Postarrival Tuberculosis Screening of High-Risk Immigrants at a Local Health Department.
We sought to characterize postimmigration tuberculosis (TB) care for Class B immigrants and refugees at the Baltimore City Health Department TB program (BCHD), and to determine the proportion of immigrants with active TB or latent TB infection (LTBI) in this high-risk population. We conducted a retrospective chart review of Class B immigrants and refugees who reported to the BCHD for postimmigration TB evaluation from 2010 to 2012. We reviewed the clinical records of 153 Class B immigrants; 4% were diagnosed with active TB and 53% were diagnosed with LTBI. Fifty percent of active TB cases were culture positive, and 67% were asymptomatic; 100% received and completed active TB therapy at the BCHD. Among those diagnosed with LTBI, 87% initiated LTBI therapy and 91% completed treatment. The high prevalence of active TB and LTBI found among Class B immigrants underscore the importance for postarrival TB screening. The absence of reported symptoms among the majority of active cases identified during this study suggest that reliance on symptom-based screening protocols to prompt sputa testing may be inadequate for identifying active TB among this high-risk group.


[Psychiatric reform and social inclusion for work].
This study aims at understanding the link among labor, mental distress, and psychosocial rehab from the point of view of people with either mental disorders or psychoactive substance addiction, regarding the meaning of laboring in their lives. The study took place in Psychosocial Attention Centers(CAPS), in the city of Goiânia, State of Goiás, Brazil. There were eight participants of both genders, who would consider labor something important in their daily lives. Two different types of data were used, as to mention, qualitative and exploratory methodology, by means of a focal group. The content analysis was used in evaluating the data provided. The results point at the importance of rescuing the history of labor among CAPS users. It is also of significance the profusion of meanings attributed to working by the users of mental health services. Labor proves to have an interface that is understood as a factor of protection and/or worsening of the condition of the subjects. The exclusion processes are reflected by the difficulty in obtaining social security/welfare benefits.


Fully Automated R-peak Detection Algorithm (FLORA) for fetal magnetoencephalographic data.
Fetal magnetoencephalography (fMEG) is a method for recording fetal brain signals, fetal and maternal heart activity simultaneously. The identification of the R-peaks of the heartbeats forms the basis for later heart rate (HR) and heart rate variability (HRV) analysis. The current procedure for the evaluation of fetal magnetocardiograms (fMCG) is either semi-automated evaluation using template matching (SATM) or Hilbert transformation algorithm (HTA). However, none of the methods available at present works reliable for all datasets. Our aim was to develop a unitary, responsive and fully automated R-peak detection algorithm (FLORA) that combines and enhances both of the methods used up to now. The evaluation of all methods on 55 datasets verifies that FLORA outperforms both of these methods as well as a combination of the two, which applies in particular to data of fetuses at earlier gestational age. The combined analysis shows that FLORA is capable of providing good, stable and reproducible results without manual intervention.


The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases.
We studied 26 patients belonging to 20 families with a disorder caused by mutations in the POLG gene. The patients were homozygous for 1399 G/A or 2243 G/C (giving the amino acid changes A467T and W748S, respectively) or compound heterozygotes for these two mutations. Irrespective of genotype, the patients exhibited a progressive neurological disorder usually starting in their teens and characterized by epilepsy, headache, ataxia, neuropathy, myoclonus and late onset ophthalmoplegia. However, major differences in survival were seen depending on genotype, with compound heterozygotes having a significantly shorter survival time than patients homozygous either for the A467T or W748S (P = 0.006). Epilepsy occurred in 22 of the 26 patients and in the majority of these there was an occipital EEG focus. Episodes of both generalized and focal motor status epilepticus were common and highly resistant to treatment, even with generalized anaesthesia. Status epilepticus was the recorded cause of death in 9 of 11 patients. Liver failure was the sole cause of death in two patients and evolved terminally in six others, all but one of whom were being treated with sodium valproate. Two patients underwent liver transplantation, but only one survived. Delayed psychomotor development and subsequent cognitive decline also occurs. This study demonstrates the clinical spectrum of a disorder that combines features of Alpers' syndrome and a later onset mitochondrial spinocerebellar ataxia with epilepsy and headache. Patients with this disorder are at high risk of death from status epilepticus and from liver failure, if exposed to sodium valproate. Each mutation appears capable of producing a disorder that is recessively inherited, although we also find evidence in one patient suggesting that heterozygotes may manifest. Compound heterozygotes have a significantly more severe phenotype raising the possibility of a dominant negative effect.


The illusion of owning a third arm.
Could it be possible that, in the not-so-distant future, we will be able to reshape the human body so as to have extra limbs? A third arm helping us out with the weekly shopping in the local grocery store, or an extra artificial limb assisting a paralysed person? Here we report a perceptual illusion in which a rubber right hand, placed beside the real hand in full view of the participant, is perceived as a supernumerary limb belonging to the participant's own body. This effect was supported by questionnaire data in conjunction with physiological evidence obtained from skin conductance responses when physically threatening either the rubber hand or the real one. In four well-controlled experiments, we demonstrate the minimal required conditions for the elicitation of this "supernumerary hand illusion". In the fifth, and final experiment, we show that the illusion reported here is qualitatively different from the traditional rubber hand illusion as it is characterised by less disownership of the real hand and a stronger feeling of having two right hands. These results suggest that the artificial hand 'borrows' some of the multisensory processes that represent the real hand, leading to duplication of touch and ownership of two right arms. This work represents a major advance because it challenges the traditional view of the gross morphology of the human body as a fundamental constraint on what we can come to experience as our physical self, by showing that the body representation can easily be updated to incorporate an additional limb.


Mobile phone use and the risk for malignant brain tumors: a case-control study on deceased cases and controls.
We investigated the use of mobile or cordless phones and the risk for malignant brain tumors in a group of deceased cases. Most previous studies have either left out deceased cases of brain tumors or matched them to living controls and therefore a study matching deceased cases to deceased controls is warranted. Recall error is one issue since it has been claimed that increased risks reported in some studies could be due to cases blaming mobile phones as a cause of the disease. This should be of less importance for deceased cases and if cancer controls are used. In this study brain tumor cases aged 20-80 years diagnosed during 1997-2003 that had died before inclusion in our previous studies on the same topic were included. Two control groups were used: one with controls that had died from another type of cancer than brain tumor and one with controls that had died from other diseases. Exposure was assessed by a questionnaire sent to the next-of-kin for both cases and controls. Replies were obtained for 346 (75%) cases, 343 (74%) cancer controls and 276 (60%) controls with other diseases. Use of mobile phones gave an increased risk, highest in the >10 years' latency group yielding odds ratio (OR) = 2.4, and 95% confidence interval (CI) = 1.4-4.1. The risk increased with cumulative number of lifetime hours for use, and was highest in the >2,000 h group (OR = 3.4, 95% CI = 1.6-7.1). No clear association was found for use of cordless phones, although OR = 1.7, 95% CI = 0.8-3.4 was found in the group with >2,000 h of cumulative use. This investigation confirmed our previous results of an association between mobile phone use and malignant brain tumors.


The introduction of an occupational health management system for solving issues in occupational health activities in Japan.
An important challenge to occupational health services in Japan is the necessary shift from regulation-based occupational health program to health risk-based program. The Occupational Safety and Health Management System (OSHMS) is an effective tool for introducing risk-based activities. To date, the Five Management system has been used to manage occupational health activities. This classification, however, does not show the interactions among the listed activities. Nor is it clear how this system contributes to the PDCA (Plan/Do/Check/Act) cycle for continual improvement. The category in the Five Management system called "Roles of the Occupational Physician" covers most of the occupational health services required in Japan. The items listed in the Five Management system were compared to the guidelines of OSHMS from the International Labour Office and issues that should be solved for occupational health activities with OSHMS were clarified. Seven issues are discussed in this paper; (1) occupational safety and health policy and audit that can drive the PDCA cycle effectively, (2) reclassification of occupational health activities with several different objectives, (3) set up of targets, (4) risk assessment methods that can prioritize health risks compared to safety risks, (5) exposure assessment methods for risk assessment, (6) flexibility of laws and regulations, and (7) development of talented professionals for risk-based occupational health activities.


A strong constitutive gene expression system derived from ibAGP1 promoter and its transit peptide.
To develop a strong constitutive gene expression system, the activities of ibAGP1 promoter and its transit peptide were investigated using transgenic Arabidopsis and a GUS reporter gene. The ibAGP1 promoter directed GUS expression in almost entire tissues including rosette leaf, inflorescence stem, inflorescence, cauline leaf and root, suggesting that the ibAGP1 promoter is a constitutive promoter. GUS expression mediated by ibAGP1 promoter was weaker than that by CaMV35S promoter in all tissue types, but when GUS protein was targeted to plastids with the aid of the ibAGP1 transit peptide, GUS levels increased to higher levels in lamina, petiole and cauline leaf compared to those produced by CaMV35S promoter. The enhancing effect of ibAGP1 transit peptide on the accumulation of foreign protein was tissue-specific; accumulation was high in lamina and inflorescence, but low in root and primary inflorescence stem. The transit peptide effect in the leaves was maintained highly regardless of developmental stages of plants. The ibAGP1 promoter and its transit peptide also directed strong GUS gene expression in transiently expressed tobacco leaves. These results suggest that the ibAGP1 promoter and its transit peptide are a strong constitutive foreign gene expression system for transgenesis of dicot plants.


"Am I a student or a Healthcare Assistant?" A qualitative evaluation of a programme of prenursing care experience.
To examine the experiences of prenursing healthcare assistants (HCA) during a 6-month programme of prenursing care experience. Care experience prior to commencing programmes of nurse education is broadly considered to be advantageous. However, it is not clear how formal care experience prior to nurse education has an impact on the values and behaviours of the aspirant nurse. A longitudinal prospective qualitative study using focus group discussions. Data were collected from 23 prenursing HCA during September 2013-February 2014. Three focus groups were held at the beginning, middle, and end of the programme of care experience at each of the participating hospitals. A thematic analysis was used to analyse data sets from each hospital. Findings from each hospital were then compared to reach final themes. Five major themes were identified in the analysis of qualitative data: personal development; positioning of role in the healthcare team; support and supervision; perceived benefits; and advice and recommendations. These themes were underpinned by deep aspirations for better care and better nurses in the future. Prenursing care experience can positively prepare aspirant nurses for programmes of nurse education. The benefits identified were confirmation of aspiration (or otherwise) to pursue nursing, learning opportunities, and aspiration to improve patient experience. Risks for the programme included poor supervision, role ambiguity or confusion, demotivation through a deteriorating view of nursing, and poor treatment by others. The longer term impact on values and behaviours of this cohort requires further evaluation.


