The role of potassium channels in the vasodilatory effect of caffeine in human internal mammary arteries.
There is little information about the direct effect of caffeine in human blood vessels. The purpose of this study was to evaluate the direct vascular effect of caffeine on human internal mammary artery (IMA) and the involvement of potassium channels in this response. Segments of IMA were obtained from 29 patients who underwent coronary artery bypass graft surgery. They were cut into rings, suspended between two wire hooks in organ bath chambers and constricted submaximally with norepinephrine. Caffeine (3.16x10(-9) to 10(-4) mol/L) was added in a cumulative fashion to rings with or without functional endothelium and concentration response curves were constructed. The response to caffeine was also evaluated after incubation with adenosine 3',5'-triphosphate (ATP)-dependent potassium channel blocker glibenclamide, voltage-dependent potassium channel blocker 4-aminopyridine and large-conductance calcium-activated potassium channel inhibitor tetraethylammonium. Caffeine produced a potent, concentration-dependent relaxation of IMA. The relaxant responses did not differ significantly between endothelium-intact and endothelium-denuded preparations. Incubation with different potassium channel inhibitors (glibenclamide, 4-aminopyridine and tetraethylammonium) did not cause significant alterations in the relaxant responses to caffeine. These results suggest that the vasodilatory response to caffeine in human IMA is independent of endothelial function and is not mediated by potassium channels.


Possible mechanisms involved in the down-regulation of translation during transient global ischaemia in the rat brain.
The striking correlation between neuronal vulnerability and down-regulation of translation suggests that this cellular process plays a critical part in the cascade of pathogenetic events leading to ischaemic cell death. There is compelling evidence supporting the idea that inhibition of translation is exerted at the polypeptide chain initiation step, and the present study explores the possible mechanism/s implicated. Incomplete forebrain ischaemia (30 min) was induced in rats by using the four-vessel occlusion model. Eukaryotic initiation factor (eIF)2, eIF4E and eIF4E-binding protein (4E-BP1) phosphorylation levels, eIF4F complex formation, as well as eIF2B and ribosomal protein S6 kinase (p70(S6K)) activities, were determined in different subcellular fractions from the cortex and the hippocampus [the CA1-subfield and the remaining hippocampus (RH)], at several post-ischaemic times. Increased phosphorylation of the alpha subunit of eIF2 (eIF2 alpha) and eIF2B inhibition paralleled the inhibition of translation in the hippocampus, but they normalized to control values, including the CA1-subfield, after 4--6 h of reperfusion. eIF4E and 4E-BP1 were significantly dephosphorylated during ischaemia and total eIF4E levels decreased during reperfusion both in the cortex and hippocampus, with values normalizing after 4 h of reperfusion only in the cortex. Conversely, p70(S6K) activity, which was inhibited in both regions during ischaemia, recovered to control values earlier in the hippocampus than in the cortex. eIF4F complex formation diminished both in the cortex and the hippocampus during ischaemia and reperfusion, and it was lower in the CA1-subfield than in the RH, roughly paralleling the observed decrease in eIF4E and eIF4G levels. Our findings are consistent with a potential role for eIF4E, 4E-BP1 and eIF4G in the down-regulation of translation during ischaemia. eIF2 alpha, eIF2B, eIF4G and p70(S6K) are positively implicated in the translational inhibition induced at early reperfusion, whereas eIF4F complex formation is likely to contribute to the persistent inhibition of translation observed at longer reperfusion times.


Effect of localized hyperthermia on TA3Ha tumor transplanted subcutaneously in the tails of mice.
Localized hyperthermia (43 degrees) in single or multiple fractions was applied to mouse mammary adenocarcinoma TA3Ha implanted into the s.c. tail tissue of strain A mice. The effects of heat on the growth of local tumors, on the pattern of metastasis, and on the survival periods of the hosts were studied. Hyperthermia was administered by heating the tumor-bearing tails in a water bath. Multiple 30-min hyperthermia treatments at 5- or 7-day intervals controlled local tumor growth better than did a single 30-min treatment or multiple 30-min treatments at 3-day intervals or at intervals longer than 7 days. Heat treatments that produced cytostatic effects on tumors, sparing the normal tissue, had no effect on either the survival of the hosts or the extent of metastasis to the lungs and the lumbar lymph nodes. However, local treatments reduced the frequency of renal lymph node metastasis, indicating that concurrent metastases in different sites may exhibit differential heat sensitivities.


