, based on the electron density and its derivatives. Our approach reveals the underlying chemistry that compliments the covalent structure. It provides a rich representation of van der Waals interactions, hydrogen bonds, and steric repulsion in small molecules, molecular complexes, and solids. Most importantly, the method, requiring only knowledge of the atomic coordinates, is efficient and applicable to large systems, such as proteins or DNA. Across these applications, a view of nonbonded interactions emerges as continuous surfaces rather than close contacts between atom pairs, offering rich insight into the design of new and improved ligands.


Dosimetric comparison of vaginal vault brachytherapy vs applicator-guided stereotactic body radiotherapy with volumetric modulated arc therapy and helical tomotherapy for endometrium cancer patients.
We performed this dosimetric study to compare a nonstandard volumetric modulated arc therapy (VMAT) and helical tomotherapy (HT) techniques with high-dose rate (HDR) brachytherapy (BRT) plan of vaginal vault in patients with postoperative endometrial cancer (EC). Twelve postoperative patients with early stage EC were included in this study. Three plans were performed for each patient; dosimetric and radiobiological comparisons were made using dose-volume histograms and equivalent dose for determining the planning target volume (PTV) coverages in brachytherapy and external beam radiotherapy, and organs-at-risk (OARs) doses between three different delivery techniques. All the plans achieved adequate dose coverage for PTV; however, the VMAT plan yielded better dose conformity, and the HT plan showed better homogeneity for target volume. With respect to the OARs, the bladder D2cc was significantly lower in the BRT plan than in the VMAT and HT plans, with the highest bladder D2cc value being observed in the HT plan. However, no difference was observed in the rectum D2cc of the three plans. Other major advantages of the BRT plan over the VMAT and HT plans were the relatively lower body integral doses and femoral head doses as well as the fact that the integral doses were significantly lower in the BRT plan than in the VMAT and HT plans. This is the first dosimetric comparison of vaginal vault treatment for EC with BRT, VMAT, and HT plans. Our analyses showed the feasibility of stereotactic body radiotherapy technique as an alternative to HDR-BRT for postoperative management of EC patients.


Incidental finding of a retained intracorneal wooden foreign body.
We present a case of an intracorneal wooden foreign body that remained undetected for 15 years following an ocular injury sustained during gardening. The patient presented with stable visual acuity despite the long-standing presence of a wooden splinter embedded in the cornea. Interestingly, Pentacam corneal tomography did not show any abnormalities despite the foreign body piercing through the corneal stroma and endothelium. This case may serve as an opportunity to re-examine the approach to managing chronic and stable intracorneal wooden foreign bodies and explore the implications of continued observation rather than surgical management.


Polyisobutylene Urolithiasis Due to Ileal Conduit Urostomy Appliance: An Index Case.
Polyisobutylene (PIB) is a synthetic elastomer that is a component of sealants, adhesives, and chewing gum base. We report a case of bilateral PIB urolithiasis in a patient with an ileal conduit urinary diversion due to neurogenic bladder from spinal cord injury. Infrared spectroscopy confirmed the composition of bilateral stones and adhesive from the patient's urostomy appliance to be PIB. No previous cases of PIB urolithiasis are reported in the literature.


Isolation and regional localization of a large collection (2,000) of single-copy DNA fragments on human chromosome 3 for mapping and cloning tumor suppressor genes.
A collection of 2,000 lambda phage-carrying human single-copy inserts (greater than 700 bp) were isolated from two chromosome-3 flow-sorted libraries. The single-copy DNA fragments were first sorted into 3p and 3q locations and about 700 3p fragments were regionally mapped using a deletion mapping panel comprised of two human-hamster and two-human-mouse cell hybrids, each containing a chromosome 3 with different deletions in the short arm. The hybrids were extensively mapped with a set of standard 3p markers physically localized or ordered by linkage. The deletion mapping panel divided the short arm into five distinct subregions (A-E). The 3p fragments were distributed on 3p regions as follows: region A, 26%; B, 31%; C, 4%; D, 4% and E, 35%. We screened 300 single-copy DNA fragments from the distal part of 3p (regions A and B) with ten restriction endonucleases for their ability to detect restriction fragment length polymorphisms (RFLPs). Of these fragments 110 (36%) were found to detect useful RFLPs; 35% detected polymorphisms with frequency of heterozygosity of 40% or higher, and 25% with frequency of 30% or higher. All polymorphisms originated from single loci and most of them were of the base pair substitution type. These RFLP markers make it possible to construct a fine linkage map that will span the distal part of chromosome 3p and encompasses the von Hippel-Lindau disease locus. The large number of single-copy fragments (2,000) spaced every 100-150 kb on chromosome 3 will make a significant contribution to mapping and sequencing the entire chromosome 3. The 300 conserved chromosome 3 probes will increase the existing knowledge of man-mouse homologies.


Correlation between experimentally and clinically demonstrated activity of two new cytotoxic agents in breast cancer.
Experimental evidence of the cytotoxic activity of two new agents was obtained using five lines of human breast carcinoma serially transplanted into immunosuppressed mice. Tumor growth delay was used to compare the effect of the new agents with that of cytotoxic drugs of known value in human breast cancer. The mean specific growth delay (number of tumor volume doubling times saved) for each agent against the five lines was: CL232/315 (mitoxantrone) 1.9; M-AMSA (4'[9 - acridinyl] amino-methane sulphon - M - ansidine) 0.5; cyclophosphamide, 1.9; adriamycin, 1.8; melphalan 2.2. There was no significant difference between the activity of mitoxantrone and the clinically useful drugs, but m-AMSA (amsacrine) was significantly less active than the other agents. A clinical trial of mitoxantrone at the Royal Marsden Hospital has confirmed the prediction of useful activity against breast cancer. Objective responses (CR + PR, UICC response criteria) were noted in 21 out of 70 (30%) patients with advanced breast cancer treated with the drug. The responses were of 4-7 months plus duration, and the 30% response rate compares favorably with other single agents. Although amsacrine is active in many forms of malignant disease, several Phase II studies have shown it to have little effect in breast cancer. By using panels of xenografts of different tumor types, it should be possible to select the most appropriate human tumors against which to test a new cytotoxic agent in Phase II studies.


Mitochondrial complexes I, II, III, IV, and V in myocardial ischemia and autolysis.
Ischemic myocardium was produced by occluding the left circumflex coronary artery in anesthetized dogs. Autolyzed myocardium was produced by incubating transmural samples of canine left ventricle at 37 degrees C. Tissue pH was recorded continuously in each model using a microcombination pH electrode impaled into the midmyocardium. The activities of the five mitochondrial inner membrane enzyme complexes of electron transport and coupled oxidative phosphorylation were assayed as a function of time of ischemia or autolysis. While the activities of complex II (succinate-CoQ reductase) and IV (cytochrome c oxidase) were completely stable, that of complex I (NADH-CoQ reductase) decreased markedly, but largely only after 20 min of ischemia or autolysis. At 20 min and beyond, the decrease in the activity of complex I paralleled closely the decrease in whole mitochondrial oxygen uptake with NAD-linked substrates in both models. The activity of complex III (CoQH2-c reductase) decreased at a more gradual rate during ischemia or autolysis, and its rate of decrease paralleled that of succinate-supported oxygen uptake. The activity of complex V (oligomycin-sensitive ATPase) decreased most rapidly (by 40% in only 5 min of autolysis) but nearly leveled off beyond 20 min in the two models. A strikingly similar pattern of differential enzyme lability was observed in isolated control mitochondria incubated at lowered pH values. The results demonstrate 1) differential enzyme lability within the mitochondrial inner membrane, 2) a connection between severity of acidosis and the degree of enzyme activity loss, and 3) the usefulness of simple tissue autolysis as an analogue of in situ myocardial ischemia.


Trends in socioeconomic inequalities in self-assessed health in 10 European countries.
Changes over time in inequalities in self-reported health are studied for increasingly more countries, but a comprehensive overview encompassing several countries is still lacking. The general aim of this article is to determine whether inequalities in self-assessed health in 10 European countries showed a general tendency either to increase or to decrease between the 1980s and the 1990s and whether trends varied among countries. Data were obtained from nationally representative interview surveys held in Finland, Sweden, Norway, Denmark, England, The Netherlands, West Germany, Austria, Italy, and Spain. The proportion of respondents with self-assessed health less than 'good' was measured in relation to educational level and income level. Inequalities were measured by means of age-standardized prevalence rates and odds ratios (ORs). Socioeconomic inequalities in self-assessed health showed a high degree of stability in European countries. For all countries together, the ORs comparing low with high educational levels remained stable for men (2.61 in the 1980s and 2.54 in the 1990s) but increased slightly for women (from 2.48 to 2.70). The ORs comparing extreme income quintiles increased from 3.13 to 3.37 for men and from 2.43 to 2.86 for women. Increases could be demonstrated most clearly for Italian and Spanish men and women, and for Dutch women, whereas inequalities in health in the Nordic countries showed no tendency to increase. The results underscore the persistent nature of socioeconomic inequalities in health in modern societies. The relatively favourable trends in the Nordic countries suggest that these countries' welfare states were able to buffer many of the adverse effects of economic crises on the health of disadvantaged groups.


Spasticity assessment with muscle coactivation of elbow flexors during passive stretch in Post-stroke Hemiplegia.
the assessment of muscle properties is an essential prerequisite in the treatment of post-stroke muscle spasticity. Previous studies have shown that muscle coactivation, which reflects the simultaneous activation of agonist and antagonist muscle groups, is associated with muscle spasticity during voluntary contraction. However, current spasticity assessment approaches do not often consider muscle coactivation for passive contraction measured with surface electromyography (sEMG). The purpose here is to evaluate the validity and reliability of muscle co-activation based on sEMG for assessing spasticity of post-stroke patients. This study was conducted on 39 chronic hemiplegia post-stroke patients with varying degrees of elbow flexor spasticity. The severity of spasticity was assessed with Modified Ashworth Scale (MAS). The patients produced elbow flexion passively on affected arm. Two-channel surface sEMG recordings were acquired simultaneously for the biceps and triceps muscles. The effectiveness and reliability of the EMG-based spasticity assessment method were evaluated using Spearman's correlation analysis and intra class correlation coefficients (ICCs). The results showed that there was a statistically significant positive relationship between the level of activity and the coactivation index (R=0.710, P=0.003), while the ICCs for intra trial measures ranged between 0.928 and 0.976. Muscle coactivation is a promising tool for continuously quantifying muscle spasticity in post-stroke patients, suggesting that the EMG-based muscle coactivation index could be useful for assessing motor function.


