Associations between activity patterns and cardio-metabolic risk factors in children and adolescents: A systematic review.
Total volumes of physical activity and sedentary behaviour have been associated with cardio-metabolic risk profiles; however, little research has examined whether patterns of activity (e.g., prolonged bouts, frequency of breaks in sitting) impact cardio-metabolic risk. The aim of this review was to synthesise the evidence concerning associations between activity patterns and cardio-metabolic risk factors in children and adolescents aged 5-19 years. A systematic search of seven databases was completed in October 2017. Included studies were required to report associations between objectively-measured activity patterns and cardio-metabolic risk factors in children and/or adolescents, and be published between 1980 and 2017. At least two researchers independently screened each study, extracted data, and undertook risk of bias assessments. From the 15,947 articles identified, 29 were included in this review. Twenty-four studies were observational (cross-sectional and/or longitudinal); five were experimental. Ten studies examined physical activity patterns, whilst 19 studies examined sedentary patterns. Only one study examined both physical activity and sedentary time patterns. Considerable variation in definitions of activity patterns made it impossible to identify which activity patterns were most beneficial to children's and adolescents' cardio-metabolic health. However, potential insights and current research gaps were identified. A consensus on how to define activity patterns is needed in order to determine which activity patterns are associated with children's and adolescents' cardio-metabolic risk. This will inform future research on the impact of activity patterns on children's and adolescents' short- and longer-term health.


Evolution of Precision Medicine and Surgical Strategies for Bicuspid Aortic Valve-Associated Aortopathy.
Bicuspid aortic valve (BAV) is a common congenital cardiac malformation affecting 1-2% of people. BAV results from fusion of two adjacent aortic valve cusps, and is associated with dilatation of the aorta, known as bicuspid valve associated aortopathy. Bicuspid valve aortopathy is progressive and associated with catastrophic clinical events, such as aortic dissection and rupture. Therefore, frequent monitoring and early intervention with prophylactic surgical resection of the proximal aorta is often recommended. However, the specific pattern of aortopathy is highly variable among patients, with different segments of the ascending aorta being affected. Individual patient risks are sometimes difficult to predict. Resection strategies are informed by current surgical guidelines which are primarily based on aortic size and growth criteria. These criteria may not optimally reflect the risk of important aortic events. To address these issues in the care of patients with bicuspid valve aortopathy, our translational research group has focused on validating use of novel imaging techniques to establish non-invasive hemodynamic biomarkers for risk-stratifying BAV patients. In this article, we review recent efforts, successes, and ongoing challenges in the development of more precise and individualized surgical approaches for patients with bicuspid aortic valves and associated aortic disease.


Characterisation of asthma subgroups associated with circulating YKL-40 levels.
The chitinase-like protein YKL-40 mediates airway inflammation and serum levels are associated with asthma severity. However, asthma phenotypes associated with YKL-40 levels have not been precisely defined.We conducted an unsupervised cluster analysis of asthma patients treated at the Yale Center for Asthma and Airways Disease (n=156) to identify subgroups according to YKL-40 level. The resulting YKL-40 clusters were cross-validated in cohorts from the Severe Asthma Research Programme (n=167) and the New York University/Bellevue Asthma Repository (n=341). A sputum transcriptome analysis revealed molecular pathways associated with YKL-40 subgroups.Four YKL-40 clusters (C1-C4) were identified. C3 and C4 had high serum YKL-40 levels compared with C1 and C2. C3 was associated with earlier onset and longer duration of disease, severe airflow obstruction, and near-fatal asthma exacerbations. C4 had the highest serum YKL-40 levels, adult onset and less airflow obstruction, but frequent exacerbations. An airway transcriptome analysis in C3 and C4 showed activation of non-type 2 inflammatory pathways.Elevated serum YKL-40 levels were associated with two distinct clinical asthma phenotypes: one with irreversible airway obstruction and another with severe exacerbations. The YKL-40 clusters are potentially useful for identification of individuals with severe or exacerbation-prone asthma.


Liberation of Hydrogen Sulfide from Dicysteinyl Polysulfanes in Model Wine.
Diorganopolysulfanes can be generated when hydrogen sulfide (H2S) and thiols are oxidized in the presence of Cu(II) under conditions usually aimed at removing H2S from wine. This work sought to understand if polysulfanes could act as latent sources of H2S during postbottling storage. The stability of the polysulfanes formed in situ in model wine containing cysteine, H2S, and transition metals was dependent both on the number of sulfur linking atoms (Sn) and on the presence of a reducing agent, such as sulfur dioxide or ascorbic acid. A polysulfane containing three linking sulfur atoms was the most stable, with 84% of the relative initial amount remaining in solution after six months, compared to polysulfanes containing four or more linking sulfur atoms that decomposed rapidly, with 26% remaining after six months. Importantly, sulfur dioxide was associated with the rapid degradation of polysulfanes and subsequent liberation of H2S. Three cysteine- S-sulfonates were also tentatively identified, which gives insight into the possible release mechanisms involved with H2S reappearance.


Are nature lovers happy? On various indicators of well-being and connectedness with nature.
Connectedness with nature (CN) is seen as a personal disposition relevant for environmental as well as human health. In five questionnaire studies (N = 547) we systematically investigated the relationship between various operationalizations of well-being and CN. CN was assessed with two different tools in parallel. All significant correlations were controlled for the effects of age and gender. Psychological well-being, meaningfulness and vitality were found to be robustly correlated with CN. We highlight the relevance of CN with respect to human health and further discuss conceptual differences unraveled by the concurrent application of two CN-tools.


Trigeminal cardiac reflex: new thinking model about the definition based on a literature review.
Trigeminocardiac reflex (TCR) is a brainstem reflex that manifests as sudden onset of hemodynamic perturbation in blood pressure (MABP) and heart rate (HR), as apnea and as gastric hypermotility during stimulation of any branches of the trigeminal nerve. The molecular and clinical knowledge about the TCR is in a constant growth since 1999, what implies a current need of a review about its definition in this changing context. Relevant literature was identified through searching in PubMed (MEDLINE) and Google scholar database for the terms TCR, oculocardiac reflex, diving reflex, vasovagale response. The definition of the TCR varies in clinical as well as in research studies. The main difference applies the required change of MABP and sometimes also HR, which most varies between 10% and 20%. Due to this definition problem, we defined, related to actual literature, 2 major (plausibility, reversibility) and 2 minor criteria (repetition, prevention) for a more proper identification of the TCR in a clinical or research setting. Latest research implies that there is a need for a more extended classification with 2 additional subgroups, considering also the diving reflex and the brainstem reflex. In this review, we highlighted criteria for proper definition and classification of the TCR in the light of increased knowledge and present a thinking model to overcome this complexity. Further we separately discussed the role of HR and MABP and their variation in this context. As another subtopic we gave attention to is the chronic TCR; a variant that is rarely seen in clinical medicine.


High prevalence of high-risk HPV genotypes other than 16 and 18 in cervical cancers of Curaçao: implications for choice of prophylactic HPV vaccine.
Curaçao is a Dutch-Caribbean Island located in a high-risk area for cervical cancer.Prior to introduction of a prophylactic human papillomavirus (HPV) vaccine, knowledge of the prevalence of high-risk HPV vaccine genotypes (HPV16, 18, 31, 33, 45, 52 and 58) in cervical (pre)cancer is required. To investigate the prevalence of HPV genotypes in invasive cervical cancers (ICC) and cervical intraepithelial neoplasia (CIN) grade 1, 2 and 3 in Curaçao. Paraffin-embedded blocks of 104 cervical cancers (89 squamous, 15 adenocarcinoma), 41 CIN3, 39 CIN2 and 40 CIN1 lesions were analysed for the presence of HPV. Sections were stained by H&E for histopathological evaluation, and DNA was extracted using proteinase K. HPV genotypes were detected using Short PCR Fragment (SPF10) PCR DNA enzyme immunoassay and a Line Probe Assay (LiPA25) . HPV was found in 92 (88.5%) ICC; 87 (94.6%) had a single HPV infection and 86 (93.5%) were high-risk human papillomavirus (hrHPV)-type positive.The three most common HPV types in ICC were 16 (38.5%), 18 (13.5%) and 45 (6.7%), covering 58.7%.HrHPV vaccine genotypes 16, 18, 31, 35, 45, 52 and 58 were responsible for 73.1% of ICC. For precancerous lesions, the HPV attribution was 85.4% for CIN3, 66.7% for CIN2% and 42.5% for CIN1. Our study, the largest in the Caribbean region in (pre)cancer, shows that the prevalence of HPV-type 16 and 18 in cervical cancer is lower compared with the world population but no differences in prevalence of these two HPV types are seen in precancerous lesions.When considering HPV vaccination in Curaçao, the relatively high contribution of non-HPV 16/18 genotypes in ICC should be taken into account.


Team climate for innovation: what difference does it make in general practice?
Teamwork in primary healthcare is associated with patient care processes and staff outcomes. The ability of teams to be innovative is a hypothesized mechanism. We examined the characteristics of general practices with good team climate for innovation, and assessed the impact of climate on chronically ill patients' assessment of their care and on the job satisfaction of the staff. Large cross-sectional study. Australian general practices. A total of 654 general practitioners and staff and 7505 chronically ill patients from 93 general practices in 6 Australian states and territories. The Team Climate Inventory and the Overall Job Satisfaction Scale, customized for use with general practices, were administered to general practitioners and practice staff, and the General Practice Assessment Survey was administered to patients. Practice characteristics were collected by survey from the principal doctor or practice manager. Mean scores of team climate in Australian general practices were similar to those reported in the UK, except that in our study there was no association between the number of doctors in a practice and their team climate. Better team climate was found in practices with fewer non-clinical staff. Team climate predicted the job satisfaction of the general practitioners and staff, irrespective of the number of practice staff. Better team climate was associated with greater satisfaction by patients with their care. Team climate is important for patient and staff satisfaction. In large general practices, separate sub-cultures may exist between administrative and clinical staff, which has implications for designing effective team interventions.


[Clinical use and action mechanism of propranolol].
Propranololum reduces the intraocular tension by inhibiting the production of aqueous humour. In about 50% of all cases the medicament, given as 1% drops, proves an effective anti-glaucomatous agent. Combined with adrenaline it is particularly effective and well tolerated.