Single-cell gel/comet assay applied to the analysis of UV radiation-induced DNA damage in Rhodomonas sp. (Cryptophyta).
The single-cell gel/comet assay is an electrophoretic technique used to detect single-strand breaks in DNA. Damage is assessed examining individual cells under an epifluorescent microscope. UV-induced DNA damage consists mostly of the formation of pyrimidine dimers; therefore, most of the damage cannot be detected using a standard comet assay. The enzyme T4 endonuclease V breaks DNA strands at sites of pyrimidine dimers. The main objective of this work is to evaluate the comet assay to detect UV-induced damage in DNA after an initial treatment of cells with T4 endonuclease V. This work was conducted on Rhodomonas sp. (Cryptophyta), a marine unicellular flagellate. Cells of Rhodomonas sp. were exposed to 12 h visible + ultraviolet-A + ultraviolet-B (VIS + UVA + UVB) and VIS (control), with and without T4 endonuclease V. Cells exposed to VIS + UVA + UVB showed approximately 200% more damage than control if these were treated with T4 endonuclease V. Rhodomonas sp. were exposed to 3, 6, 9 and 12 h of VIS, VIS + UVA and VIS + UVA + UVB. Damage induced by VIS + UVA + UVB as detected by the comet assay increased along with exposure time. However, damage caused by VIS and VIS + UVA remained relatively constant at all times. Results of this study indicate that the comet assay is more sensitive to UV radiation damage when used in conjunction with T4 endonuclease V. This modification of the comet assay can be used as an alternative technique to detect DNA damage in single cells caused by UV radiation.


Dimensions of ecological validity for usability evaluations in clinical settings.
The development, evaluation, and eventual deployment of novel medical devices is a complex process involving various areas of expertise. Although the need for a User Centred Design approach to the development of both hardware and software has long been established, both current regulatory guidelines and widespread evaluation approaches fail to reflect the challenges encountered during day-to-day clinical practice. As such, the results from these evaluations may not provide a realistic account of the problems encountered by users when introduced to clinical practice. In this paper, we present a case study on designing the evaluation of a novel device to support laparoscopic liver surgery. Through a reflective account of the design of our usability evaluation, we identify and describe seven primary dimensions of ecological validity encountered in clinical usability evaluations. These dimensions are: 'user roles', 'environment', 'training', 'scenario', 'patient involvement', 'software', and 'hardware'. We analyse three recently published clinical usability evaluation articles to assess (and illustrate) the applicability and completeness of these dimensions. Finally, we discuss the compromises encountered during clinical usability evaluations and how to best report on these considerations. The framework presented here aims to further the agenda of ecologically valid evaluation practice, reflecting the constraints of medical practice.


Facilitatory coupling between a glutamate metabotropic receptor and dihydropyridine-sensitive calcium channels in cultured cerebellar granule cells.
The effect of metabotropic glutamate receptor activation on Ca dihydropyridine (DHP)-sensitive channels recorded in the presence of 1 microM Bay K 8644 was examined on cultured cerebellar granule cells using the patch-clamp technique in the cell-attached configuration. Bath-applied agonist (trans-ACPD, 1S,3R-, and 1R,3S-ACPD isomers, and glutamate or quisqualate in the presence of CPP and CNQX) evoked an increase in Ca channel activity with a variable latency of 8.9 +/- 8.6 sec in 40% of the recorded cells. Neither L-CCG1, L-AP3, L-AP4, nor AMPA or NMDA activated Ca channels. Two dihydropyridine-sensitive channels present in this cell type were activated by trans-ACPD: the classical 24 pS L-type channel and a smaller-conductance 7 pS channel. The effect was shown to be mediated by neither intracellular Ca2+ nor a pertussis toxin (PTX)-sensitive G protein. Interestingly treatment with BAPTA-AM increased the number of responding patches and the activity was more sustained throughout the drug application. After overnight PTX treatment, activation of the Ca channels persisted even after washout of the agonist. These results indicate that mGluR1/mGluR5 probably mediate the facilitation of dihydropyridine-sensitive Ca channels.