Recent trends in State Children's Health Insurance Program eligibility and coverage for CSHCN.
Policy makers and physicians need to understand recent trends in State Children's Health Insurance Program (SCHIP) eligibility and coverage given the ongoing debate on SCHIP. Although many studies have examined these issues, few have focused on children with special health care needs (CSHCN). With this study we aimed to fill this gap in the literature. Data on state-specific SCHIP eligibility criteria were merged with the National Survey of Children With Special Health Care Needs to determine SCHIP eligibility and coverage in 2001 and 2005. In addition to descriptive analysis, a multilevel analysis was performed to identify personal and state-level factors that significantly affected uninsurance among the SCHIP-eligible CSHCN. Our analyses showed that there was a slight increase in SCHIP eligibility for CSHCN between 2001 and 2005 (8.44% vs 9.83%; P < .05, chi(2) test). Among the SCHIP-eligible CSHCN, we found a substantial decrease in the uninsurance rate from 21.15% in 2001 to 10.87% in 2005 (P < .05, chi(2) test). After controlling for covariates, our analyses indicated that CSHCN in 2005 were 57% less likely to be uninsured than those in 2001. Our multilevel analysis also identified state policies that significantly affected uninsurance among the SCHIP-eligible CSHCN, including asset tests (positive effects) and presumptive eligibility (negative effects). Our results show a dramatic decrease in the uninsurance rate among SCHIP-eligible CSHCN between 2001 and 2005.


Acute Lymphoblastic Leukemia Following Incomplete Kawasaki Disease.
Kawasaki disease (KD) is a multisystemic vasculitis of unknown etiology, typically affecting children younger than 5 years of age. A direct relationship between KD and the development of malignant tumors has not been demonstrated, however, the immunological alterations of KD could be associated with its development. An 11-month-old male was diagnosed with incomplete KD. No coronary abnormalities were detected. He was treated with intravenous immunoglobulin (IVIG) and aspirin. Four weeks later, he developed fever, otitis media, bullous pharyngitis, irritability, anemia and hyperleukocytosis, and neutropenia. Blasts forms were observed in peripheral blood. Bone marrow smear demonstrated acute lymphoblastic leukemia (ALL). KD has diverse clinical presentations, atypical manifestations, and several complications such as macrophage activation syndrome. As our case highlights, lymphoid neoplasms may follow KD.


Reproductive capacities of control bobwhite quail (Colinus virginianus) during one-generation reproduction studies.
The Bobwhite quail (Colinus virginianus) is the avian model of choice for testing the reproductive impairment potential of pesticides and environmental contaminants. While the literature contains numerous reports on the effects of pesticides on eggshell development for quail, mallards and other avian species (Haegele and Tucker, 1974; Kolaja, 1977; Jenkins et al., 1974) limited control data for reproductive evaluation of pesticides can be found. This paper summarizes the control data from three one-generation reproductive studies in Bobwhite quail. One male and two female adult quail were housed in clean pens with tap water and game bird breeder ration available ad libitum. The pre-laying cycle was ten weeks in duration. The photoperiod was seven hours of light per day for the first eight weeks and was increased to 17 hours of light per day in order to induce egg laying. Eggs were collected daily for eight weeks and incubated. Biweekly, one egg from each pen was removed and used for determination of eggshell thickness. The mean reproductive indices for these studies are: Eggs cracked/Eggs laid--8.2%, Viable 11-day embryos/Eggs set--73.6%, Viable 21-day embryos/Viable 14-day embryos--98.9%, Hatchlings/Viable 21-day embryos--82.0%, 14-day survivors/Hatchlings--76.3%. The mean eggshell thickness for 144 eggs was 0.301 mm.


Acute myeloid leukemias with UBTF tandem duplications are sensitive to Menin inhibitors.
UBTF tandem duplications (UBTF-TDs) have recently emerged as a recurrent alteration in pediatric and adult acute myeloid leukemia (AML). UBTF-TD leukemias are characterized by a poor response to conventional chemotherapy and a transcriptional signature that mirrors NUP98-rearranged and NPM1-mutant AMLs, including HOX gene dysregulation. However, the mechanism of how UBTF-TD drives leukemogenesis remains unknown. In this study, we investigated the genomic occupancy of UBTF-TD in transformed cord-blood CD34+ (cbCD34+) cells and patient-derived xenograft models. We found that UBTF-TD protein maintained genomic occupancy at ribosomal DNA (rDNA) loci while also occupying genomic targets commonly dysregulated in UBTF-TD myeloid malignancies, such as the HOXA/HOXB gene clusters and MEIS1. These data suggest that UBTF-TD is a gain-of-function alteration that results in mislocalization to genomic loci dysregulated in UBTF-TD leukemias. UBTF-TD also co-occupies key genomic loci with KMT2A and Menin, which are known to be key partners involved in HOX-dysregulated leukemias. Using a protein degradation system, we showed that stemness, proliferation, and transcriptional signatures are dependent on sustained UBTF-TD localization to chromatin. Finally, we demonstrate that primary cells from UBTF-TD leukemias are sensitive to the Menin inhibitor SNDX-5613, resulting in markedly reduced in vitro and in vivo tumor growth, myeloid differentiation, and abrogation of the UBTF-TD leukemic expression signature. These findings provide a viable therapeutic strategy for patients with this high-risk AML subtype.


Enhanced stimulation of diacylglycerol and lipid synthesis by insulin in denervated muscle. Altered protein kinase C activity and possible link to insulin resistance.
Denervated muscle is generally regarded as insulin resistant because the ability of insulin to stimulate glucose transport and glycogen synthesis is impaired. Previous studies indicate that insulin resistance in these muscles is likely due to a defect at a postreceptor site in the signaling pathway. Because glucose transport into cells has been reported to be linked to changes in diacylglycerol (DAG) and protein kinase C (PKC), we investigated the effect of denervation on the content and synthesis of DAG and the activity and distribution of PKC in the soleus muscle. The DAG content in muscles denervated for 24 h was 40% greater than in control muscles. This was associated with a two- to threefold increase in the percentage of total PKC activity that was membrane associated, with no significant change in total PKC activity, suggesting an increase in PKC activity in vivo. Studies of glucose disposition confirmed that the stimulation of glycogen synthesis by insulin and, to a lesser extent, 2-deoxyglucose uptake were impaired by denervation. However, the stimulation by insulin of glucose incorporation into DAG and other lipids was two- to threefold greater in denervated than in control muscles, and conversion of glucose to lactate and pyruvate and glucose oxidation to CO2 were unchanged. The results reveal a dichotomy in the effects of denervation on various actions of insulin, with both insulin resistance and hyperresponsiveness occurring in different pathways of glucose metabolism. They also reveal a potential mechanism for the elevation of muscle DAG after denervation. The results do not support a direct link between DAG-PKC and glucose transport.(ABSTRACT TRUNCATED AT 250 WORDS)


Cross-reactivity of steroid hormone immunoassays: clinical significance and two-dimensional molecular similarity prediction.
Immunoassays are widely used in clinical laboratories for measurement of plasma/serum concentrations of steroid hormones such as cortisol and testosterone. Immunoassays can be performed on a variety of standard clinical chemistry analyzers, thus allowing even small clinical laboratories to do analysis on-site. One limitation of steroid hormone immunoassays is interference caused by compounds with structural similarity to the target steroid of the assay. Interfering molecules include structurally related endogenous compounds and their metabolites as well as drugs such as anabolic steroids and synthetic glucocorticoids. Cross-reactivity of a structurally diverse set of compounds were determined for the Roche Diagnostics Elecsys assays for cortisol, dehydroepiandrosterone (DHEA) sulfate, estradiol, progesterone, and testosterone. These data were compared and contrasted to package insert data and published cross-reactivity studies for other marketed steroid hormone immunoassays. Cross-reactivity was computationally predicted using the technique of two-dimensional molecular similarity. The Roche Elecsys Cortisol and Testosterone II assays showed a wider range of cross-reactivity than the DHEA sulfate, Estradiol II, and Progesterone II assays. 6-Methylprednisolone and prednisolone showed high cross-reactivity for the cortisol assay, with high likelihood of clinically significant effect for patients administered these drugs. In addition, 21-deoxycortisol likely produces clinically relevant cross-reactivity for cortisol in patients with 21-hydroxylase deficiency, while 11-deoxycortisol may produce clinically relevant cross-reactivity in 11β-hydroxylase deficiency or following metyrapone challenge. Several anabolic steroids may produce clinically significant false positives on the testosterone assay, although interpretation is limited by sparse pharmacokinetic data for some of these drugs. Norethindrone therapy may impact immunoassay measurement of testosterone in women. Using two-dimensional similarity calculations, all compounds with high cross-reactivity also showed a high degree of similarity to the target molecule of the immunoassay. Compounds producing cross-reactivity in steroid hormone immunoassays generally have a high degree of structural similarity to the target hormone. Clinically significant interactions can occur with structurally similar drugs (e.g., prednisolone and cortisol immunoassays; methyltestosterone and testosterone immunoassays) or with endogenous compounds such as 21-deoxycortisol that can accumulate to very high concentrations in certain disease conditions. Simple similarity calculations can help triage compounds for future testing of assay cross-reactivity.