Prevention of colon cancer by low doses of celecoxib, a cyclooxygenase inhibitor, administered in diet rich in omega-3 polyunsaturated fatty acids.
Epidemiologic and animal studies suggest that a high-fat diet containing mixed lipids promotes colorectal cancer, whereas fish oil lacks promoting effect. Although cyclooxygenase-2 (COX-2) inhibitors are effective chemopreventive agents against colon carcinogenesis, administration of high doses of these agents over time may induce side effects. Here, we compared the efficacy of moderately high and low doses of celecoxib administered in diets high in mixed lipids (HFML) or fish oil (HFFO) against azoxymethane-induced colon carcinogenesis in male F344 rats. One day after the last azoxymethane treatment (15 mg/kg body weight once weekly for 2 weeks), groups of rats were fed the HFML and HFFO diets containing 0, 250, 500, and 1,000 ppm celecoxib. Rats were killed 26 weeks later and colon tumors were subjected to histopathologic examination and analyzed for total COX and COX-2 synthetic activities and COX-2 expression. Rats fed the HFFO diet showed significantly lower colon tumor incidence and multiplicity compared with rats fed the HFML diet. Celecoxib at 250, 500, and 1,000 ppm in either diet significantly suppressed colon carcinogenesis. Inhibition of colon adenocarcinomas were more pronounced in animals given 250 ppm celecoxib in HFFO diet compared with 250 ppm celecoxib given in HFML diet, suggesting some synergism between omega-3 polyunsaturated fatty acids (PUFA) and celecoxib. Inhibition of colon tumors by celecoxib was associated with lower levels of COX-2 activity and expression in colon tumors. These studies support the use of low doses of celecoxib in omega-3 PUFA-rich diet as a promising approach for clinical trials.


Rk1, a ginsenoside, is a new blocker of vascular leakage acting through actin structure remodeling.
Endothelial barrier integrity is essential for vascular homeostasis and increased vascular permeability and has been implicated in many pathological processes, including diabetic retinopathy. Here, we investigated the effect of Rk1, a ginsenoside extracted from sun ginseng, on regulation of endothelial barrier function. In human retinal endothelial cells, Rk1 strongly inhibited permeability induced by VEGF, advanced glycation end-product, thrombin, or histamine. Furthermore, Rk1 significantly reduced the vessel leakiness of retina in a diabetic mouse model. This anti-permeability activity of Rk1 is correlated with enhanced stability and positioning of tight junction proteins at the boundary between cells. Signaling experiments revealed that Rk1 induces phosphorylation of myosin light chain and cortactin, which are critical regulators for the formation of the cortical actin ring structure and endothelial barrier. These findings raise the possibility that ginsenoside Rk1 could be exploited as a novel prototype compound for the prevention of human diseases that are characterized by vascular leakage.


Computer calculation of the dose distribution in the electron build-up region.
A procedure has been developed for producing accurate computer-calculated dose distributions at the air-tissue boundaries for oblique incidence of a photon beam. Measurements of the dose distribution under conditions of tangential incidence are presented for a Siemens 6 MV linear accelerator. These measurements have been compared with calculated distributions using the standard Cunningham-Clarkson calculation technique. Based on this comparison, two changes are suggested for improving the accuracy of the calculation. The grid spacing for the calculation is decreased in order that the rapid dose variations that occur at the boundary may be better followed. Furthermore, the dose calculation scheme is modified to take into account the differences in the amount of electron build-up which occurs. An algorithm is presented for making this modification. Also, the calculated dose at the exit surface had to be modified to handle the deficit of scatter material behind the calculation points. The results of these changes are shown as a comparison of a typical chest wall irradiation treatment plan using two opposing tangential fields.


Management of trigeminal autonomic cephalalgias in children and adolescents.
Primary headache disorders that are more frequently encountered in the paediatric population include migraine and tension-type headaches. The trigeminal autonomic cephalalgias (TACs), which includes cluster headache (CH), paroxysmal hemicrania (PH) and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), are rarely reported in the paediatric population. The 1-year prevalence of CH seems to be 0.03 %. The clinical features of childhood and adolescence onset CH seem to be similar to those of adult onset. Cranial autonomic features and restlessness seem to less prominent in children than in adults. When restlessness is present, it often manifests as thrashing around in children and can distract attention from the headache, thereby contributing to a delay in diagnosis. The frequency of cluster periods seems to be lower in childhood. Similarly, the duration of the single cluster period seems to be shorter. The temporal pattern shows a trend towards a gradual increase of frequency and duration of symptoms in adult life. In terms of management of paediatric CH, oxygen has been used successfully in several paediatric CH patients, and given its good side-effect profile, it is considered the abortive agent of choice for paediatric CH. Verapamil is the preventative drug of choice in both episodic and chronic CH, though paediatric patients should be started on lower doses and titrated according to age. Paediatric-onset PH and SUNCT are very rarely reported. The clinical phenotype and response to treatment seem to resemble the adult-onset form. Paediatric-onset TACs are poorly recognized and there is often a delay of several months or years before the diagnosis is made. Awareness of typical clinical pictures of these excruciating headaches is essential to allow prompt initiation of the appropriate management.


The APC tumor suppressor promotes transcription-independent apoptosis in vitro.
The APC tumor suppressor is found in nonproliferating epithelial cells of the colonic crypts and is mutated in most colorectal tumors. To understand the function of APC in normal epithelium and how its loss leads to tumor formation, we tested whether APC is a mediator of apoptosis using an in vitro assay that monitors caspase-3-mediated cleavage of lamin B protein or a colorimetric substrate in a cell-free Xenopus egg extract. Recombinant APC protein accelerates apoptosis-associated caspase activity independently of ongoing transcription and protein synthesis. Conversely, the addition of mutant APC and immunodepletion of Xenopus APC decelerates apoptosis-associated caspase activity. Acceleration of apoptosis by APC is abolished by the caspase-8 inhibitor Z-IETD-FMK, demonstrating that caspase-8 is an essential component of APC-mediated apoptosis. These results suggest that the induction of apoptosis may be one role of APC in tumor suppression and that this mechanism is independent of beta-catenin-mediated effects on transcription.


Evidence for platelet alphaIIb beta3 activation despite elevated cytosolic cAMP.
Cyclic nucleotides, such as cAMP, are known to inhibit the multistep cascade that results in platelet aggregation. In the present study we provide evidence that it is possible to bypass cAMP inhibitory effect on fibrinogen binding site exposure induced by the thromboxane A2 synthetic analogue U46619, the snake venom toxin convulxin, or by the direct PKC activator OAG, by concomitantly activating a G1-coupled receptor by means of epinephrine or by inducing cytosolic calcium influx by means of ionomycin. In fact, in our study we demonstrate that, in iloprost-treated platelets, the inhibition of both platelet aggregation and fibrinogen binding was overcome by adding epinephrine or ionomycin. To further confirm this, we used the cAMP analogue dibutyryl cAMP and we obtained platelet aggregation in response to U46619, convulxin or OAG plus epinephrine. Moreover, a complete inhibition of platelet aggregation in the presence of high concentrations of cAMP was observed only in the case of U46619, while a small percentage of aggregation persisted when convulxin or OAG were used, due to the small amount of ADP that both convulxin and OAG are able to release. Since PKC inhibition didn't allow platelet aggregation to occur in response to the concomitant activation of U46619 or convulxin, plus epinephrine or ionomycin, we can conclude that cAMP-induced inhibition of aggregation can be counteracted by the simultaneous activation of PKC in the presence of an activated G1-coupled receptor or of an induced calcium influx.


Identification and Validation of Three Autophagy-Related Long Noncoding RNAs as Prognostic Signature in Cholangiocarcinoma.
Cholangiocarcinoma (CCA) is featured by common occurrence and poor prognosis. Autophagy is a biological process that has been extensively involved in the progression of tumors. Long noncoding RNAs (lncRNAs) have been discovered to be critical in diagnosing and predicting various tumors. It may be valuable to elaborate autophagy-related lncRNAs (ARlncRNAs) in CCA, and indeed, there are still few studies concerning the role of ARlncRNAs in CCA. Here, a prognostic ARlncRNA signature was constructed to predict the survival outcome of CCA patients. Through identification, three differentially expressed ARlncRNAs (DEARlncRNAs), including CHRM3.AS2, MIR205HG, and LINC00661, were screened and were considered predictive signatures. Furthermore, the overall survival (OS) of patients with high-risk scores was significantly lower than that of patients with low scores. Interestingly, the risk score was an independent factor for the OS of patients with CCA. Moreover, receiver operating characteristic (ROC) curve analysis showed that the screened and constructed prognosis signature for 1 year (AUC = 0.884), 3 years (AUC =0.759), and 5 years (AUC = 0.788) presented a high score of accuracy in predicting OS of CCA patients. Gene set enrichment analysis (GSEA) revealed that the three DEARlncRNAs were significantly enriched in CCA-related signaling pathways, including "pathways of basal cell carcinoma", "glycerolipid metabolism", etc. Quantitative real-time PCR (qRT-PCR) showed that expressions of CHRM3.AS2, MIR205HG, and LINC00661 were higher in CCA tissues than those in normal tissues, similar to the trends detected in the CCA dataset. Furthermore, Pearson's analysis reported an intimate correlation of the risk score with immune cell infiltration, indicating a predictive value of the signature for the efficacy of immunotherapy. In addition, the screened lncRNAs were found to have the ability to modulate the expression of mRNAs by interacting with miRNAs based on the established lncRNA-miRNA-mRNA network. In conclusion, our study develops a novel nomogram with good reliability and accuracy to predict the OS of CCA patients, providing a significant guiding value for developing tailored therapy for CCA patients.


