Cloning and expression of CD24 gene in human hepatocellular carcinoma: a potential early tumor marker gene correlates with p53 mutation and tumor differentiation.
To search for genes related to hepatocarcinogenesis, the differential display technique for eukaryotic mRNA was conducted. We have cloned a gene that encodes the CD24 protein from the cDNA library of human hepatocellular carcinoma (HCC). A single 2.1-kb mRNA was identified in HCC specimens and the HuH-7 HCC cell line but only rarely in small amounts in nontumor livers. In 79 unicentric HCC, CD24 mRNA was overexpressed in 52 cases (66%), found in trace amounts in 11, and not detectable in 16 (20%). In 12 cases of multicentric HCC, CD24 mRNA was overexpressed in 21 (68%) of 31 tumor nodules and was helpful for the determination of tumor clonal origin. There was an increased frequency of CD24 mRNA overexpression in patients younger than 50 years with HCC (86% versus 59%, P < 0.025), in serum hepatitis B surface antigen-positive individuals (74% versus 48%, P < 0.023), in those with an elevated serum alpha-fetoprotein level (82%, versus 56%, P < 0.04), and in HCC with alpha-fetoprotein mRNA expression (82% versus 56%, P < 0.04). There was a strong correlation of CD24 mRNA overexpression with p53 gene mutation in HCC (91% versus 46%, P < 0.0005) and poorly differentiated HCC (82% versus 53%, P < 0.0008). Despite its correlation with p53 mutation and the unfavorable outcome of HCC with p53 mutation, the CD24 mRNA expression did not correlate with tumor size, tumor invasiveness, or patient's prognosis. Thus, the CD24 gene expression appears to be a common event in HCC and may serve as an early but not prognostic biomarker for malignant transformation of hepatocytes.


Assessment of success on the RHIA certification examination: a comparison of baccalaureate program graduates and postbaccalaureate certificate program graduates.
The demand for registered health information administrators continues to outpace the available supply of credentialed graduates. One solution to address this shortfall has been the availability of postbaccalaureate certificate programs. A health information administration department at an academic health sciences center, which has historically offered a traditional bachelor of science degree in health information administration, has offered a postbaccalaureate certificate program in health information administration since 2001. As part of the program's ongoing quality review/performance improvement process, program faculty conducted an analysis to determine whether success on the registered health information administrator (RHIA) certification examination was the same, regardless of the program type or method of course delivery. Results of this analysis demonstrated that the postbaccalaureate certificate program is a viable alternative for producing successful health information administration graduates, increasing program enrollment, and increasing the number of RHIAs in the workforce. Health information administration programs may consider a postbaccalaureate certificate program as a way to increase the number of graduates and in turn increase the health information administration workforce.


Effect of Message Type on the Visual Attention of Adults With Traumatic Brain Injury.
The purpose of this investigation was to measure the effect of message type (i.e., action, naming) on the visual attention patterns of individuals with and without traumatic brain injury (TBI) when viewing grids composed of 3 types of images (i.e., icons, decontextualized photographs, and contextualized photographs). Fourteen adults with TBI and 14 without TBI-assigned either to an action or naming message condition-viewed grids composed of 3 different image types. Participants' task was to select/sustain visual fixation on the image they felt best represented a stated message (i.e., action or naming). With final fixation location serving as a proxy for selection, participants in the naming message condition selected decontextualized photographs significantly more often than the other 2 image types. Participants in the action message condition selected contextualized photographs significantly more frequently than the other 2 image types. Minimal differences were noted between participant groups. This investigation provides preliminary evidence of the relationship between image and message type. Clinicians involved in the selection of images used for message representation should consider the message being represented when designing supports for people with TBI. Further research is necessary to fully understand the relationship between images and message type.


Reasons for medical help-seeking behaviour of patients with recent-onset arthralgia.
Patient delay in seeking medical help may cause suboptimal use of the therapeutic window in rheumatoid arthritis. We aimed to assess the motivations and the urgency with which patients with arthralgia seek medical help. 612 patients with arthralgia-visiting two Dutch Early Arthritis Recognition Clinics-were studied. Patients filled out a questionnaire with questions on their symptoms and their reasons for seeking medical help. Comparisons were made for patients with short or prolonged patient delay, patients with and without arthritis, age and gender. The median symptom duration was 4 weeks. A prolonged delay in seeking help was associated with a gradual onset of symptoms (78%) and the perception that symptoms would not be serious or would go away (16% and 48%, respectively). Arthralgia patients who promptly sought medical help more often had an acute onset of symptoms and more frequently reported impairments at work or in daily functioning than patients who postponed seeking help (all p<0.005). Patients with and without arthritis generally had similar reasons for seeking help. The proportion of patients who had a prolonged patient delay was comparable between male and female subjects and between age categories. Particularly younger patients postponed seeking help because they thought their symptoms would disappear spontaneously. This large-scale study observed several reasons and symptom characteristics influencing the help-seeking behaviour of persons with arthralgia. These data can be helpful to define strategies aiming at early identification of arthritis.


Topical review. Dental pain and odontoblasts: facts and hypotheses.
Dental pain arises from exposed dentin following bacterial, chemical, or mechanical erosion of enamel and/or recession of gingiva. Thus, dentin tissue and more specifically patent dentinal tubules represent the first structure involved in dentin sensitivity. Interestingly, the architecture of dentin could allow for the transfer of information to the underlying dental pulp via odontoblasts (dentin-forming cells), via their apical extension bathed in the dentinal fluid running in the tubules, or via a dense network of trigeminal sensory axons intimately related to odontoblasts. Therefore, external stimuli causing dentinal fluid movements and odontoblasts and/or nerve complex responses may represent a unique mechanosensory system bringing a new role for odontoblasts as sensor cells. How cells sense signals and how the latter are transmitted to axons represent the main questions to be resolved. However, several lines of evidence have demonstrated that odontoblasts express mechano- and/or thermosensitive transient receptor potential ion channels (TRPV1, TRPV2, TRPV3, TRPV4, TRPM3, KCa, TREK-1) that are likely to sense heat and/or cold or movements of dentinal fluid within tubules. Added to this, voltage-gated sodium channels confer excitable properties of odontoblasts in vitro in response to injection of depolarizing currents. In vivo, sodium channels co-localize with nerve terminals at the apical pole of odontoblasts and correlate with the spatial distribution of stretch-activated KCa channels. This highlights the terminal web as the pivotal zone of the pulp/dentin complex for sensing external stimuli. Crosstalk between odontoblasts and axons may take place by the release of mediators in the gap space between odontoblasts and axons in view of evidence for nociception-transducing receptors on trigeminal afferent fibers and expression of putative effectors by odontoblasts. Finally, how axons are guided to the target cells and which kind of signaling molecules are involved is extensively discussed in this review.


Cost-effectiveness of risk assessment and tailored treatment for peripheral arterial disease patients.
The objective of this study was to explore the cost-effectiveness of D-dimer biomarker and the societal value (headroom) of a hypothetical perfect biomarker for risk assessment and subsequent treatment stratification of prophylactic treatment for peripheral arterial disease (PAD). Decision analytic modeling. Use of the D-dimer biomarker to prescribe oral anticoagulants in the high-risk subset of patients is a cost-effective healthcare intervention. The headroom (societal willingness to pay multiplied by incremental quality-adjusted life years) available for the hypothetical perfect biomarker amounted to €83,877. D-dimer-based PAD risk assessment and treatment tailoring is cost effective. Identification of high-risk PAD patients and prescription of oral anticoagulants could potentially save substantial costs and improve chances of survival for high-risk PAD patients. However, further research of risk stratifying biomarkers test accuracy is needed to support and strengthen the results of this modeling study.


PI4KIIIβ is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma.
Heightened secretion of protumorigenic effector proteins is a feature of malignant cells. Yet, the molecular underpinnings and therapeutic implications of this feature remain unclear. Here, we identify a chromosome 1q region that is frequently amplified in diverse cancer types and encodes multiple regulators of secretory vesicle biogenesis and trafficking, including the Golgi-dedicated enzyme phosphatidylinositol (PI)-4-kinase IIIβ (PI4KIIIβ). Molecular, biochemical, and cell biological studies show that PI4KIIIβ-derived PI-4-phosphate (PI4P) synthesis enhances secretion and accelerates lung adenocarcinoma progression by activating Golgi phosphoprotein 3 (GOLPH3)-dependent vesicular release from the Golgi. PI4KIIIβ-dependent secreted factors maintain 1q-amplified cancer cell survival and influence prometastatic processes in the tumor microenvironment. Disruption of this functional circuitry in 1q-amplified cancer cells with selective PI4KIIIβ antagonists induces apoptosis and suppresses tumor growth and metastasis. These results support a model in which chromosome 1q amplifications create a dependency on PI4KIIIβ-dependent secretion for cancer cell survival and tumor progression.


Histocompatibility screening by molecular techniques: use of polymerase chain reaction products and heteroduplex formation.
Novel molecular approaches have recently become available allowing improved major histocompatibility complex (MHC) matching of potential allogeneic bone marrow donors and recipients. Current cellular and serological assays are hindered by aberrant cell populations and limited reagents which only detect an individuals' phenotype. Therefore, a molecular screening protocol which discriminates at the genotypic level would be advantageous. Here we describe a two-step DNA-based approach that can be applied to large-scale screening of potential donors. A primary screen, utilizing polymerase chain reaction (PCR), reduces the potential donor population, whereas a secondary or fine resolution screen uses DNA heteroduplex analysis to determine identity or non-identity at specific loci. Heteroduplex analysis generates a DNA migration pattern that is unique for alleles at a given locus, and is more sensitive than serology in discriminating among individuals. Here we demonstrate the potential feasibility of this approach by analyzing results at one MHC locus, HLA-DQ. Since this method does not rely on typing sera or viable lymphocytes, it is not subject to the variability found in the traditional methods. In contrast to traditional methods, these molecular techniques can provide the critical information needed to select a potential bone marrow donor.