Neonatal androgenization affects the intrathymic T-cell maturation in rats.
The thymus structure, expression of CD4/CD8/TCRalphabeta on thymocytes and thymocyte proliferative and apoptotic indexes were analyzed in sexually immature 30-day-old and in sexually mature 60-day-old female rats neonatally androgenized (NA) by subcutaneous injection of 500 microg testosterone propionate/day on days 1-3 and in their vehicle-administered counterparts. The treatment affected normal thymus development. Thus, at 30 days of age, there was a reduction in the thymus weight, reflecting a decrease in the main thymic compartments. However, at 60 days of age, thymus weight did not significantly differ from that in age-matched controls, since the cortical volume enlargement was followed by a proportional decrease in the medullary volume. In rats of both ages, the changes in thymic compartments most likely reflected alterations in the size of both lymphoid and nonlymphoid components. Furthermore, in NA rats, substantial changes in thymocyte phenotypic characteristics were registered, in spite of their age. In both groups of NA rats, a decrease in the relative proportion of the least mature CD4-8-TCRalphabeta- cells and in that of CD4+8- TCRalphabeta-/TCRalphabeta(low) cells followed by an increase in the percentage of their successor CD4+8+TCRalphabeta-/TCRalphabeta(low) cells was detected. In addition, in 30-day-old NA rats, the relative proportions of CD4+8+TCRalphabeta(high) cells (just positively selected) and that of mature single positive (CD4+8- and CD4-8+) and CD4-8- double negative TCRalphabeta(high) cells, were reduced, while in 60-day-old NA rats only the percentage of CD4+8+TCRalphabeta(high) thymocytes was decreased. Thus, the study showed that the changes in the development of the hypothalamo-pituitary-gonadal axis induced by neonatal androgenization may affect the thymus development and intrathymic T-cell maturation.


Evidence from simultaneous intracellular recordings in rat hippocampal slices that area CA3 pyramidal cells innervate dentate hilar mossy cells.
1. Simultaneous intracellular recordings of area CA3 pyramidal cells and dentate hilar "mossy" cells were made in rat hippocampal slices to test the hypothesis that area CA3 pyramidal cells excite mossy cells monosynaptically. Mossy cells and pyramidal cells were differentiated by location and electrophysiological characteristics. When cells were impaled near the border of area CA3 and the hilus, their identity was confirmed morphologically after injection of the marker Neurobiotin. 2. Evidence for monosynaptic excitation of a mossy cell by a pyramidal cell was obtained in 7 of 481 (1.4%) paired recordings. In these cases, a pyramidal cell action potential was followed immediately by a 0.40 to 6.75 (mean, 2.26) mV depolarization in the simultaneously recorded mossy cell (mossy cell membrane potentials, -60 to -70 mV). Given that pyramidal cells used an excitatory amino acid as a neurotransmitter (Cotman and Nadler 1987; Ottersen and Storm-Mathisen 1987) and recordings were made in the presence of the GABAA receptor antagonist bicuculline (25 microM), it is likely that the depolarizations were unitary excitatory postsynaptic potentials (EPSPs). 3. Unitary EPSPs of mossy cells were prone to apparent "failure." The probability of failure was extremely high (up to 0.72; mean = 0.48) if the effects of all presynaptic action potentials were examined, including action potentials triggered inadvertently during other spontaneous EPSPs of the mossy cell. Probability of failure was relatively low (as low as 0; mean = 0.24) if action potentials that occurred during spontaneous activity of the mossy cell were excluded. These data suggest that unitary EPSPs produced by pyramidal cells are strongly affected by concurrent synaptic inputs to the mossy cell. 4. Unitary EPSPs were not clearly affected by manipulation of the mossy cell's membrane potential. This is consistent with the recent report that area CA3 pyramidal cells innervate distal dendrites of mossy cells (Kunkel et al. 1993). Such a distal location also may contribute to the high incidence of apparent failures. 5. Characteristics of unitary EPSPs generated by pyramidal cells were compared with the properties of the unitary EPSPs produced by granule cells. In two slices, pyramidal cell and granule cell inputs to the same mossy cell were compared. In other slices, inputs to different mossy cells were compared. In all experiments, unitary EPSPs produced by granule cells were larger in amplitude but similar in time course to unitary EPSPs produced by pyramidal cells. Probability of failure was lower and paired-pulse facilitation more common among EPSPs triggered by granule cells.(ABSTRACT TRUNCATED AT 400 WORDS)