Patient-provider communication about gestational weight gain among nulliparous women: a qualitative study of the views of obstetricians and first-time pregnant women.
In 2009 the Institute of Medicine updated its guidelines for weight gain during pregnancy, in part because women of childbearing age now weigh more pre-pregnancy and tend to gain more weight during pregnancy than women did when the previous set of guidelines were released in 1990. Women who begin pregnancy overweight or obese and women who gain weight outside IOM recommendations are at risk for poor maternal and fetal health outcomes. With these concerns in mind, we examined what obstetricians communicate about gestational weight gain to their pregnant patients and how nulliparous patients perceive weight-related counseling from their obstetricians. We conducted one-on-one, semi-structured interviews with 19 nulliparous women and 7 obstetricians recruited from a single clinic at a large academic medical center in the United States. Interviews were transcribed verbatim and analyzed inductively using thematic analysis. We identified 4 major themes: 1) Discussions about the amount and pace of gestational weight gain: obstetricians reported variation in the frequency and timing of weight-related discussions with patients while most patients said that weight was not emphasized by their obstetricians; 2) The content of communication about nutrition and physical activity: obstetricians said they discuss nutrition and activity with all patients while most patients reported that their obstetrician either discussed these topics in general terms or not at all; 3) Communication about postpartum weight loss: obstetricians said that they do not typically address postpartum weight loss with patients during prenatal visits while patients had concerns about postpartum weight; and 4) Patient feelings about obstetrician advice: most patients said that their obstetrician does not tend to offer "unsolicited advice", instead offering information in response to patient questions or concerns. Women were divided about whether they desired more advice from their obstetrician on weight gain, nutrition, and activity. Our analysis revealed discrepancies between obstetricians' and patients' perceptions of their weight-related clinical interactions. Our findings suggest that there is a missed opportunity to use prenatal visits as opportunities to discuss healthy eating and exercise during pregnancy, the postpartum period, and beyond. Additional research on the design, implementation, and testing of interventions to address prenatal nutrition and physical activity is warranted.


Perioperative assessment of segmental left ventricular function in man. Effects of nitroprusside after bypass operations.
Direct on-line assessment of postoperative ventricular function has not been possible. We assessed the feasibility of using pulse-transit sonomicrometry to measure regional function in man postoperatively. Ultrasonic transducers (3 mm in diameter) were implanted along the minor axis of the left ventricle at midwall depth into a region supplied by a bypass graft. All wires were tunneled subcutaneously. Pressures, ECG, and regional dimensions were monitored in eight patients continuously, and at 48 to 72 hours postoperatively, the effects of sodium nitroprusside were assessed. The transducers were withdrawn with no complications. Nitroprusside was associated with an increase in systolic shortening from 1.60 +/- 0.19 to 1.92 +/- 0.25 mm and rate of shortening from 12.13 +/- 1.85 to 15.34 +/- 2.38 mm/s at constant end-diastolic lengths. Using this technique for recording regional dimensions, nitroprusside therapy augmented function at a constant preload.


Self-management and cognitive rehabilitation in early stage dementia - merging methods to promote coping and adoption of assistive technology. A pilot study.
Objectives: It is essential to develop interventions that meet individual needs for coping and self-management of people with dementia. This study explored the feasibility and applicability of an intervention merging methods of cognitive rehabilitation and self-management groups for people with early stage dementia. The potential of this intervention to promote adoption of assistive technology was also explored.Method: People with early stage Alzheimer's disease (N = 19) participated in the programme comprising both individual and group sessions. Caregivers were involved in the individual session and a separate group meeting. The intervention both addressed individual goals and more general self-management approaches. In addition, both participants and caregivers were introduced to the ReACT app, a holistic solution tailormade to meet self-management needs of people with early stage dementia.Results: There was significant improvement in the participants' attainment of individual goals and satisfaction with goal attainment from pre- to post-intervention. Participants and caregivers generally reported a positive attitude towards the intervention, attendance rate was high, and all participants completed the intervention. Qualitative results also indicated that the intervention promoted awareness, acceptance and coping among participants. The specific benefits of using the ReACT app for self-management were also emphasised. Forty-two percent of the participants adopted the app and continued using it after completing the intervention.Conclusion: Results from this pilot study indicated that the intervention is both feasible and applicable and can be an effective method to promote coping and adoption of assistive technology among people with early stage dementia.


Brownian dynamics of confined suspensions of active microrollers.
We develop efficient numerical methods for performing many-body Brownian dynamics simulations of a recently observed fingering instability in an active suspension of colloidal rollers sedimented above a wall [M. Driscoll, B. Delmotte, M. Youssef, S. Sacanna, A. Donev, and P. Chaikin, Nat. Phys. (2016), preprint arXiv:1609.08673. We present a stochastic Adams-Bashforth integrator for the equations of Brownian dynamics, which has the same cost but is more accurate than the widely used Euler-Maruyama scheme, and use a random finite difference to capture the stochastic drift proportional to the divergence of the configuration-dependent mobility matrix. We generate the Brownian increments using a Krylov method and show that for particles confined to remain in the vicinity of a no-slip wall by gravity or active flows, the number of iterations is independent of the number of particles. Our numerical experiments with active rollers show that the thermal fluctuations set the characteristic height of the colloids above the wall, both in the initial condition and the subsequent evolution dominated by active flows. The characteristic height in turn controls the time scale and wavelength for the development of the fingering instability.


Distinctive electrophoretic isoenzyme profiles in Saccharomyces sensu stricto.
Genetic variation among 35 strains representing the four currently recognized species of Saccharomyces sensu stricto (Saccharomyces cerevisiae, Saccharomyces bayanus, Saccharomyces pastorianus/carlsbergensis and Saccharomyces paradoxus) was estimated by analysing the electrophoretic mobilities of nonspecific esterases, acid phosphatase, lactate dehydrogenase and glucose-6-phosphate dehydrogenase isoenzymes. Twenty-two electrophoretic types were identified, a result in agreement with the phenotypic and genetic polymorphisms reported for this group of yeasts. However, the four species were clearly distinguishable based on the patterns obtained using three of the enzymes assayed, the resolving power not being improved by the introduction of data correspondent to lactate dehydrogenase. The overall diversity was higher among S. cerevisiae isolates, in contrast with S. paradoxus which showed only two patterns, one of which was common to four of the five strains studied. Concordant results from the application of the method and DNA hybridization experiments demonstrate its value for identification purposes.


Potential drug targets for myocardial infarction identified through Mendelian randomization analysis and Genetic colocalization.
Myocardial infarction (MI) is a major cause of death and disability worldwide, but current treatments are limited by their invasiveness, side effects, and lack of efficacy. Novel drug targets for MI prevention are urgently needed. In this study, we used Mendelian randomization to identify potential therapeutic targets for MI using plasma protein quantitative trait loci as exposure variables and MI as the outcome variable. We further validated our findings using reverse causation analysis, Bayesian co-localization analysis, and external datasets. We also constructed a protein-protein interaction network to explore the relationships between the identified proteins and known MI targets. Our analysis revealed 2 proteins, LPA and APOA5, as potential drug targets for MI, with causal effects on MI risk confirmed by multiple lines of evidence. LPA and APOA5 are involved in lipid metabolism and interact with target proteins of current MI medications. We also found 4 other proteins, IL1RN, FN1, NT5C, and SEMA3C, that may have potential as drug targets but require further confirmation. Our study demonstrates the utility of Mendelian randomization and protein quantitative trait loci in discovering novel drug targets for complex diseases such as MI. It provides insights into the underlying mechanisms of MI pathology and treatment.


Effects of Chronic Ochratoxin A Exposure on p53 Heterozygous and p53 Homozygous Mice.
Exposure to the mycotoxin ochratoxin A (OTA) causes nephropathy in domestic animals and rodents and renal tumors in rodents and poultry. Humans are exposed to OTA by consuming foods made with contaminated cereal grains and other commodities. Management of human health risks due to OTA exposure depends, in part, on establishing a mode of action (MOA) for OTA carcinogenesis. To further investigate OTA's MOA, p53 heterozygous (p53+/-) and p53 homozygous (p53+/+) mice were exposed to OTA in diet for 26 weeks. The former are susceptible to tumorigenesis upon chronic exposure to genotoxic carcinogens. OTA-induced renal damage but no tumors were observed in either strain, indicating that p53 heterozygosity conferred little additional sensitivity to OTA. Renal changes included dose-dependent increases in cellular proliferation, apoptosis, karyomegaly, and tubular degeneration in proximal tubules, which were consistent with ochratoxicosis. The lowest observed effect level for renal changes in p53+/- and p53+/+ mice was 200 μg OTA/kg bw/day. Based on the lack of tumors and the severity of renal and body weight changes at a maximum tolerated dose, the results were interpreted as suggestive of a primarily nongenotoxic (epigenetic) MOA for OTA carcinogenesis in this mouse model.


Update on prescription monitoring in clinical practice: a survey study of prescription monitoring program administrators.
Prescription drug abuse and undertreatment of pain are public health priorities in the United States. Few options to manage these problems are balanced, in simultaneously supporting pain relief and deterring prescription drug abuse. Prescription monitoring programs (PMPs) potentially offer a balanced approach; however, the medical/scientific communities are not well informed about their current status and potential risks/benefits. The purpose of this study was to provide a benchmark of the current status of PMPs for healthcare providers upon which to engage PMP administrators. A Web survey of current PMP directors with a telephone follow-up conducted in June-July 2006 regarding goals, data captured, data sharing procedures, healthcare provider training, and evaluation efforts. Eighteen of 23 states with operating PMPs at that time participated. Eleven programs allowed physician access to PMP data. Data were delivered by mail (N = 6), fax (N = 8), e-mail (N = 1), and Websites (N = 8). Eight programs provided data to providers within 1 hour. Three states have developed provider PMP usage guidelines. Eight states developed or are developing educational programs. Two states completed or are conducting evaluations of the public health impact of PMP implementation. Five states have begun utilizing PMP data as an epidemiological tool. Initial public safety orientation of PMPs is evolving to include improving public health and patient care. Beginning with efforts to engage healthcare providers through data sharing and education, and progressively including program evaluation on public health and patient care, our results suggest a rapid movement in the direction of utilization of PMPs to improve health care.


Phytotoxic Allelochemicals From Roots and Root Exudates of Leafy Spurge (Euphorbia esula L.).
Invasive plants are a widespread problem but the mechanisms used by these plants to become invasive are often unknown. The production of phytotoxic natural products by invasive weeds is one mechanism by which these species may become successful competitors. Here we conducted a bioactivity-driven fractionation of root extracts and exudates from the invasive plant leafy spurge (Euphorbia esula L.), and structurally characterized jatrophane diterpenes and ellagic acid derivatives. Ellagic acid derivatives and one of the jatrophane diterpenes, esulone A, have been previously reported from leafy spurge, but another of the jatrophane diterpenes, kasuinine B, has not. We show that these compounds are phytotoxic but affect plants in different ways, either inducing overall plant necrosis or reducing root branching and elongation.