Nonsecretory IgA1 autoantibodies targeting desmosomal component desmoglein 3 in intraepidermal neutrophilic IgA dermatosis.
Intraepidermal neutrophilic IgA dermatosis, a rare skin disease entity manifested with blisters and pustules clinically and lower epidermal blister, acantholysis, and neutrophilic infiltration pathologically, was first reported in 1985. Although the disease is characterized by IgA autoantibodies targeting the epithelial cell surface component, the target antigen has not been determined. We investigated a patient with this disease by histopathology, direct and indirect immunofluorescence, immunoblotting, and immunoadsorption studies. The pustular lesion was characterized by blister at the lower epidermis, acantholysis, and neutrophilic infiltration. Nonsecretory IgA1 subclass autoantibodies targeting the lower epithelial cell surfaces were detected in the patient's skin and serum. The patient's IgA autoantibodies labeled a recombinant desmosomal protein desmoglein 3 on immunoblotting and the immunolabeling of epithelial cell surfaces was eliminated by preadsorption with desmoglein 3. Thus, desmoglein 3 is identified as a target antigen in intraepidermal neutrophilic IgA dermatosis. The ability of IgA1 autoantibodies to bind neutrophils may be responsible for the prominent neutrophilic infiltration observed histopathologically and for the pustular lesions observed clinically.


Diagnosis of asymptomatic atrial septal aneurysms using two-dimensional color Doppler and contrast transthoracic echocardiography.
To evaluate the dimensions of atrial septal aneurysm (ASA), the presence and characteristics of interatrial shunt, the movement of the wall of the aneurysm, and correlation between these findings and sign and/or symptoms suggesting embolism in Manisa, a district of a western Anatolian city of Turkey. Two thousand five hundred cases were examined by routine transthoracic echocardiography (TTE) in both pediatric and adult cardiology outpatient clinics. ASA was detected in 20 cases and evaluated by two-dimensional color Doppler echocardiography (CDE). The length of the base, the maximum radius and the maximum displacement of ASA were measured. The shunt between the atria was examined by CDE. In cases where a shunt could not be found, galactose and palmitic acid was injected. Standard 12-lead electrocardiogram (ECG) and exercise stress test were also performed. No clinical signs or symptoms were found, suggesting a systemic or cerebral embolism. The maximum displacement of ASA was between 2 and 5 mm. All of the aneurysms were localized in the right atrium, and the walls of the aneurysm did not move beyond the base of the left atrium during the maximum displacement. Interatrial shunt was detected in 14 of 20 patients (70%) by CDE and in the remaining six cases by contrast TTE. Frequent ventricular ectopic beats were observed in one patient. During routine TTE we observed 0.8% asymptomatic ASA in our population. The use of a contrast agent was found to be a valuable additional method in patients with ASA when the shunt could not be detected by CDE. The risk for embolism is not high when the maximum displacement of the wall of ASA was 5 mm or less and no bulge into the left atrium was observed. Based on our experience with this method, TTE is easy to perform, well-tolerated and acceptable.


A Signal Through the Noise: Do Professionalism Concerns Impact the Decision Making of Competence Committees?
To characterize how professionalism concerns influence individual reviewers' decisions about resident progression using simulated competence committee (CC) reviews. In April 2017, the authors conducted a survey of 25 Royal College of Physicians and Surgeons of Canada emergency medicine residency program directors and senior faculty who were likely to function as members of a CC (or equivalent) at their institution. Participants took a survey with 12 resident portfolios, each containing hypothetical formative and summative assessments. Six portfolios represented residents progressing as expected (PAE) and 6 represented residents not progressing as expected (NPAE). A professionalism variable (PV) was developed for each portfolio. Two counterbalanced surveys were developed in which 6 portfolios contained a PV and 6 portfolios did not (for each PV condition, 3 portfolios represented residents PAE and 3 represented residents NPAE). Participants were asked to make progression decisions based on each portfolio. Without PVs, the consistency of participants giving scores of 1 or 2 (i.e., little or no need for educational intervention) to residents PAE and to those NPAE was 92% and 10%, respectively. When a PV was added, the consistency decreased by 34% for residents PAE and increased by 4% for those NPAE (P = .01). When reviewing a simulated resident portfolio, individual reviewer scores for residents PAE were responsive to the addition of professionalism concerns. Considering this, educators using a CC should have a system to report, collect, and document professionalism issues.


Appalachian Status Is a Negative Predictor of Breast Reconstruction Following Breast Cancer Resection.
Health care disparities in Appalachia are well documented. However, no previous studies have examined possible differences in the utilization of breast reconstruction (BR) in Appalachia. This study aims to determine if a disparity in BR utilization exists in women from Appalachia Kentucky. A retrospective, population-based cohort study was conducted from January 1, 2006, to December 31, 2015. The Kentucky Cancer Registry was queried to identify population-level data for female patients diagnosed with breast cancer and treated with mastectomy. A multivariate logistic regression model controlling for patient, disease, and treatment characteristics was constructed to predict the likelihood of BR. Bivariate testing showed differences (P < 0.0001) in BR utilization between Appalachian and non-Appalachian women in Kentucky (15.0% and 26.3%, respectively). Multivariate analysis showed that women from Appalachia (odds ratio, 0.54; confidence interval (95), 0.48-0.61; P < 0.0001) were less likely to undergo BR than non-Appalachian women. Interestingly, the rate of BR increased over time in both Appalachian (r = 0.115; P < 0.0001) and non-Appalachian women (r = 0.148; P < 0.0001). Despite the benefits of BR, women from Appalachia undergo BR at lower rates and are less likely to receive BR than non-Appalachian Kentuckians. Although the rates of BR increased over time in both populations, access to comprehensive breast cancer care remains a challenge for women from Kentucky's Appalachian region.


Synergistic T cell signaling by 41BB and CD28 is optimally achieved by membrane proximal positioning within parallel chimeric antigen receptors.
Second generation (2G) chimeric antigen receptors (CARs) contain a CD28 or 41BB co-stimulatory endodomain and elicit remarkable efficacy in hematological malignancies. Third generation (3G) CARs extend this linear blueprint by fusing both co-stimulatory units in series. However, clinical impact has been muted despite compelling evidence that co-signaling by CD28 and 41BB can powerfully amplify natural immune responses. We postulate that effective dual co-stimulation requires juxta-membrane positioning of endodomain components within separate synthetic receptors. Consequently, we designed parallel (p)CARs in which a 2G (CD28+CD3ζ) CAR is co-expressed with a 41BB-containing chimeric co-stimulatory receptor. We demonstrate that the pCAR platform optimally harnesses synergistic and tumor-dependent co-stimulation to resist T cell exhaustion and senescence, sustaining proliferation, cytokine release, cytokine signaling, and metabolic fitness upon repeated stimulation. When engineered using targeting moieties of diverse composition, affinity, and specificity, pCAR T cells consistently elicit superior anti-tumor activity compared with T cells that express traditional linear CARs.


Campylobacter seroconversion rates in selected countries in the European Union.
As a major foodborne pathogen, Campylobacter is frequently isolated from food sources of animal origin. In contrast, human Campylobacter illness is relatively rare, but has a considerable health burden due to acute enteric illness as well as severe sequelae. To study silent transmission, serum antibodies can be used as biomarkers to estimate seroconversion rates, as a proxy for infection pressure. This novel approach to serology shows that infections are much more common than disease, possibly because most infections remain asymptomatic. This study used antibody titres measured in serum samples collected from healthy subjects selected randomly in the general population from several countries in the European Union (EU). Estimates of seroconversion rates to Campylobacter were calculated for seven countries: Romania, Poland, Italy, France, Finland, Denmark and The Netherlands. Results indicate high infection pressures in all these countries, slightly increasing in Eastern EU countries. Of these countries, the differences in rates of notified illnesses are much greater, with low numbers in France and Poland, possibly indicating lower probability of detection due to differences in the notification systems, but in the latter case it cannot be excluded that more frequent exposure confers better protection due to acquired immunity.


Direct and correlated responses to artificial selection on acute thermal stress tolerance in a livebearing fish.
Tradeoffs in performance or fitness across environments have important implications regarding the nature of evolutionary constraints. It remains controversial whether tradeoffs such as these reflect genetic correlations that are genuine evolutionary constraints. However, if such long-term genetic constraints do exist, they must be due to underlying pleiotropy such that alleles that confer high performance in one environment invariably confer low performance in another. The distribution of genetic correlations within and among populations can provide insight about the existence of such pleiotropic tradeoffs. The long-term association of certain teleost fish taxa with particular abiotic environments suggests that tradeoffs in performance across environments have constrained the geographic distribution of those taxa. Here we report the results of an experiment in which we artificially selected on acute heat- and cold-stress tolerance in two stocks of the poeciliid fish Heterandria formosa from source populations with different thermal histories. Unexpectedly, we observed no direct responses to selection. Under certain conditions, fish from the different source populations differed significantly in cold tolerance, but not in heat tolerance. The results suggest there are no strong pleiotropic tradeoffs between heat- and cold-stress tolerance in these populations.


Characterization of potentially foetotropic Palyam serogroup orbiviruses isolated in Zimbabwe.
Twelve Palyam serogroup orbiviruses isolated in Zimbabwe from aborted cattle foetuses, plus one isolated from the visceral organs of a cow and another from vulture faeces, were examined in comparison with known members of the serogroup by complement fixation, indirect immunofluorescence, fluorescent focus reduction neutralization tests and PAGE of the segmented, dsRNA genomes. The viruses were indistinguishable from known members of the serogroup by complement fixation and indirect immunofluorescence, but two novel viruses, for which the names Gweru and Marondera are proposed, and two previously described viruses, Nyabira and Abadina, were identified by neutralization tests. The dsRNA profiles of Abadina serotype isolates differed from that of the Abadina prototype virus, indicating that different electropherotypes may occur within serotypes.