Reliability and validity evidence of multiple balance assessments in athletes with a concussion.
An estimated 300 000 sport-related concussion injuries occur in the United States annually. Approximately 30% of individuals with concussions experience balance disturbances. Common methods of balance assessment include the Clinical Test of Sensory Organization and Balance (CTSIB), the Sensory Organization Test (SOT), the Balance Error Scoring System (BESS), and the Romberg test; however, the National Collegiate Athletic Association recommended the Wii Fit as an alternative measure of balance in athletes with a concussion. A central concern regarding the implementation of the Wii Fit is whether it is reliable and valid for measuring balance disturbance in athletes with concussion. To examine the reliability and validity evidence for the CTSIB, SOT, BESS, Romberg test, and Wii Fit for detecting balance disturbance in athletes with a concussion. Literature considered for review included publications with reliability and validity data for the assessments of balance (CTSIB, SOT, BESS, Romberg test, and Wii Fit) from PubMed, PsycINFO, and CINAHL. We identified 63 relevant articles for consideration in the review. Of the 63 articles, 28 were considered appropriate for inclusion and 35 were excluded. No current reliability or validity information supports the use of the CTSIB, SOT, Romberg test, or Wii Fit for balance assessment in athletes with a concussion. The BESS demonstrated moderate to high reliability (interclass correlation coefficient = 0.87) and low to moderate validity (sensitivity = 34%, specificity = 87%). However, the Romberg test and Wii Fit have been shown to be reliable tools in the assessment of balance in Parkinson patients. The BESS can evaluate balance problems after a concussion. However, it lacks the ability to detect balance problems after the third day of recovery. Further investigation is needed to establish the use of the CTSIB, SOT, Romberg test, and Wii Fit for assessing balance in athletes with concussions.


In Silico Trial of MR-Guided Midtreatment Adaptive Planning for Hypofractionated Stereotactic Radiation Therapy in Centrally Located Thoracic Tumors.
Hypofractionated (>5 fraction) stereotactic radiation therapy (HSRT) may allow for ablative biologically equivalent dose to tumors with a lower risk of organ-at-risk (OAR) toxicity in central thoracic tumors. Adaptive planning may further improve OAR sparing while maintaining planning target volume (PTV) coverage. We hypothesized that midtreatment adaptive replanning would offer dosimetric advantages during HSRT for central thorax malignancies using magnetic resonance imaging (MRI)-guided radiation therapy. Twelve patients with central thorax tumors received HSRT using MRI-guided radiation therapy. Clinically delivered regimens were 60 Gy in 12 fractions or 62.5 Gy in 10 fractions, with low-field magnetic resonance (0.35 T) volumetric setup imaging acquired at each fraction. Daily gross tumor volume (GTV) and OARs were retrospectively redefined on fraction 1, 6, and 10 MRIs, and GTV response was recorded. Simulated initial plans prescribed a dose of 60 Gy in 12 fractions based on fraction 1 MRI. Midtreatment adaptive plans were created based on fraction 6 anatomy-of-the-day. All plans were created using an isotoxicity approach with a goal of 95% PTV coverage, subject to hard OAR constraints, to represent clinically ideal OAR sparing. Plans were then compared for projected OAR sparing and PTV coverage. Patients demonstrated significant on-treatment MRI-defined GTV reduction (median 41.8%; range 16.7%-65.7%). At fraction 6, median reduction was 26.7%. All initial plans met OAR constraints. Initial plan application to fraction 6 and fraction 10 anatomy resulted in 8 OAR violations (5 of 13 patients) and 10 OAR violations (6 of 13 patients). All fraction 6 violations persisted at fraction 10. Midpoint adaptive planning reversed 100% of midpoint OAR violations and tended to reduce the magnitude of OAR violations incurred at fraction 10. In 40% of fractions (2 of 5) in which OAR violation resulted from initial plan application to fraction 6 anatomy, PTV coverage was increased concomitant with violation reversal. Midtreatment adaptive planning based on tumor response may be dosimetrically advantageous for sparing of surrounding critical structures in HSRT for central thorax malignancies and could be applied using either an online or offline paradigm.


Automatic detection of whole night snoring events using non-contact microphone.
Although awareness of sleep disorders is increasing, limited information is available on whole night detection of snoring. Our study aimed to develop and validate a robust, high performance, and sensitive whole-night snore detector based on non-contact technology. Sounds during polysomnography (PSG) were recorded using a directional condenser microphone placed 1 m above the bed. An AdaBoost classifier was trained and validated on manually labeled snoring and non-snoring acoustic events. Sixty-seven subjects (age 52.5 ± 13.5 years, BMI 30.8 ± 4.7 kg/m(2), m/f 40/27) referred for PSG for obstructive sleep apnea diagnoses were prospectively and consecutively recruited. Twenty-five subjects were used for the design study; the validation study was blindly performed on the remaining forty-two subjects. To train the proposed sound detector, >76,600 acoustic episodes collected in the design study were manually classified by three scorers into snore and non-snore episodes (e.g., bedding noise, coughing, environmental). A feature selection process was applied to select the most discriminative features extracted from time and spectral domains. The average snore/non-snore detection rate (accuracy) for the design group was 98.4% based on a ten-fold cross-validation technique. When tested on the validation group, the average detection rate was 98.2% with sensitivity of 98.0% (snore as a snore) and specificity of 98.3% (noise as noise). Audio-based features extracted from time and spectral domains can accurately discriminate between snore and non-snore acoustic events. This audio analysis approach enables detection and analysis of snoring sounds from a full night in order to produce quantified measures for objective follow-up of patients.


Nature of the multiple forms of sweet-potato glucose phosphate isomerase.
The previously reported isoenzymes of sweet-potato glucose 6-phosphate isomerase were resolved by DEAE-cellulose chromatography. The multiple forms exhibited identical electrophoretic properties and electrofocused as a single component with an apparent isoelectric pH of 4.0. Chromatographic studies also suggest that the multiple forms do not represent true isoenzymes.


Precursor chemistry matters in boosting photoredox activity of graphene/semiconductor composites.
Considerable effort has been made to fabricate graphene (GR)/semiconductor composite photocatalysts, by using graphene oxide (GO) as the most widely used precursor of GR, toward an improved efficacy of solar energy conversion. However, thus far, the role of GO in the preparation and photocatalytic activity of GR/semiconductor composites has remained rather elusive. Herein, we report a simple yet efficient approach to significantly improve the photocatalytic activity of GR/semiconductor CdS composites via the acid treatment of GO, which downsizes GO sheets into smaller ones with enhanced colloidal stability and oxygenated functional groups. The graphene/CdS composites, which are prepared using this type of downsized GO as the precursor of GR, exhibit remarkably higher visible-light photoredox activity than those prepared from the direct reduction of GO without acid treatment. Our comparative results directly highlight the important effect of physico-chemical features of GO on the preparation and thus photoactivity of GR/semiconductor composites; in particular, the rational tailoring of GO could open a new doorway to optimize the activity of GO-derived GR/semiconductor composite photocatalysts.


Correlation between work impairment, scores of rhinitis severity and asthma using the MASK-air® App.
In allergic rhinitis, a relevant outcome providing information on the effectiveness of interventions is needed. In MASK-air (Mobile Airways Sentinel Network), a visual analogue scale (VAS) for work is used as a relevant outcome. This study aimed to assess the performance of the work VAS work by comparing VAS work with other VAS measurements and symptom-medication scores obtained concurrently. All consecutive MASK-air users in 23 countries from 1 June 2016 to 31 October 2018 were included (14 189 users; 205 904 days). Geolocalized users self-assessed daily symptom control using the touchscreen functionality on their smart phone to click on VAS scores (ranging from 0 to 100) for overall symptoms (global), nose, eyes, asthma and work. Two symptom-medication scores were used: the modified EAACI CSMS score and the MASK control score for rhinitis. To assess data quality, the intra-individual response variability (IRV) index was calculated. A strong correlation was observed between VAS work and other VAS. The highest levels for correlation with VAS work and variance explained in VAS work were found with VAS global, followed by VAS nose, eye and asthma. In comparison with VAS global, the mCSMS and MASK control score showed a lower correlation with VAS work. Results are unlikely to be explained by a low quality of data arising from repeated VAS measures. VAS work correlates with other outcomes (VAS global, nose, eye and asthma) but less well with a symptom-medication score. VAS work should be considered as a potentially useful AR outcome in intervention studies.


Basis for the altered arterial wall mechanics in the spontaneously hypertensive rat.
Carotid and tail arteries from 20-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were used to compare mechanics and biochemical properties. Measurements of pressure-diameter relations were made on isolated segments under conditions of active (145 mM K+) and passive (O mM Ca+2 and 2 mM EGTA) smooth muscle. Connective tissue, water and electrolyte contents, and extracellular water spaces were determined. Chemical data were also obtained from segments of thoracic aorta. The passive mechanics of arteries from the SHR were stiffer compared to those from WKY. Total connective tissue content (collagen + elastin) and collagen/elastin ratio were both smaller in the SHR arteries. Differences in the characteristics of the connective tissue matrix other than total content must exist in SHR and WKY arteries. Maximum values of active stress (force/area) developed by SHR arteries were larger and occurred at smaller values of wall strain compared to WKY arteries. The maximum reduction in wall diameter with smooth muscle activation was larger in the WKY arteries, but these constriction responses were better maintained at higher pressures by SHR arteries. Extracellular water space was lower in SHR arteries, while total water content was not different. The fraction of the wall of SHR arteries occupied by smooth muscle cells was larger than that of WKY arteries. When values of maximum active stress were normalized to the relative cell content, no difference was found for SHR and WKY carotids, but SHR tail arteries still produced a significantly larger active cell stress than WKY tail arteries. This suggests that intrinsic differences exist in the properties of smooth muscle cells of SHR and WKY tail arteries.