Pseudomonas aeruginosa exotoxin A induces human mast cell apoptosis by a caspase-8 and -3-dependent mechanism.
Mast cells play an important role in both allergy and innate immunity. Recently, we demonstrated an active interaction between human mast cells and Pseudomonas aeruginosa leading to the production of multiple cytokines. Here, we show that both primary cultured human cord blood-derived mast cells and the human mast cell line HMC-1 undergo apoptosis as determined by single-stranded DNA (ssDNA) formation after stimulation with P. aeruginosa exotoxin A (ETA), a major toxin produced by this bacterium. ETA-induced ssDNA formation was completely inhibited by Z-VAD (where Z is benzyloxycarbonyl), which blocks multiple caspases, suggesting a role for caspases in this process. Active caspase-3 formation in mast cells after an ETA challenge was detected by both Western blotting and flow cytometry analysis. ETA-induced caspase-3 activity in human mast cells was demonstrated by the detection of a characteristic 23 kDa product of D4-GDI (where GDI is guanine nucleotide dissociation inhibitor), an endogenous caspase-3 substrate. Interestingly, a specific caspase-8 inhibitor, Z-IETD-fmk (where fmk is fluoromethyl ketone), blocked ETA-induced cleavage of D4-GDI, but a caspase-9 inhibitor (Z-LEHD-fmk) did not. Treatment of mast cells with caspase-3 inhibitor Z-DEVD-fmk or caspase-8 inhibitor Z-IETD-fmk reduced the generation of ssDNA induced by ETA, suggesting a role for caspase-8 and -3 in ETA-induced mast cell apoptosis. Furthermore, treatment of mast cells with ETA induced decreases of the short form and a long form (p43) of Fas-associated death domain protein (FADD)-like interleukin-1beta-converting enzyme (FLICE) (caspase-8)-inhibitory proteins (FLIPs), which are endogenous caspase-8 inhibitors. Taken together, these results suggest that ETA-induced mast cell apoptosis involves down-regulation of antiapoptotic proteins, FLIPs, and activation of caspase-8 and -3 pathways.


Xanthogranulomatous pyelonephritis in childhood.
Xanthogranulomatous pyelonephritis is a severe, atypical form of chronic renal parenchymal infection accounting for 6/1000 surgically proved cases of chronic pyelonephritis. Its manifestations mimic those of neoplastic and other inflammatory renal parenchymal diseases and, consequently, it is often misdiagnosed preoperatively. To examine the relation between clinical history and the results of renal investigations performed in children with xanthogranulomatous pyelonephritis. A retrospective review of 31 cases presenting with the histopathological diagnosis of xanthogranulomatous pyelonephritis between 1963 and 1999. The mean follow up was 8.2 years. The male:female ratio was 1:1.1. The left kidney was affected in 26 of the 31 patients. The positive findings on examination and investigation at presentation were: fever, 16 children; pyuria, 26 children; positive urine culture, 16 children. A haemoglobin of < 100 g/l was measured in 27 of 31 patients and 15 of 18 patients tested had a raised erythrocyte sedimentation rate of > 20 mm in the first hour. Twenty six children had renal calculi, with a large reduction in the function of the affected kidney on isotope scintigraphy in 27 of the 29 patients tested. Hypertrophy of the contralateral kidney, shown on imaging, was present in 17 of 31 patients. Increasing awareness of this condition should lead to the diagnosis being suspected preoperatively.


Development and validation of a 3ABC antibody ELISA in Australia for foot and mouth disease.
To measure the diagnostic performance of an Australian-developed ELISA for the detection of antibodies against the non-structural proteins (NSP) 3ABC of the foot and mouth disease (FMD) virus. Test development and validation study. The diagnostic specificity was determined using 2535 sera from naïve animals and 1112 sera from vaccinated animals. Diagnostic sensitivity was calculated from the data for 995 sera from experimentally and field-infected animals from FMD-endemic countries in South East Asia. A commercial ELISA detecting antibodies against FMD virus NSP was used as the reference test to establish relative sensitivity and specificity. Bayesian latent class analysis was performed to corroborate results. The diagnostic window and rate of detection were determined at different times using sera from cattle, sheep and pigs before and after infection, and after vaccination and subsequent infection. Repeatability and reproducibility data were established. At 35% test cut-off, the 3ABC ELISA had an overall diagnostic sensitivity of 91.5% and diagnostic specificity of 96.4%. The diagnostic sensitivity in vaccinated and subsequently infected cattle was 68.4% and diagnostic specificity in vaccinated cattle was 98.0%. The 3ABC ELISA identified field and experimentally infected animals, as well as vaccinated and subsequently infected animals. Diagnostic sensitivity and specificity estimates for other FMD NSP tests are comparable with the results obtained in this study. This NSP ELISA was found to be 'fit for purpose' as a screening assay at the herd level to detect viral infection and also to substantiate absence of infection.


Successful mechanical thrombectomy in acute ischemic stroke: revascularization grade and functional independence.
Most studies define the technical success of endovascular thrombectomy (EVT) as a Thrombolysis in Cerebral Infarction (TICI) revascularization grade of 2b or higher. However, growing evidence suggests that TICI 3 is the best angiographic predictor of improved functional outcomes. To assess the association between successful TICI revascularization grades and functional independence at 90 days, we performed a systematic review and network meta-analysis of thrombectomy studies that reported TICI scores and functional outcomes, measured by the modified Rankin Scale, using the semi-automated AutoLit software platform. Forty studies with 8691 patients were included in the quantitative synthesis. Across TICI, modified TICI (mTICI), and expanded TICI (eTICI), the highest rate of good functional outcomes was observed in patients with TICI 3 recanalization, followed by those with TICI 2c and TICI 2b recanalization, respectively. Rates of good functional outcomes were similar among patients with either TICI 2c or TICI 3 grades. On further sensitivity analysis of the eTICI scale, the rates of good functional outcomes were equivalent between eTICI 2b50 and eTICI 2b67 (OR 0.81, 95% CI 0.52 to 1.25). We conclude that near complete or complete revascularization (TICI 2c/3) is associated with higher rates of functional outcomes after EVT.


Review of the histopathological findings in appendices removed for acute appendicitis in Nigerians.
The vermiform appendix is a frequent surgical specimen in most routine histopathology laboratories. This is because acute appendicitis is one of the commonest reasons for undertaking emergency laparotomy in most hospitals, even in developing countries. Three hundred and sixteen appendices removed for acute appendix in our hospital over a 10-year period were analysed, of which 37 (11.7%) were found to be normal while 221 (69.9%) showed histopathological evidence of acute inflammation. There were 25 cases of chronic appendicitis, four (1.3%) of which were granulomatous. Of these, schistosomal appendicitis was observed in three cases (0.95%) and tuberculous appendicitis was seen in one case. Of the 33 cases classified as miscellaneous, intraluminal ova of parasites with phlegmonous eosinophilic infiltration of the appendix was observed in 17 cases (5.4%) and Toxoplasma appendicitis was observed in five cases. Carcinoid tumour was diagnosed in three cases (0.95%), and in two of these the tumour had spread beyond the appendix.


Review of surgical devices using small aperture optics.
Small aperture optics work by blocking unfocused peripheral light rays while allowing central light rays to focus on the retina. This pinhole effect creates an extended depth of focus and has been used in presbyopia correction, improving intermediate and near vision without markedly affecting distance vision. Another beneficial effect of small aperture optics is reducing aberrations caused by irregular corneas or irregular pupils. The first small aperture surgical device was the Kamra corneal inlay used on the nondominant eyes of presbyopic emmetropes. The pinhole concept was also adapted into the IC-8 intraocular lens (IOL) for presbyopia correction during cataract surgery and by the XtraFocus piggyback device to lessen unwanted aberrations in eyes with irregular corneas or pupils. The IC-8 IOL can be placed monocularly or binocularly with mini-monovision for further near vision improvement. The XtraFocus piggyback device can be placed either in the sulcus or capsular bag. The aim of this literature review is to synthesize evidence on the efficacy, safety, and patient-reported outcomes on surgical devices utilizing small aperture optics. A comprehensive search on PubMed was conducted with the keywords "small aperture optics," "small aperture corneal inlay," "small aperture IOL," "Kamra corneal inlay," "IC-8 IOL," and "XtraFocus." In this review, we describe the progression of small aperture surgical devices, patient criteria, visual outcomes, complications, satisfaction, and recommendations for surgical success.


Recent decline in age at menarche: the Fels Longitudinal Study.
A number of recent reports suggest that the average age at menarche of US girls has declined over the past 20 years. Because the putative declines in the age at menarche are concurrent with increases in childhood body mass index (BMI), it has been suggested that these two trends may be causally linked. We examined differences in mean age of menarche in Fels Longitudinal Study girls who were born in six 10-year birth cohorts (1930s, 1940s, 1950s, 1960s, 1970s, and 1980s) and simultaneous cohort changes in mean BMI measured cross-sectionally at selected ages from 3-35 years (n = 371). Girls born in the 1980s had a mean age at menarche of 12.34 years, which was approximately 3-6 months earlier than that of girls born previously (P < 0.001). While the mean BMI values at ages 25 and 35 generally increased from the 1930s to the 1970s, the mean BMI during childhood and adolescence remained constant across the six birth cohorts. In summary, we found no evidence that the recent decline in the age at menarche in the Fels Longitudinal Study girls was reflected in concurrent increases in BMI at any point in childhood or adolescence. Conversely, girls born in the 1960s and 1970s have subsequently become heavier in young and mid-adulthood than were girls from earlier birth cohorts, without any concurrent change in the mean age at menarche over that time period. These two findings suggest that population-level shifts in BMI and the timing of menarche are largely independent, although sometimes coincident, processes.


PCR assay confirms diagnosis in syndrome with variably expressed phenotype: mutation detection in Stickler syndrome.
Stickler syndrome is an autosomal dominant disease with ocular (severe myopia, vitreal degeneration, and retinal detachment) and other systemic manifestations (hearing loss, cleft palate, epiphyseal dysplasia, and premature osteoarthritis). As with other dominantly inherited conditions, the clinical phenotype of Stickler syndrome varies considerably. To date, all mutations have been located in the type II procollagen (COL2A1) gene. Analysis of a C-->T mutation we had identified previously, in COL2A1 gene in exon 40, in a three generation pedigree showed the loss of a cleavage site for the TaqI restriction enzyme. We designed a rapid PCR based restriction enzyme assay to detect this mutation and used it to establish the diagnosis in a neonate from the same pedigree, presenting with the first occurrence of the Pierre-Robin sequence in the family and minimal ocular findings. These results underline the potential diagnostic value of many as yet undetected DNA mutations in families affected with Stickler syndrome, since the variability of the phenotype can impede accurate diagnosis, appropriate genetic counselling, and effective intervention and prophylactic treatment for affected people.