Sarcoidosis and pregnancy.
Sarcoidosis is usually a benign and self-limited disease, but it can occasionally be quite severe. It affects individuals most often during the reproductive years. This report reviews cases of sarcoidosis and pregnancy during a ten-year period at Downstate Medical Center. Eleven patients were stable, two experienced disease progression, and two died from complications of severe sarcoidosis. Factors indicating a poor prognosis included parenchymal lesions on chest x-ray, advanced roentgenologic staging, advanced maternal age, low inflammatory activity, requirement for drugs other than steroids, and presence of extrapulmonary sarcoidosis. Management plans are delineated for patients with advanced sarcoidosis. Some patients require evaluation before pregnancy to establish chronicity, baseline pulmonary function, inflammatory activity, roentgenographic staging, and response to treatment. Only then can the patient be given an accurate prognosis for either an uncomplicated pregnancy or one requiring intensive management by the pulmonary and perinatal teams.


The Legal Foundation of Student Dismissal in Professional Education Programs.
Professional education programs are bound to ensuring that their graduates meet both academic and professional standards of performance. These standards are often set through disciplinary expectations, professional associations, accrediting bodies, and/or licensure. Due to the association of post-graduate sanctions of licensed providers with professional conduct issues at the pre-licensure or pre-graduate level, academic programs should be concerned with modeling, monitoring, and assessing these standards of their students. However, literature suggests that professional programs are not always acting on their concerns of student performance in these domains due to concern of legal action. Therefore, the purpose of this commentary is to offer a synopsis of the legal foundations and guiding principles that support the decision-making of professional education programs and its faculty. With proper structure and guidance though interpretation of existing case law, professional education programs are best positioned to not only evaluate cognitive ability, but also non-cognitive behaviors and professional expectations of students in their professional education programs.


Cellular level classification of breast cancer through proteomic markers using nanochannel array sensors.
A nanochannel-based sensor for cellular level classification of breast cancer metastasis has been designed. Our approach to the classification of cell's likelihood to metastasize is based on screening for levels of expression of specific proteomic biomarkers associated with breast cancer stem cells. Proteomic activity for four breast cancer cell lines for three specific markers (PDGFR, ALDH1A1 and ALDH1A3) was quantified. The nanochannel sensor is an electrochemical immunoassay and comprises of alumina nanochannel arrays integrated on to a gold microelectronic platform. The sensor operates on the principle of electrochemical impedance spectroscopy. Test cell lysate samples from SUM159 invasive, SUM159 noninvasive, HC1143 and DCIS cell lines were classified as those having a high likelihood of metastases based on the levels of proteomic activity evaluated against the three key markers. The lowest proteomic activity measured was 0.1 ng/ml with PDGFR, 100 ng/ml with ALDH1A1 and 100 ng/ml with ALDH1A3, correlating to the detection of unit stem cell count. Original submitted 9 November 2012; Revised submitted 29 July 2013.