The Atlas of human African trypanosomiasis: a contribution to global mapping of neglected tropical diseases.
Following World Health Assembly resolutions 50.36 in 1997 and 56.7 in 2003, the World Health Organization (WHO) committed itself to supporting human African trypanosomiasis (HAT)-endemic countries in their efforts to remove the disease as a public health problem. Mapping the distribution of HAT in time and space has a pivotal role to play if this objective is to be met. For this reason WHO launched the HAT Atlas initiative, jointly implemented with the Food and Agriculture Organization of the United Nations, in the framework of the Programme Against African Trypanosomosis. The distribution of HAT is presented for 23 out of 25 sub-Saharan countries having reported on the status of sleeping sickness in the period 2000-2009. For the two remaining countries, i.e. Angola and the Democratic Republic of the Congo, data processing is ongoing. Reports by National Sleeping Sickness Control Programmes (NSSCPs), Non-Governmental Organizations (NGOs) and Research Institutes were collated and the relevant epidemiological data were entered in a database, thus incorporating (i) the results of active screening of over 2.2 million people, and (ii) cases detected in health care facilities engaged in passive surveillance. A total of over 42 000 cases of HAT and 6 000 different localities were included in the database. Various sources of geographic coordinates were used to locate the villages of epidemiological interest. The resulting average mapping accuracy is estimated at 900 m. Full involvement of NSSCPs, NGOs and Research Institutes in building the Atlas of HAT contributes to the efficiency of the mapping process and it assures both the quality of the collated information and the accuracy of the outputs. Although efforts are still needed to reduce the number of undetected and unreported cases, the comprehensive, village-level mapping of HAT control activities over a ten-year period ensures a detailed and reliable representation of the known geographic distribution of the disease. Not only does the Atlas serve research and advocacy, but, more importantly, it provides crucial evidence and a valuable tool for making informed decisions to plan and monitor the control of sleeping sickness.


A randomized phase II presurgical trial of weekly low-dose tamoxifen versus raloxifene versus placebo in premenopausal women with estrogen receptor-positive breast cancer.
We previously demonstrated that 1 or 5 mg per day of tamoxifen (T) given for four weeks before surgery reduces Ki-67 in breast cancer (BC) patients to the same extent as the standard 20 mg/d. Given the long half-life of T, a weekly dose (10 mg per week (w)) may be worth testing. Also, raloxifene (R) has shown Ki-67 reduction in postmenopausal patients in a preoperative setting, but data in premenopausal women are limited. We conducted a randomized trial testing T 10 mg/w vs. R 60 mg/d vs. placebo in a presurgical model. Out of 204 screened subjects, 57 were not eligible, 22 refused to participate and 125 were included in the study. The participants were all premenopausal women with estrogen receptor-positive BC. They were randomly assigned to either T 10mg/w or R 60 mg/d or placebo for six weeks before surgery. The primary endpoint was tissue change of Ki-67. Secondary endpoints were modulation of estrogen and progesterone receptors and several other circulating biomarkers. Ki-67 was not significantly modulated by either treatment. In contrast, both selective estrogen receptor modulators (SERMs) significantly modulated circulating IGF-I/IGFBP-3 ratio, cholesterol, fibrinogen and antithrombin III. Estradiol was increased with both SERMs. Within the tamoxifen arm, CYP2D6 polymorphism analysis showed a higher concentration of N-desTamoxifen, one of the tamoxifen metabolites, in subjects with reduced CYP2D6 activity. Moreover, a reduction of Ki-67 and a marked increase of sex hormone-binding globulin (SHBG) were observed in the active phenotype. A weekly dose of tamoxifen and a standard dose of raloxifene did not inhibit tumor cell proliferation, measured as Ki-67 expression, in premenopausal BC patients. However, in the tamoxifen arm women with an extensive phenotype for CYP2D6 reached a significant Ki-67 modulation.


Intermittent hypothermia is neuroprotective in an in vitro model of ischemic stroke.
To investigate whether the intermittent hypothermia (IH) protects neurons against ischemic insult and the potential molecular targets using an in vitro ischemic model of oxygen glucose deprivation (OGD). Fetal rat cortical neurons isolated from Day E18 rat embryos were subjected to 90-min OGD and hypothermia treatments during reoxygenation before examining the changes in microscopic morphology, cell viability, microtubule- associated protein 2 (MAP-2) release, intracellular pH value and calcium, reactive oxygen species (ROS) generation, mitochondrial membrane potential (△Ψm) and neuronal death using cell counting kit (CCK-8), enzyme-linked immunosorbent assay (ELISA), BCECF AM, Fluo-3 AM, DCFH-DA and dihydroethidium (DHE), JC-1 staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), respectively. 90-min OGD induced morphologic abnormalities, cell viability decline, MAP-2 release, intracellular acidosis, calcium overload, increased ROS generation, △Ψm decrease and cell death in primary neurons, which was partially inhibited by continuous hypothermia (CH) and intermittent hypothermia (IH). Interestingly, 6-h CH was insufficient to reduce intracellular calcium overload and stabilize mitochondrial membrane potential (△Ψm), while 12-h CH was effective in reversing the above changes. All IH treatments (6×1 h, 4×1.5 h or 3×2 h) effectively attenuated intracellular free calcium overload, inhibited ROS production, stabilized mitochondrial membrane potential (△Ψm) and reduced delayed cell death in OGD-treated cells. However, only IH intervals longer than 1.5 h appeared to be effective in preventing cell viability loss and intracellular pH decline. Both CH and IH were neuroprotective in an in vitro model of ischemic stroke, and in spite of shorter hypothermia duration, IH could provide a comparable neuroprotection to CH.


EVALUATING MMP-2 AND TGFß-RI EXPRESSION IN CIRCULATING TUMOR CELLS OF PANCREATIC CANCER PATIENTS AND THEIR CORRELATION WITH CLINICAL EVOLUTION.
Metastasis is common in the diagnosis of pancreatic cancer, and the presence of epithelial-mesenchymal transition markers in circulating tumor cells may suggest worse prognosis. To correlate the number of circulating tumor cells (CTCs) in the peripheral blood of patients with a locally advanced or metastatic pancreatic tumor and the protein expression involved in epithelial-mesenchymal transition (EMT) in CTCs with clinical characteristics, progression-free survival (PFS) and overall survival (OS). This was a prospective study conducted using peripheral blood samples collected at three different times. CTCs were quantified by the ISET test and analyzed by immunocytochemistry. Proteins involved in EMT (vimentin, TGFß-RI and MMP2) were analyzed in all CTCs. Twenty-one patients were included. Median CTCs detected were 22, 20 and 8 CTCs/8 ml blood at baseline, first and second follow-up, respectively. No statistically significant correlation was found in correlating the number of CTCs and the evaluated clinical characteristics, PFS, or OS. There was no difference in PFS and OS among the EMT markers in the groups with and without markers. CTC analysis was not relevant in this sample for comparing clinical findings, PFS and OS in patients with pancreatic cancer. However, marker analysis in CTCs could be useful for the MMP-2 and/or TGFß-RI expression, as observed by the separate PFS curve.


Accuracy of staging in primary biliary cirrhosis.
To evaluate sampling variability of liver biopsy in patients with primary biliary cirrhosis (PBC). Sections from 50 PBC liver specimens obtained at transplantation were examined. The degree of fibrosis was assessed on a scale of 0-4 using two methods: (1) simulated needle biopsy in fields approximately the size of conventional needle biopsy; and (2) whole section scanning in areas with little and extensive fibrosis. Considerable variation in the range of stages of fibrosis was found when the whole section scanning method was used. Only 10 (20%) samples had a consistent degree of fibrosis in all sections scanned. By contrast, the same fibrosis stage was assigned in 30 (60%) specimens examined using the simulated needle biopsy method. When the results obtained by the two methods were compared, there was a discrepancy of one or two stages in 32 samples. This discrepancy was the result of discovering areas with a lesser degree of fibrosis in whole sections compared with the simulated needle biopsy specimens. There is considerable variation in the degree of fibrosis in the livers of patients with PBC, even when end stage specimens obtained at transplantation are examined. Consistent results were obtained when simulated needle biopsy specimens were examined. This, however, may be a reflection of the procedure applied when staging liver needle biopsy specimens, where the greatest degree of abnormality is used in determining the stage. The practice of staging of PBC in small needle biopsy specimens is valuable as long as the appearances are interpreted with caution, bearing in mind that there is considerable variability in the degree of fibrosis.


Developing expert medical teams: toward an evidence-based approach.
Current health care literature cites communication breakdown and teamwork failures as primary threats to patient safety. The unique, dynamic environment of the emergency department (ED) and the complexity of patient care necessitate the development of strong interdisciplinary team skills among emergency personnel. As part of the 2008 Academic Emergency Medicine Consensus Conference on "The Science of Simulation in Healthcare," our workshop group identified key theory and evidence-based recommendations for the design and implementation of team training programs. The authors then conducted an extensive review of the team training literature within the domains of organizational psychology, aviation, military, management, and health care. This review, in combination with the workshop session, formed the basis for recommendations and need for further research in six key areas: 1) developing and refining core competencies for emergency medicine (EM) teams; 2) leadership training for emergency physicians (EPs); 3) conducting comprehensive needs analyses at the organizational, personnel, and task levels; 4) development of training platforms to maximize knowledge transfer; 5) debriefing and provision of feedback; and 6) proper implementation of simulation technology. The authors believe that these six areas should form an EM team training research platform to advance the EM literature, while leveraging the unique team structures present in EM to expand team training theory and research.


Antibacterial activity of antisera against homologous and heterologous Escherichia coli of porcine origin.
Fourteen enteropathogenic and five nonenterotoxigenic Escherichia coli strains isolated from pigs were used for producing antisera in rabbits and pigs. These antisera were used in an vitro test system for antibacterial activity against homologous and heterologous porcine E. coli strains. Antibacterial titres were determined against the homologous strains and the percent reduction in CFU/ml caused by a 1/200 dilution of the sera against heterologous strains was determined. The results indicated that following immunization the antibacterial activity of serum against homologous and heterologous strains was significantly increased. This activity did not appear to be influenced by O and K antigen relationships among the organisms or by enterotoxigenicity of the vaccine strains. When antiserum produced against a combination of three enteropathogenic E. coli was tested against 20 strains a wider spectrum of heterologous antibacterial activity was obtained than with antiserum produced against any individual strain. The results indicate the existence in E. coli strains of porcine origin of common antigenic determinants not related to the serological formula and that a selected combination of strains can be expected to induce antibacterial acitivity against a wide variety of serological types of porcine enteropathogenic E. coli.