A giant superinfected uterine angioleiomyoma with distant septic metastases: an extremely rare presentation of a benign process and a systematic review of the literature.
Uterine angioleiomyoma is a rare type of leiomyoma variant and there are few cases reported in the literature. The definitive diagnosis is usually obtained only after the histopathologic examination because there are no specific imaging criteria for this disease. The objective of this article is to review published cases about this clinical condition. We report a case of giant angioleiomyoma superinfected by S. agalactiae with the development of latero-cervical distant metastasis in a premenopausal woman. Firstly, the case herein reported was orientated as an endometrial stroma sarcoma in the peri-operative histologic examination by frozen sections. It was treated with laparotomic total hysterectomy, bilateral salpingo-oophorectomy, inframesocolic omentectomy and pelvic and paraaortic lymph node dissection. Postoperative definitive anatomopathological analyses using a proper immunohistochemical panel revealed a case of uterine angioleiomyoma. We also review other case reports published about this clinical condition. We present the first case reported in the literature, in our knowledge, of a giant angioleiomyoma superinfected by S. agalactiae with the development of distant septic metastases. Immunohistochemistry permitted the definitive diagnosis of angioleiomyoma. Treatments previously reported are hysterectomy or tumor resection and any patient recurred. The definitive diagnosis is usually obtained after the definitive histopathologic examination since the use of immunohistochemical study has an important role in this regard. Complete surgical removal of the lesion is the treatment of choice, with no recurrent cases reported to date.


Acute geriatrics at the front door.
Older people with frailty and urgent care needs are major uses of health and social care services. Comprehensive geriatric assessment (CGA) is an evidence-based approach to improving their outcomes, as well as improving service outcomes. Geriatricians form a small proportion of the overall workforce and cannot address the population need alone, so all clinicians (doctors, nurses, therapists and so on) need to engage in delivering CGA as a process of care, underpinned by specific competencies - which can be developed. Delivery of this care pathway needs to be measured and improved as rigorously as campaigns like those for improving sepsis or eradicating methicillin-resistant Staphylococcus aureus.


Angiogenic growth factors and endostatin in non-Hodgkin's lymphoma.
A number of clinical studies have demonstrated the prognostic significance of angiogenesis and angiogenic growth factors in solid tumours; however, very little is known about the relevance of these parameters in haematological malignancies. We evaluated circulating levels of angiogenic growth factors and endostatin in 36 non-Hodgkin's lymphoma (NHL) patients. Baseline vascular endothelial growth factor (VEGF) levels of patients in complete remission (CR) after a median follow-up of 21 months were significantly lower than those of patients with progressive disease (P = 0.016). Event-free survival (EFS) rate was significantly higher in patients who had baseline VEGF and basic-fibroblast growth factor (b.FGF) levels below the median values of 147 and 19.5 pg/ml (P = 0.018 and 0.039 by log-rank test, respectively). Conversely, the levels of endostatin, angiogenin and leptin were not different in CR patients compared to relapsed patients and did not correlate with EFS. Our data suggest that b-FGF and, particularly, VEGF might be considered prognostic factors in NHL staging and management.


Prediction and rationalization of protein pKa values using QM and QM/MM methods.
We describe the development and application of a computational method for the prediction and rationalization of pKa values of ionizable residues in proteins, based on ab initio quantum mechanics (QM) and the effective fragment potential (EFPs) method (a hybrid QM/MM method). The theoretical developments include (1) a covalent boundary method based on frozen localized orbitals, (2) divide-and-conquer methods for the ab initio computation of protein EFPs consisting of multipoles up to octupoles and dipole polarizability tensors, (3) a method for computing vibrational free energies for a localized molecular region, and (4) solutions of the polarized continuum model of bulk solvation equations for protein-sized systems. The QM-based pKa prediction method is one of the most accurate methods currently available and can be used in cases where other pKa prediction methods fail. Preliminary analysis of the computed results indicate that many pKa values (1) are primarily determined by hydrogen bonds rather than long-range charge-charge interactions and (2) are relatively insensitive to large-scale dynamical fluctuations of the protein structure.


Plasma volume and estimated liver plasma flow during hyperbaric and hyperoxic exposures in awake dogs.
Five different experiments were conducted to determine if estimated liver plasma flow and/or plasma volume were changed as a result of exposure to 2.8 atmospheres absolute (ATA) while breathing 100% oxygen or 6 ATA while breathing compressed air. The experiments were designed to separate the relative roles of the ambient pressure, the partial pressure of oxygen, the time of high oxygen exposure or some combination of these factors on any observed changes. We found that time was not a factor in the changes seen. Hyperbaria resulted in a decrease in estimated liver plasma flow at all pressures greater than 1 ATA. There was an apparent increase in plasma volume at 1.3 ATA and a return towards 1 ATA values at higher pressures. Hyperoxia resulted in a decrease in estimated liver plasma flow at 975 mm Hg but not at 912 mm Hg. The flow was then increased again at 2128 mm Hg. Plasma volume decreased significantly at 912 mm Hg returned to baseline (152 mm Hg) values at 975 mm Hg and then decreased again at 1054 and 2128 mm Hg PO2.


Quick and simple evaluation of sudomotor function for screening of diabetic neuropathy.
Objective. The aim of this study was to compare SUDOSCAN, a new device to evaluate sweat function (reflecting peripheral small C-fiber status), with conventional measures of peripheral and cardiac neuropathy in patients with type 2 diabetes. Methods. 265 diabetic patients were tested for symptoms and clinical signs of neuropathy using Michigan Neuropathy Screening Instrument (MNSI), vibration perception threshold (VPT) using biothesiometer, and cardiac autonomic neuropathy (CAN) using Ewing's protocol. Sudomotor function was investigated with SUDOSCAN through measurement of electrochemical skin conductance (ESC) of hands and feet. Lower ESC is suggestive of sudomotor dysfunction. Results. Lower ESC at feet was significantly associated both with increasing symptoms (MNSI A) and increasing score on physical abnormalities (MNSI B). Lower ESC at feet was also significantly associated with increasing VPT by biothesiometry (P < 0.01), and with higher number of abnormal CAN results (P < 0.05). ESC was associated with postural fall in blood pressure (sympathetic abnormality) (P < 0.05), but not with heart rate variability (HRV) tests (parasympathetic abnormalities). Conclusions. Sudomotor dysfunction testing may be a simple test to alert physicians to peripheral nerve and cardiac sympathetic dysfunction. Ease of performance could make it useful in a busy diabetic clinic. Further studies with hard clinical outcomes are indicated.


Metal ion-assisted drug-loading model for novel delivery system of cisplatin solid lipid nanoparticles with improving loading efficiency and sustained release.
Metal ion-assisted drug loading model, in which metal ion was used to modify the microstructure of lipid layer, has been developed to improve drug loading efficiency of solid lipid nanoparticles (SLNs). The microstructure and properties of metal ion-assisted cisplatin-loading SLNs were investigated by infra-red spectroscopy, fluorescence spectroscopy and zetasizer. The reactions of hydrogenated soybean lecithin with Zn(2+), Cu(2+), Mn(2+ )and Mg(2+ )have been detected; the mechanism for higher drug encapsulation efficiency (EE) has been investigated. In metal ion introduction SLNs, the compact degree of the lipid molecules was increased due to the electrostatic interaction between metal ions and phospholipid acyl and choline polarity groups, which result in increasing of drug EE. Meanwhile, these electrostatic interactions slowed the releasing rate of encapsulated drug. The study of cytotoxic activity in vitro indicated that the cell cytotoxicity of metal ions introduction SLNs depended on both cell uptake of SLNs and drug releasing from SLNs.


Evolution of p53 in hypoxia-stressed Spalax mimics human tumor mutation.
The tumor suppressor gene p53 controls cellular response to a variety of stress conditions, including DNA damage and hypoxia, leading to growth arrest and/or apoptosis. Inactivation of p53, found in 40-50% of human cancers, confers selective advantage under hypoxic microenvironment during tumor progression. The mole rat, Spalax, spends its entire life cycle underground at decidedly lower oxygen tensions than any other mammal studied. Because a wide range of respiratory adaptations to hypoxic stress evolved in Spalax, we speculated that it might also have developed hypoxia adaptation mechanisms analogous to the genetic/epigenetic alterations acquired during tumor progression. Comparing Spalax with human and mouse p53 revealed an arginine (R) to lysine (K) substitution in Spalax (Arg-174 in human) in the DNA-binding domain, identical to known tumor associated mutations. Multiple p53 sequence alignments with 41 additional species confirmed that Arg-174 is highly conserved. Reporter assays uncovered that Spalax p53 protein is unable to induce apoptosis-regulating target genes, resulting in no expression of apaf1 and partial expression of puma, pten, and noxa. However, cell cycle arrest and p53 stabilization/homeostasis genes were overactivated by Spalax p53. Lys-174 was found critical for apaf1 expression inactivation. A DNA-free p53 structure model predicts that Arg-174 is important for dimerization, whereas Spalax Lys-174 prevents such interactions. Similar neighboring mutations found in human tumors favor growth arrest rather than apoptosis. We hypothesize that, in an analogy with human tumor progression, Spalax underwent remarkable adaptive p53 evolution during 40 million years of underground hypoxic life.


Racial disparities in term induction of labor rates in Illinois.
To determine whether the increase in the rate of labor induction at term is significantly different among women of different races. Data from the National Center for Health Statistics were used to identify pregnant women with singletons at 37-41 weeks gestation from 1991 to 2003 in Illinois. The independent association between the induction rate at term and maternal race was evaluated using longitudinal regression. Covariates considered were maternal demographic and obstetrical characteristics; those that changed the estimated association between race and induction of labor by at least 20% were included in the final model. The mean annual induction rates rose significantly during the study period both for the entire population and for each racial group. After adjusting for maternal demographic characteristics, obstetrical risk factors for medically-indicated induction, and for county-level malpractice premium charges, each 1% increase in the proportion of the white and non-white/non-African American populations within a county was associated with significantly higher induction rates (74% and 92%, respectively) in the county. Although induction rates have increased for all women, the rate of rise has increased disproportionately among women of non-African American race.