Proximal femoral replacement for the treatment of periprosthetic fractures.
A periprosthetic fracture around the femoral component is a rare but potentially problematic complication after total hip arthroplasty. Reconstruction can be challenging, especially when severe bone stock deficiency is encountered. Proximal femoral replacement is one method of treating the severely deficient proximal part of the femur. The present report describes the outcomes of revision total hip arthroplasty with use of a proximal femoral replacement in a cohort of patients who had a Vancouver type-B3 periprosthetic fracture. With use of a computerized institutional database, all patients in whom a Vancouver type-B3 fracture (characterized by severe proximal bone deficiency and a loose femoral stem) had been treated with a proximal femoral replacement were identified. A modular femoral replacement with proximal porous coating had been used in all cases. The twenty-one patients who were identified had had a mean age of 78.3 years (range, fifty-two to ninety years) at the time of the index operation. The clinical and radiographic records of these patients were reviewed. At the time of the latest follow-up (mean, 3.2 years), all but one of the patients were able to walk and had minimal to no pain. Complications included persistent wound drainage that was treated with incision and drainage (two hips), dislocation (two hips), refracture of the femur distal to the stem (one hip), and acetabular cage failure (one hip). Despite a relatively high complication rate, we believe that proximal femoral replacement is a viable option for the treatment of periprosthetic fractures in older patients with severe bone deficiency. If a proximal femoral replacement is used, the stability of the hip must be tested diligently intraoperatively and a constrained acetabular liner should be utilized if instability is encountered. In order to enhance the bone stock, the proximal part of the femur, however poor in quality, should be retained for reapproximation onto the implant.


Rapid interactome profiling by massive sequencing.
We have developed a high-throughput protein expression and interaction analysis platform that combines cDNA phage display library selection and massive gene sequencing using the 454 platform. A phage display library of open reading frame (ORF) fragments was created from mRNA derived from different tissues. This was used to study the interaction network of the enzyme transglutaminase 2 (TG2), a multifunctional enzyme involved in the regulation of cell growth, differentiation and apoptosis, associated with many different pathologies. After two rounds of panning with TG2 we assayed the frequency of ORFs within the selected phage population using 454 sequencing. Ranking and analysis of more than 120,000 sequences allowed us to identify several potential interactors, which were subsequently confirmed in functional assays. Within the identified clones, three had been previously described as interacting proteins (fibronectin, SMOC1 and GSTO2), while all the others were new. When compared with standard systems, such as microtiter enzyme-linked immunosorbant assay, the method described here is dramatically faster and yields far more information about the interaction under study, allowing better characterization of complex systems. For example, in the case of fibronectin, it was possible to identify the specific domains involved in the interaction.


Quality of abstracts of original research articles in CMAJ in 1989.
To evaluate the quality of abstracts of original research articles. Blind, criterion-based survey. Systematic sample of 33 abstracts of original research articles published in CMAJ in 1989. The quality of abstracts was measured against a checklist of evaluation criteria, which were divided into eight categories. A score for each abstract was obtained by dividing the number of criteria present by the number applicable. The overall mean score was also determined. The overall mean score of abstract quality was 0.63 (standard deviation 0.13) out of 1. Of the abstracts reporting study design 56% did not include specific technical descriptors. About 52% did not explicitly describe the study variables. In describing subject selection 79% failed to use specific technical terms. Of the abstracts reporting results 66% did not provide appropriate supporting data. Of those that gave conclusions 86% did not address study limitations and 93% made no recommendations for future study. Most of the abstracts provided some information pertaining to each evaluation criterion but did not provide detail sufficient to enhance the reader's understanding of the article. On the basis of the study sample the abstracts need improvement in description of research design, reporting of subject selection and results, and statements of limitations and recommendations. The small sample from one journal and the absence of comparison between the contents of the abstracts and the contents of the articles were limitations. Future studies should address these issues and compare the quality of traditional and structured abstracts.


The low FODMAP diet in the management of irritable bowel syndrome: an evidence-based review of FODMAP restriction, reintroduction and personalisation in clinical practice.
Dietary restriction of fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) is effective in the management of functional gastrointestinal symptoms that occur in irritable bowel syndrome (IBS). Numerous reviews have been published regarding the evidence for their restriction in the low FODMAP diet; however, few reviews discuss the implementation of the low FODMAP diet in practice. The aim of this review is to provide practical guidance on patient assessment and the implementation and monitoring of the low FODMAP diet. Broadly speaking, the low FODMAP diet consists of three stages: FODMAP restriction; FODMAP reintroduction; and FODMAP personalisation. These stages can be covered in at least two dietetic appointments. The first appointment focuses on confirmation of diagnosis, comprehensive symptom and dietary assessment, detailed description of FODMAPs and their association with symptom induction, followed by counselling regarding FODMAP restriction. Dietary counselling should be tailored to individual needs and appropriate resources provided. At the second appointment, symptoms and diet are re-assessed and, if restriction has successfully reduced IBS symptoms, education is provided on FODMAP reintroduction to identify foods triggering symptoms. Following this, the patient can follow FODMAP personalisation for which a less restrictive diet is consumed that excludes their personal FODMAP triggers and enables a more diverse dietary intake. This review provides evidence and practice guidance to assist in delivering high-quality clinical service in relation to the low FODMAP diet.


Nitric oxide activity in the peripheral vasculature during normotensive and preeclamptic pregnancy.
We investigated the role of nitric oxide (NO) in the vascular resistance changes of normotensive and preeclamptic pregnancy. Forearm blood flow (FBF) responses to brachial artery infusion of N(G)-monomethyl-L-arginine (L-NMMA), an NO synthase inhibitor, and angiotensin II (ANG II), an NO-independent vasoconstrictor, were determined by plethysmography in 20 nonpregnant women, 20 normotensive primigravidae, and 15 primigravidae with untreated preeclampsia. In pregnant subjects, FBF was reduced to nonpregnancy levels by infusion of norepinephrine (NE), which was then coinfused with ANG II (2, 4, and 8 ng/min) and L-NMMA (200, 400, and 800 microgram/min) each for 5 min. In separate studies, responses to NE (20, 50, and 100 ng/min) were determined in 8 nonpregnant women, with FBF elevated to pregnancy levels by concomitant infusion of glyceryl trinitrate, and 10 pregnant women. Vasoconstrictor responses to L-NMMA were increased in pregnant compared with nonpregnant subjects [mean +/- SE summary measure (in arbitrary units): 60 +/- 7 vs. 89 +/- 8, respectively; P < 0.01], whereas responses to ANG II were blunted (125 +/- 11 vs. 79 +/- 7, respectively; P < 0.001). Compared with normotensive pregnant subjects, preeclamptic subjects had an enhanced response to ANG II (79 +/- 7 vs. 103 +/- 8, respectively; P < 0.05) but no difference in response to L-NMMA (89 +/- 8 vs. 73 +/- 10, respectively; P = 0.30). Responses to NE were similar in pregnant and nonpregnant subjects (110 +/- 20 vs. 95 +/- 33, respectively; P = 0.66). During the third trimester of pregnancy, forearm constrictor responses to L-NMMA are increased. The responses to NE are unchanged, whereas responses to ANG II are blunted. Increased NO activity contributes to the fall in peripheral resistance. In preeclampsia, forearm constrictor responses to ANG II but not L-NMMA are increased compared with those in normal pregnancy. Changes in vascular NO activity are unlikely to account for the increased vascular tone in this condition.


Manipulation of plant cells by cyst and root-knot nematode effectors.
A key feature of sedentary plant-parasitic nematodes is the release of effector proteins from their esophageal gland cells through their stylets into host roots. These proteinaceous stylet secretions have been shown to be crucial for successful parasitism by mediating the transition of normal root cells into specialized feeding sites and by negating plant defenses. Recent technical advances of purifying mRNA from esophageal gland cells of plant-parasitic nematodes coupled with emerging sequencing technologies is steadily expanding our knowledge of nematode effector repertoires. Host targets and biological activities of a number of nematode effectors are continuously being reported and, by now, a first picture of the complexity of sedentary nematode parasitism at the molecular level is starting to take shape. In this review, we highlight effector mechanisms that recently have been uncovered by studying the host-pathogen interaction. These mechanisms range from mediating susceptibility of host plants to the actual triggering of defense responses. In particular, we portray and discuss the mechanisms by which nematode effectors modify plant cell walls, negate host defense responses, alter auxin and polyamine signaling, mimic plant molecules, regulate stress signaling, and activate hypersensitive responses. Continuous molecular characterization of newly discovered nematode effectors will be needed to determine how these effectors orchestrate host signaling pathways and biological processes leading to successful parasitism.


Arachidicoccus ginsenosidivorans sp. nov., with ginsenoside-converting activity isolated from ginseng cultivating soil.
A Gram-reaction-negative, catalase- and oxidase-positive, aerobic, non-motile, light yellow and rod-shaped bacterium (designated Gsoil 809T) isolated from soil of ginseng field, was characterized by a polyphasic approach to clarify its taxonomic position. Strain Gsoil 809T was observed to grow optimally at 30 °C and at pH 7.0 on nutrient agar medium. Strain Gsoil 809T possessed β-glucosidase activity, which was responsible for its ability to transform protopanaxatriol-type ginsenoside Rg1 to ginsenoside Rh1. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain Gsoil 809T belongs to the genus Arachidicoccus of the family Chitinophagaceae and was most closely related to Arachidicoccusrhizosphaerae Vu-144T (98.1 % 16S rRNA gene sequence similarity). The DNA G+C content was 39.4 mol%. The DNA-DNA hybridization value between strain Gsoil 809T and A.rhizosphaerae Vu-144T was 41.27±1.03 %. The major polar lipids were phosphatidylethanolamine and an unknown polar lipid. The predominant quinone was MK-7. The major fatty acids were iso-C15 : 0, iso-C15 : 1 G, iso-C17 : 0 3-OH and summed feature 3, which supported the affiliation of Gsoil 809T to the genus Arachidicoccus. Strain Gsoil 809T contained homospermidineas the major polyamine. Moreover, the physiological and biochemical test results and low DNA-DNA relatedness value allowed the phenotypic and genotypic differentiation of strain Gsoil 809T from recognized species of the genus Arachidicoccus. Therefore, strain Gsoil 809T represents a novel species of the genus Arachidicoccus, for which the name Arachidicoccus ginsenosidivorans sp. nov. is proposed. The type strain is Gsoil 809T (=KCTC 22820T=JCM 30984T).