Helium and methane sources and fluxes of shallow submarine hydrothermal plumes near the Tokara Islands, Southern Japan.
Shallow submarine volcanoes have been newly discovered near the Tokara Islands, which are situated at the volcanic front of the northern Ryukyu Arc in southern Japan. Here, we report for the first time the volatile geochemistry of shallow hydrothermal plumes, which were sampled using a CTD-RMS system after analyzing water column images collected by multi-beam echo sounder surveys. These surveys were performed during the research cruise KS-14-10 of the R/V Shinsei Maru in a region stretching from the Wakamiko Crater to the Tokara Islands. The 3He flux and methane flux in the investigated area are estimated to be (0.99-2.6) × 104 atoms/cm2/sec and 6-60 t/yr, respectively. The methane in the region of the Tokara Islands is a mix between abiotic methane similar to that found in the East Pacific Rise and thermogenic one. Methane at the Wakamiko Crater is of abiotic origin but affected by isotopic fractionation through rapid microbial oxidation. The helium isotopes suggest the presence of subduction-type mantle helium at the Wakamiko Crater, while a larger crustal component is found close to the Tokara Islands. This suggests that the Tokara Islands submarine volcanoes are a key feature of the transition zone between the volcanic front and the spreading back-arc basin.


Effects of dietary lipid, vitamins and minerals on total amounts and redox status of glutathione and ubiquinone in tissues of Atlantic salmon (Salmo salar): a multivariate approach.
The hypothesis of the present study was that Atlantic salmon (Salmo salar) would respond to large variations in supplementation of dietary pro- and antioxidants, and marine lipid, with adjustment of the endogenously synthesised antioxidants, glutathione (GSH) and ubiquinone (UQ). An experiment with 2(7-3) reduced factorial design (the number of cases reduced systematically from 2(7) (full design) to 2(4) (reduced design)) was conducted, where vitamins, minerals and lipid were supplemented in the diet at high and low levels. For the vitamins and minerals the high levels were chosen to be just below anticipated toxic levels and the low levels were just above the requirement (vitamin C, 30 and 1000 mg/kg; vitamin E, 70 and 430 mg/kg; Fe, 70 and 1200 mg/kg; Cu, 8 and 110 mg/kg; Mn, 12 and 200 mg/kg). For astaxanthin, the dietary levels were 10 and 50 mg/kg and for lipid, 150 and 330 g/kg. The experiment was started with post-smolts (148 (sd 17 g)) and lasted for 5 months. The only effect on GSH was a minor increase ( < 10 %) in total concentration in the liver in response to high dietary lipid. GSH redox state was not affected. UQ responded to dietary lipid, astaxanthin and vitamin E, both with regard to total concentration and redox state. Except for an effect of Fe on plasma GSH, the trace elements and vitamin C had no effect on tissue levels and oxidation state of GSH and UQ. This shows that the endogenous redox state is quite robust with regard to variation of dietary pro- and antioxidants in Atlantic salmon.


The effects of resistance training interventions on vertical jump performance in basketball players: a meta-analysis.
Vertical jump performance is one of the key factors in basketball. In order to determine the effectiveness of previously published interventions and their influencing factors we performed a meta-analysis. A computerized search was conducted using the databases PubMed (1966), Web of Science (1900), SPORTDiscus™ (1975),Medline (1966) and SportPilot (2008). Studies involving healthy male or female basketball players at any age and performance level were included. All trials had to investigate the benefits of resistance training programs on jumping performance in basketball players and provide a control group. The effect size (ES) was computed and the relationship between ESs and continuous variables was examined by meta-regressions, whereas subgroup meta-analyses and z-tests were used to assess the impact of categorical moderator variables. The meta-analysis included 14 studies with 20 subgroups and a total of 37 outcomes. A total of 399 participants were examined, N.=157 served as control and N.=242 took part in particular training interventions. The overall weighted ES of 0.78 (95% CI 0.41, 1.15) was significantly greater than zero (P<0.001). None of the categorical moderator variables affected the training effect. However, positive correlations were found for training duration (r=0.68; P=0.02). The present meta-analysis demonstrates that resistance training throughout the year, using bodyweight or external weight, significantly improves vertical jump performance in healthy basketball players. Since vertical jump improvements were independent of intervention period but dependent on the duration of each individual training session the total training amount should be based on longer training sessions.


Vaginal bleeding and adverse reproductive outcomes: a meta-analysis.
The objective of this paper is to characterise and quantify the association between vaginal bleeding and pregnancy outcome. A meta-analysis was performed in order to quantify the risk of adverse reproductive outcome by combining evidence from all previous studies of vaginal bleeding. The reproductive endpoints considered were low birthweight, preterm birth, stillbirth, perinatal death and congenital malformation. The meta-analysis confirms an association of vaginal bleeding with adverse pregnancy outcomes, but identified discrepancies in the reported risks of vaginal bleeding and magnitudes of association between bleeding and adverse reproductive outcomes, observed across studies. These discrepancies may be attributed to inconsistent definitions of the timing and severity of vaginal bleeding. The implications of such inconsistencies are discussed, suggesting a need for more standardised definitions of vaginal bleeding and reproductive endpoints in future studies.


Tai Chi practitioners have better postural control and selective attention in stepping down with and without a concurrent auditory response task.
To compare the performance of older experienced Tai Chi practitioners and healthy controls in dual-task versus single-task paradigms, namely stepping down with and without performing an auditory response task, a cross-sectional study was conducted in the Center for East-meets-West in Rehabilitation Sciences at The Hong Kong Polytechnic University, Hong Kong. Twenty-eight Tai Chi practitioners (73.6 ± 4.2 years) and 30 healthy control subjects (72.4 ± 6.1 years) were recruited. Participants were asked to step down from a 19-cm-high platform and maintain a single-leg stance for 10 s with and without a concurrent cognitive task. The cognitive task was an auditory Stroop test in which the participants were required to respond to different tones of voices regardless of their word meanings. Postural stability after stepping down under single- and dual-task paradigms, in terms of excursion of the subject's center of pressure (COP) and cognitive performance, was measured for comparison between the two groups. Our findings demonstrated significant between-group differences in more outcome measures during dual-task than single-task performance. Thus, the auditory Stroop test showed that Tai Chi practitioners achieved not only significantly less error rate in single-task, but also significantly faster reaction time in dual-task, when compared with healthy controls similar in age and other relevant demographics. Similarly, the stepping-down task showed that Tai Chi practitioners not only displayed significantly less COP sway area in single-task, but also significantly less COP sway path than healthy controls in dual-task. These results showed that Tai Chi practitioners achieved better postural stability after stepping down as well as better performance in auditory response task than healthy controls. The improved performance that was magnified by dual motor-cognitive task performance may point to the benefits of Tai Chi being a mind-and-body exercise.


[Evidence-based management of right heart failure: a systematic review of an empiric field].
In recent years, several studies have shown that right ventricular function is an important predictor of survival in patients with congenital heart disease, pulmonary hypertension or left heart failure. Our understanding of right heart failure has improved considerably over the last two decades. In this review article, our objective was to provide a critical summary of the evidence underlying the management of right heart failure. A systematic review of the literature was performed using PubMed and the latest issue of the Cochrane Central Register of Controlled Trials to identify studies conducted between January 1975 and January 2010. The literature search encompassed observational studies, randomized controlled trials and meta-analyses. The evidence underlying the use of beta-blockade, angiotensin-converting enzyme inhibitors, inhaled nitric oxide, hydralazine, warfarin, and resynchronization therapy in right heart failure was systematically reviewed. Emerging new therapies, such as metabolic modulators, and the pearls and pitfalls of managing right heart failure are also discussed in the article.


Effects of duration of isoflurane anesthesia and mode of ventilation on intracranial and cerebral perfusion pressures in horses.
To test the hypothesis that isoflurane-anesthetized horses during controlled ventilation and spontaneous ventilation exhibit temporal changes in cerebral hemodynamics, as measured by intracranial pressure and cerebral perfusion pressure, that reflect temporal changes in systemic arterial pressure. 6 healthy adult horses. Horses were anesthetized in left lateral recumbency with 1.57% isoflurane in O2 for 5 hours in 2 experiments by use of either controlled ventilation (with normocapnia) or spontaneous ventilation (with hypercapnia) in a randomized crossover design. Intracranial pressure was measured with a subarachnoid strain-gauge transducer. Carotid artery pressure, central venous pressure, airway pressures, blood gases, and minute ventilation also were measured. Intracranial pressure during controlled ventilation significantly increased during constant dose isoflurane anesthesia and thus contributed to decreasing cerebral perfusion pressure. Intracranial pressure was initially higher during spontaneous ventilation than during controlled ventilation, but this difference disappeared over time; no significant differences in cerebral perfusion pressures were observed between horses that had spontaneous or controlled ventilation. Cerebral hemodynamics and their association with ventilation mode are altered over time in isoflurane-anesthetized horses and could contribute to decreased cerebral perfusion during prolonged anesthesia.


Manual segmentation qualification platform for the EADC-ADNI harmonized protocol for hippocampal segmentation project.
The use of hippocampal volumetry as a biomarker for Alzheimer's disease (AD) requires that tracers from different laboratories comply with the same segmentation method. Here we present a platform for training and qualifying new tracers to perform the manual segmentation of the hippocampus on magnetic resonance images (MRI) following the European Alzheimer's Disease Consortium and Alzheimer's Disease Neuroimaging Initiative (EADC-ADNI) Harmonized Protocol (HarP). Our objective was to demonstrate that the training process embedded in the platform leads to increased compliance and qualification with the HarP. Thirteen new tracers' segmentations were compared with benchmark images with respect to: (a) absolute segmentation volume; (b) spatial overlap of contour with the reference using the Jaccard similarity index; and (c) spatial distance of contour with the reference. Point by point visual feedback was provided through three training phases on 10 MRI. Tracers were then tested on 10 different MRIs in the qualification phase. Statistical testing of training over three phases showed a significant increase of Jaccard (i.e. mean Jaccard overlap P < .001) between phases on average for all raters, demonstrating that training positively increased compliance with the HarP. Based on these results we defined qualification thresholds which all tracers were able to meet. This platform is an adequate infrastructure allowing standardized training and evaluation of tracers' compliance with the HarP. This is a necessary step allowing the use of hippocampal volumetry as a biomarker for AD in clinical and research centers.