Development of ionized hypomagnesemia is associated with higher mortality rates.
Previous studies have shown a wide variation in the prevalence of total serum hypomagnesemia in intensive are unit (ICU) patients and in associated mortality rates. As the ionized part of magnesium is the active portion, we sought to define the prevalence of ionized hypomagnesemia in critically ill patients and to evaluate its relationship with organ dysfunction, length of stay, and mortality. Prospective observational study. A 31-bed, medical-surgical, university hospital ICU. A total of 446 consecutive patients admitted to the ICU over a 3-month period. None. The ionized magnesium level (normal value, 0.42-0.59 mmol/L) was measured at admission and then every day until discharge from the ICU. At admission, 18% of patients had ionized hypomagnesemia, 68% had normal ionized magnesium levels, and 14% had ionized hypermagnesemia. There was no significant difference in the length of stay or in the mortality rate between these three groups of patients. Hypomagnesemic patients more frequently had total and ionized hypocalcemia, hypokalemia, and hypoproteinemia. A total of 23 patients developed ionized hypomagnesemia during their ICU stay; these patients had higher Acute Physiology And Chronic Health Evaluation II (14.9 +/- 5.4 vs. 11.0 +/- 6.2) and Sequential Organ Failure Assessment (SOFA; 7.1 +/- 5.4 vs. 3.9 +/- 2.8) scores at admission (p <.01 for both), a higher maximum SOFA score during their ICU stay (10.0 +/- 5.6 vs. 4.4 +/- 3.2, p <.01), a higher prevalence of severe sepsis and septic shock (57 vs. 11%, p <.01), a longer ICU stay (15.4 +/- 15.5 vs. 2.8 +/- 4.7 days, p <.01), and a higher mortality rate (35% vs. 12%, p <.01) than the other patients. The major risk factors for developing hypomagnesemia during the ICU stay were a prolonged ICU stay, treatment with diuretics, and sepsis. Development of ionized hypomagnesemia during an ICU stay is associated with a worse prognosis. It is often associated with the use of diuretics and the development of sepsis. Monitoring of ionized magnesium levels may have prognostic, and perhaps therapeutic, implications.


Antigen-specific antibody response in juvenile-onset SLE patients following routine immunization with tetanus toxoid.
Infection is now the most common cause of morbidity in Systemic Lupus Erythematosus (SLE). There is lack of information regarding the specific antibody formation in response to vaccines in young SLE patients. To determine the efficacy of anti-tetanus antibody response in young patients with SLE. Forty SLE patients with mean age of 14.1 years (range: 7-21) and 60 age and sex matched normal controls were enrolled in this study over a period of one year. Diagnosis was made according to the ACR criteria and disease activity was determined based on SLE Disease Activity Index (SLEDAI). All patients and controls had received the complete schedule of tetanus vaccinations consisting of three primary doses and two boosters by the age of six. Serum immunoglobulins and anti-tetanus antibody titers were determined by Nephelometry and ELISA. Anti-tetanus antibody levels greater than 0.1 IU/ml have been suggested as protective. In all of the patients and controls anti-tetanus antibody titer was > 0.1 IU/ml. IgG, IgA, and IgM levels were in the normal range for their age. Mean disease activity score was 4.9 (range: 0-16). There was no association between SLEDAI score and anti-tetanus antibody response. School age onset and immunosuppressive therapy does not seem to interfere with development of consistent immunity to tetanus vaccine in young SLE patients.


Day and night changes in energy expenditure of patients on automated peritoneal dialysis.
Automated peritoneal dialysis (APD) treatment for end-stage kidney disease affords patients a degree of autonomy in everyday life. Clinical investigations of their energy expenditure (EE) are usually based on resting EE, which could mask day and night variations in EE. The aim of this study, therefore, was to compare the components of EE in APD patients and healthy control (C) subjects. Patients treated with APD for more than 3 months were compared with C volunteers matched for age and lean body mass (LBM). Biochemical analyses were performed and body composition was determined by DEXA to adjust EE to LBM. Total EE, its different components and respiratory quotients (RQ) were measured by a gas exchange method in calorimetric chambers. Spontaneous total and activity-related EE (AEE) were also measured in free-living conditions over 4 days by a calibrated accelerometer and a heart rate monitor. APD (n = 7) and C (n = 7) patients did not differ in age and body composition. REE did not differ between the two groups. However, prandial increase in EE adjusted for dietary energy intake was higher in APD patients (+57.5 ± 12.71 kcal/h) than in C subjects (+33.8 ± 10.5 kcal/h, p = 0.003) and nocturnal decrease in EE tended to be lower in APD patients undergoing dialysis sessions (- 4.53 ± 8.37 kcal/h) than in subjects (- 11.8 ± 7.69 kcal/h, p = 0.059). Resting RQ (0.91 ± 0.09 vs 0.81 ± 0.04, p = 0.032) and nocturnal RQ (0.91 ± 0.09 vs 0.81 ± 0.04, p = 0.032) were significantly higher in APD patients, indicating a preferential use of glucose substrate potentially absorbed across the peritoneum. AEE was lower in APD patients (595.9 ± 383.2 kcal/d) than in C subjects (1205.2 ± 370.5 kcal/d, p = 0.011). In contrast, energy intakes were not significantly different (1986 ± 465 vs 2083 ± 377 kcal/d, p = 0.677). Although the two groups had identical resting EE, APD patients had a higher prandial increase in EE, a lower activity-related EE and higher resting and nocturnal RQ than healthy subjects.


[Recent advances in neuropsychopharmacology of the central histaminergic neuron system].
Recent immunohistochemical studies have shown the distribution of histaminergic neurons in the mammalian brain, which are concentrated in the tuberomammillary nucleus of the posterior hypothalamus and project efferent fibers to almost all parts of the brain from the olfactory bulb to the spinal cord. Histaminergic neurons co-express other neuroactive substances, such as gamma-aminobutyric acid, adenosine, substance P, galanin and Met-enkephalin-Arg-Phe. In addition, pharmacological studies have demonstrated the presence of presynaptic histamine H3-receptors (autoreceptor) in addition to H1- and H2-receptors. The specific agonist (alpha-methylhistamine) and antagonist (thioperamide) of H3-receptors were developed. Results from a number of studies indicate a variety of physiological roles of neuronal histamine such as thermoregulation, feeding behavior, sexual activity, sleep-wakefulness cycle, hormonal regulation and so on. Moreover, histaminergic drugs affect not only the emotional behavior, but also are effective to treat some patients of depression, Parkinson's disease, akathisia, motion sickness and so on. The central histaminergic neuron system is also affected by mental disorders and neuropsychopharmacological drugs. This review especially focused on these points and suggests that the central histaminergic neuron system may play an important role in the regulation of mental functions.


Sad Dads and Troubled Tots: Protective Factors Related to the Stability of Paternal Depression and Early Childhood Internalizing Problems.
The present study tested the moderating role of interparental relationship quality and child inhibitory control on the stability of paternal depression over time and associations between paternal depression and child internalizing problems in early childhood. Participants were a subsample (n = 166) of families from the Early Steps Multisite study, a longitudinal study of low-income parents and children. Interparental relationship quality (age 2) attenuated the association between paternal depressive symptoms at age 2 and paternal depressive symptoms at age 3. Both interparental relationship quality (age 3) and child inhibitory control (age 3) attenuated the association between paternal depressive symptoms (age 3) and age 4 child internalizing problems. Results suggest that high interparental relationship quality may be a protective factor in terms of lessening the stability of paternal depressive symptoms over time, as well as the association between paternal depression and later child internalizing problems. Similarly, high levels of inhibitory control may buffer children from the negative effects of paternal depression on the development of internalizing problems.


The United States and Canada as a coupled epidemiological system: an example from hepatitis A.
Hepatitis A (HA) is a low-incidence, non-endemic disease in Canada and the United States (US). However, a large difference in HA incidence between Canada and HA-endemic countries has made travel an important contributor to hepatitis A prevalence in Canada. There is also a (smaller) incidence differential between Canada and the US. Although the US has only moderately higher HA incidence, the volume of travel by Canadians to the US is many times higher than travel volume to endemic countries. Hence, travel to the US may constitute a source of low to moderate risk for Canadian travelers. To our knowledge, travel to the US has never been included as a potential risk factor for HA infection in Canadian epidemiologic analyses. The objective of this study was to use dynamic models to investigate the possible effects on hepatitis A incidence in Canada due to (1) implementing vaccination in the US, and (2) varying the volume of travel by Canadians to the US. We developed and analyzed age-structured compartmental models for the transmission and vaccination of hepatitis A, for both Canada and the US. Models were parameterized using data on seroprevalence, case reporting, and travel patterns. The potential effect of hepatitis A prevalence in the US on hepatitis A prevalence in Canada was captured through a term representing infection of Canadians due to travel in the US. The model suggests that approximately 22% of HA cases in Canada in the mid 1990s may have been attributable to travel to the US. A universal vaccination programme that attained 70% coverage in young children in the US in the mid 1990s could have reduced Canadian incidence by 21% within 5 years. Since not all necessary data were available to parameterize the model, the results should be considered exploratory. However, the analysis shows that, under plausible assumptions, the US may be more important for determining HA prevalence in Canada than is currently supposed. As international travel continues to grow, making vaccination policies ever more relevant to populations beyond a country's borders, such multi-country models will most likely come into wider use as predictive aids for policy development.


Picocyanobacteria Community and Cyanophage Infection Responses to Nutrient Enrichment in a Mesocosms Experiment in Oligotrophic Waters.
Prochlorococcus and Synechococcus are pico-sized cyanobacteria that play a fundamental role in oceanic primary production, being particularly important in warm, nutrient-poor waters. Their potential response to nutrient enrichment is expected to be contrasting and to differ from larger phytoplankton species. Here, we used a metagenomic approach to characterize the responses to nutrient enrichment in the community of picocyanobacteria and to analyze the cyanophage response during a mesocosms experiment in the oligotrophic Red Sea. Natural picoplankton community was dominated by Synechococcus clade II, with marginal presence of Prochlorococcus (0.3% bacterial reads). Increased nutrient input triggered a fast Synechococcus bloom, with clade II being the dominant, with no response of Prochlorococcus growth. The largest bloom developed in the mesocosms receiving a single initial input of nutrients, instead of daily additions. The relative abundances of cyanophage sequences in cellular metagenomes increased during the experiment from 12.6% of total virus reads up to 40% in the treatment with the largest Synechococcus bloom. The subsequent collapse of the bloom pointed to a cyanophage infection on Synechococcus that reduced its competitive capacity, and was then followed by a diatom bloom. The cyanophage attack appears to have preferentially affected the most abundant Synechococcus clade II, increasing the evenness within the host population. Our results highlight the relevance of host-phage interactions on determining population dynamics and diversity of Synechococcus populations.