β2-Adrenergic receptor-dependent attenuation of hypoxic pulmonary vasoconstriction prevents progression of pulmonary arterial hypertension in intermittent hypoxic rats.
In sleep apnea syndrome (SAS), intermittent hypoxia (IH) induces repeated episodes of hypoxic pulmonary vasoconstriction (HPV) during sleep, which presumably contribute to pulmonary arterial hypertension (PAH). However, the prevalence of PAH was low and severity is mostly mild in SAS patients, and mild or no right ventricular hypertrophy (RVH) was reported in IH-exposed animals. The question then arises as to why PAH is not a universal finding in SAS if repeated hypoxia of sufficient duration causes cycling HPV. In the present study, rats underwent IH at a rate of 3 min cycles of 4-21% O2 for 8 h/d for 6 w. Assessment of diameter changes in small pulmonary arteries in response to acute hypoxia and drugs were performed using synchrotron radiation microangiography on anesthetized rats. In IH-rats, neither PAH nor RVH was observed and HPV was strongly reversed. Nadolol (a hydrophilic β(1, 2)-blocker) augmented the attenuated HPV to almost the same level as that in N-rats, but atenolol (a hydrophilic β1-blocker) had no effect on the HPV in IH. These β-blockers had almost no effect on the HPV in N-rats. Chronic administration of nadolol during 6 weeks of IH exposure induced PAH and RVH in IH-rats, but did not in N-rats. Meanwhile, atenolol had no effect on morphometric and hemodynamic changes in N and IH-rats. Protein expression of the β1-adrenergic receptor (AR) was down-regulated while that of β2AR was preserved in pulmonary arteries of IH-rats. Phosphorylation of p85 (chief component of phosphoinositide 3-kinase (PI3K)), protein kinase B (Akt), and endothelial nitric oxide synthase (eNOS) were abrogated by chronic administration of nadolol in the lung tissue of IH-rats. We conclude that IH-derived activation of β2AR in the pulmonary arteries attenuates the HPV, thereby preventing progression of IH-induced PAH. This protective effect may depend on the β2AR-Gi mediated PI3K/Akt/eNOS signaling pathway.


Activation primes human B lymphocytes to respond to heat shock.
Crosslinkage of the B cell antigen receptor by anti-mu beads or SAC results in the selective induction of hsp70. We have observed that activated cells, having enhanced expression of hsp70, survive lethal stimuli much better than their unactivated counterparts. These results are in accordance with the proposal that hsp70 is essential for cells to survive lethal environmental stresses. Moreover, the activation event itself primes B cells thereby enabling them to increase the expression of both hsp70 mRNA and protein. This is the first demonstration that triggering of B cells via crosslinkage of sIg is accompanied by the induction of thermotolerance without the need for a prior sublethal heat treatment.


A review of medical image data augmentation techniques for deep learning applications.
Research in artificial intelligence for radiology and radiotherapy has recently become increasingly reliant on the use of deep learning-based algorithms. While the performance of the models which these algorithms produce can significantly outperform more traditional machine learning methods, they do rely on larger datasets being available for training. To address this issue, data augmentation has become a popular method for increasing the size of a training dataset, particularly in fields where large datasets aren't typically available, which is often the case when working with medical images. Data augmentation aims to generate additional data which is used to train the model and has been shown to improve performance when validated on a separate unseen dataset. This approach has become commonplace so to help understand the types of data augmentation techniques used in state-of-the-art deep learning models, we conducted a systematic review of the literature where data augmentation was utilised on medical images (limited to CT and MRI) to train a deep learning model. Articles were categorised into basic, deformable, deep learning or other data augmentation techniques. As artificial intelligence models trained using augmented data make their way into the clinic, this review aims to give an insight to these techniques and confidence in the validity of the models produced.


Research-Based Educational Support of Undergraduate Students with Autism Spectrum Disorders.
The numbers of college and university students with autism spectrum disorders (ASD) are steadily rising, but research on their academic performance reports mixed results. The diversity of the population makes it necessary to target each student individually. This paper describes an ongoing study and experience with pedagogical intervention for ten undergraduate IT students at Oslo Metropolitan University (OsloMet) over several years. The intervention design is based on knowledge of research in the field and evidence-based practices, as well as professional skills. Data about student challenges and needs are collected from informal, open-ended interviews with students, in addition to conversations and observation. The goal is to ensure that the students achieve academical success. Plans are currently being made to develop a formal program that will target all students with autism spectrum disorders at OsloMet.


Aggressive surgical management of peritoneal carcinomatosis with low mortality in a high-volume tertiary cancer center.
Cytoreductive surgery (CS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for treatment of peritoneal carcinomatosis (PC) traditionally involves high perioperative morbidity and mortality. We report our experience performing CS-HIPEC in a high-volume regional perfusion program designed to limit morbidity and mortality. A total of 122 patients underwent 124 CS-HIPEC procedures. Common tumors treated with CS-HIPEC included appendiceal (38.5%), colorectal (24.6%), and ovarian cancers (13.1%), and peritoneal mesothelioma (12.3%). Complete cytoreduction was performed in all patients, with organ resections performed as necessary. R0 resection was achieved in 28.7% of cases, R1 in 54.9%, and R2 in 16.4%. Median operative time was 460 minutes (range, 250-840 minutes), and median blood loss was 1150 mL (range, 10-14,000 mL). Median hospital and intensive care unit stays were 12 days (range, 6-50 days) and 3 days (range, 0-41 days), respectively. Grade 3 or 4 morbidity by National Cancer Institute criteria (major morbidity) was seen in 29.8% of cases, with overall morbidity 56.5%. Independent prognostic variables for major morbidity included number of anastomoses and degree of cytoreduction. In-hospital and 30-day mortality rates were 0% and 1.6%, respectively. The most favorable diagnosis was appendiceal cancer, for which 2-year survival was 66.7%, with lower-grade histologic subtypes of appendiceal cancer reaching 85.7% 2-year survival. Colorectal cancer had 2-year survival of 36.7%. In a high-volume center with extensive experience treating peritoneal malignancies, perioperative mortality can be lowered to nearly zero, although morbidity remains high. CS-HIPEC procedures should be studied further in a controlled manner to help define their important role in the care of patients with PC.


Structural principles of RNA catalysis in a 2'-5' lariat-forming ribozyme.
RNA-catalyzed lariat formation is present in both eukaryotes and prokaryotes. To date we lack structural insights into the catalytic mechanism of lariat-forming ribozymes. Here, we study an artificial 2'-5' AG1 lariat-forming ribozyme that shares the sequence specificity of lariat formation with the pre-mRNA splicing reaction. Using NMR, we solve the structure of the inactive state of the ribozyme in the absence of magnesium. The reaction center 5'-guanosine appears to be part of a helix with an exceptionally widened major groove, while the lariat-forming A48 is looped out at the apex of a pseudoknot. The model of the active state built by mutational analysis, molecular modeling, and small-angle X-ray scattering suggests that A48 is recognized by a conserved adenosine, juxtaposed to the 5'-guanosine in one base-pair step distance, while the G1-N7 coordinates a magnesium ion essential for the activation of the nucleophile. Our findings offer implications for lariat formation in RNA enzymes including the mechanism of the recognition of the branch-site adenosine.


Poor validity of residual volumes as a marker for risk of aspiration in critically ill patients.
Elevated residual volumes (RV), considered a marker for the risk of aspiration, are used to regulate the delivery of enteral tube feeding. We designed this prospective study to validate such use. Critically ill patients undergoing mechanical ventilation in the medical, coronary, or surgical intensive care units in a university-based tertiary care hospital, placed on intragastric enteral tube feeding through nasogastric or percutaneous endoscopic gastrostomy tubes, were included in this study. Patients were fed Probalance (Nestle USA) to provide 25 kcal/kg per day (to which 10 yellow microscopic beads and 4.5 mL of blue food coloring per 1,500 mL was added). Patients were randomized to one of two groups based on management of RV: cessation of enteral tube feeding for RV >400 mL in study patients or for RV >200 mL in controls. Acute Physiology and Chronic Health Evaluation (APACHE) III, bowel function score, and aspiration risk score were determined. Bedside evaluations were done every 4 hrs for 3 days to measure RV, to detect blue food coloring, to check patient position, and to collect secretions from the trachea and oropharynx. Aspiration/regurgitation events were defined by the detection of yellow color in tracheal/oropharyngeal samples by fluorometry. Analysis was done by analysis of variance, Spearman's correlation, Student's t-test, Tukey's method, and Cochran-Armitage test. Forty patients (mean age, 44.6 yrs; range, 18-88 yrs; 70% male; mean APACHE III score, 40.9 [range, 12-85]) were evaluated (21 on nasogastric, 19 on percutaneous endoscopic gastrostomy feeds) and entered into the study. Based on 1,118 samples (531 oral, 587 tracheal), the mean frequency of regurgitation per patient was 31.3% (range, 0% to 94%), with a mean RV for all regurgitation events of 35.1 mL (range, 0-700 mL). The mean frequency of aspiration per patient was 22.1% (range, 0% to 94%), with a mean RV for all aspiration events of 30.6 mL (range, 0-700 mL). The median RV for both regurgitation and aspiration events was 5 mL. Over a wide range of RV, increasing from 0 mL to >400 mL, the frequency of regurgitation and aspiration did not change appreciably. Aspiration risk and bowel function scores did not correlate with the incidence of aspiration or regurgitation. Blue food coloring was detected on only three of the 1,118 (0.27%) samples. RV was < or =50 mL on 84.1% and >400 mL on 1.4% of bedside evaluations. Sensitivities for detecting aspiration per designated RV were as follows: 400 mL = 1.5%; 300 mL = 2.3%; 200 mL = 3.0%; and 150 mL = 4.5%. Low RV did not assure the absence of events, because the frequency of aspiration was 23.0% when RV was <150 mL. Raising the designated RV for cessation of enteral tube feeding from 200 mL to 400 mL did not increase the risk, because the frequency of aspiration was no different between controls (21.6%) and study patients (22.6%). The frequency of regurgitation was significantly less for patients with percutaneous endoscopic gastrostomy tubes compared with those with nasogastric tubes (20.3% vs. 40.7%, respectively; p = .046). There was no correlation between the incidence of pneumonia and the frequency of regurgitation or aspiration. Blue food coloring should not be used as a clinical monitor. Converting nasogastric tubes to percutaneous endoscopic gastrostomy tubes may be a successful strategy to reduce the risk of aspiration. No appropriate designated RV level to identify aspiration could be derived as a result of poor sensitivity over a wide range of RV. Study results do not support the conventional use of RV as a marker for the risk of aspiration.