KMD-3213, a novel, potent, alpha 1a-adrenoceptor-selective antagonist: characterization using recombinant human alpha 1-adrenoceptors and native tissues.
alpha 1-Adrenoceptors (ARs) comprise a heterogeneous family, and subtype-selective ligands are valuable for studying the functional role of each receptor subtype. We characterized a newly synthesized, alpha 1-AR antagonist, KMD-3213, by using Chinese hamster ovary cells stably expressing the three cloned human alpha 1-ARs (alpha 1a, alpha 1b, and alpha 1d), as well as native rat and human tissues. KMD-3213 potently inhibited 2-[2-(4-hydroxy-3-[125I]iodophenyl)ethylaminomethyl]-alpha-tetralone binding to the cloned human alpha 1a-AR, with a Ki value of 0.036 nM, but had 583- and 56-fold lower potency at the alpha 1b- and alpha 1d-ARs, respectively. KMD-3213 inhibited norepinephrine-induced increases in intracellular Ca2+ concentrations in alpha 1a-AR-expressing Chinese hamster ovary cells with an IC50 of 0.32 nM but had a much weaker inhibitory effect on the alpha 1b- and alpha 1d-ARs. Using pharmacologically well characterized native rat tissues [submaxillary gland (alpha 1A-AR-expressing tissue), liver (alpha 1B-AR-expressing tissue), and heart (mixed alpha 1A- and alpha 1B-AR-expressing tissue)], binding studies showed that inhibition curves for KMD-3213 in submaxillary gland and liver best fit a one-site model (with Ki values of 0.15 and 16 nM, respectively), whereas KMD-3213 had high and low affinity sites in heart membranes. Chloroethylclonidine treatment of rat heart membranes completely eliminated the low affinity sites for KMD-3213. Furthermore, in human liver and prostate KMD-3213 could identify high and low affinity sites, the Ki values of which corresponded well to those for the cloned human alpha 1a- and alpha 1b-ARs, respectively. Moreover, the affinity of KMD-3213 was found to be approximately 10-fold higher at the cloned human alpha 1a-AR than at the cloned rat alpha 1a-AR. KMD-3213 is a potent and highly selective antagonist for the human alpha 1a-AR and would be useful for studying the physiological roles of human alpha 1-AR subtypes.


Premalignant lesions of the stomach.
Recent studies indicate that chronic gastritis induced by Helicobacter pylori infection is a predisposing condition for the development of both gastric adenocarcinoma and primary gastric B-cell mucosal associated lymphoid tissue (MALT) lymphoma. The chronic gastritis induced by H pylori may evolved in specific individuals in response to additional genetic, environmental, and bacterial-virulence factors. The transitions from chronic gastritis to gastric atrophy with small intestinal (type I) metaplasia, incomplete small intestinal (type II) metaplasia, large intestinal (type III) metaplasia, low-grade dysplasia, and finally high-grade dysplasia are associated with respectively increasing cancer risk. H pylori infection may also lead to the development of an abnormal clone of B-cells and formation of low-grade MALT lymphoma, which is thought to be a precursor for the development of metastatic high-grade MALT lymphoma. In some patients, low grade MALT lymphoma has been shown to regress after eradication of the H pylori infection. The specific genetic abnormalities associated with these premalignant stages of gastric carcinogenesis are currently being defined. Other conditions associated with an increased risk of gastric adenocarcinoma include autoimmune atrophic gastritis, adenomatous polyps, postgastrectomy remnants, and possibly Ménétrier's disease.


Promoting clinical pharmacy services through advanced medication review in the emergency department.
To determine if an advanced medication review carried out in the emergency department (ED) increases the number of pharmacotherapy recommendations (PR) and the severity of the detected prescribing errors. We designed an analytic observational prospective cohort study with preintervention assessment (PRE) and postintervention assessment (POST). In PRE, prescription review was done by pharmacists located in the pharmacy department; they took into account only the information provided by the computerised physician order entry system. In POST, pharmacists were physically present in the ED and performed an advanced medication review. The main variables were number of PR and the severity of detected prescribing errors according to the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) severity index. Clinical variables were number of calls to physicians on duty during the first 48 hours of admission, readmissions at 30 days, visits to the ED at 30 days, inhospital mortality and length of stay. The study population comprised 102 patients (51 in PRE and 51 in POST). In PRE, the number of PR per patient was 1.1; in POST, this value increased by 53% (1.7 PR per patient; P=0.014), especially in the case of PR related to home medications. The severity of prescribing errors was higher in POST (P=0.004). There was a trend towards better results for all clinical outcomes in POST although statistical significance was not reached. An advanced medication review in the ED increases the number of PR and the severity of the detected prescribing errors.


Giving and Receiving Effective Feedback: A Review Article and How-To Guide.
Feedback is the delivery of information based on direct observation that is meant to improve performance. Learning is at the heart of feedback, and as such, feedback is a required competency in pathology resident education. In the laboratory setting, the ability of laboratory professionals in all practice settings and experience levels to give and receive feedback is crucial to workflow and ultimately patient care. To summarize the importance of feedback, strategies for optimizing feedback exchange, and overcoming barriers to giving and receiving feedback. Peer-reviewed original articles, review articles, medical education literature, and published books on feedback and communication were reviewed to explore ideal methods of giving and receiving feedback and to identify common barriers to feedback exchange. Medical education literature emphasizes techniques for giving feedback and describes barriers often encountered to feedback exchange in medical practice. Effective feedback requires that the giver, receiver, and environment be carefully considered. Likewise, each of these factors can impose barriers to feedback exchange. Various methods for giving feedback have been described. All feedback should address a specific behavior, be nonevaluative in nature, and be followed by confirmation of understanding and an action plan. Few articles describe the importance of receiving feedback. Receiving feedback can be difficult, but it is enhanced by learning to listen and making conscious decisions regarding implementing the messages heard. Giving and receiving feedback become easier with practice.


Travel and Social Isolation of People With Spinal Cord Injury.
People with spinal cord injury (SCI) are at high risk for social isolation because they face barriers to social participation owing to limitations in physical functioning, secondary health conditions, and environmental barriers. Research has shown that social isolation, an objective lack of contact with others, can lead to loneliness, mental health issues, and low life satisfaction. Leisure travel, which involves interactions with others, may have the potential to reduce social isolation. To explore the association of travel participation with social isolation among people with SCI. A total of 11,091 cases from 2016-2021 in the SCI Model Systems database were included in the study. Participants were categorized into low and high social isolation groups. A hierarchical logistic regression was performed with social isolation as the dependent variable and travel groups as the independent variable, while controlling for age, family income, and health conditions. Travel participation is negatively associated with social isolation. People with SCI who traveled for one to two nights (odd ratio [OR] 0.52, 95% CI 0.40-0.67), three to four nights (OR 0.56, 95% CI 0.43-0.72), or more than five nights (OR 0.41, 95% CI 0.35-0.49) in the past 12 months are less likely to be socially isolated compared to those who have not traveled in the past 12 months. Travel participation may help reduce the social isolation of individuals with SCI. Therapists and rehabilitation professionals should design effective travel training programs that encourage patients with SCI to travel more often.


Genetic vaccination for re-establishing T-cell tolerance in type 1 diabetes.
Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease resulting in the destruction of the insulin-secreting β cells. Currently, there is no established clinical approach to effectively suppress long-term the diabetogenic response. Genetic-based vaccination offers a general strategy to reestablish β-cell specific tolerance within the T-cell compartment. The transfer of genes encoding β-cell autoantigens, anti-inflammatory cytokines and/or immunomodulatory proteins has proven to be effective at preventing and suppressing the diabetogenic response in animal models of T1D. The current review will discuss genetic approaches to prevent and treat T1D with an emphasis on plasmid DNA- and adeno-associated virus-based vaccines.


Contraceptive technologies for global health: ethically getting to safe, effective and acceptable options for women and men.
While the contributions of science, biomedicine, and engineering to contraceptive development offer wonder and promise to the community, what inspires many of us in the not-for-profit sector about the process of contraceptive product development is the integration of consultations with users, providers and policy makers, good clinical and manufacturing practice in product design and development, and the delivery of approved products at affordable prices to those in greatest need. The commitment to have an impact on the reproductive lives of women and men along with the ethical principles embedded in this process of achieving safe, effective, and acceptable options include the respect for persons, i.e., eventual users, beneficence for those using the product and justice in ensuring that it is available to those who are most vulnerable, including those in developing countries. It is the inspiration that drives the scientists and developers to produce public benefit and additional social value.


Meningothelial cells react to elevated pressure and oxidative stress.
Meningothelial cells (MECs) are the cellular components of the meninges enveloping the brain. Although MECs are not fully understood, several functions of these cells have been described. The presence of desmosomes and tight junctions between MECs hints towards a barrier function protecting the brain. In addition, MECs perform endocytosis and, by the secretion of cytokines, are involved in immunological processes in the brain. However, little is known about the influence of pathological conditions on MEC function; e.g., during diseases associated with elevated intracranial pressure, hypoxia or increased oxidative stress. We studied the effect of elevated pressure, hypoxia, and oxidative stress on immortalized human as well as primary porcine MECs. We used MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) bioreduction assays to assess the proliferation of MECs in response to treatment and compared to untreated control cells. To assess endocytotic activity, the uptake of fluorescently labeled latex beads was analyzed by fluorescence microscopy. We found that exposure of MECs to elevated pressure caused significant cellular proliferation and a dramatic decrease in endocytotic activity. In addition, mild oxidative stress severely inhibited endocytosis. Elevated pressure and oxidative stress impact MEC physiology and might therefore influence the microenvironment of the subarachnoid space and thus the cerebrospinal fluid within this compartment with potential negative impact on neuronal function.