Protein design by binary patterning of polar and nonpolar amino acids.
The design of large libraries of well-folded de novo proteins is a powerful approach toward the ultimate goal of producing proteins with novel structures and functions for use in industry or medicine. A method for library design that incorporates both rational design and combinatorial diversity relies on the "binary patterning" of polar and nonpolar amino acids. Binary patterning is based on the premise that the appropriate arrangement of polar and nonpolar residues can direct a polypeptide chain to fold into amphipathic elements of secondary structure that anneal together to form a desired tertiary structure. A designed binary pattern exploits the periodicities inherent in protein secondary structure, and allows the identity of the side chain at each polar and nonpolar position to be varied combinatorially. This chapter provides an overview of the considerations necessary to use binary patterning to design libraries of novel proteins.


On the formation of hydrogen peroxide in water microdroplets.
Recent reports on the formation of hydrogen peroxide (H2O2) in water microdroplets produced via pneumatic spraying or capillary condensation have garnered significant attention. How covalent bonds in water could break under such mild conditions challenges our textbook understanding of physical chemistry and water. While there is no definitive answer, it has been speculated that ultrahigh electric fields at the air-water interface are responsible for this chemical transformation. Here, we report on our comprehensive experimental investigation of H2O2 formation in (i) water microdroplets sprayed over a range of liquid flow-rates, (shearing) air flow rates, and air composition, and (ii) water microdroplets condensed on hydrophobic substrates formed via hot water or humidifier under controlled air composition. Specifically, we assessed the contributions of the evaporative concentration and shock waves in sprays and the effects of trace O3(g) on the H2O2 formation. Glovebox experiments revealed that the H2O2 formation in water microdroplets was most sensitive to the air-borne ozone (O3) concentration. In the absence of O3(g), we could not detect H2O2(aq) in sprays or condensates (detection limit ≥250 nM). In contrast, microdroplets exposed to atmospherically relevant O3(g) concentration (10-100 ppb) formed 2-30 µM H2O2(aq), increasing with the gas-liquid surface area, mixing, and contact duration. Thus, the water surface area facilitates the O3(g) mass transfer, which is followed by the chemical transformation of O3(aq) into H2O2(aq). These findings should also help us understand the implications of this chemistry in natural and applied contexts.


[Spontaneous resolution of vanishing bile duct syndrome in Hodgkin's lymphoma].
Cholestasis in a patient with Hodgkin's disease is uncommon, and the causes of cholestasis are mainly direct tumor involvement of the liver, hepatotoxic effects of drugs, viral hepatitis, sepsis and opportunistic infections. Vanishing bile duct syndrome (VBDS) represents a very rare cause for cholestasis in this disease. We report here on a case of a 45-year-old man who developed VBDS during the complete remission stage of Hodgkin's lymphoma. There was no history of hepatitis or intravenous drug abuse, and the patient had negative results for hepatitis A virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, and human immunodeficiency virus. The serological studies for antinuclear antibodies, anti-mitochondrial antibodies and anti-smooth muscle antibodies were also negative. Liver biopsy disclosed the absence of interlobular bile ducts in 9 of 10 portal tracts without any active lymphocyte infiltration and there were no Reed-Sternberg cell in the liver. The patient's cholestasis was in remission and the serum bililrubin level was normalized after two months without treatment, but tumor recurrence was noted at multiple sites of the abdominal lymph nodes on follow-up abdomino-pelvic computed tomogram.


Population-based study of hypoglycemia in patients with type 1 diabetes mellitus requiring emergency medical services.
To report the population burden of hypoglycemia necessitating emergency medical services (EMS) and the long-term outcomes in patients with type 1 diabetes mellitus (T1DM) receiving different insulin treatments. We retrieved all EMS calls because of hypoglycemia in patients with T1DM in Olmsted County, Minnesota, between January 1, 2003, and December 31, 2009, and reviewed the related medical records. During the 7-year study period, 531 EMS calls were made involving 208 patients with T1DM (112 men, 96 women; mean age 47 ± 13 years). Of the 208 patients, 137 (66%) were receiving multiple daily insulin (MDI) injections, 50 (24%) were receiving continuous subcutaneous insulin infusion, 15 (7%) were receiving simple insulin (SI), 4 (2%) were treated with metformin + MDI, and 2 (1%) were not receiving treatment for diabetes (after pancreas transplantation). The last 2 groups were excluded from further analysis because of small sample size. The remaining 3 treatment groups differed by age (P<.02), with the oldest patients receiving SI. Repeated calls, emergency department transportation (EDT), and hospitalization had a 33%, 49%, and 18% frequency, respectively, and did not differ among the treatment groups. In a multivariate model, mortality was significantly associated with treatment type (the SI group had a higher risk for mortality than did the MDI group [P = .03] after exclusion of 27 patients who changed treatment during follow-up), age (P<.0001), and EDT (P = .04). The population burden of EMS-requiring hypoglycemia in patients with T1DM is high. Medical resource utilization was similar among the 3 treatment groups. Mortality was higher in the SI group (limited by small sample size) and among patients requiring EDT and increased with advancing age. Further research could be directed toward understanding the effect of expert evaluation of high-risk patients on long-term outcomes.


Cost-effectiveness of laparoscopic gastric banding and bypass for morbid obesity.
To assess the cost-effectiveness of laparoscopic adjustable gastric banding (LAGB) and laparoscopic Roux-en-Y gastric bypass (LRYGB) as treatment for morbid obesity. A Markov model was developed to simulate weight loss, health consequences, and costs for surgical treatment of morbid obesity. The model was used to estimate incremental cost-effectiveness ratios (ICERs) in terms of cost per quality-adjusted life-year (QALY) gained. Estimates of procedure effectiveness were derived from published results of a head-to-head randomized controlled trial. Other model parameters, including complication rates, costs of treatment, adverse events and obesity, mortality rates, and utilities, were estimated from published literature and publicly available databases. Costs (2006 US dollars) and QALYs were discounted by 3% per annum. Under conservative assumptions, both LAGB and LRYGB improved health outcomes, at a higher cost, compared with no treatment. ICERs for both LAGB and LRYGB versus no treatment were below $25,000 per QALY gained. ICERs were lower for individuals with higher initial body mass index and higher for older individuals. ICERs for men were generally higher than those of women. Sensitivity analyses showed these results to be robust to reasonable variation in model parameters and overall parameter uncertainty. Base-case ICERs for LRYGB versus LAGB were below $25,000 per QALY gained, but were highly sensitive to model assumptions. Both LAGB and LRYGB provide significant weight loss and are cost-effective compared with no treatment at conventionally accepted thresholds for medical interventions.


Kinetic analysis of Arabidopsis glucosyltransferase UGT74B1 illustrates a general mechanism by which enzymes can escape product inhibition.
Plant genomes encode numerous small molecule glycosyltransferases which modulate the solubility, activity, immunogenicity and/or reactivity of hormones, xenobiotics and natural products. The products of these enzymes can accumulate to very high concentrations, yet somehow avoid inhibiting their own biosynthesis. Glucosyltransferase UGT74B1 (UDP-glycosyltransferase 74B1) catalyses the penultimate step in the core biosynthetic pathway of glucosinolates, a group of natural products with important functions in plant defence against pests and pathogens. We found that mutation of the highly conserved Ser284 to leucine [wei9-1 (weak ethylene insensitive)] caused only very mild morphological and metabolic phenotypes, in dramatic contrast with knockout mutants, indicating that steady state glucosinolate levels are actively regulated even in unchallenged plants. Analysis of the effects of the mutation via a structural modelling approach indicated that the affected serine interacts directly with UDP-glucose, but also predicted alterations in acceptor substrate affinity and the kcat value, sparking an interest in the kinetic behaviour of the wild-type enzyme. Initial velocity and inhibition studies revealed that UGT74B1 is not inhibited by its glycoside product. Together with the effects of the missense mutation, these findings are most consistent with a partial rapid equilibrium ordered mechanism. This model explains the lack of product inhibition observed both in vitro and in vivo, illustrating a general mechanism whereby enzymes can continue to function even at very high product/precursor ratios.


A review of video review: new processes for the 21st century.
Reviewing with resident physicians their preciously recorded video of patient encounters is an effective method for teaching not only communications and interpersonal skills but also such subjects as agenda negotiation, visit efficiency, shared decision making, and overall medical care. Video allows for effective coaching while minimizing observer effect. Many residency programs use video review processes for evaluation and coaching, yet there is paucity of literature on the subject, and no consensus on best processes or equipment. Recent advances in the design of digital media devices has made it easier to conduct video review in everyday medical settings, but also creates new challenges in ensuring security and confidentiality. In this article, we have outlined the infrastructure and process needed to design and implement such a program as well as possible pitfalls that should be attended to in order to ensure patient confidentiality as well as resident safety.


Scapular inclination and inferior stability of the shoulder.
Eleven fresh-frozen cadaver shoulders were studied to examine the influence of scapular inclination on inferior stability of the glenohumeral joint. All muscles except the rotator cuff were removed, and the capsule was vented. Inferior stability tests in the hanging position (sulcus test) and in 90° abduction (abduction inferior stability [ABIS] test) were simulated by the application of a 1.5 kg load with the scapula inclined at - 15°, 0°, 15°, and 30° in the sulcus test and at 15°, 30°, 45°, and 60° in the ABIS test. An electromagnetic tracking device was used to record the position of the humerus in relation to the glenoid. In the sulcus test all of the shoulders dislocated when the scapula was inclined at - 15°. However, when the scapula was inclined at 30°, no shoulder dislocated before loading, and one shoulder dislocated after loading. As a result both the loaded and unloaded positions of the humeral head shifted significantly to the superior direction as the scapular inclination increased (p < 0.0001). In the ABIS test, however, the positions of the humeral head shifted interiorly with an increase in scapular inclination (p < 0.0001), although none of the shoulders dislocated in any of the inclination angles. We conclude that scapular inclination contributes significantly to inferior stability of the glenohumeral joint. Increased scapular inclination prevents inferior displacement of the humeral head, probably because of a bony cam effect that causes tightening of the superior capsule.