The Effect of Donor Age and Recipient Characteristics on Renal Outcomes in Patients Receiving Prolonged-Release Tacrolimus After Liver Transplantation: Post-Hoc Analyses of the DIAMOND Study.
BACKGROUND The DIAMOND study of de novo liver transplant patients showed that prolonged-release tacrolimus exposure in the acute post-transplant period maintained renal function over 24 weeks of treatment. To assess these findings further, we performed a post-hoc analysis in patients according to baseline kidney function, Model for End-stage Liver Disease [MELD] scores, and donor age. MATERIAL AND METHODS Patients received prolonged-release tacrolimus (initial-dose, Arm 1: 0.2 mg/kg/day, Arm 2: 0.15-0.175 mg/kg/day, Arm 3: 0.2 mg/kg/day delayed until Day 5), mycophenolate mofetil and 1 steroid bolus. Arms 2 and 3 also received basiliximab. The recommended tacrolimus target trough levels to Day 42 post-transplantation were 5-15 ng/mL in all arms. In this post-hoc analysis, change in renal outcome, based on estimated glomerular filtration rate (eGFR), Modified Diet in Renal Disease-4 (MDRD4), values from baseline to Week 24 -post-transplantation, were assessed according to baseline patient factors: eGFR (≥60 and ˂60 mL/min/1.73 m²), MELD score (˂25 and ≥25) and donor age (˂50 and ≥50 years). RESULTS Baseline characteristics were comparable (Arms 1-3: n=283, n=287, n=274, respectively). Patients with baseline renal function, eGFR ≥60 mL/min/1.73 m², experienced a decrease in eGFR in all tacrolimus treatment arms. In patients with lower baseline renal function (eGFR ˂60 mL/min/1.73 m²), an advantage for renal function was observed with both the early lower-dose and delayed higher-dose tacrolimus regimens compared with the early introduction of higher-dose tacrolimus. At Week 24, renal function was higher in the early-lower tacrolimus arm with older donors, and the delayed higher-dose tacrolimus arm with younger donors, both compared with early higher-dose tacrolimus. CONCLUSIONS Pre-transplantation factors, such as renal function and donor age, could guide the choice of prolonged-release tacrolimus regimen following liver transplantation.


Visualization of a Ran-GTP gradient in interphase and mitotic Xenopus egg extracts.
The small guanosine triphosphatase Ran is loaded with guanosine triphosphate (GTP) by the chromatin-bound guanine nucleotide exchange factor RCC1 and releases import cargoes in the nucleus during interphase. In mitosis, Ran-GTP promotes spindle assembly around chromosomes by locally discharging cargoes that regulate microtubule dynamics and organization. We used fluorescence resonance energy transfer-based biosensors to visualize gradients of Ran-GTP and liberated cargoes around chromosomes in mitotic Xenopus egg extracts. Both gradients were required to assemble and maintain spindle structure. During interphase, Ran-GTP was highly enriched in the nucleoplasm, and a steep concentration difference between nuclear and cytoplasmic Ran-GTP was established, providing evidence for a Ran-GTP gradient surrounding chromosomes throughout the cell cycle.


Power of three multitrait methods for QTL detection in crossbred populations.
The multitrait detections of QTL applied to a mixture of full- and half-sib families require specific strategies. Indeed, the number of parameters estimated by the multivariate methods is excessive compared with the size of the population. Thus, only multitrait methods based on a univariate analysis of a linear combination (LC) of the traits can be extensively performed. We compared three strategies to obtain the LC of the traits. Two linear transformations were performed on the overall population. The last one was performed within each half-sib family. Their powers were compared on simulated data depending on the frequency of the two QTL alleles in each of the grand parental populations of an intercross design. The transformations from the whole population did not lead to a large loss of power even though the frequency of the QTL alleles was similar in the two grand parental populations. In these cases, applying the within-sire family transformation improved the detection when the number of progeny per sire was greater than 100.


Magnetic resonance imaging of bone marrow in the pelvis and femur of young dogs.
The purpose of this study was to determine the magnetic resonance (MR) imaging characteristics of bone marrow in the pelvis and femur of normal, young dogs. Six greyhounds were imaged at 4, 8, 12, and 16 months of age. Sagittal images of the femur and dorsal images of the pelvis were obtained with T1-weighted, fast spin echo (FSE) T2-weighted, and short tau (T1) inversion recovery (STIR) sequences. On T1-weighted images areas with high signal intensity, similar to fat, included the femoral heads, mid-diaphysis of the femur, femoral condyles, and the body of the ilium. T2-weighted images were characterized by uniform intermediate signal intensity (less than fat, but greater than muscle) in the femoral head, high signal intensity, similar to fat, in the mid-diaphysis of the femur and ilial body, and intermediate to high signal intensity in the femoral condyle. By 16 months high signal intensity was seen in the diaphysis and distal metaphysis on both T1- and T2-weighted images. On STIR images the femoral head had intermediate to low signal intensity, compared with muscle. The mid-diaphysis of the femur was of low signal intensity, similar to fat, and the body of the ilium had mixed signal intensity at all ages. The femoral condyle had inhomogenous, intermediate to low signal intensity at 4 months, but was of uniform low signal intensity at 8-16 months.


PTOP interacts with POT1 and regulates its localization to telomeres.
Telomere maintenance has been implicated in cancer and ageing, and requires cooperation between a multitude of telomeric factors, including telomerase, TRF1, TRF2, RAP1, TIN2, Tankyrase, PINX1 and POT1 (refs 1-12). POT1 belongs to a family of oligonucleotide-binding (OB)-fold-containing proteins that include Oxytricha nova TEBP, Cdc13, and spPot1, which specifically recognize telomeric single-stranded DNA (ssDNA). In human cells, the loading of POT1 to telomeric ssDNA controls telomerase-mediated telomere elongation. Surprisingly, a human POT1 mutant lacking an OB fold is still recruited to telomeres. However, the exact mechanism by which this recruitment occurs remains unclear. Here we identify a novel telomere protein, PTOP, which interacts with both POT1 and TIN2. PTOP binds to the carboxyl terminus of POT1 and recruits it to telomeres. Inhibition of PTOP by RNA interference (RNAi) or disruption of the PTOP-POT1 interaction hindered the localization of POT1 to telomeres. Furthermore, expression of the respective interaction domains on PTOP and POT1 alone extended telomere length in human cells. Therefore, PTOP heterodimerizes with POT1 and regulates POT1 telomeric recruitment and telomere length.


Intrinsic cytoskeleton-dependent clustering of influenza virus M2 protein with hemagglutinin assessed by FLIM-FRET.
The hemagglutinin (HA) of influenza virus organizes the virus bud zone, a domain of the plasma membrane enriched in raft lipids. Using fluorescence lifetime imaging microscopy-fluorescence resonance energy transfer (FLIM-FRET), a technique that detects close colocalization of fluorescent proteins in transfected cells, we show that the viral proton channel M2 clusters with HA but not with a marker for inner leaflet rafts. The FRET signal between M2 and HA depends on the raft-targeting signals in HA and on an intact actin cytoskeleton. We conclude that M2 contains an intrinsic signal that targets the protein to the viral bud zone, which is organized by raft-associated HA and by cortical actin.


Symptoms associated with mild traumatic brain injury/concussion: the role of bother.
Traumatic brain injury (TBI) affects 1.4 million Americans annually, and mild TBI (MTBI) accounts for approximately 75% of those injured. For those with mild injury who seek treatment in an emergency department, there is inconsistency in the management and follow-up recommendations. Approximately, 38% of patients treated in the emergency department for MTBI are discharged with no recommendations for follow-up. In addition, there are an unknown number of persons with MTBI who do not seek healthcare after their injury. Persons with MTBI are, for the most part, managing their concussion symptoms on their own. The purpose of this study was to describe the symptom experience for persons with mild TBI and identify whether there was an association between being bothered by symptoms and self-management of symptoms. The sample for this study included 30 persons with MTBI and a 30-person comparison group. Results indicate that persons within 3 months of their MTBI report an average of 19 symptoms, whereas the comparison group reported six symptoms, and that the most frequently reported symptoms are not always the symptoms rated as most severe or most bothersome. Persons with MTBI reported their most common symptoms to be headache (n = 25, 83%), feeling tired (n = 24, 80%), difficulty thinking and being irritable (each n = 22, 73%), dizziness, trouble remembering, and being forgetful (each n = 21, 70%). There is a significant relationship between overall reports of being bothered by symptoms and the use of symptom management strategies (F = 8.322, p = .008). Persons are more likely to use symptom management strategies when they are bothered by the symptoms. Nurses can assist with symptom self-management by providing simple symptom management strategies to assist with the symptom management process. Early symptom management for the MTBI population may improve the outcomes such as return to work and role functions, for this population.