Frequency of co-seropositivities for certain pathogens and their relationship with clinical and histopathological changes and parasite load in dogs infected with Leishmania infantum.
In canine leishmaniosis caused by the protozoan Leishmania infantum, little is known about how co-infections with or co-seropositivities for other pathogens can influence aggravation of this disease. Therefore, the objectives of this study were to evaluate the frequency of co-infections with or co-seropositivities for certain pathogens in dogs seropositive for L. infantum and their relationship with clinical signs, histological changes and L. infantum load. Sixty-six L. infantum-seropositive dogs were submitted to clinical examination, collection of blood and bone marrow, culling, and necropsy. Antibodies against Anaplasma spp., Borrelia burgdorferi sensu lato, Ehrlichia spp. and Toxoplasma gondii and Dirofilaria immitis antigens were investigated in serum. Samples from different tissues were submitted to histopathology and immunohistochemistry for the detection of Leishmania spp. and T. gondii. Quantitative real-time PCR was used to assess the L. infantum load in spleen samples. For detection of Coxiella burnetii, conventional PCR and nested PCR were performed using bone marrow samples. All 66 dogs tested positive for L. infantum by qPCR and/or culture. Fifty dogs (76%) were co-seropositive for at least one pathogen: T. gondii (59%), Ehrlichia spp., (41%), and Anaplasma spp. (18%). Clinical signs were observed in 15 (94%) dogs monoinfected with L. infantum and in 45 (90%) dogs co-seropositive for certain pathogens. The L. infantum load in spleen and skin did not differ significantly between monoinfected and co-seropositive dogs. The number of inflammatory cells was higher in the spleen, lung and mammary gland of co-seropositive dogs and in the mitral valve of monoinfected dogs. These results suggest that dogs infected with L. infantum and co-seropositive for certain pathogens are common in the region studied. However, co-seropositivities for certain pathogens did not aggravate clinical signs or L. infantum load, although they were associated with a more intense inflammatory reaction in some organs.


Coronary calcium score predicts cardiovascular mortality in diabetes: diabetes heart study.
In type 2 diabetes mellitus (T2DM), it remains unclear whether coronary artery calcium (CAC) provides additional information about cardiovascular disease (CVD) mortality beyond the Framingham Risk Score (FRS) factors. A total of 1,123 T2DM participants, ages 34-86 years, in the Diabetes Heart Study followed up for an average of 7.4 years were separated using baseline computed tomography scans of CAC (0-9, 10-99, 100-299, 300-999, and ≥1,000). Logistic regression was performed to examine the association between CAC and CVD mortality adjusting for FRS. Areas under the curve (AUC) with and without CAC were compared. Net reclassification improvement (NRI) compared FRS (model 1) versus FRS+CAC (model 2) using 7.4-year CVD mortality risk categories 0% to <7%, 7% to <20%, and ≥20%. Overall, 8% of participants died of cardiovascular causes during follow-up. In multivariate analysis, the odds ratios (95% CI) for CVD mortality using CAC 0-9 as the reference group were, CAC 10-99: 2.93 (0.74-19.55); CAC 100-299: 3.17 (0.70-22.22); CAC 300-999: 4.41(1.15-29.00); and CAC ≥1,000: 11.23 (3.24-71.00). AUC (95% CI) without CAC was 0.70 (0.67-0.73), AUC with CAC was 0.75 (0.72-0.78), and NRI was 0.13 (0.07-0.19). In T2DM, CAC predicts CVD mortality and meaningfully reclassifies participants, suggesting clinical utility as a risk stratification tool in a population already at increased CVD risk.


Characterization of Diarrheagenic Escherichia coli Isolated in Organic Waste Products (Cattle Fecal Matter, Manure and, Slurry) from Cattle's Markets in Ouagadougou, Burkina Faso.
Cattle farming can promote diarrheal disease transmission through waste, effluents or cattle fecal matter. The study aims to characterize the diarrheagenic Escherichia coli (DEC) isolated from cattle feces, manure in the composting process and slurry, collected from four cattle markets in Ouagadougou. A total of 585 samples (340 cattle feces, 200 slurries and 45 manures in the composting process) were collected from the four cattle markets between May 2015 and May 2016. A multiplex Polymerase Chain Reaction (PCR), namely 16-plex PCR, was used to screen simultaneously the virulence genes specific for shiga toxin-producing E. coli (STEC), enteropathogenic E. coli (EPEC), enterotoxigenic E. coli (ETEC), enteroinvasive E. coli (EIEC) and enteroaggregative E. coli (EAEC). DEC was detected in 10.76% of samples. ETEC was the most prevalent (9.91%). STEC and EAEC have been observed with the same rate (0.51%). ETEC were detected in 12.64% of cattle feces, in 6.66% of manure in the composting process and in 5% of slurry. STEC were detected in 0.58% of cattle feces and in 2.22% of manure in the composting process. EAEC was detected only in 1% of slurry and in 2.22% of manure in the composting process. ETEC strains were identified based on estIa gene and/or estIb gene and/or elt gene amplification. Of the 58 ETEC, 10.34% contained astA, 17.24% contained elt, 3.44% contained estIa and 79.31% contained estIb. The two positive EAEC strains contained only the aggR gene, and the third was positive only for the pic gene. The results show that effluent from cattle markets could contribute to the spreading of DEC in the environment in Burkina Faso.


Current paradigms in the management of refractory Helicobacter pylori infection.
Helicobacter pylori is the most prevalent chronic bacterial infection, with approximately half of the world's population estimated to be colonized. The World Health Organization (WHO) has classified Helicobacter pylori as a class-I carcinogen. All main society guidelines recommend its eradication in infected individuals. The global trend indicates that eradication rates are decreasing annually and the likelihood of eradication decreases with each unsuccessful therapeutic attempt. Resistance to antibiotics in H. pylori strains is the leading cause for eradication failure. Still, drug resistance and treatment failure may be complex, multi-dimensional and associated with several other factors. Knowledge of these factors can aid in optimizing eradication rates. This review will focus on the factors associated with refractory H. pylori, with a particular emphasis on antibiotic resistance mechanisms and their clinical implications. Also, the most recent literature and recommendations available for determining an appropriate regimen after the failure of the first attempt at eradication will be discussed.


Effects of the COVID-19 pandemic on the behavior and physical health of dogs in Rio de Janeiro state: Reflections on the quality of life of dogs and their owners.
The COVID-19 pandemic changed the routines of people, consequently changing the daily lives of their pets. Behavioral and emotional changes caused by the stress resulting from restrictions of social isolation and their consequences in the human-animal relationship have been discussed. However, there are still no studies that identify the factors that affect behavior and which are the most susceptible groups. The purpose of this study is to identify behavioral and emotional changes on dogs during the COVID-19 pandemic and their effects on the quality of life of animals and their owners. The methodology used was online questionnaires, which were posted on social networks aimed to dog owners in Rio de Janeiro state, Brazil. The results showed that age, sex, dog size, type of home, and restrictions imposed differently affected the type of behavioral change. However, the most frequent type of change was the worsening of previous conditions. Neutered behaviors directly interfered in the lives of owners and their pets, as owners managed the situation and sought information without guidance from a veterinarian, with the possibly consequence of worsening the situation in the future. Veterinarians should actively investigate behavioral changes that have occurred through anamnesis to avoid abandonment and instability in the human-animal relationship.


Mitochondrial dynamics modulate the expression of pro-inflammatory mediators in microglial cells.
Over-activation of microglia cells in the brain contributes to neurodegenerative processes promoted by the production of various neurotoxic factors including pro-inflammatory cytokines and nitric oxide. Recently, accumulating evidence has suggested that mitochondrial dynamics are an important constituent of cellular quality control and function. However, the role of mitochondrial dynamics in microglial activation is still largely unknown. In this study, we determined whether mitochondrial dynamics are associated with the production of pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated immortalization of murine microglial cells (BV-2) by a v-raf/v-myc carrying retrovirus (J2). Excessive mitochondrial fission was observed in lentivirus-transfected BV-2 cells stably expressing DsRed2-mito following LPS stimulation. Furthermore, mitochondrial localization of dynamin-related protein 1 (Drp1) (a key regulator of mitochondrial fission) was increased and accompanied by de-phosphorylation of Ser637 in Drp1. Interestingly, inhibition of LPS-induced mitochondrial fission and reactive oxygen species (ROS) generation by Mdivi-1 and Drp1 knock-down attenuated the production of pro-inflammatory mediators via reduced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling. Our results demonstrated for the first time that mitochondrial fission regulates mitochondrial ROS production in activated microglial cells and influences the expression of pro-inflammatory mediators through the activation of NF-κB and MAPK. We therefore suggest that mitochondrial dynamics may be essential for understanding pro-inflammatory mediator expression in activated microglial cells. This could represent a new therapeutic approach for preventing neurodegenerative diseases.


Looking the Part: Stereotypicality in Appearance Among White Professionals Predicts Leadership Attainment and Perceived Leadership Suitability.
This project explores the effects of racial phenotypic stereotypicality, or the degree to which a person's appearance is perceived as typical of their racial group, on leadership outcomes. Building on research showing that people hold an image of the ideal leader as a White person, we propose that looking more typically White may facilitate leadership attainment. In Study 1, which used a sample of American college football coaches (N = 1,106), White (vs. Black) coaches were more likely to occupy leadership roles. Furthermore, within race, stereotypicality positively predicted occupying a leadership or head-coach role among White professionals (and negatively predicted occupying a head-coach role among Black professionals). Study 2 elucidated a possible mechanism by showing a causal effect of stereotypicality on perceived suitability for leadership among Whites. These findings advance theorizing on the White-leader link and have implications for the ability of people of color to access lucrative professional roles.


Receptor-mediated transcytosis of lactoferrin through the blood-brain barrier.
Lactoferrin (Lf) is an iron-binding protein involved in host defense against infection and severe inflammation; it accumulates in the brain during neurodegenerative disorders. Before determining Lf function in brain tissue, we investigated its origin and demonstrate here that it crosses the blood-brain barrier. An in vitro model of the blood-brain barrier was used to examine the mechanism of Lf transport to the brain. We report that differentiated bovine brain capillary endothelial cells exhibited specific high (Kd = 37.5 nM; n = 90,000/cell) and low (Kd = 2 microM; n = 900,000 sites/cell) affinity binding sites. Only the latter were present on nondifferentiated cells. The surface-bound Lf was internalized only by the differentiated cell population leading to the conclusion that Lf receptors were acquired during cell differentiation. A specific unidirectional transport then occurred via a receptor-mediated process with no apparent intraendothelial degradation. We further report that iron may cross the bovine brain capillary endothelial cells as a complex with Lf. Finally, we show that the low density lipoprotein receptor-related protein might be involved in this process because its specific antagonist, the receptor-associated protein, inhibits 70% of Lf transport.