The Accuracy of Nurses' Predictions for Clinical Outcomes in the Chronically Critically Ill.
Accurately predicting survivorship of patients in the intensive care unit is known to be difficult. Previous research has shown that nurses are more likely to recognize futile medical care than other disciplines. The purpose of this study was to describe the accuracy of nurse's predictions for survival of patients who are chronically critically ill (CCI). Using a secondary data analysis from a longitudinal, descriptive study, we evaluated nurses' predictions for survival at admission and until ICU discharge or patient death. Nurses were able to more accurately predict survival of CCI patients than death and prognostication appeared to improve with prolonged ICU stays. This is the first longitudinal study that focused on nurse prognostication in a chronically critically ill patient population. Future research should explore the relationship between ICU nurse characteristics and the accuracy of survival predictions.


Large anomalous Nernst effect and nodal plane in an iron-based kagome ferromagnet.
Anomalous Nernst effect (ANE), converting a heat flow to transverse electric voltage, originates from the Berry phase of electronic wave function near the Fermi energy EF. Thus, the ANE provides a sensitive probe to detect a topological state that produces large Berry curvature. In addition, a magnet that exhibits a large ANE using low-cost and safe elements will be useful to develop a novel energy harvesting technology. Here, we report our observation of a high ANE exceeding 3 microvolts per kelvin above room temperature in the kagome ferromagnet Fe3Sn with the Curie temperature of 760 kelvin. Our theoretical analysis clarifies that a "nodal plane" produces a flat hexagonal frame with strongly enhanced Berry curvature, resulting in the large ANE. Our discovery of the large ANE in Fe3Sn opens the path for the previously unexplored functionality of flat degenerate electronic states and for developing flexible film thermopile and heat current sensors.


Effect of alpha range activity on SSVEP decoding in brain-computer interfaces.
Brain-computer interfaces (BCIs) facilitate direct communication between the brain and external devices. For BCI technology to be commercialized for wide scale applications, BCIs should be accurate, efficient, and exhibit consistency in performance for a wide variety of users. A core challenge is the physiological and anatomical differences amongst people, which causes a high variability amongst participants in BCI studies. Hence, it becomes necessary to analyze the mechanisms causing this variability and address them by improving the decoding algorithms. In this paper, a publicly available steady-state visual evoked potential (SSVEP) dataset is analyzed to study the effect of SSVEP flicker on the endogenous alpha power and the subsequent overall effect on the classification accuracy of the participants. It was observed that the participants with classification accuracy below 95% showed increased alpha power in their brain activities. Incorrect prediction in the decoding algorithm was observed a maximum number of times when the predicted frequency was in the range 9-12 Hz. We conclude that frequencies between 9-12 Hz may result in below par performance in some participants when canonical correlation analysis is used for classification.Clinical relevance-If alpha-band frequencies are used for SSVEP stimulation, alpha power interference in EEG may alter BCI accuracy for some users.


Helicobacter pylori induces antiapoptosis through buclear factor-kappaB activation.
Although Helicobacter pylori is classified as a definite carcinogen, the mechanism underlying gastric carcinogenesis is not yet clear. We previously have shown that H. pylori activates an antiapoptotic gene, the cellular inhibitor of apoptosis protein 2 (c-IAP2), the underlying mechanism of which was investigated in the present study. cDNA array and real-time PCR analyses indicated that H. pylori showed a stimulatory effect on the expression of c-IAP2. Isogenic mutant strains with impaired cag pathogenicity island (cagPAI) expression showed weaker induction. Analyses that used the in situ terminal deoxynucleotide transferase-mediated dUTP nick end-labeling method indicated suppression of antiapoptosis by the antisense c-IAP2 oligonucleotide. Reporter assays with deletion and mutation constructs for the c-IAP2 promoter showed that nuclear factor-kappaB (NF-kappaB) binding sites are indispensable for transactivation. Super-repressor IkappaBalpha or NF-kappaB inhibitor reduced c-IAP2 transactivation by H. pylori, and exogenous expression of c-IAP2 inhibited apoptosis seen with H. pylori. In conclusion, H. pylori induces antiapoptosis through c-IAP2 transactivation following cagPAI-dependent NF-kappaB activation. The interaction of these stimuli may play a role in gastric carcinogenesis.


The three-dimensional structure of an H-2Ld-peptide complex explains the unique interaction of Ld with beta-2 microglobulin and peptide.
Solution at 2.5-A resolution of the three-dimensional structure of H-2Ld with a single nine-residue peptide provides a structural basis for understanding its unique interaction with beta-2 microglobulin (beta2m) and peptide. Consistent with the biological data that show an unusually weak association of Ld with beta2m, a novel orientation of the alpha1/alpha2 domains of Ld relative to beta2m results in a dearth of productive contacts compared with other class I proteins. Characteristics of the Ld antigen-binding cleft determine the unique motif of peptides that it binds. Ld has no central anchor residue due to the presence of several bulky side chains in its mid-cleft region. Also, its cleft is significantly more hydrophobic than that of the other class I molecules for which structures are known, resulting in many fewer H-bonds between peptide and cleft residues. The choice of Pro as a consensus anchor at peptide position 2 appears to be related to the hydrophobicity of the B pocket, and to the unique occurrence of Ile (which mirrors Pro in its inability to form H-bonds) at position 63 on the edge of this pocket. Thus, the paucity of stabilizing H-bonds combined with poor complementarity between peptide postion 2 Pro and the B pocket contribute to the weak association between Ld and its peptide antigen. The unique structural interactions of Ld with beta2m and peptide could make Ld more suited than other classical class I molecules to play a role in alternative pathways of antigen presentation.


The impact of atypical early histories on pet or performer chimpanzees.
It is widely accepted that an animal's early history, including but not limited to its rearing history, can have a profound impact on later behavior. In the case of captive animals, many studies have used categorical measures such as mother reared or human reared that do not account for both the influence of human and conspecific interaction. In order to account for the influence of both human and conspecific early exposure to later behavior, we collected 1385 h of data on 60 chimpanzees, of which 36 were former pets or performers, currently housed at accredited zoos or sanctuaries. We developed a unique metric, the Chimpanzee-Human Interaction (CHI) Index that represented a continuous measure of the proportion of human and chimpanzee exposure subjects experienced and here focused on their exposure during the first four years of life. We found that chimpanzees who experienced less exposure to other chimpanzees as infants showed a lower frequency of grooming and sexual behaviors later in life which can influence social dynamics within groups. We also found chimpanzees who experienced more exposure to other chimpanzees as infants showed a higher frequency of coprophagy, suggesting coprophagy could be a socially-learned behavior. These results help characterize some of the long-term effects borne by chimpanzees maintained as pets and performers and may help inform managers seeking to integrate these types of chimpanzees into larger social groups, as in zoos and sanctuaries. In addition, these results highlight the necessity of taking into account the time-weighted influence of human and conspecific interactions when assessing the impact that humans can have on animals living in captivity.


Facilitating Open Pit Mine Closure with Managed Aquifer Recharge.
Dewatering of open pit mines can lower the regional water table for distances of several kilometers from the pit. When the mine is closed, dewatering operations usually cease, and the water table near the pit begins to rise. If the pit is backfilled, the water table will eventually recover, but this recovery may take several hundred years. However, if the extracted water is re-injected into the subsurface, then this may accelerate recovery of the water table. We show that there is an optimal distance for re-injection, which is sufficiently far from the mine to minimize the amount of groundwater that flows back to the pit during mine operations (and hence necessitate additional pumping) but is still close enough to speed up the water table recovery post-mine closure. The optimal injection distance increases with the aquifer hydraulic diffusivity and the mine life (duration of dewatering and injection), and typically ranges between about two and nine times the radius of the mine pit. Where the mine pit is not backfilled, the relative reduction in drawdown due to injecting all the pumped water at the optimal distance is between approximately 10% and 50% after a recovery time equal to the mining period, increasing to 30% to 90% after a recovery time five times the mining period. The relative drawdown reduction due to managed aquifer recharge will be even greater for a pit which is backfilled when mining ceases.


May "Dubel" be a solution for pullout problem of the pedicle screws at osteoporotic spine?
To improve the strength of stabilization systems currently used in osteoporotic spinal fractures, essentially by increasing the fixation force of pedicle screws. Six human cadaveric vertebrae were used. Bone mineral densities of the specimens were measured with Dual Energy X-ray Absorptiometry in order to assess the osteoporosis. All vertebrae were found to be severely osteoporotic. Standard pedicle screws were applied to left pedicles of vertebrae. Pedicle screws reinforced by fixing plugs "Dubel" were applied to right pedicles of vertebrae. Afterwards the vertebrae were embedded in acrylic casts to prevent possible fracture of the osteoporotic vertebrae and to obtain a correct vertical pull-out vector. The biomechanical pullout tests were performed with biomechanical testing machine. Pullout forces in each group were recorded and compared with Mann-Whitney U test. The pedicle screws strengthened by "Dubel" were found to be four times stronger than the standard pedicle screws, in the osteoporotic human cadaveric vertebrae. "Dubel"-augmented pedicle screws may contribute to developing better stabilization systems for osteoporotic thoracolumbar fractures needing surgery and in the revision of the previous fusion surgeries of the spine.


Auto-oxidation promoted sp3 C-H arylation of glycine derivatives.
An auto-oxidation promoted sp3 C-H arylation reaction between N-aryl glycine derivatives and electron-rich arenes, leading to the formation of N-aryl α-aryl α-amino acid derivatives, is described. This atom-economical and environmentally benign reaction proceeds smoothly under mild reaction conditions and requires only Brønsted acid and oxygen (balloon). A plausible radical involved mechanism is proposed.