Circulating naive and memory CD4+ T cells and metabolic syndrome in patients with systemic lupus erythematosus: data from a primarily Mestizo population.
The aim of this study was to determine whether the proportions of naive and memory CD4(+) T cell are independently associated with the metabolic syndrome (MetS) in patients with SLE. This cross-sectional study was conducted in SLE patients seen at our rheumatology department between September 2013 and April 2014. CD4(+) T cell subpopulations were examined by flow cytometry. The association of MetS and CD4(+) T cell subpopulations was examined by Mann-Whitney U-test and by multivariable analysis, adjusting for all possible confounding variables. One hundred and seventeen patients were evaluated. Their mean age was 44.6 years (S.D. 12.6), 109 (93.2%) were female and all patients were Mestizo (mixed Caucasian and Amerindian ancestry). Fifty-two patients (44.4%) presented with MetS. Disease duration was 7.6 years (S.D. 6.8). The percentage of naive CD4(+) T cells was 25.0 (S.D. 12.7) and memory CD4(+) T cells was 66.7 (S.D. 13.2) and the memory:naive CD4(+) T cell ratio was 4.3 (S.D. 5.6). In multivariable analysis, the percentage of naive CD4(+) T cells was negatively associated with the presence of MetS [odds ratio (OR) 0.959 (95% CI 0.923, 0.997), P = 0.033], whereas the percentage of memory CD4(+)T cells and the memory:naive CD4(+) T cell ratio were positively associated with its presence [OR 1.040 (95% CI 1.003, 1.078), P = 0.031 and OR 1.238 (95% CI 1.041, 1.472), P = 0.016, respectively]. In the SLE patients studied, a lower percentage of naive CD4(+) T cells, a higher percentage of memory CD4(+) T cells and the memory:naive CD4(+) T cell ratio were independently associated with the presence of MetS. This association could reflect the impact of immunosenescence among SLE patients with cardiovascular morbidity.


A trial comparing the use of rectal misoprostol plus perivascular vasopressin with perivascular vasopressin alone to decrease myometrial bleeding at the time of abdominal myomectomy.
To compare the efficacy of rectal misoprostol plus perivascular vasopressin with perivascular vasopressin alone as hemostatic agents for the reduction of blood loss during myomectomies. Prospective, randomized, double-blind, controlled study. University of the West Indies and Andrews Memorial Hospital. Fifty women with symptomatic uterine fibroids, 25 receiving misoprostol and vasopressin and 25 receiving vasopressin alone before myomectomy. Abdominal myomectomies on patients with symptomatic uterine fibroids. Perioperative blood loss and febrile morbidity. There were no statistically significant differences in sociodemographic, clinical, or myoma characteristics between the two groups at baseline. Postoperatively, there were no statistically significant differences in perioperative febrile morbidity or blood pressure between the groups. However, the group treated with misoprostol plus vasopressin had statistically significantly lower blood loss (geometric mean with 95% confidence interval, 334 mL [261 to 428] vs. 623 mL [354 to 1,094], a smaller change in hemoglobin (1.6 ± 1.5 vs. 3.0 ± 2.0), and a lower requirement for transfusion. In addition to treatment, significant determinants of blood loss were larger size of fibroids and greater number of fibroids. We conclude that perivascular vasopressin plus misoprostol caused a significant reduction in blood loss compared with perivascular vasopressin alone. NCT01700478.


Resin-assisted enrichment of thiols as a general strategy for proteomic profiling of cysteine-based reversible modifications.
Reversible modifications of cysteine thiols have a key role in redox signaling and regulation. A number of reversible redox modifications, including disulfide formation, S-nitrosylation (SNO) and S-glutathionylation (SSG), have been recognized for their significance in various physiological and pathological processes. Here we describe a procedure for the enrichment of peptides containing reversible cysteine modifications. Starting with tissue or cell lysate samples, all of the unmodified free thiols are blocked using N-ethylmaleimide (NEM). This is followed by the selective reduction of those cysteines bearing the reversible modification(s) of interest. The reduction is achieved by using different reducing reagents that react specifically with each type of cysteine modification (e.g., ascorbate for SNO). This protocol serves as a general approach for enrichment of thiol-containing proteins or peptides derived from reversibly modified proteins. The approach uses a commercially available thiol-affinity resin (thiopropyl Sepharose 6B) to directly capture free thiol-containing proteins through a disulfide exchange reaction, followed by on-resin protein digestion and multiplexed isobaric labeling to facilitate liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based quantitative site-specific analysis of cysteine-based reversible modifications. The overall approach requires a simpler workflow with increased specificity compared with the commonly used biotinylation-based assays. The procedure for selective enrichment and analyses of SNO and the level of total reversible cysteine modifications (or total oxidation) is presented to demonstrate the utility of this general strategy. The entire protocol requires ∼3 d for sample processing with an additional day for LC-MS/MS and data analysis.


Agronomic Linked Data (AgroLD): A knowledge-based system to enable integrative biology in agronomy.
Recent advances in high-throughput technologies have resulted in a tremendous increase in the amount of omics data produced in plant science. This increase, in conjunction with the heterogeneity and variability of the data, presents a major challenge to adopt an integrative research approach. We are facing an urgent need to effectively integrate and assimilate complementary datasets to understand the biological system as a whole. The Semantic Web offers technologies for the integration of heterogeneous data and their transformation into explicit knowledge thanks to ontologies. We have developed the Agronomic Linked Data (AgroLD- www.agrold.org), a knowledge-based system relying on Semantic Web technologies and exploiting standard domain ontologies, to integrate data about plant species of high interest for the plant science community e.g., rice, wheat, arabidopsis. We present some integration results of the project, which initially focused on genomics, proteomics and phenomics. AgroLD is now an RDF (Resource Description Format) knowledge base of 100M triples created by annotating and integrating more than 50 datasets coming from 10 data sources-such as Gramene.org and TropGeneDB-with 10 ontologies-such as the Gene Ontology and Plant Trait Ontology. Our evaluation results show users appreciate the multiple query modes which support different use cases. AgroLD's objective is to offer a domain specific knowledge platform to solve complex biological and agronomical questions related to the implication of genes/proteins in, for instances, plant disease resistance or high yield traits. We expect the resolution of these questions to facilitate the formulation of new scientific hypotheses to be validated with a knowledge-oriented approach.


Presenilin and APP Regulate Synaptic Kainate Receptors.
Kainate receptors (KARs) form a family of ionotropic glutamate receptors that regulate the activity of neuronal networks by both presynaptic and postsynaptic mechanisms. Their implication in pathologies is well documented for epilepsy. The higher prevalence of epileptic symptoms in Alzheimer's disease (AD) patients questions the role of KARs in AD. Here we investigated whether the synaptic expression and function of KARs was impaired in mouse models of AD. We addressed this question by immunostaining and electrophysiology at synapses between mossy fibers and CA3 pyramidal cells, in which KARs are abundant and play a prominent physiological role. We observed a decrease of the immunostaining for GluK2 in the stratum lucidum in CA3, and of the amplitude and decay time of synaptic currents mediated by GluK2-containing KARs in an amyloid mouse model (APP/PS1) of AD. Interestingly, a similar phenotype was observed in CA3 pyramidal cells in male and female mice with a genetic deletion of either presenilin or APP/APLP2 as well as in organotypic cultures treated with γ-secretase inhibitors. Finally, the GluK2 protein interacts with full-length and C-terminal fragments of APP. Overall, our data suggest that APP stabilizes KARs at synapses, possibly through a transsynaptic mechanism, and this interaction is under the control the γ-secretase proteolytic activity of presenilin.SIGNIFICANCE STATEMENT Synaptic impairment correlates strongly with cognitive deficits in Alzheimer's disease (AD). In this context, many studies have addressed the dysregulation of AMPA and NMDA ionotropic glutamate receptors. Kainate receptors (KARs), which form the third family of iGluRs, represent an underestimated actor in the regulation of neuronal circuits and have not yet been examined in the context of AD. Here we provide evidence that synaptic KARs are markedly impaired in a mouse model of AD. Additional experiments indicate that the γ-secretase activity of presenilin acting on the amyloid precursor protein controls synaptic expression of KAR. This study clearly indicates that KARs should be taken into consideration whenever addressing synaptic dysfunction and related cognitive deficits in the context of AD.


Static tester for characterization of phase-change, dye-polymer, and magneto-optical media for optical data storage.
We have designed and built a static tester around a commercially available polarized light microscope. This device employs two semiconductor laser diodes (at 643- and 680-nm wavelengths) for the purpose of recording small marks on various media for optical data storage and for the simultaneous monitoring of the recording process. We use one of the lasers in the single-pulse mode to write a mark on the sample and operate the other laser in the cw mode to monitor the recording process. The two laser beams are brought to coincident focus on the sample through the objective lens of the microscope. The reflected beams are sent through a polarizing beam splitter and thus divided into two branches, depending on whether they are p or s polarized. In each branch the beam is further divided into two according to the wavelength. The four beams thus produced are sent to four high-speed photodetectors, and the resulting signals are used to monitor the reflectance as well as the polarization state of the beam on reflection from the sample. We provide a comprehensive description of the tester's design and operating principles. We also report preliminary results of measurements of phase-change, dye-polymer, and magneto-optical samples, which are currently of interest in the areas of writable and rewritable optical data storage.


Expression of adrenal cytochromes P-450 in testosterone-induced hypertension.
Chronic treatment of rats with the naturally occurring androgen, testosterone, leads to hypertension and cardiovascular disease. This effect is believed to be mediated through the adrenal gland and in particular by action on the steroid 11 beta-hydroxylase enzyme system. To study the possible mechanism of this effect, the enzyme system was examined at several time periods up to the time that hypertension develops. Rats were treated with testosterone (10 mg/day) for 3, 7, 21, and 42 days. Levels of cytochrome P-450(11) beta enzyme and messenger RNA (mRNA) were determined as well as 11 beta-hydroxylase enzyme activity. A significant decrease in enzyme activity was observed after 3 days of treatment. This correlates with a profound decrease in the level of cytochrome P-450(11) beta enzyme as determined by Western blot analysis. A large decrease in cytochrome P-450(11) beta mRNA was also observed after 3 days of treatment. All three parameters remained low throughout the treatment period. The decrease in 11 beta-hydroxylase enzyme activity appears to result from a lower enzyme level brought about by decreased concentrations of mRNA transcripts.