[Severe and disseminated infection by cytomegalovirus in immunocompetent patient].
Usually, cytomegalovirus infection dosen't cause symptoms in immunocompetents patients although sometimes can. In alcoholic and cirrhotic subjects can cause several and fatal infections. We describe a case of disseminated cytomegalovirus infection in an alcoholic patient with excellent response to ganciclovir.


Estimated capital costs of fish exclusion technologies for hydropower facilities.
Hydropower is a reliable source of renewable energy, and its future expansion is likely to be in the form of either smaller new stream development (NSD) projects or powering existing non-powered dams. Thresholds for entrainment risk to fish and the requirements for fish exclusion at hydropower facilities often differ depending on the species involved, the characteristics of the facility, and the goals of stakeholders, but little quantitative information is present within the literature regarding the specific costs of fish exclusion measures. Cost data associated with protection, mitigation, and enhancement (PM&E) measures related to positive barrier screening were identified using keyword searches of an existing environmental mitigation cost data set and manual extraction from regulatory licensing documents available in the Federal Energy Regulatory Commission (FERC) eLibrary. This approach yielded a total of 50 p.m.&E mitigation measures with estimated capital construction costs pertaining to positive barrier screens and represented <10% of the 171 total FERC project dockets available in the data set. These data were highly skewed toward conventional relicensing projects, as <7% were associated with NSD projects. Results indicate highly variable costs are associated with fish screening, with flow-normalized costs one to two orders of magnitude higher for screening with the highest exclusion capability (≤0.09 in. spacing) compared with coarser screening (1-2 in.). These data provide an initial baseline for estimating exclusion costs for hydropower development and may help developers consider options for more fish-friendly generation technologies, though gaps remain relating to a lack of data, particularly for NSD projects.


[THE CLINICAL COURSE OF THE ISOLATED EFFECTS OF EXTENSIVE SMALL INTESTINE RESECTION IN THE LATE POSTOPERATIVE PERIOD].
The purpose is the postoperative period study of clinical and functional status of patients after small intestine resection, which was performed in different volume 91 patients with sequelae of small intestine resection in different terms after the operation were surveyed. Patients were assessed for clinical symptoms on a scale "Method of evaluating intestinal failure after gastric resection", in our own modifications, clinical-laboratory and biochemical blood examination, ultrasound examination of abdominal cavity and kidneys, x-ray examination of the gastrointestinal tract, esophagogastroduodenoscopy with histological examination of the mucosa. We determined the scatology, the consistency of the feces on the Bristol scale, concentration and profile of short chain fatty acids in coprofiltrates. Blood serum Citrulline was determined using high performance liquid chromatography on the chromatograph "Stayer". The degree of nutritional risk was assessed using screen questionnaire NRS-2002 RESULTS: Analysis of clinical, anthropometric and laboratory data showed that patients with residual stumps of the small intestine more than 2 meters have a distinct tendency to stabilize their condition, confirmed by the level of citrulline in the serum. At the same time complete adaptation does not occur, because the main reason of the operation is adhesive intestinal obstruction with chronic relapsing course. Patients with stumps of the small intestine less than 2 m have highly individual adaptation, which may be due to a small sample of patients in this group. The detected changes in the concentration and profile of coprofiltrat short-chain fatty acids allow differentiated approach to therapy of diarrhea syndrome as the main clinical manifestations of the effects of isolated small intestine resection.


Intermediate human adenovirus type 22/H10,19,37 as a new etiological agent of conjunctivitis.
Eight strains of a new intermediate adenovirus were isolated in the course of an investigation of conjunctivitis in Hiroshima City, Japan. The strain was first isolated in July 1986. All eight strains were isolated from conjunctival swab samples from patients with conjunctivitis, mainly epidemic keratoconjunctivitis. The virus was typed as adenovirus type 22 in neutralization tests and was related closely to types 10, 19, and 37 in hemagglutination inhibition tests. The DNA cleavage patterns of the eight strains with nine restriction endonucleases were the same with one exception but different from those of the above serologically related species. We conclude that the intermediate adenovirus is a new etiological agent of conjunctivitis, mainly epidemic keratoconjunctivitis.


Axonal degeneration in peripheral nerves in a case of Leber hereditary optic neuropathy.
Leber hereditary optic neuropathy (LHON) is a mitochondrial DNA (mtDNA) genetic disorder characterized by profound bilateral loss of central vision due to selective loss of retinal ganglion cells. Most patients with LHON do not have complaints related to the peripheral nervous system. We investigated possible qualitative and quantitative histological changes in the peripheral nerve of a patient with LHON as compared to normal controls. Brachial plexus specimens were obtained at necropsy from a patient with LHON carrying the 3460/ND1 mtDNA mutation and age-matched controls without known history of neurological disease. The nerves were evaluated by light microscope coupled to a digital camera-based morphometric analysis and electron microscopy. Extensive axonal degeneration of the large heavily myelinated fibers was found in the brachial plexus from the patient with LHON. In LHON nerve fascicles, we counted over 10 times as many degenerated profiles as found in the control nerve fascicles. Microscopic examination of the brachial plexus in the patient with LHON clearly demonstrated a significant pattern of neurodegeneration. Our study suggests that peripheral neuropathy may be a subclinical feature associated with LHON.


[Intensity of lipid peroxidation and antioxidant enzyme activity in arterial and venous walls during hypervitaminosis D].
The intensity of the lipid peroxydation (LPO) and the antioxidant enzyme activity (superoxide dismutase, glutathione peroxydase and catalase) on injecting vitamin D in high doses (10,000 U/kg) was examined in the arterial and venous walls of rabbits. The increase in the amount of the intermediate and final LPO products has been found in the vessels of all types. The lowest intensity of LPO was noted in the vena cava. The decrease in the antioxidant activity has been revealed. But vena cava inferior was the exception because the activity of all studied antioxidant enzymes grew in its wall. This increase is likely to be one of the reasons for vena resistance to the action of damaging factors.


Steps forward in the treatment of pulmonary arterial hypertension: latest developments and clinical opportunities.
Pulmonary arterial hypertension (PAH) is a chronic disease that results in narrowing of the small pre-capillary pulmonary arteries leading to elevation of pulmonary artery pressure and pulmonary vascular resistance, subsequent right ventricular failure, and if unchecked, death. Advances in the treatment of PAH over the last two decades have markedly improved survival. These improvements reflect a combination of changes in treatments, improved patient care strategies, and varying disease phenotypes in the PAH population. Currently approved therapies for PAH are directed at the recognized abnormalities within the pulmonary vasculature and include endothelin receptor antagonists, phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators, and prostacyclin pathway agents. Most of these drugs have been approved on the basis of short-term trials that mainly demonstrated improvements in exercise capacity. More recently, long-term, event-driven trials of novel drugs have been performed, demonstrating new efficacy parameters. There have also been exciting advances in the understanding of right heart failure pathophysiology in PAH that have the potential to inspire the development of right ventricular targeted therapy and continued discoveries in the heterogeneity of disease and response to treatment has great potential for developing more 'personalized' therapeutic options. In this article, we review the current available data regarding the management of PAH, with an emphasis on the pharmacologic therapies and discussion of novel therapeutic directions for the treatment of this fatal disease.


Australians with Down syndrome--health matters.
The health and life expectancy of Australians with Down syndrome has improved dramatically over recent decades, resulting in more people living into adulthood and accessing community and hospital based health and social services. This article presents information and resources helpful to general practitioners providing healthcare to patients who have Down syndrome. Healthcare issues through the lifespan are explored, the importance of proactive management is emphasised and strategies are outlined. Australians with Down syndrome are an interesting and rewarding group of people with whom to work. They present us with particular challenges in the way we provide healthcare and, in doing so, offer us an opportunity to improve the way we work with other patients who have cognitive and communication difficulties; chronic, complex health and social needs; family or paid carers involved in health management and those who require health advocacy as a part of healthcare provision.


Preliminary study of low-dose photodynamic therapy on the oxidative stress response of Cutibacterium acnes.
The objective of this study was to investigate the influence of photodynamic therapy (PDT) employing different, lower 5-aminolevulinic acid (ALA) dosages on the proliferative activity of Cutibacterium acnes (C. acnes). In this in vitro bacterial experiment, we examined the effects of PDT using different doses of ALA (0.05 mmol/L; 0.1 mmol/L; 0.5 mmol/L; 1.0 mmol/L; 2.5 mmol/L). To elucidate the underlying mechanisms, we assessed colony-forming units (CFUs), bacterial staining for live/dead, antioxidant enzyme activity, and gene expression of oxidative stress markers following treatment with different doses of ALA-PDT. Our findings demonstrate that CFU, bacterial staining for live/dead, as well as the activity and gene expression of superoxide dismutase (SOD) and catalase (CAT), all exhibited significant increases when the ALA concentration was 0.1/0.5 mmol/L. However, both CFU and cell growth of C. acnes decreased when the ALA concentration reached 1.0 mmol/L. Lower concentration of ALA-PDT (0.1/0.5 mmol/L) appears to promote the growth of C.acnes while higher doses (1.0 /2.5 mmol/L) are associated with eradication. The procedure is possibly mediated by the activation of antioxidant-related genes and enzyme expression in cells.


Substance P decreases fluid absorption in the renal proximal tubule.
Substance P is a neuropeptide found principally in the central nervous system and peripheral afferent nerve fibers. It is widely distributed in the body, and its local release is thought to have important effects in the normal physiology and pathophysiology of several organ systems. Substance P releases histamine from mast cells and nitric oxide from endothelial cells. Systemic infusion of substance P causes a brisk natriuresis. Previously, proximal tubule transport in the kidney was measured in vivo during the infusion of substance P. Transport was inhibited. This could have been a direct action of substance P or secondary to the release of histamine or nitric oxide. Therefore, we have now studied the effect of substance P on isolated proximal tubules perfused in vitro. We found that 10(-10) M substance P caused a 50% reduction in the rate of fluid absorption in rabbit proximal straight tubule. This effect was reversible on removal of substance P from the bath. Inhibition of nitric oxide production with NG-monomethyl-L-arginine (10(-4) M) did not influence the action of substance P at 10(-10) M. The sensitivity of the proximal tubule to low concentrations of substance P, together with the recent findings of substance P-containing afferent fibers within the cortex of the kidney, suggest a role for substance P in the control of proximal tubule reabsorption, particularly in pathophysiological conditions associated with increased afferent nerve activity, such as ureteric occlusion.