Isolation of mononuclear cells from bovine milk by continuous-flow and density gradient centrifugation: response of cells to mitogens.
Continuous-flow centrifugation (CFC) and 2 types of discontinuous density gradients (Ficoll-diatrizoate or polyvinylpyrrolidone-coated colloidal silica) were used to obtain bovine mononuclear cells from milk. Determinants considered were efficiency of cell recovery, cell viability, and functional activity of the enriched cell population in a lymphocyte blastogenesis (LBT) assay. Milk leukocytes were recovered by CFC with an efficiency of 46% and a viability of 63%. Selective loss of a cell population due to CFC was not observed. Using density gradients, enrichment was marginally effective (73% mononuclear cells with polyvinylpyrrolidone-coated colloidal silica and 82% mononuclear cells with Ficoll-diatrizoate) and overall mononuclear cell efficiency of recovery was reduced. In comparison, using either density gradient, blood mononuclear cells were harvested with efficiencies of 61.5% and 63.4%, with 85.6% and 89.3% viability and greater than 99% purity. Compared with peripheral blood lymphocytes, milk mononuclear cells were less viable. When evaluated using the LBT assay, milk mononuclear cells were hyporesponsive to mitogenic stimulation, regardless of the density gradient used. The methods used allowed for the collection of a sufficient number of nonelicited milk mononuclear cells for replicate evaluation of several mitogens or antigens, using the LBT assay. Mononuclear cells recovered had a consistently reproducible blastogenic response to T-cell mitogens.


Is there a common definition for massive pleurisy?
The concept of massive pleurisy (MP) is frequently used to emphasize the significance of the amount of pleural effusion. However, there are significant disagreements about it due to the lack of a universal definition for MP. In our study, we sought to elucidate these distinctions. We employed a questionnaire comprised of visual and true/false sections. In the visual section, participants were shown real-time lung radiographs and schematic drawings and asked which ones were MP. On the other hand, suggestions regarding diagnosis, treatment, and consultations for MP were questionnaired. The study was comprised of 150 physicians from four distinct centers. On true/false and radiograph questions, physicians from the same branch exhibited differences of up to 50% (p < 0.05). On the level question, each branch involved reached a consensus (p = 0.003). In questions 3, 4, and 5, which also contained a true-false section, the branches gave varying responses, with the exception of the opinion that tube thoracostomy is unquestionably indicated in MP (p < 0.05). Establishing a common language for MP is crucial for clinician collaboration and appropriate patient management. Our study elucidates the divergences of opinion between branches and highlights the need for a unified definition.


Specialisation of thymic epithelial cells for positive selection of CD4+8+ thymocytes.
Following their migration into the thymus, hemopoeitic stem cell precursors enter a complex developmental pathway involving proliferation, differentiation and alphabetaT-cell receptor (alphabetaTCR)-mediated selection procedures, in order to generate mature T-cell populations ready for export to the periphery. Thus, a critical stage during intrathymic T-cell development involves the generation of functionally mature CD4+8- and CD4-8+ cells from immature CD4+8- precursor thymocytes, a poorly understood process referred to as positive selection. While interactions between the alphabetaTCR and MHC-peptide complexes are known to be essential for the initiation of positive selection, additional unknown signals are also required. Using an in vitro reaggregate thymic organ culture system which allows comparison of the abilities of various cell types to induce maturation of CD4+8+ precursors, we provide evidence that both MHC-peptide complexes and specialised accessory molecules must be provided by thymic epithelium for efficient mediation of positive selection. Moreover, analysis of positive selection in the presence of thymic and non-thymic stromal cells expressing MHC class II molecules with the same limited peptide array suggests that this unique ability of thymic epithelium to mediate positive selection of CD4+8- cells is not solely due to presentation of a specialised peptide repertoire, but is dependent upon provision of specialised accessory interactions.


Effectiveness of cervical hemilaminectomy in canine Hansen Type I and Type II disc disease: a retrospective study.
Medical records of 41 dogs, including 15 small breed dogs (<15 kg) and 26 large breed dogs (>15 kg), with cervical intervertebral disc disease (IVDD) that underwent a hemilaminectomy were reviewed. Dogs were diagnosed using myelography, computed tomography/myelography, or MRI, and dogs were classified as having either Hansen Type I disc extrusion or Hansen Type II disc protrusion located ventrally, ventrolaterally, or laterally within the cervical spinal canal. The most common clinical presentation was ambulatory tetraparesis and/or lameness (44%). The most affected sites for cervical IVDD were between the sixth and seventh cervical vertebrae (C6-C7; 78% of Hansen Type II discs) and C2-C3 (86% of Hansen Type I discs). Treatment was effective in 88% of dogs. Five large breed dogs (12%) did not improve. In dogs with a Hansen Type I disc extrusion, clinical signs improved in 96% of the cases. In dogs with a Hansen Type II disc protrusion, an excellent and good outcome was seen in 47% and 32% of cases, respectively. Outcome was significantly better for small breed dogs and dogs with Hansen Type I disc disease compared with large breed dogs and dogs with Hansen Type II disc disease.


Physicochemical and sensory evaluation of biscuits enriched with chicory fiber.
Nowadays, there has been increasing interest of using the chicory and its constituents in food production. The aim of this study was to compare physicochemical and sensory parameters of biscuits without (control) and with addition of 1, 3, and 5% of chicory fiber extract. The biscuits were subjected to physical (volume, maximum width, maximum height, aspect ratio at max. width, aspect ratio at max. height), chemical (dry matter content, crude protein, ash, fat, and crude fiber content), and sensory evaluation (flavor, chicory flavor (intensity), chicory flavor (presence), taste, chicory taste (presence), chicory taste (intensity), aftertaste, character of biscuit taste, overall acceptability). The volume, width, and height of biscuit increased after addition of chicory fiber extract and the highest values were obtained after enrichment with 5% of fiber extract. The crude protein content in biscuits increased from 6.76% (control) to 7.88% (5% of chicory fiber). Also the ash content increased from 0.68% (control) to 0.84% (5%) and the crude fiber content from 0.51% (control) to 0.56% (5%), respectively. Fat content was similar in all tested biscuit (∼24%). During the sensory evaluation, the highest scores were received with addition of 1 and 3% chicory fiber extract. We can recommend the application of chicory fiber in production of biscuits to improve nutritional (3 and 5% addition) and sensorial properties (1 and 3% addition) of this bakery product.


Toxicologic Pathology Forum*: Opinion on Considerations for the Use of Whole Slide Images in GLP Pathology Peer Review.
Whole slide imaging (WSI) technology has advanced to a point where it has replaced the glass slide as the primary means of pathology evaluation within many areas of medical pathology. The deployment of WSI in the field of toxicologic pathology has been delayed by a lack of clarity around the degree of validation required for its use on Good Laboratory Practice (GLP) studies. The current opinion piece attempts to provide a high-level overview of WSI technology to include basic methodology, advantages and disadvantages over a conventional microscope, validation status of WSI scanners, and perceived concerns over regulatory acceptance for the use of WSI for (GLP) peer review in the field of toxicologic pathology. Observations are based on the extensive use by AstraZeneca of WSI for the peer review of non-GLP studies conducted at Charles River facilities and represent the experiences of the authors. Note: This is an opinion article submitted to the Toxicologic Pathology Forum. It represents the views of the author(s). It does not constitute an official position of the Society of Toxicologic Pathology, British Society of Toxicological Pathology, or European Society of Toxicologic Pathology, and the views expressed might not reflect the best practices recommended by these Societies. This article should not be construed to represent the policies, positions, or opinions of their respective organizations, employers, or regulatory agencies.


Partially Reversible Acute Renal Cortical Necrosis Secondary to Hyperhomocysteinemia - A Case Report and Literature Review.
Acute renal cortical necrosis (ACN) is a potentially fatal renal condition. Our objective is to report a case of ACN in a young man who had developed premature atherosclerotic vascular disease and required intermittent hemodialysis support. His renal biopsy showed diffuse cortical necrosis. Subsequently, 2 weeks after the renal insult, he developed a cardioembolic stroke and was anticoagulated with low-molecular-weight heparin. Thrombophilia screen revealed elevated serum homocystein and he was treated with folate supplement and vitamin B12 injection. With these treatments, he had partial renal recovery and became dialysis independent. In conclusion, this is a rare case of ACN, which may have occurred as a complication of hyperhomocysteinemia.


Sensitivity of Individual and Composite Test Scores from the Cogstate Brief Battery to Mild Cognitive Impairment and Dementia Due to Alzheimer's Disease.
The Cogstate Brief Battery (CBB) is a computerized cognitive test battery used commonly to identify cognitive deficits related to Alzheimer's disease (AD). However, AD and normative samples used to understand the sensitivity of the CBB to AD in the clinic have been limited, as have the outcome measures studied. This study investigated the sensitivity of CBB outcomes, including potential composite scores, to cognitive impairment in mild cognitive impairment (MCI) and dementia due to AD, in carefully selected samples. Samples consisted of 4,871 cognitively unimpaired adults and 184 adults who met clinical criteria for MCI (Clinical Dementia Rating (CDR) = 0.5) or dementia (CDR > 0.5) due to AD and CBB naive. Speed and accuracy measures from each test were examined, and theoretically- and statistically-derived composites were created. Sensitivity and specificity of classification of cognitive impairment were compared between outcomes. Individual CBB measures of learning and working memory showed high discriminability for AD-related cognitive impairment for CDR 0.5 (AUCs ∼ 0.79-0.88), and CDR > 0.5 (AUCs ∼ 0.89-0.96) groups. Discrimination ability for theoretically derived CBB composite measures was high, particularly for the Learning and Working Memory (LWM) composite (CDR 0.5 AUC = 0.90, CDR > 0.5 AUC = 0.97). As expected, statistically optimized linear composite measures showed strong discrimination abilities albeit similar to the LWM composite. In older adults, the CBB is effective for discriminating cognitive impairment due to MCI or AD-dementia from unimpaired cognition with the LWM composite providing the strongest sensitivity.


Three unusual cases where cardiopulmonary bypass was used in thoracic surgery.
Cardiopulmonary bypass (CPB) is a technique which is commonly performed without any problem in cardiac surgery. CPB can also be used in patients with a tumoral mass adherent to the great vessels, in patients with critically narrowed airway, if cross-table intubation of the distal trachea is not feasible and in patients necessitating re-do surgery with extensive adhesions because it allows extensive mobilization of the heart and great vessels without compromising their function. It also allowed the central pulmonary artery to be controlled without comprising oxygenation and complete resection of a tumor localized in the A-P window. Herein we report such patients operated with CPB without any problem.