Reflectance decreases before thickness changes in the retinal nerve fiber layer in glaucomatous retinas.
Glaucoma damages the retinal never fiber layer (RNFL). RNFL thickness, measured with optical coherence tomography (OCT), is often used in clinical assessment of the damage. In this study the relation between the RNFL reflectance and thickness at early stages of glaucoma was investigated. A rat model of glaucoma was used that involved laser photocoagulation of the trabecular meshwork. The reflectance of the RNFL in an isolated retina was measured, followed by immunohistochemical staining of the axonal cytoskeleton. RNFL thickness was measured by confocal fluorescence imaging. RNFL reflectance was calculated for bundle areas located at radii of 0.22, 0.33, and 0.44 mm from the optic nerve head (ONH) center. Linear regression was used to study the relation between reflectance and thickness. For glaucomatous eyes, only those bundles with no apparent structural damage were used. Bundles in 11 control retinas and 10 treated retinas were examined. Bundle thickness of both groups at each radius was similar (P = 0.89). The reflectance of the bundles at radii of 0.33 and 0.44 mm was found to be similar in both control and treated retinas (P > 0.5). However, the reflectance of the bundles at the 0.22-mm radius decreased significantly in the treated group (P = 0.005). Elevation of intraocular pressure causes decrease in RNFL reflectance for bundles near the ONH. Change in RNFL reflectance precedes thinning of the RNFL. The results suggest that a decrease in RNFL reflectance near the ONH is an early sign of glaucomatous damage.


Preexercise aminoacidemia and muscle protein synthesis after resistance exercise.
We have previously shown that the aminoacidemia caused by the consumption of a rapidly digested protein after resistance exercise enhances muscle protein synthesis (MPS) more than the amino acid (AA) profile associated with a slowly digested protein. Here, we investigated whether differential feeding patterns of a whey protein mixture commencing before exercise affect postexercise intracellular signaling and MPS. Twelve resistance-trained males performed leg resistance exercise 45 min after commencing each of three volume-matched nutrition protocols: placebo (PLAC, artificially sweetened water), BOLUS (25 g of whey protein + 5 g of leucine dissolved in artificially sweetened water; 1 × 500 mL), or PULSE (15 × 33-mL aliquots of BOLUS drink every 15 min). The preexercise rise in plasma AA concentration with PULSE was attenuated compared with BOLUS (P < 0.05); this effect was reversed after exercise, with two-fold greater leucine concentrations in PULSE compared with BOLUS (P < 0.05). One-hour postexercise, phosphorylation of p70 S6K(thr389) and rpS6(ser235/6) was increased above baseline with BOLUS and PULSE, but not PLAC (P < 0.05); furthermore, PULSE > BOLUS (P < 0.05). MPS throughout 5 h of recovery was higher with protein ingestion compared with PLAC (0.037 ± 0.007), with no differences between BOLUS or PULSE (0.085 ± 0.013 vs. 0.095 ± 0.010%.h(-1), respectively, P = 0.56). Manipulation of aminoacidemia before resistance exercise via different patterns of intake of protein altered plasma AA profiles and postexercise intracellular signaling. However, there was no difference in the enhancement of the muscle protein synthetic response after exercise. Protein sources producing a slow AA release, when consumed before resistance exercise in sufficient amounts, are as effective as rapidly digested proteins in promoting postexercise MPS.


Comparison of the effects of linseed oil and different doses of fish oil on mononuclear cell function in healthy human subjects.
Studies on animal and human subjects have shown that greatly increasing the amount of linseed (also known as flaxseed) oil (rich in the n-3 polyunsaturated fatty acid (PUFA) alpha-linolenic acid (ALNA)) or fish oil (FO; rich in the long-chain n-3 PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) in the diet can decrease a number of markers of immune function. The immunological effects of more modest doses of n-3 PUFA in human subjects are unclear, dose-response relationships between n-3 PUFA supply and immune function have not been established and whether ALNA has the same effects as its long-chain derivatives is not known. Therefore, the objective of the present study was to determine the effect of enriching the diet with different doses of FO or with a modest dose of ALNA on a range of functional responses of human monocytes and lymphocytes. In a randomised, placebo-controlled, double-blind, parallel study, forty healthy males aged 18-39 years were randomised to receive placebo or 3.5 g ALNA/d or 0.44, 0.94 or 1.9 g (EPA+DHA)/d in capsules for 12 weeks. The EPA:DHA ratio in the FO used was 1.0:2.5. ALNA supplementation increased the proportion of EPA but not DHA in plasma phospholipids. FO supplementation decreased the proportions of linoleic acid and arachidonic acid and increased the proportions of EPA and DHA in plasma phospholipids. The interventions did not alter circulating mononuclear cell subsets or the production of tumour necrosis factor-alpha, interleukin (IL) 1beta, IL-2, IL-4, IL-10 or interferon-gamma by stimulated mononuclear cells. There was little effect of the interventions on lymphocyte proliferation. The two higher doses of FO resulted in a significant decrease in IL-6 production by stimulated mononuclear cells. It is concluded that, with the exception of IL-6 production, a modest increase in intake of either ALNA or EPA+DHA does not influence the functional activity of mononuclear cells. The threshold of EPA+DHA intake that results in decreased IL-6 production is between 0.44 and 0.94 g/d.


Use of three-dimensional MRI-angiography in preoperative evaluation and postoperative management of hemangiomas of head and neck region.
Hemangiomas (proliferating endothelial tumors) are the most common benign tumors of infancy. Most often hemangiomas are self-regressing lesions without any treatment. Approximately 10% of hemangiomas cause complications such as major ulceration/destruction, distortion of involved tissues, and obstruction of a vital structure. When the situation becomes complicated, there are different treatment alternatives, ranging from systemic or local corticosteroid use to surgery. Sclerotherapy using intralesional polidocanol (Aethoxysklerol) injection may be used before surgery to decrease blood loss or when a vital structure of the face is in danger because of sudden increase in size of a surrounding hemangioma. Before any kind of treatment for both hemangiomas and vascular malformations, preoperative diagnosis and anatomic position of the lesion must be documented thoroughly. With the help of magnetic resonance imaging, tridimensional vascular pattern of such lesions can be shown successfully. We used three-dimensional contrast-enhanced time-resolved magnetic resonance angiography to detect the changes of lesions for 2 children who have large hemangiomas on their faces, before and after sclerotherapy with polidocanol injection. The findings of three-dimensional magnetic resonance imaging studies help to better assess the success rate of treatment not only for us as the physicians but also for the parents of these children who cannot understand anything with standard two-dimensional radiologic imaging.


"Do it All by Myself": A Salutogenic Approach of Masculine Health Practice Among Farming Men Coping With Stress.
Farming is often considered one of the most stressful occupations. At the same time, farming men symbolically represent a strong, traditional, or hegemonic form of masculinity based on stoicism, resourcefulness, and resilience to adversity. A contrast is observed between this social representation and their health status, marked by higher levels of stress, social isolation, psychological distress, and suicide than many other subgroups of men. A salutogenic approach was taken in this study to enable the investigation of the social contexts in which farming men positively engage in health-promoting behaviors that may prevent or ameliorate mental health problems. A focus was placed on how farming men cope with stress on their own, and the relationship of this to their popular image of being resourceful and resilient. Thirty-two individual in-depth interviews with farming men and a focus group with five key informants working in rural areas within the Province of Quebec, Canada, were carried out. Self-distraction and cognitive strategies emerged as the most relevant for participants. Notably, taking work breaks conflicted with the discourse of the "relentless worker" that farmers are expected to be. Pathways to positive coping and recovery implied an ambivalence between contemplation of strategies aligned with negative aspects of traditional masculinity norms in North America and strategies aligned with more positive, progressive aspects of these norms based on the importance of family and work life balance. Health promotion and future research should investigate how various positive masculine practices can be aligned with farmers' health and well-being and that of their family.


Distinct and stage-specific contributions of TET1 and TET2 to stepwise cytosine oxidation in the transition from naive to primed pluripotency.
Cytosine DNA bases can be methylated by DNA methyltransferases and subsequently oxidized by TET proteins. The resulting 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) are considered demethylation intermediates as well as stable epigenetic marks. To dissect the contributions of these cytosine modifying enzymes, we generated combinations of Tet knockout (KO) embryonic stem cells (ESCs) and systematically measured protein and DNA modification levels at the transition from naive to primed pluripotency. Whereas the increase of genomic 5-methylcytosine (5mC) levels during exit from pluripotency correlated with an upregulation of the de novo DNA methyltransferases DNMT3A and DNMT3B, the subsequent oxidation steps turned out to be far more complex. The strong increase of oxidized cytosine bases (5hmC, 5fC, and 5caC) was accompanied by a drop in TET2 levels, yet the analysis of KO cells suggested that TET2 is responsible for most 5fC formation. The comparison of modified cytosine and enzyme levels in Tet KO cells revealed distinct and differentiation-dependent contributions of TET1 and TET2 to 5hmC and 5fC formation arguing against a processive mechanism of 5mC oxidation. The apparent independent steps of 5hmC and 5fC formation suggest yet to be identified mechanisms regulating TET activity that may constitute another layer of epigenetic regulation.


The role of juvenile hormone in dominance behavior, reproduction and cuticular pheromone signaling in the caste-flexible epiponine wasp, Synoeca surinama.
The popular view on insect sociality is that of a harmonious division of labor among two morphologically distinct and functionally non-overlapping castes. But this is a highly derived state and not a prerequisite for a functional society. Rather, caste-flexibility is a central feature in many eusocial wasps, where adult females have the potential to become queens or workers, depending on the social environment. In non-swarming paper wasps (e.g., Polistes), prospective queens fight one another to assert their dominance, with losers becoming workers if they remain on the nest. This aggression is fueled by juvenile hormone (JH) and ecdysteroids, major factors involved in caste differentiation in most eusocial insects. We tested whether these hormones have conserved aggression-promoting functions in Synoeca surinama, a caste-flexible swarm-founding wasp (Epiponini) where reproductive competition is high and aggressive displays are common. We observed the behavioral interactions of S. surinama females in field nests before and after we had removed the egg-laying queen(s). We measured the ovarian reproductive status, hemolymph JH and ecdysteroid titers, ovarian ecdysteroid content, and analyzed the cuticular hydrocarbon (CHC) composition of females engaged in competitive interactions in both queenright and queenless contexts. These data, in combination with hormone manipulation experiments, revealed that neither JH nor ecdysteroids are necessary for the expression of dominance behaviors in S. surinama. Instead, we show that JH likely functions as a gonadotropin and directly modifies the cuticular hydrocarbon blend of young workers to match that of a reproductive. Hemolymph ecdysteroids, in contrast, are not different between queens and workers despite great differences in ovarian ecdysteroid content. The endocrine profile of S. surinama shows surprising differences from those of other caste-flexible wasps, although a rise in JH titers in replacement queens is a common theme. Extensive remodeling of hormone functions is also evident in the highly eusocial bees, which has been attributed to the evolution of morphologically defined castes. Our results show that hormones which regulate caste-plasticity can lose these roles even while caste-plasticity is preserved.