Treatment of urinary tract infections in the era of antimicrobial resistance and new antimicrobial agents.
Urinary tract infections (UTIs) caused by antibiotic-resistant Gram-negative bacteria are a growing concern due to limited treatment options. Knowledge of the common uropathogens in addition to local susceptibility patterns is essential in determining appropriate empiric antibiotic therapy of UTIs. The recommended first-line empiric antibiotic therapy for acute uncomplicated bacterial cystitis in otherwise healthy adult nonpregnant females is a 5-day course of nitrofurantoin, a 3-g single dose of fosfomycin tromethamine, or a 5-day course of pivmecillinam. High rates of resistance for trimethoprim-sulfamethoxazole and ciprofloxacin preclude their use as empiric treatment of UTIs in several communities, particularly if patients who were recently exposed to them or in patients who are at risk of infections with extended-spectrum β-lactamases (ESBLs)-producing Enterobacteriales. Second-line options include oral cephalosporins such as cephalexin or cefixime, fluoroquinolones and β-lactams, such as amoxicillin-clavulanate. Current treatment options for UTIs due to AmpC- β -lactamase-producing Enterobacteriales include nitrofurantoin, fosfomycin, pivmecillinam, fluoroquinolones, cefepime, piperacillin-tazobactam and carbapenems. Treatment oral options for UTIs due to ESBLs-E coli include nitrofurantoin, fosfomycin, pivmecillinam, amoxicillin-clavulanate, finafloxacin, and sitafloxacin while pivmecillinam, fosfomycin, finafloxacin, and sitafloxacin are treatment oral options for ESBLs- Klebsiella pneumoniae. Parenteral treatment options for UTIs due to ESBLs-producing Enterobacteriales include piperacillin-tazobactam (for ESBL-E coli only), carbapenems including meropenem/vaborbactam, imipenem/cilastatin-relebactam, and sulopenem, ceftazidime-avibactam, ceftolozane-tazobactam, aminoglycosides including plazomicin, cefiderocol, fosfomycin, sitafloxacin, and finafloxacin. Ceftazidime-avibactam, meropenem/vaborbactam, imipenem/cilastatin-relebactam, colistin, fosfomycin, aztreonam and ceftazidime-avibactam, aztreonam and amoxicillin-clavulanate, aminoglycosides including plazomicin, cefiderocol, tigecycline are treatment options for UTIs caused by carbapenem-resistant Enterobacteriales (CRE). Treatment options for UTIs caused by multidrug resistant (MDR)-Pseudomonas spp. include fluoroquinolones, ceftazidime, cefepime, piperacillin-tazobactam, carbapenems including imipenem-cilastatin/relebactam, meropenem, and fosfomycin, ceftolozane-tazobactam, ceftazidime-avibactam, aminoglycosides including plazomicin, aztreonam and ceftazidime-avibactam, cefiderocol, and colistin. It is important to use the new antimicrobials wisely for treatment of UTIs caused by MDR-organisms to avoid resistance development.


Refined sorghum flours precooked by extrusion enhance the integrity of the colonic mucosa barrier and promote a hepatic antioxidant environment in growing Wistar rats.
The effects of precooked-refined sorghum flour consumption on antioxidant status, lipid profile, and colonic and bone health were evaluated. Twenty-four male Wistar rats were fed with control diet (C), or red or white precooked-refined sorghum based diets (SD) for 60 days. The intake of SD was lower than that of C, but the efficiency of all diets was similar. Rats fed with SD showed lower feces excretion, cecal pH and enzyme activities (β-glucosidase, β-glucuronidase and mucinase) than C. White SD improved intestinal architecture, cell proliferation and apoptosis, upregulated ZO1 and occludin tight junction proteins and stimulated goblet cell differentiation, enhancing the integrity of the mucosa barrier in both proximal and distal colonic mucosa in a better way than red SD. Consumption of SD significantly decreased serum triglyceride levels compared with the C diet. The mineral content of the right femur was not different among diets. The liver enzyme activities (superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase) did not show differences among diets. Liver reducing power and reduced glutathione/oxidize glutathione ratio were higher for animals consuming SD than C. It can be concluded that the consumption of precooked refined sorghum flours still has beneficial effects for health, mainly at the colonic level, despite the lower phenolics and fibre contents of refined flours with respect to whole grain flours.


-455G/A polymorphism of the beta-fibrinogen gene is associated with the progression of coronary atherosclerosis in symptomatic men: proposed role for an acute-phase reaction pattern of fibrinogen. REGRESS group.
Increased plasma fibrinogen levels have been identified as a risk indicator for myocardial infarction, stroke, and thrombosis. Both environmental and genetic factors make an important contribution to plasma fibrinogen levels in humans. In the present study we evaluated, in patients with serum cholesterol levels between 4 and 8 mmol/L, the relation of plasma levels and polymorphisms of fibrinogen with coronary artery disease (CAD), cross-sectionally at baseline and after a 2-year follow-up period in which they received either a placebo or pravastatin. Higher plasma fibrinogen levels (3.9 g/L) were observed at baseline in patients with the -455AA genotype than in patients with the -455GA (3.2 g/L) and -455GG (3.1 g/L) genotypes of the -455G/A fibrinogen beta gene polymorphism (P<.05). Plasma levels of fibrinogen were not related to the baseline angiographic variables (mean segment diameter [MSD] and minimum obstruction diameter [MOD]), nor to the quantitative changes in these angiographic variables. However, in the placebo group, patients with the -455AA genotype had more progression of CAD, expressed by a significantly greater decrease of the MSD and MOD, after the 2-year follow-up period than patients with the other genotypes. The -455G/A polymorphism was related to the progression of CAD, and pravastatin therapy seemed to offset this deleterious effect. We hypothesized that the -455A allele may promote a stronger acute-phase response in fibrinogen and that the resulting higher fibrinogen levels may form the pathogenetic basis for the stronger progression of coronary atherosclerosis. Experiments to verify this hypothesis are being proposed and advocated, in view of the possibility of identifying a genetic marker that can recognize a subgroup of patients with an increased risk who may benefit from early treatment with lipid-lowering or anticoagulant drugs.


Role of absolute reticulocyte count in evaluation of pancytopenia-a hospital based study.
Pancytopenia is a common hematological entity encountered in our laboratory practice. Evaluating the causes of pancytopenia is essential for the diagnostic as well as therapeutic management of the patients. Absolute Reticulocyte count (ARC) plays a pivotal role in identifying the cause of pancytopenia in most of the cases but it has grossly been overlooked. Hence, we attempted to identify the significance of ARC as a deciding parameter in evaluating the causes of pancytopenia. The study was conducted in a tertiary health care hospital, Chennai, India. A cross-sectional descriptive study was conducted over a period of two years (2011-2013). Patients who satisfied the criteria for pancytopenia were evaluated with clinical details. Pancytopenia work-up including Peripheral blood picture, Complete blood counts, Reticulocyte count, Serum Ferritin, B12, Folate and Bone marrow aspirate was carried out. ARC was calculated and an algorithm to approach the cases of pancytopenia was derived considering ARC as the key factor. A total of 429 cases of pancytopenia were evaluated and based on our algorithm results were tabulated. ARC was found to be <25x10^(9)/L for cases of Aplastic anaemia; 25-50x10^(9)/L for Nutritional anaemia; and, >100x10^(9)/L in Marrow infiltrative disorders and in cases of sepsis and malaria. We found that ARC plays an important role in differentiating various causes of pancytopenia and hence should be routinely included in pancytopenia work up in order to avoid unnecessary bone marrow aspirations in pancytopenic patients.


Splenic artery ligation in selected patients with hepatic cirrhosis and in Sprague-Dawley rats.
The effects of splenic artery ligation were studied in Sprague-Dawley rats and in eight selected symptomatic patients with hepatic cirrhosis. In rats, this maneuver induced splenic infarction, reduced functional splenic mass, transiently raised platelet and reticulocyte counts and was without local complications. In seven selected patients with cirrhosis and prominent splenomegaly, the splenic artery was markedly enlarged, splenic arterial flow was greatly increased and splenic artery ligation partially lowered portal pressure. In three patients with varying cytopenias secondary to hypersplenism splenic artery ligation uniformly improved peripheral blood elements, although varying degrees of hypersplenism later recurred necessitating splenectomy in one. In five other patients, splenic artery ligation in conjunction with coronary vein ligation in four was performed for bleeding esophageal varices. Two patients later required portacaval shunting, and one other in whom operation was undertaken in desperation died of hepatic failure. Celiac-mesenteric arterioportography, operative portography, hemodynamic measurements and examination of peripheral blood elements in these eight patients suggests that splenic artery ligation in conjunction, where appropriate, with coronary vein ligation has several potentially beneficial effects. Hypersplenism may be sufficiently controlled to alleviate clinical symptoms. Arterial inflow into the portal system is reduced tending to lower portal pressure. Transheptic portal flow from the mesenteric bed is preserved. Venous anastomotic channels still functioning around the splenic pedicle and no longer draining a hyperdynamic splenic circuit may be converted into an escape route for mesenteric venous blood entering the portal system under high pressure. Nonetheless, each of these effects and their interrelationships require further study before this operation assumes a larger role in the treatment of complications of portal hypertension.