Helicobacter pylori infection in patients with selective immunoglobulin a deficiency.
Selective immunoglobulin A (IgA) deficiency (IgAD) is the most common primary immunodeficiency in the western world. The aim of the study was to investigate the prevalence and clinical characteristics of Helicobacter pylori-infected dyspeptic patients with IgAD. Case samples were drawn from all subjects ≥ 12 years of age (n = 104729) who had undergone serum total IgA measurements during 2004-14 for any reason at Leumit Healthcare Services (Israel) and had serum total IgA < 0·07 g/l. The control group was comprised of a random sample of remaining patients with a case-control ratio of 10 controls for each case. The dyspeptic diseases were identified and retrieved from Leumit Health Care Services electronic database using specific ICD-9-CM diagnostic codes. The case group included 347 subjects and the control group 3470 subjects. There were no significant differences in the prevalence of patients with dyspepsia [84 (24·2%) versus 821 (23·6%) for cases and controls, respectively]. Additionally, there was no difference in a proportion of dyspeptic H. pylori-positive subjects [59 (17·1%) versus 524 (15·1%)] between the case and control groups. Only 59 (17%) among the 347 IgAD patients underwent gastroscopy. A significantly larger proportion of case subjects experienced several forms of gastritis [13 (61·9%) versus 38 (21·6%), P < 0·001), duodenal ulcers [seven (33·3%) versus 19 (10·8%); P = 0·01] and nodular lymphoid hyperplasia (NLH) [two (9·5%) versus none; P = 0·011]. IgAD is not associated with increased prevalence of H. pylori-associated dyspepsia; nevertheless, H. pylori-infected dyspeptic IgAD subjects experience more EGD-proved gastritis, duodenal ulcers and NLH.


Concomitant Polyoma BK Virus and West Nile Virus in Renal Allografts.
Surveillance of the renal allograft recipient is essential when monitoring renal function to detect the early onset of rejection and alter therapeutic treatments to treat acute rejection or other causes and improve long-term graft function. If renal function begins to deteriorate, a renal biopsy is often indicated to assess the Banff grade of potential rejection or other causes, especially in the setting of polyoma BK viral load elevation. Although BK infection in the allograft is asymptomatic, reactivation of the virus is known to be associated with the acceleration of pathologic change and a poor outcome in the allograft. BK reactivation in a transplant kidney is not uncommon, and determining inflammation related to the virus versus acute rejection is paramount for appropriate immunosuppressive therapy management. We identified a concomitant polyoma BK virus and West Nile Virus (WNV) infection in two renal transplant patients which, to our knowledge, has not previously been reported. However, other concomitant infections have been reported in renal allografts including BK virus and cytomegalovirus (CMV), CMV and hepatitis C (HCV), and HCV and human immunodeficiency virus (HIV). As WNV has become endemic in many regions of the United States, and since the transmission of the virus via transplanted organs is associated with significant morbidity and mortality, it may be prudent to consider serologic screening for WNV in living donors prior to organ procurement. Regardless, the observation we made and report here should underscore the potential for concomitant viral infections that may be masked when a renal allograft has a significant inflammatory response to BK virus.


Phosphoproteomic profiling of tumor tissues identifies HSP27 Ser82 phosphorylation as a robust marker of early ischemia.
Delays between tissue collection and tissue fixation result in ischemia and ischemia-associated changes in protein phosphorylation levels, which can misguide the examination of signaling pathway status. To identify a biomarker that serves as a reliable indicator of ischemic changes that tumor tissues undergo, we subjected harvested xenograft tumors to room temperature for 0, 2, 10 and 30 minutes before freezing in liquid nitrogen. Multiplex TMT-labeling was conducted to achieve precise quantitation, followed by TiO2 phosphopeptide enrichment and high resolution mass spectrometry profiling. LC-MS/MS analyses revealed phosphorylation level changes of a number of phosphosites in the ischemic samples. The phosphorylation of one of these sites, S82 of the heat shock protein 27 kDa (HSP27), was especially abundant and consistently upregulated in tissues with delays in freezing as short as 2 minutes. In order to eliminate effects of ischemia, we employed a novel cryogenic biopsy device which begins freezing tissues in situ before they are excised. Using this device, we showed that the upregulation of phosphorylation of S82 on HSP27 was abrogated. We thus demonstrate that our cryogenic biopsy device can eliminate ischemia-induced phosphoproteome alterations, and measurements of S82 on HSP27 can be used as a robust marker of ischemia in tissues.


Far-field intensity distribution of a beam generated by a resonator with a phase-unifying mirror.
The far-field intensity distribution (FFID) of a beam generated by a phase-unifying mirror resonator was investigated based on scalar diffraction theory. Attention was paid to the parameters, such as obscuration ratio and reflectivity of the phase-unifying mirror, that determine the FFID. All analyses were limited to the TEM00 fundamental mode.