Polyglycolic acid-collagen tube combined with collagen-binding basic fibroblast growth factor accelerates gait recovery in a rat sciatic nerve critical-size defect model.
Several nerve conduits have been investigated for their potential as alternative sources of autografts for bridging neural gaps. However, autologous nerve transplants remain the most effective for nerve repair. We examined clinically approved nerve conduits containing collagen and polyglycolic acid (PGA-c) combined with collagen-binding basic fibroblast growth factor (bFGF) containing a polycystic kidney disease (PKD) domain and collagen binding domain (CBD) (bFGF-PKD-CBD) in a rat 15-mm sciatic nerve critical-size defect model. The treatment groups were: PGA-c immersed in phosphate-buffered saline (PBS) (PGA-c/PBS group), bFGF (PGA-c/bFGF group), or bFGF-PKD-CBD (PGA-c/bFGF-PKD-CBD group), and no treatment (Defect group). Gait and histological analyses were performed. Four weeks after treatment, the recovery rate of the paw print area was significantly greater in the PGA-c/bFGFPKD-CBD group than the PGA-c/PBS and PGA-c/bFGF groups. Mean intensity of paw prints was significantly greater in the PGA-c/bFGF-PKD-CBD group than the PGA-c/PBS and Defect groups. Swing time was significantly greater in the PGA-c/PBS, PGA-c/bFGF, and PGA-c/bFGF-PKD-CBD groups than the Defect group. At 8 weeks, all three parameters were significantly greater in the PGA-c/PBS, PGA-c/bFGF, and PGA-c/bFGF-PKD-CBD groups than the Defect group. Regenerated myelinated fibers were observed in 7/8 (87.5%) rats in the PGA-c/bFGF-PKD-CBD group after 8 weeks, and in 1/8 (12.5%) and 3/8 (37.5%) rats in the PGA-c/PBS and PGA-c/bFGF groups, respectively. PGA-c/bFGF-PKD-CBD composites may be promising biomaterials for promoting functional recovery of long-distance peripheral nerve defects in clinical practice.


Asymmetric organocatalysis: an enabling technology for medicinal chemistry.
The efficacy and synthetic versatility of asymmetric organocatalysis have contributed enormously to the field of organic synthesis since the early 2000s. As asymmetric organocatalytic methods mature, they have extended beyond the academia and undergone scale-up for the production of chiral drugs, natural products, and enantiomerically enriched bioactive molecules. This review provides a comprehensive overview of the applications of asymmetric organocatalysis in medicinal chemistry. A general picture of asymmetric organocatalytic strategies in medicinal chemistry is firstly presented, and the specific applications of these strategies in pharmaceutical synthesis are systematically described, with a focus on the preparation of antiviral, anticancer, neuroprotective, cardiovascular, antibacterial, and antiparasitic agents, as well as several miscellaneous bioactive agents. The review concludes with a discussion of the challenges, limitations and future prospects for organocatalytic asymmetric synthesis of medicinally valuable compounds.


Validating a dimensionless number for glucose homeostasis in humans.
Understanding type 2 diabetes is challenged by the diversity of patient phenotypes. Translating data across species and among individuals is a barrier for understanding the genetic loci that underpin this multifactorial disease. Dynamic scaling, based upon dimensional analysis, is a common technique in engineering used to translate data among different systems. The objective of this study was to gain insight using dimensional analysis into the relative changes in insulin production capacity vs. insulin-dependent glucose metabolism in patient groups that represent distinct stages of disease progression. A dimensionless number was derived using variables involved in the production of insulin and in the sensitivity of glucose metabolism to insulin. The resulting dynamic scaling relationship was validated against patient data obtained for over 2000 individuals that range in phenotype from normal to severe type 2 diabetes. Individuals were identified in the third National Health and Nutrition Evaluation Survey. Patient groups clustered in different regions based upon the severity of clinical symptoms. The cross-sectional comparison among patient groups shows that progression from normal to clinical onset of type 2 diabetes exhibits a non-linear change in the ratio of insulin production to insulin-dependent glucose metabolism: normals are balanced, pre-diabetic individuals exhibit an increase, and individuals with clinical type 2 diabetes exhibit a decrease in this ratio. This dimensionless number provides a method for discriminating between patient groups from first principles. By analogy with other dimensionless numbers, this number may be used to monitor basic physiological variables responsible for glucose homeostasis. In addition, a similar dynamic trajectory to the clinical populations could provide a criterion for selecting relevant animal models for diabetes.


Parental caregiver burden and recovery of adolescent anorexia nervosa after multi-family therapy.
This study investigated whether parental caregiving burden changed during adjunct multi-family therapy of adolescent anorexia nervosa and eating disorders not otherwise specified (EDNOS) and whether caregiver burden at baseline and changes in caregiver burden during treatment were associated with treatment outcome.Twenty-four females, 13 to 16 years old, and their parents, participated in the study. Caregiver burden was measured with the Eating Disorders Symptom Impact Scale, by mothers (n = 23) and fathers (n = 22). Treatment outcome was measured by adolescent body mass index, level of global functioning and self-rated eating disorder symptoms by the Eating Disorders Examination Questionnaire 4.0.All patient outcomes improved and overall caregiver burden decreased significantly during treatment. When broken down in aspects of caregiver burden the decrease in parental perceived isolation, was found to be associated with improvement of BMI and Children's Global Assessment Scale. When analyzing fathers and mothers separately, we found that maternal feelings of guilt and paternal perceived burden of dysregulated behaviors at base-line were correlated to treatment outcome. Future studies are needed to clarify the role of caregiver burden as a potential mediator of treatment results.


Regulation of endoplasmic reticulum-associated degradation by RNF5-dependent ubiquitination of JNK-associated membrane protein (JAMP).
Clearance of misfolded proteins by endoplasmic reticulum (ER)-associated degradation (ERAD) requires concerted activity of chaperones, adaptor proteins, ubiquitin ligases, and proteasomes. RNF5 is a ubiquitin ligase anchored to the ER membrane implicated in ERAD via ubiquitination of misfolded proteins. Among RNF5-associated proteins is JNK-associated membrane protein (JAMP), a 7-transmembrane protein located within the ER membrane that facilitates degradation of misfolded proteins through recruitment of proteasomes and ERAD regulatory components. Here we demonstrate that RNF5 associates with JAMP in the ER membrane. This association results in Ubc13-dependent RNF5-mediated noncanonical ubiquitination of JAMP. This ubiquitination does not alter JAMP stability but rather inhibits its association with Rpt5 and p97. Consequently, clearance of misfolded proteins, such as CFTRDelta508 and T cell receptor alpha, is less efficient, resulting in their greater accumulation. Significantly, the RNF5 effect on JAMP is seen prior to and after ER stress response, thereby highlighting a novel mechanism to limit ERAD and proteasome assembly at the ER, to the actual ER stress response.


Comparison of an algebraic multigrid algorithm to two iterative solvers used for modeling ground water flow and transport.
Numerical solution of large-scale ground water flow and transport problems is often constrained by the convergence behavior of the iterative solvers used to solve the resulting systems of equations. We demonstrate the ability of an algebraic multigrid algorithm (AMG) to efficiently solve the large, sparse systems of equations that result from computational models of ground water flow and transport in large and complex domains. Unlike geometric multigrid methods, this algorithm is applicable to problems in complex flow geometries, such as those encountered in pore-scale modeling of two-phase flow and transport. We integrated AMG into MODFLOW 2000 to compare two- and three-dimensional flow simulations using AMG to simulations using PCG2, a preconditioned conjugate gradient solver that uses the modified incomplete Cholesky preconditioner and is included with MODFLOW 2000. CPU times required for convergence with AMG were up to 140 times faster than those for PCG2. The cost of this increased speed was up to a nine-fold increase in required random access memory (RAM) for the three-dimensional problems and up to a four-fold increase in required RAM for the two-dimensional problems. We also compared two-dimensional numerical simulations of steady-state transport using AMG and the generalized minimum residual method with an incomplete LU-decomposition preconditioner. For these transport simulations, AMG yielded increased speeds of up to 17 times with only a 20% increase in required RAM. The ability of AMG to solve flow and transport problems in large, complex flow systems and its ready availability make it an ideal solver for use in both field-scale and pore-scale modeling.


Alteration in cyclic AMP-dependent protein kinases and polyamine biosynthetic enzymes during hypertrophy and hyperplasia of the thyroid in the rat.
After 2 weeks of goitrogen treatment [propylthiouracil (PTU), 0.02% in drinking water], the thyroids of rats increased to 280% of control wet weight, 270% of dry weight, and 250% of control DNA content. Two phases of growth were apparent, an initial hypertrophy phase lasting 3 days (increase in cell size and gland weight with no detectable increase in DNA) and a hyperplastic phase (increase in DNA with histological evidence of cell proliferation) starting at 3-4 days and continuing through 14 days. The cyclic AMP-dependent protein kinase activity ratio (-cyclic AMP/+cyclic AMP) showed a biphasic pattern during the 2-week thyroid growth period, with maxima at day 1 (132% of control) and day 6 (148% of control). Ornithine decarboxylase (EC 18.104.22.168), the initial enzyme in polyamine biosynthesis, showed a similar biphasic pattern with a 6- to 7-fold elevation in activity at 2-3 days and a 4-fold elevation at 6 days. S-Adenosyl-L-methionine decarboxylase (EC 22.214.171.124), the enzyme which catalyzes spermidine synthesis, was elevated 4-fold at 9 days of treatment. The thyroid total supernatant protein kinase activity (+cyclic AMP) increased to 160% of control by 4 days, returning to control by 14 days of PTU treatment. The thyroid had 10% Type I activity and 90% Type II cyclic AMP-dependent protein kinase activity. The specific activity of both Types I and II remained unchanged for the first 2 days of PTU treatment. Both types increased to 150% of control by 4 days. Type I remained elevated throughout the remainder of the 14 days, in contrast to Type II, which decreased conspicuously to control levels by 6 days. A single injection of thyroid-stimulating hormone (TSH, 1.0 unit/100 g of body weight, i.p.) resulted in a 20-fold increase in thyroid ornithine decarboxylase activity by 4 hr. The same dose of TSH produced only a 3-fold induction of ODC in rats hypophysectomized 2 weeks previously. The thyroid specific activity of Types I and II protein kinase was only 55% and 57% of control, respectively, in these unresponsive rats. Thyroids from rats chronically stimulated for 14 days showed an increase in ornithine decarboxylase following TSH administration similar to that of control rats. Changes in the activation as well as specific activity of Types I and II protein kinase during hypertrophy and hyperplasia underlie the complexity of a cyclic AMP-mediated response.