Stimulation of lumbar sympathetic trunk produces vasoconstriction of the vasa nervorum in the sciatic nerve via alpha-adrenergic receptors in rats.
The effects of repetitive electrical stimulation of a lumbar sympathetic trunk (LST) for 30 s at various frequencies and supramaximum intensity on the nerve blood flow in a sciatic nerve were studied by laser Doppler flowmetry in anesthetized Fischer-344 male rats. The response was biphasic; i.e. an initial increase and then a decrease. The maximum mean increase after 2 Hz stimulation was 22 +/- 8%, while the maximum mean decrease after 20-50 Hz stimulation was 79 +/- 3%, of the prestimulus control level. The initial increase, which was greater at lower frequencies and existed even after local sympathetic denervation, was passive, and was caused by the systemic pressor response to LST stimulation. The decrease, which was nearly abolished by an i.v. alpha-adrenergic blocker, phentolamine (10 mg/kg), resulted from vasoconstriction in the vasa nervorum, mainly via activation of alpha-adrenergic receptors.


The clinical utility of the AUSDRISK tool in assessing change in type 2 diabetes risk in overweight/obese volunteers undertaking a healthy lifestyle intervention.
The objective of this study was to assess the clinical utility of the AUSDRISK tool for determining risk of Type 2 diabetes mellitus (T2DM). In this secondary analysis from the HealthTrack study, the AUSDRISK tool was applied to data from overweight/obese volunteers completing a lifestyle intervention trial. Participants were volunteer residents of the Illawarra region recruited in 2014-2015. From 377 trial participants (BMI 25-40 kg/m2, 25-54 yr), 161 provided data required for measurement of AUSDRISK, collected at 0 and 12 months. They had been randomised to one of two lifestyle interventions (±a healthy food sample, 30 g walnuts/day, I and IW) delivered by dietitians, or a control intervention (C) delivered by nurse practitioners. HbA1c measures were considered for comparison. At baseline the AUSDRISK score indicated n = 83 (51.5%) were at high risk of T2DM within 5 years (≥12 points). After 12 months the proportion scored as high risk significantly decreased in the IW group (51.5% vs 33.3%; p = 0.005), but not I (51.2% vs 39.0%; p = 0.063) or C group (51.9% vs 38.9%; p = 0.065). By comparison, HbA1c measures indicated high risk in n = 24 (17%) of 139 participants at baseline and borderline non-significant changes over time in the randomised groups. In conclusion, the AUSDRISK tool has reasonable clinical utility in identifying T2DM risk in clinical samples of overweight/obese individuals.


[The changes of plasma levels of soluble TNF-alpha and TNF-R1 ratio is a prognostic marker and key element of the stroke pathogenesis].
The goal of the present study was to investigate the plasma levels of sTNF-alpha, sTNF-R1 in acute stroke patients, to study the relation between ones, the neurological stroke severity and functional disability. The investigations comprised 60 ischemic stroke patients, 25 patients form control group. Plasma levels of sTNF-alpha, sTNF-R1 were detected by means of ELISA. The conclusion of interaction of sTNF-alpha and tmTNF-R1 increases inflammatory and apoptotic brain tissue damage on the first day of stroke is drawn. On the 7-th and 21-st days of stroke sTNF-alpha realize a neuroprotective effect. The interaction sTNF-alpha and sTNF-R1 blockade of damage expansion. As the result, prognostic significance of sTNF-alpha/sTNF-R1 is showed.


Evidence for concerted movement of nuclear and mitochondrial clines in a lizard hybrid zone.
Moving hybrid zones provide compelling examples of evolution in action, yet long-term studies that test the assumptions of hybrid zone stability are rare. Using replicated transect samples collected over a 10-year interval from 2002 to 2012, we find evidence for concerted movement of genetic clines in a plateau fence lizard hybrid zone (Sceloporus tristichus) in Arizona. Cline-fitting analyses of SNP and mtDNA data both provide evidence that the hybrid zone shifted northward by approximately 2 km during the 10-year interval. For each sampling period, the mtDNA cline centre is displaced from the SNP cline centre and maintaining an introgression distance of approximately 3 km. The northward expansion of juniper trees into the Little Colorado River Basin in the early 1900s provides a plausible mechanism for hybrid zone formation and movement, and a broadscale quantification of recent land cover change provides support for increased woody species encroachment at the southern end of the hybrid zone. However, population processes can also contribute to hybrid zone movement, and the current stability of the ecotone habitats in the centre of the hybrid zone suggests that movement could decelerate in the future.


Community-based study of atrial fibrillation and stroke prevention.
The benefits of anticoagulation and antiplatelet agents for stroke prevention in atrial fibrillation (AF) have been established. There is little data on the use of this form of stroke prevention in patients with AF in Ireland. To determine whether adequate stroke prevention measures are taken regarding anticoagulation and aspirin use for patients in the community with chronic AF. Audit of general medical services (GMS) patients with atrial fibrillation in two Dublin general practices. A total of 70 patients with AF were identified from 2684 GMS patients in the two practices: contraindications to anticoagulation were established in 26 of these. In those for whom warfarin was indicated, 21 of 44 (47%) were not anticoagulated. In those not anticoagulated and where aspirin was not contra-indicated, 20 of 42 were not on aspirin. Our study found that almost one third of patients with AF could be anticoagulated but were not, and the alternative of aspirin was only used in just over one half of patients. This represents a lost opportunity for stroke prevention. Various approaches should be explored to remedy this.


Neurophysiological Predictors of Self-Reported Difficulty in a Virtual-Reality Driving Scenario.
Our perception of subjective difficulty in complex tasks, such as driving, is a judgment that is likely a result of dynamic interactions between distributed brain regions. In this paper, we investigate how neurophysiological markers associated with arousal state are informative of this perceived difficulty throughout a driving task. We do this by classifying subjective difficulty reports of subjects using set of features that include neural, autonomic, and eye behavioral markers. We subsequently assess the importance of these features in the classification. We find that though multiple EEG linked to cognitive control and, motor performance linked to classification of subjective difficulty, only pupil diameter, a measure of pupil-linked arousal, is strongly linked to both measured self-reported difficulty and actual task performance. We interpret our findings in the context of arousal pathways influencing performance and discuss their relevance to future brain-computer interface systems.


Nurse-initiated defibrillation? Reality or rhetoric.
Evidence indicates that hospital nurse-initiated defibrillation improves survival following cardiac arrest. Accordingly, hospitals are changing their policies to permit nurses to initiate defibrillation. However, if nurse-initiated defibrillation is to be successful implemented, nurses' beliefs about this practice need to be understood. Therefore, the aim of this study was to explore the attitudes of rural nurses towards defibrillation to assist in the development of nurse-initiated defibrillation programmes. This cross-sectional study examined the defibrillation beliefs of registered nurses in rural areas. A proportionally stratified sample of registered nurses (n = 436) were drawn from 51 rural acute care hospitals in Australia. Most (n = 224; 52%) of the participants were not permitted to initiate defibrillation. A one-way between-groups multivariate analysis of variance showed that nurses who were permitted to initiate defibrillation held stronger positive beliefs towards defibrillation than nurses not permitted (10,410) = 13.88, p < 0.001. Nurses not permitted were more concerned about the challenge of learning rhythms, incurring litigation and harming the patient or themselves. If it is accepted that defibrillation will become an essential part of all nurses' roles, these beliefs should be explored and integrated into educational programmes as inappropriate beliefs about defibrillation may impede implementation and skills development.


Aortic sinotubular atherosclerotic debris associated with cerebral embolic events can be identified by transthoracic echocardiography.
To evaluate the association between the presence of aortic sinotubular debris (STAD) identified by transthoracic echocardiography (TTE) and embolic strokes. The presence of atherosclerotic debris in the ascending aorta or aortic arch detected by transesophageal echocardiography or epiaortic echocardiography has been well established to be correlated with embolic stroke or other thromboembolic events. No data are available on the role of TTE in describing aortic pathology in thromboembolic events. We identified 60 transthoracic echocardiographic studies from 11,275 studies, in which STAD was diagnosed. The charts of these patients (group 1; mean age 67 +/- 10 years) were reviewed and compared with those of 57 patients (group 2) without STAD, matched for age, gender and risk factors for advanced atherosclerosis. The results of brain imaging procedures, carotid duplex and coronary angiography were also reviewed. Ischemic stroke was found in 15 of group 1 (25%) and 4 patients of group 2 (7%, odds ratio = 4.4; 95% confidence interval, 1.3-19.4, p = 0.008). The average thickness of STAD was 0.7 +/- 0.2 cm in stroke patients and 0.6 +/- 0.2 cm in patients without stroke (p = n.s.). STAD was associated with </=40% carotid artery stenosis. STAD detected by TTE is strongly associated with embolic strokes. Our findings expand the role of TTE in the evaluation of patients with embolic strokes.


Differential roles of Arg97, Asp293, and Arg108 in enzyme stability and substrate specificity of CYP2C9.
CYP2C9 metabolizes a wide range of drugs, many of which are negatively charged at physiological pH. Therefore, it has been thought that complementarily charged amino acid(s) are critically involved in substrate binding. Previous studies have implicated arginine residues at positions 97, 105, and 108 and aspartate at position 293 in the normal catalytic function of the enzyme. To elucidate the role of these amino acids in the substrate specificity of CYP2C9, a series of mutants were constructed and analyzed for functional activity, thermal stability, and ligand binding. Charge-modifying mutations at positions 97, 105, and 293 decreased catalytic activity toward diclofenac, (S)-warfarin, and pyrene in a substrate-independent manner with Arg105 the least, and Arg97 the most, sensitive amino acids in this regard. Decreases in functional activity paralleled thermal instability of the mutants, suggesting that loss of function reflects more generalized structural changes rather than the absence of a specifically charged amino acid at these three positions. The R108H mutant was inactive toward all three substrates because of unexpected nitrogen ligation to the heme. Conversely, the R108F mutant exhibited substrate-dependent catalytic behavior, with almost complete loss of activity toward (S)-warfarin and diclofenac, but preservation of pyrene metabolism. In addition, the R108F mutation abrogated the Type I difference spectra induced by flurbiprofen and benzbromarone, obligate anions at physiological pH. These data identify critical roles for Arg97 and Asp293 in the structural stability of the enzyme and demonstrate a selective role for Arg108 in the binding and metabolism of negatively charged substrates of CYP2C9.