Autonomous intelligent agents for accelerated materials discovery.
We present an end-to-end computational system for autonomous materials discovery. The system aims for cost-effective optimization in large, high-dimensional search spaces of materials by adopting a sequential, agent-based approach to deciding which experiments to carry out. In choosing next experiments, agents can make use of past knowledge, surrogate models, logic, thermodynamic or other physical constructs, heuristic rules, and different exploration-exploitation strategies. We show a series of examples for (i) how the discovery campaigns for finding materials satisfying a relative stability objective can be simulated to design new agents, and (ii) how those agents can be deployed in real discovery campaigns to control experiments run externally, such as the cloud-based density functional theory simulations in this work. In a sample set of 16 campaigns covering a range of binary and ternary chemistries including metal oxides, phosphides, sulfides and alloys, this autonomous platform found 383 new stable or nearly stable materials with no intervention by the researchers.


Bacteriophage therapy and the mutant selection window.
We use kinetic models to investigate how to design antimicrobial phage therapies to minimize emergence of resistant bacteria. We do this by modifying the "mutant selection window" hypothesis in a way that accounts for the ongoing self-replication of the phage. We show that components of combination phage therapies need to be appropriately matched if treatment is to avoid the emergence of resistant bacteria. Matching of components is more easily achieved when phage dosages are high enough that ongoing phage replication is not needed for the clearance of the bacteria. Theoretical predictions such as ours need to be tested experimentally if applications of phage therapy are to avoid the problems of widespread resistance that have beset chemical antibiotics.


Multiscale image fusion using the undecimated wavelet transform with spectral factorization and nonorthogonal filter banks.
Multiscale transforms are among the most popular techniques in the field of pixel-level image fusion. However, the fusion performance of these methods often deteriorates for images derived from different sensor modalities. In this paper, we demonstrate that for such images, results can be improved using a novel undecimated wavelet transform (UWT)-based fusion scheme, which splits the image decomposition process into two successive filtering operations using spectral factorization of the analysis filters. The actual fusion takes place after convolution with the first filter pair. Its significantly smaller support size leads to the minimization of the unwanted spreading of coefficient values around overlapping image singularities. This usually complicates the feature selection process and may lead to the introduction of reconstruction errors in the fused image. Moreover, we will show that the nonsubsampled nature of the UWT allows the design of nonorthogonal filter banks, which are more robust to artifacts introduced during fusion, additionally improving the obtained results. The combination of these techniques leads to a fusion framework, which provides clear advantages over traditional multiscale fusion approaches, independent of the underlying fusion rule, and reduces unwanted side effects such as ringing artifacts in the fused reconstruction.


Economic evaluation of a behavioral-graded activity program compared to physical therapy for patients following lumbar disc surgery.
An economic evaluation was conducted alongside a randomized controlled trial. Little is known about the effectiveness of cognitive-behavioral treatment options for patients following lumbar disc surgery. If the knowledge available was supported by an economic evaluation, the information could then be used to make recommendations for the implementation of cognitive-behavioral treatment in the routine of rehabilitation following lumbar disc surgery. To examine the cost-effectiveness of a behavioral-graded activity program, which is an operant treatment, compared to usual care as delivered by a physical therapist for patients following first-time lumbar disc surgery. For the economic evaluation, a societal viewpoint was applied. The primary outcome measures (measured at the 12-month follow-up) were global perceived effect and functional status. To evaluate the economic consequences of the treatments, direct health care and non-health care costs were considered, as well as indirect costs. The clinical outcomes showed no relevant differences between behavioral-graded activity (n = 52) and UC (n = 53). Treatment costs were almost identical in the two intervention groups. The difference in direct health care costs was, although not statistically significant, 264 EURO [95% CI: -3-525] higher in behavioral-graded activity than in usual care per patient-year. It was mainly the excess cost of visiting the physiotherapist in the behavioral-graded activity group that accounted for this difference. The difference in direct non-health care costs, although not statistically significant, was 388 EURO [95% CI: -217; 992] lower in the usual care group due to unpaid help by friends or family. Consequently, although again not statistically significant, the total direct costs in behavioral-graded activity are 639 EURO [95% CI: -91; 1368] higher than in usual care. For the indirect costs, there was a statistically significant difference, behavioral-graded activity being more expensive. The sensitivity analysis showed that these results are fairly robust. This study concludes that there are no differences between the two treatment conditions on any of the clinical outcome measures but that behavioral-graded activity is associated with higher costs. Consequently, there is no reason for the implementation of behavioral-graded activity as the standard treatment for patients following lumbar disc surgery.


Elimination of speckle noise in holograms with redundancy.
Holograms made of diffusely reflecting or diffusely illuminated objects can be scratched, spotted with dirt, and even broken into pieces without serious loss of information. This remarkable property is due to the redundancy introduced by diffuse illumination which, in effect, spreads information all over the hologram. Unfortunately, an unwanted by-product of diffuse illumination is speckle noise. This noise becomes more severe as hologram size is reduced. We show that, in order to obtain an acceptably high signal-to-noise ratio, the area of this type hologram must be more than 100 times the area needed to achieve a desired image resolution, making it prohibitively large for most data storage applications. In this paper we described a multibeam recording technique that produces redundant holograms that yield speckle free images of transparencies. We show that (1) achievable redundancy is equal to the ratio of actual hologram area to that area which just satisfies resolution requirements, (2) a two-dimensional phase grating provides a simple, efficient means for generating multiple beams, an optimized grating producing nine equally intense beams with 81% efficiency, (3) an optimized phase grating having a spatial period just equal to desired image resolution yields fourfold redundancy in holograms that are just large enough to encompass both side bands of the central (or zero order) beam, and (4) holograms having fourfold redundancy give reasonably good immunity to dust and scratches.


Polycythemia vera: new clinicopathologic perspectives.
Polycythemia vera (PV) is a clonal myeloproliferative disease characterized by an erythroid dominant trilineage proliferation of hematopoietic precursor cells. Classified as a chronic myeloproliferative disease, PV represents a histopathologic spectrum of 2 recognized stages, the polycythemic and postpolycythemic phase. The clinical manifestations of hemorrhage, thrombosis, and increased red cell mass are directly related to primary bone marrow dysfunction. Prognosis is strongly associated with thrombosis risk and disease progression; thus, treatment is directed toward minimizing coagulopathic complications and preventing leukemic transformation. Recently, a specific point mutation in the Janus kinase 2 (JAK2) gene was described in a majority of PV patients. The potential diagnostic and/or prognostic value of JAK2V617F is discussed. To review important developments from the recent and historical literature. Modern diagnostic criteria and emerging molecular findings are emphasized. A comprehensive review was performed of the relevant literature indexed in PubMed (National Library of Medicine) and referenced medical texts. Modified clinical, histologic, and laboratory criteria have clarified the diagnosis of PV. Also, continuing studies on the recently discovered JAK2V617F gene mutation may significantly improve our understanding of PV pathogenesis and facilitate its medical management.


Radiolabeled inhibitors as probes for imaging mutant IDH1 expression in gliomas: Synthesis and preliminary evaluation of labeled butyl-phenyl sulfonamide analogs.
Malignant gliomas frequently harbor mutations in the isocitrate dehydrogenase 1 (IDH1) gene. Studies suggest that IDH mutation contributes to tumor pathogenesis through mechanisms that are mediated by the neomorphic metabolite of the mutant IDH1 enzyme, 2-hydroxyglutarate (2-HG). The aim of this work was to synthesize and evaluate radiolabeled compounds that bind to the mutant IDH1 enzyme with the goal of enabling noninvasive imaging of mutant IDH1 expression in gliomas by positron emission tomography (PET). A small library of nonradioactive analogs were designed and synthesized based on the chemical structure of reported butyl-phenyl sulfonamide inhibitors of mutant IDH1. Enzyme inhibition assays were conducted using purified mutant IDH1 enzyme, IDH1-R132H, to determine the IC50 and the maximal inhibitory efficiency of the synthesized compounds. Selected compounds, 1 and 4, were labeled with radioiodine ((125)I) and/or (18)F using bromo- and phenol precursors, respectively. In vivo behavior of the labeled inhibitors was studied by conducting tissue distribution studies with [(125)I]1 in normal mice. Cell uptake studies were conducted using an isogenic astrocytoma cell line that carried a native IDH1-R132H mutation to evaluate the potential uptake of the labeled inhibitors in IDH1-mutated tumor cells. Enzyme inhibition assays showed good inhibitory potency for compounds that have iodine or a fluoroethoxy substituent at the ortho position of the phenyl ring in compounds 1 and 4 with IC50 values of 1.7 μM and 2.3 μM, respectively. Compounds 1 and 4 inhibited mutant IDH1 activity and decreased the production of 2-HG in an IDH1-mutated astrocytoma cell line. Radiolabeling of 1 and 4 was achieved with an average radiochemical yield of 56.6 ± 20.1% for [(125)I]1 (n = 4) and 67.5 ± 6.6% for [(18)F]4 (n = 3). [(125)I]1 exhibited favorable biodistribution characteristics in normal mice, with rapid clearance from the blood and elimination via the hepatobiliary system by 4 h after injection. The uptake of [(125)I]1 in tumor cells positive for IDH1-R132H was significantly higher compared to isogenic WT-IDH1 controls, with a maximal uptake ratio of 1.67 at 3 h post injection. Co-incubation of the labeled inhibitors with the corresponding nonradioactive analogs, and decreasing the normal concentrations of FBS (10%) in the incubation media substantially increased the uptake of the labeled inhibitors in both the IDH1-mutant and WT-IDH1 tumor cell lines, suggesting significant non-specific binding of the synthesized labeled butyl-phenyl sulfonamide inhibitors. These data demonstrate the feasibility of developing radiolabeled probes for the mutant IDH1 enzyme based on enzyme inhibitors. Further optimization of the labeled inhibitors by modifying the chemical structure to decrease the lipophilicity and to increase potency may yield compounds with improved characteristics as probes for imaging mutant IDH1 expression in tumors.