The anti-inflammatory properties of cocoa flavanols.
Signs of chronic or acute inflammation have been demonstrated in most cardiovascular diseases of multifactorial pathogenesis, including atherosclerosis and chronic heart failure. The triggers and mechanisms leading to inflammation may vary between clinical conditions but they share many common mediators, including specific patterns of eicosanoid and cytokine production. Certain cocoa-based products can be rich in a subclass of flavonoids known as flavanols, some of which have been found in model systems to possess potential anti-inflammatory activity relevant to cardiovascular health. Indeed, experimental evidence demonstrates that some cocoa-derived flavanols can reduce the production and effect of pro-inflammatory mediators either directly or by acting on signaling pathways. However, it should be noted that the evidence for any beneficial effects of cocoa flavanols in providing a meaningful anti-inflammatory action has been gathered predominantly from in vitro experiments. Therefore, additional research in well-designed human clinical experiments, using cocoa properly characterized in terms of flavanol content, would be a welcome addition to the evidence base to determine unambiguously if this benefit does indeed exist. If so, then flavanol-rich cocoa could be a potential candidate for the treatment, or possibly prevention, of the broad array of chronic diseases that are linked to dysfunctional inflammatory responses.


High accuracy mass spectrometry analysis as a tool to verify and improve gene annotation using Mycobacterium tuberculosis as an example.
While the genomic annotations of diverse lineages of the Mycobacterium tuberculosis complex are available, divergences between gene prediction methods are still a challenge for unbiased protein dataset generation. M. tuberculosis gene annotation is an example, where the most used datasets from two independent institutions (Sanger Institute and Institute of Genomic Research-TIGR) differ up to 12% in the number of annotated open reading frames, and 46% of the genes contained in both annotations have different start codons. Such differences emphasize the importance of the identification of the sequence of protein products to validate each gene annotation including its sequence coding area. With this objective, we submitted a culture filtrate sample from M. tuberculosis to a high-accuracy LTQ-Orbitrap mass spectrometer analysis and applied refined N-terminal prediction to perform comparison of two gene annotations. From a total of 449 proteins identified from the MS data, we validated 35 tryptic peptides that were specific to one of the two datasets, representing 24 different proteins. From those, 5 proteins were only annotated in the Sanger database. In the remaining proteins, the observed differences were due to differences in annotation of transcriptional start sites. Our results indicate that, even in a less complex sample likely to represent only 10% of the bacterial proteome, we were still able to detect major differences between different gene annotation approaches. This gives hope that high-throughput proteomics techniques can be used to improve and validate gene annotations, and in particular for verification of high-throughput, automatic gene annotations.


Front-face fluorescence measurement of photosensitizers and lipid oxidation products during the photooxidation of butter.
This paper shows that fluorescence spectroscopy can measure both degradation of photosensitizers and formation of lipid oxidation products in light-exposed butter. The photosensitizers were already notably degraded after 4 h of light exposure, whereas fluorescent lipid oxidation products were detected after 5 d. The fluorescence measurements were highly correlated with sensory assessments of acidic and rancid flavor. Photosensitizer degradation is therefore a promising indirect indicator of the onset of lipid oxidation in butter. Sensory analysis and measurement of peroxide value showed that the level of lipid oxidation was significantly higher for butter stored in air compared with butter stored in nitrogen (N2). This might be explained by the formation of singlet oxygen from direct photooxidation and type II photosensitized oxidation. Addition of the singlet oxygen quencher beta-carotene reduced the rancid flavor intensity in the air and N2 packages from 9.0 to 4.9 and from 6.5 to 4.7, respectively. Results indicate that lipid oxidation in the butter stored in N2 was mainly caused by type I photosensitized reactions, because addition of beta-carotene had little effect on the rancid flavor intensity.


How the International Special Training Centre Is Training World-Class Medics: An Outline of the NATO Special Operations Combat Medic Course.
The North Atlantic Treaty Organization (NATO) Special Operations Combat Medic (NSOCM) course is specifically designed to train 24 highly selected Special Operations Forces (SOF) members to treat trauma and nontrauma patients who have life-threatening diseases and/or injuries. The NSOCM course is held at the International Special Training Centre (ISTC) in Pfullendorf, Germany, and exemplifies ISTC's mission to build interoperability and strengthening alliances between multinational partners. The 24-week NSOCM course is taught by subject matter experts and SOF members from around the globe. Building interoperability and capacity with common NATO standards is crucial to medical support of all future SOF missions where military units and other small elements will be vitally dependent on each other for combined missions at the regional, national, or NATO level. A better understanding and knowledge of the current SOF medic role and the capabilities they need to bring to the battlefield will help advance their scope from the "classic" trauma scenarios to the more advanced clinical medicine and prolonged field care situations. The NSOCM must become a critical-thinker and be able to recognize and treat these health risks and conditions in remote, austere environments, finding the right solution with a limited arsenal at their disposal. The ISTC-NSOCM course is designed to help bridge this gap and raise situational awareness for the NATO on-the-ground medical professionals to ensure "the more they know the more apt they are to save a life." In essence, it is ISTC's goal to meet these challenges by training NSOCMs to meet these multidimensional demands. This article outlines ISTC's development and design of the NSOCM course and new adaptations as we move forward into our third year of training world-class medics.


Winning the genetic lottery: biasing birth sex ratio results in more grandchildren.
Population dynamics predicts that on average parents should invest equally in male and female offspring; similarly, the physiology of mammalian sex determination is supposedly stochastic, producing equal numbers of sons and daughters. However, a high quality parent can maximize fitness by biasing their birth sex ratio (SR) to the sex with the greatest potential to disproportionately outperform peers. All SR manipulation theories share a fundamental prediction: grandparents who bias birth SR should produce more grandoffspring via the favored sex. The celebrated examples of biased birth SRs in nature consistent with SR manipulation theories provide compelling circumstantial evidence. However, this prediction has never been directly tested in mammals, primarily because the complete three-generation pedigrees needed to test whether individual favored offspring produce more grandoffspring for the biasing grandparent are essentially impossible to obtain in nature. Three-generation pedigrees were constructed using 90 years of captive breeding records from 198 mammalian species. Male and female grandparents consistently biased their birth SR toward the sex that maximized second-generation success. The most strongly male-biased granddams and grandsires produced respectively 29% and 25% more grandoffspring than non-skewing conspecifics. The sons of the most male-biasing granddams were 2.7 times as fecund as those of granddams with a 50∶50 bias (similar results are seen in grandsires). Daughters of the strongest female-biasing granddams were 1.2 times as fecund as those of non-biasing females (this effect is not seen in grandsires). To our knowledge, these results are the first formal test of the hypothesis that birth SR manipulation is adaptive in mammals in terms of grandchildren produced, showing that SR manipulation can explain biased birth SR in general across mammalian species. These findings also have practical implications: parental control of birth SR has the potential to accelerate genetic loss and risk of extinction within captive populations of endangered species.


Suppression of extracellular signal-related kinase and activation of p38 MAPK are two critical events leading to caspase-8- and mitochondria-mediated cell death in phytosphingosine-treated human cancer cells.
We previously demonstrated that the phytosphingosine-induced apoptosis was accompanied by the concomitant induction of both the caspase-8-mediated and mitochondrial activation-mediated apoptosis pathways. In the present study, we investigated the role of mitogen-activated protein kinases (MAPKs) in the activation of these two distinct cell death pathways induced by phytosphingosine in human cancer cells. Phytosphingosine caused strong induction of caspase-8 activity and caspase-independent Bax translocation to the mitochondria. A rapid decrease of phosphorylated ERK1/2 and a marked increase of p38 MAPK phosphorylation were observed within 10 min after phytosphingosine treatment. Activation of ERK1/2 by pretreatment with phorbol 12-myristate 13-acetate or forced expression of ERK1/2 attenuated phytosphingosine-induced caspase-8 activation. However, Bax translocation and caspase-9 activation was unaffected, indicating that down-regulation of the ERK activity is specifically required for the phytosphingosine-induced caspase-8-dependent cell death pathway. On the other hand, treatment with SB203580, a p38 MAPK-specific inhibitor, or expression of a dominant negative form of p38 MAPK suppressed phytosphingosine-induced translocation of the proapoptotic protein, Bax, from the cytosol to mitochondria, cytochrome c release, and subsequent caspase-9 activation but did not affect caspase-8 activation, indicating that activation of p38 MAPK is involved in the mitochondrial activation-mediated cell death pathway. Our results suggest that phytosphingosine can utilize two different MAPK signaling pathways for amplifying the apoptosis cascade, enhancing the understanding of the molecular mechanisms utilized by naturally occurring metabolites to regulate cell death. Molecular dissection of the signaling pathways that activate the apoptotic cell death machinery is critical for both our understanding of cell death events and development of cancer therapeutic agents.


The genetic variants of thymic stromal lymphopoietin protein in children with asthma and allergic rhinitis.
Thymic stromal lymphopoietin (TSLP) is expressed by airway epithelial cells and plays a key role in immunological events in asthma. Data on the genetic variants of TSLP and its association with asthma and allergic rhinitis are scarce. We aimed to investigate the effects of the genetic variants of TSLP in children with asthma and allergic rhinitis. The genetic variants of the TSLP gene were determined by sequencing 25 asthmatic and 25 healthy children. In an association study, a population of 506 asthmatics and 157 healthy controls was screened for the following single-nucleotide polymorphisms (SNPs): rs3806933 and rs2289276 in the promoter region; rs11466741, rs11466742, and rs2289278 in intron 2; rs10073816, rs11466749, and rs11466750 in exon 4, and rs11466754 in 3'-UTR. In Multifactor Dimensionality Reduction analysis, presence of the rs11466749 AA genotype with atopy was significantly associated with a diagnosis of asthma (testing set accuracy: 0.720 and cross validation: 9/10). Two functional SNPs showed a gender-specific association with allergy, i.e. the rs3806933 CC genotype with asthma in boys (p = 0.032, nonsignificant after multiple testing) and the rs2289276 CC genotype with higher eosinophil numbers in asthmatic girls (p = 0.003). The presence of allergic rhinitis in asthmatic children strengthened the association of the rs11466749 GG genotype with asthma (p = 0.001), and rs2289276 was significantly associated with lower FEV1 levels in asthmatics without allergic rhinitis (p = 0.003). Variants in the gene encoding the TSLP protein may have differential effects on asthma phenotypes depending on gender, atopy, and the presence of allergic rhinitis.