On the linkage between AMPA and NMDA receptor-mediated EPSPs in homosynaptic long-term depression in the hippocampal CA1 region of young rats.
Homosynaptic long-term depression (LTD) was studied in hippocampal slices from 12-18-d-old rats using field EPSP recording in the apical dendritic layer of CA1 pyramidal cells. Independent estimates of the alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) and the N-methyl-D-aspartic acid (NMDA) receptor-mediated components of the field EPSP were obtained in parallel using early and late measurements of a dual-component EPSP in a low-magnesium solution. LTD was induced by low-frequency stimulation (LFS; 2 Hz for 10 min), resulting in equal relative changes of the AMPA and NMDA receptor-mediated components. Under conditions when the AMPA receptor-mediated component was fully blocked, a similarly sized LTD was observed for the pure NMDA receptor-mediated EPSP (measured as initial slope or peak amplitude). Equal changes in AMPA and NMDA receptor-mediated components occurred also upon application of the adenosine agonist N6-cyclohexyladenosine (CHA), known to act by decreasing transmitter release. On the other hand, LTD was found to interact in a multiplicative manner with the presynaptic release changes induced by CHA and by paired-pulse facilitation. The induction of the LTDs of both AMPA and NMDA receptor-mediated EPSPs was blocked by the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid and by the phosphatase inhibitor okadaic acid. Partial blockade of LTD by okadaic acid resulted in equal partial blockade of the LTDs of the AMPA and NMDA receptor-mediated components. On the other hand, the L-type calcium channel blocker nifedipine, the metabotropic glutamate receptor antagonist (RS)-alpha-methyl-4-carboxyphenylglycine, the nitric oxide synthase inhibitor N omega-nitro-L-arginine, and the heme oxygenase inhibitor protoporphyrin IX zinc(II) had no effect on LTD of either the AMPA or the NMDA receptor-mediated component. These results of equal changes of AMPA and NMDA receptor-mediated components of the field EPSP in association with LTD, and the consistent parallelism of effects or noneffects on these components by various receptor antagonists and enzyme inhibitors, seem more easily explained by a presynaptic locus for LTD than by a postsynaptic one.


Age-of-onset heterogeneity in Huntington disease families.
Ten Huntington disease (HD) families are analyzed using maximum likelihood methods to study age-of-onset (AO) heterogeneity. Both age of onset and age at examination are used in calculating an individual's likelihood of being affected; familial correlations and family structure are not included in the model. The model allows for differences in current age distributions by considering the distribution of age of onset conditional on age at examination. Families are grouped according to family type (ie, juvenile-onset families and adult-onset families) and then analyzed within each family type as well as between the two types, using both a chi-square test for heterogeneity and F-ratios. The results of the chi-square analyses indicate heterogeneity in AO among the individual families as well as between the two family types. However, the results of the F-ratios show no significant difference between the two family types, indicating that the difference in the chi-square analysis between the two family types is mostly owing to variation among the families. Thus, the results demonstrate that the existing variation in age of onset between these two family types is dwarfed by the magnitude of the variation among the families within each type. This implies that families of sufficient size should be evaluated individually for age-of-onset data for the purpose of either genetic counseling or linkage studies.


Teaching and evaluating smartphone applications: The effectiveness of a curriculum expansion.
Mobile health (mHealth) technology is increasingly utilized to support lifestyle recommendations through nutrient and blood pressure tracking. As patients pose questions regarding the validity and use of this technology, curriculum targeting mHealth technology is essential for the future health professionals. This study evaluated the effectiveness of a curriculum expansion which addressed mHealth technology provided to physician assistant (PA) and clinical nutrition (CN) students enrolled in an academic health center. In addition, the validity of the mobile application (app), MyNetDiary, was determined. A smartphone application appraisal tool, based on scientific recommendations, was developed. Students were taught how to use this tool to evaluate mobile apps. Students received instruction on providing patient education on mobile apps used to track calories and nutrients and mobile medical apps to measure blood pressure. Pre-/post-surveys and objectively structured clinical examinations measured students' confidence and abilities in teaching patients to use MyNetDiary and Withings Health Mate apps. Wilcoxon rank sum tests evaluated statistical significance. Validity of nutrient estimates was determined using Spearman correlations. Confidence levels improved significantly on all items measured for both PA and CN students (P < 0.001). During the objectively structured clinical examination, all students demonstrated effective communication skills with 98.4% successfully demonstrating of how to enter foods into the MyNetDiary app and 94.3% connecting the blood pressure cuff with the withings app. Significant correlations were found when comparing MyNetDiary to SuperTracker (all P < 0.001). This study investigated and demonstrated the effectiveness of an expanded curriculum designed to enhance students' confidence and skills in providing lifestyle counseling incorporating the use of mHealth technology.


Round window membrane motion with air conduction and bone conduction stimulation.
The vibration patterns of the round window (RW) membrane in human cadaver temporal bone specimens were assessed by measurements of the velocity of reflective targets placed on the RW membrane with an approximate spacing of 0.2 mm. The velocity was measured in the frequency range 0.1-10 kHz by a laser Doppler vibrometer in four specimens with air conduction (AC) stimulation and in four specimens with bone conduction (BC) stimulation. The response pattern was investigated by analyzing the velocity response of all targets on the RW membrane, by making iso-amplitude and iso-phase contour plots of the membrane surface, and by creating animations of the surface vibration at several frequencies. Similar response pattern was found with AC and BC stimulations. At frequencies below 1.5 kHz, the RW membrane vibrates nearly as a whole in an in-and-out motion and above 1.5 kHz, the membrane moves primarily in two sections that vibrate with approximately 180 degrees difference. Indication of some traveling wave motion of the RW membrane at those frequencies was also found. At higher frequencies, above 3 kHz, the membrane motion is complex with a mixture of modal and traveling wave motion. An increase of the stimulation level did not alter the vibration pattern; it only gave an increase of the RW membrane vibration amplitude corresponding to the increase in stimulation. When the mode of stimulation at the oval window was altered, by the insertion of a 0.6 mm piston, the vibration pattern of the RW membrane changed.


Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1.
Mutations in presenilins are responsible for approximately 40% of all early-onset familial Alzheimer disease (FAD) cases in which a genetic cause has been identified. In addition, a number of mutations in presenilin-1 (PS1) have been suggested to be associated with the occurrence of frontal temporal dementia (FTD). Presenilins are highly conserved transmembrane proteins that support cleavage of the amyloid precursor protein by gamma-secretase. Recently, we discovered that presenilins also function as passive ER Ca(2+) leak channels. Here we used planar lipid bilayer reconstitution assays and Ca(2+) imaging experiments with presenilin-null mouse embryonic fibroblasts to analyze ER Ca(2+) leak function of 6 FAD-linked PS1 mutants and 3 known FTD-associated PS1 mutants. We discovered that L166P, A246E, E273A, G384A, and P436Q FAD mutations in PS1 abolished ER Ca(2+) leak function of PS1. In contrast, A79V FAD mutation or FTD-associated mutations (L113P, G183V, and Rins352) did not appear to affect ER Ca(2+) leak function of PS1 in our experiments. We validated our findings in Ca(2+) imaging experiments with primary fibroblasts obtained from an FAD patient possessing mutant PS1-A246E. Our results indicate that many FAD mutations in presenilins are loss-of-function mutations affecting ER Ca(2+) leak activity. In contrast, none of the FTD-associated mutations affected ER Ca(2+) leak function of PS1, indicating that the observed effects are disease specific. Our observations are consistent with the potential role of disturbed Ca(2+) homeostasis in Alzheimer disease pathogenesis.


Between policy and practice: Japan's Silver Human Resource Centers as viewed from the inside.
The Silver Human Resource Centers (SHRC) were first established in 1980 to address the economic and psychological needs of Japan's growing numbers of senior citizens. The Centers, through which people are introduced to jobs in their locales and from which they receive remuneration for services performed, are by now well established throughout Japan. This article examines the gap between SHRC members' evaluations of the Centers and the Center guidelines, as stated in their published literature and in interviews with program administrators. The analysis is fourfold: (1) it explores the members' reasons for participating in the program; (2) it discusses their assessments of it; (3) it examines gender and social class differences in program planning and participation; and (4) it analyzes the Ministry of Labor's plan for new directions for the Centers. Although new policy directions do address many members' concerns, they do not attempt to question or change the status quo of the gendered division of labor in Japanese society.


NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology.
Failure to translate successful neuroprotective preclinical data to a clinical setting in Alzheimer's disease (AD) indicates that amyloidopathy and tauopathy alone provide an incomplete view of disease. We have tested here the relevance of additional homeostatic deviations that result from loss of activity of transcription factor NRF2, a crucial regulator of multiple stress responses whose activity declines with ageing. A transcriptomic analysis demonstrated that NRF2-KO mouse brains reproduce 7 and 10 of the most dysregulated pathways of human ageing and AD brains, respectively. Then, we generated a mouse that combines amyloidopathy and tauopathy with either wild type (AT-NRF2-WT) or NRF2-deficiency (AT-NRF2-KO). AT-NRF2-KO brains presented increased markers of oxidative stress and neuroinflammation as well as higher levels of insoluble phosphorylated-TAU and Aβ*56 compared to AT-NRF2-WT mice. Young adult AT-NRF2-KO mice exhibited deficits in spatial learning and memory and reduced long term potentiation in the perforant pathway. This study demonstrates the relevance of normal homeostatic responses that decline with ageing, such as NRF2 activity, in the protection against proteotoxic, inflammatory and oxidative stress and provide a new strategy to fight AD.