Intracellular trafficking of metallocarboxypeptidase D in AtT-20 cells: localization to the trans-Golgi network and recycling from the cell surface.
Carboxypeptidase D (CPD) is a recently discovered membrane-bound metallocarboxypeptidase that has been proposed to be involved in the post-translational processing of peptides and proteins that transit the secretory pathway. In the present study, the intracellular distribution of CPD was examined in AtT-20 cells, a mouse anterior pituitary-derived corticotroph. Antisera to CPD stain the same intracellular structures as those labeled with furin and wheat germ agglutinin. This distribution is distinct from carboxypeptidase E, which is localized to the secretory vesicles in the cell processes. The perinuclear distribution of CPD is detected even when the AtT-20 cells are treated with brefeldin A for 1-30 minutes, suggesting that CPD is present in the trans-Golgi network (TGN). Although CPD is predominantly found in the TGN, an antiserum to the full length protein is internalized within 15-30 minutes of incubation at 37 degrees C. In contrast, an antiserum raised against the C-terminal region of CPD does not become internalized, suggesting that this domain is cytosolic. The antiserum to the full length CPD is internalized to a structure that co-stains with furin and wheat germ agglutinin, but is distinct from transferrin recycling endosomes. The internalization of CPD is not substantially affected by treatment of the AtT-20 cells with brefeldin A. These data are consistent with the cycling of CPD to the cell surface and back to the TGN. The TGN localization of CPD raises the possibility of a role for this enzyme in the processing of proteins that transit the secretory pathway.


Dendritic cell homeostasis.
Dendritic cells (DCs) are a heterogeneous fraction of rare hematopoietic cells that coevolved with the formation of the adaptive immune system. DCs efficiently process and present antigen, move from sites of antigen uptake to sites of cellular interactions, and are critical in the initiation of immune responses as well as in the maintenance of self-tolerance. DCs are distributed throughout the body and are enriched in lymphoid organs and environmental contact sites. Steady-state DC half-lives account for days to up to a few weeks, and they need to be replaced via proliferating hematopoietic progenitors, monocytes, or tissue resident cells. In this review, we integrate recent knowledge on DC progenitors, cytokines, and transcription factor usage to an emerging concept of in vivo DC homeostasis in steady-state and inflammatory conditions. We furthermore highlight how knowledge of these maintenance mechanisms might impact on understanding of DC malignancies as well as posttransplant immune reactions and their respective therapies.


[Scientific articles in the Icelandic Medical Journal 2004-2008: an overview].
In the past 5 years the Icelandic Medical Journal has undergone many changes during a period of flourishing research in Iceland. The process of reviewing and editing scientific articles has been revised since the Journal joined the Medline database in 2005 and the proportion of rejected articles has risen. New columns have been launched covering medical history, professionalism, ethics and hobbies of the medical profession. We categorized all scientific articles from the period 2004-2008, that is research articles, review articles, case reports and clinical guidelines, according to types of articles and to which medical speciality or subspeciality the publication should belong. The number of scientific articles rose during the period but the number of research articles remained around 20 most years during the period. The relative proportion of research articles therefore fell whereas the number and proportion of review articles and case reports increased. Clinical guidelines ceased to appear in the Journal. The contribution of individual specialities to the Journal varied widely. Researchers amongst doctors and related professions need be encouraged to submit scientific articles to the Journal. The publication of scientific articles in English in the web-based form of the Journal may prove to be stimulating in this regard for Icelandic doctors abroad as well as for some researchers in Iceland.


Climatic ice core records from the tropical quelccaya ice cap.
The Quelccaya Ice Cap in the easternmost glaciated mountain chain of the Peruvian Andes has been studied in four recentfield seasons. Ice cores to a depth of 15 meters have been retrieved at the summit dome (elevation, 5650 meters) and two other locations and used for microparticle, isotope, and beta radioactivity measurements. A concurrent study of the present climate and the heat and mass budgets is being made to permit a paleoclimatic interpretation of deep core records. The results indicate the need for a revision of the isotope "thermometry" for application in the tropics. However, the seasonality of the beta radioactivity, microparticle content, and isotope ratios offers the prospect of a mass balance chronology. This is important in that precipitation is believed to be a more indicative paleoclimatic parameter than temperature in the tropics.


Standard Lexicons, Coding Systems and Ontologies for Interoperability and Semantic Computation in Imaging.
Standard clinical terms, codes, and ontologies promote clarity and interoperability. Within radiology, there is a variety of relevant content resources, tools and technologies. These provide the basis for fundamental imaging workflows such as reporting and billing, and also facilitate a range of applications in quality improvement and research. This article reviews the key characteristics of lexicons, coding systems, and ontologies. A number of standards are described, including International Classification of Diseases-10-Clinical Modification (ICD-10-CM), Current Procedural Terminology (CPT), Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT), Logical Observation Identifiers Names and Codes (LOINC), and RadLex. Tools for accessing this material are reviewed, such as the National Center for Biomedical Ontology BioPortal system. Web services are discussed as a mechanism for semantic application development. Several example systems, workflows, and research applications using semantic technology are also surveyed.


Ticrynafen-associated hepatic injury: analysis of 340 cases.
Ticrynafen, a uricosuric diuretic, was withdrawn from clinical use in the United States in 1980 after having been implicated as the cause of a number of instances of serious hepatic injury. In this report, we analyze 340 cases of ticrynafen-associated hepatic disease reported to the manufacturer from the time of initial marketing until shortly after the drug had been recalled. Jaundice was recorded in 246 of 287 patients with sufficient clinical information, and 25 (10.2%) of these icteric patients died. The high levels of serum aminotransferase and the case fatality rate are consistent with the hepatocellular injury that was evident in all of the histologic material. In three-fourths of the cases available to us for histologic study, the lesion was that of acute hepatocellular injury. In the remaining cases there was evidence of chronic active hepatitis and/or cirrhosis. Comparison of demographic characteristics of the total population exposed to ticrynafen with the subset developing hepatic injury suggests a proportionately higher risk of injury for females over the age of 60 years. The variable and unusually prolonged latent period and lack of reported eosinophilia or rash generally suggest a mechanism other than hypersensitivity. However, the recurrence of hepatic injury in 15 of the 16 patients challenged with the drug and the prominence of eosinophils in hepatic tissue in some of the cases suggests that hypersensitivity may also play a pathogenetic role. Accordingly, there is reason to incriminate both metabolic idiosyncrasy and hypersensitivity in the mechanism of injury.


Low Calcium Intake in Midpregnancy Is Associated with Hypertension Development within 10 Years after Pregnancy: The Norwegian Mother and Child Cohort Study.
Background: Low dietary calcium intake may be a risk factor for hypertension, but studies conflict.Objective: We evaluated the ability to predict hypertension within 10 y after delivery based on calcium intake during midpregnancy.Methods: The Norwegian Mother and Child Cohort Study of women delivering in 2004-2009 was linked to the Norwegian Prescription Database (2004-2013) to ascertain antihypertensive medication usage >90 d after delivery. Women with hypertension before pregnancy were excluded, leaving 60,027 mothers for analyses. Age and energy-adjusted cubic splines evaluated dose-response curves, and Cox proportional hazard analyses evaluated HR and 95% CIs by calcium quartiles adjusting for 7 covariates. Analyses were stratified by gestational hypertension and by sodium-to-potassium intake ratio (<0.76 compared with ≥0.76).Results: Participants had a mean ± SD age of 30.5 ± 4.6 y, a body mass index (in kg/m2) of 24.0 ± 4.3 before pregnancy, and a mean follow-up duration of 7.1 ± 1.6 y. Cubic spline graphs identified a threshold effect of low calcium intake only within the range of dietary inadequacy related to increased risk. The lowest calcium quartile (≤738 mg/d; median: 588 mg/d), relative to the highest quartile (≥1254 mg/d), had an HR for hypertension of 1.34 (95% CI: 1.05, 1.70) among women who were normotensive during pregnancy, and an HR of 1.62 (95% CI: 1.14, 2.35) among women who had gestational hypertension, after adjusting for covariates. Women with gestational hypertension, who were in the lowest quartile of calcium intake, and who had a high sodium-to-potassium intake ratio had a risk of hypertension more than double that of their counterparts with a calcium intake in the highest quartile. Results were attenuated by adjusting for covariates (HR: 1.92; 95% CI: 1.09, 3.39).Conclusions: The results suggest that low dietary calcium intake may be a risk factor or risk marker for the development of hypertension, particularly for women with a history of gestational hypertension.


Wuchereria bancrofti in a community with seasonal transmission: stability of microfilaraemia, antigenaemia and filarial-specific antibody concentrations.
The effect of seasonal transmission on microfilaraemia, antigenaemia and filarial-specific antibody levels in individuals infected with Wuchereria bancrofti was investigated in a follow-up study in an endemic community in north-eastern Tanzania. The subjects were 37 adult male residents who were found to be positive for circulating filarial antigen (CFA) at the beginning of the study (26 of whom were also found microfilaraemic with W. bancrofti at this time). Blood samples were collected from each subject in July 1998, January 1999 and July 1999, during the seasons when transmission intensity was high, low and high, respectively. The mean intensities of microfilaraemia and the mean concentrations of CFA were each slightly higher during the low-transmission season than during the two high-transmission seasons but the differences were not statistically significant (P > 0.05). Similarly, the mean levels of filarial-specific IgG1, IgG2, IgG3, IgG4 or IgE did not differ to a statistically significant degree between the three examination times. Microfilaraemias and the levels of CFA and filarial-specific antibodies all therefore appeared to be remarkably stable and largely unaffected by the seasonal variation in transmission. That no variation in the mean IgG4/IgE ratio was observed over the study period may indicate that the level of resistance to W. bancrofti infection in the study subjects was also unaffected by the transmission season.


Ancient evolutionary origin of the neural crest gene regulatory network.
The vertebrate neural crest migrates from its origin, the neural plate border, to form diverse derivatives. We previously hypothesized that a neural crest gene regulatory network (NC-GRN) guides neural crest formation. Here, we investigate when during evolution this hypothetical network emerged by analyzing neural crest formation in lamprey, a basal extant vertebrate. We identify 50 NC-GRN homologs and use morpholinos to demonstrate a critical role for eight transcriptional regulators. The results reveal conservation in deployment of upstream factors, suggesting that proximal portions of the network arose early in vertebrate evolution and have been conserved for >500 million years. We found biphasic expression of neural crest specifiers and differences in deployment of some specifiers and effectors expected to confer species-specific properties. By testing the collective expression and function of neural crest genes in a single, basal vertebrate, we reveal the ground state of the NC-GRN and resolve ambiguities between model organisms.