Impact of perceived cognitive impairment in breast cancer survivors.
Cognitive impairment is commonly reported by breast cancer survivors, yet little is known regarding its impact on quality of life. The purpose of this study was to obtain a better understanding of breast cancer survivors' experiences of perceived cognitive impairment, its trajectory, and its impact on relationships, daily functioning, work and overall life satisfaction after breast cancer diagnosis and treatment. The results are based on qualitative interviews with 22 breast cancer survivors who reported cognitive impairment and who were at least 1 year post-chemotherapy treatment. Interviews were recorded, transcribed verbatim, and analyzed using a content analysis approach. Breast cancer survivors' primarily expressed concerns in 6 major domains including: short-term memory, long-term memory, speed of processing, attention and concentration, language and executive functioning. Concerns emerged as salient after treatment ended as other problems resolved. All of the survivors found these impairments frustrating, and some also reported these changes as detrimental to their self-confidence and social relationships. Employed survivors reported working harder to perform tasks and use of compensatory strategies to complete work tasks. Validation of perceived cognitive impairment by family, friends, and healthcare providers was perceived as important to adjustment. Perceived cognitive deficits have broad implications for the well-being of breast cancer survivors. Study findings underscore the broad consequences of this symptom, provide direction for theory development, measurement selection, and additional intervention targets. A greater understanding of cognitive impairment in breast cancer survivors may lead to the development of effective treatment of this symptom.


Digital PCR cluster predictor: a universal R-package and shiny app for the automated analysis of multiplex digital PCR data.
Digital polymerase chain reaction (dPCR) is an emerging technology that enables accurate and sensitive quantification of nucleic acids. Most available dPCR systems have two channel optics, with ad hoc software limited to the analysis of single and duplex assays. Although multiplexing strategies were developed, variable assay designs, dPCR systems, and the analysis of low DNA input data restricted the ability for a universal automated clustering approach. To overcome these issues, we developed dPCR Cluster Predictor (dPCP), an R package and a Shiny app for automated analysis of up to 4-plex dPCR data. dPCP can analyse and visualize data generated by multiple dPCR systems carrying out accurate and fast clustering not influenced by the amount and integrity of input of nucleic acids. With the companion Shiny app, the functionalities of dPCP can be accessed through a web browser.


The Roosevelt years: crucial milieu for Carl Rogers' innovation.
This study explores broad features of political culture and event of the 1930s and World War 2 years, viewed in relation to the emergence and rapid early growth of the new therapy of Carl Rogers. The paper traces Rogers' early professional life and examines distinctive emphases in sociopolitical thought and development during Franklin D. Roosevelt's leadership as President over the prolonged emergency of the Great Depression and the crisis of the War. The study includes a focus on the President's own outlook and style, pertinent New Deal innovations, and wartime needs. Twelve features of this larger context are discriminated as together having vital importance for the new therapy and its founder. The congruent courses of the macrocontext and of Rogers' innovation are followed to the ending of Roosevelt's life. Direct causation is not attributed, but the evidence adduced newly points to particular contours of a larger environment favorable for the expression of Rogers' values and rare ability. In sum, the author concludes that a synergy of highly conducive historical circumstance and individual exceptionality contributed to the philosophical underpinnings, attitudinal values and early momentum of Rogers' client-centered therapy.


How to take care of nurses in your organization: two types of exchange relationships compared.
To explore the relationships between climate for well-being, economic and social exchange, affective ward commitment and job strain among nurses in the Netherlands. This study focuses on the immediate work environment of nurses by exploring the way nurse perceptions about the extent to which the ward values and cares for their welfare influence their levels of affective ward commitment and job strain. Second, this study extends previous research on exchange relationships by examining the potential differential impact of social and economic exchange relationships on commitment and job strain. A cross-sectional survey among nurses. The study was conducted in the Netherlands in 2011. Validated measures of climate for well-being, social exchange, economic exchange, ward commitment and job strain were used. Hypotheses were tested using regression analyses. MacKinnon et al.'s (2007) guidelines to assess mediation were used. The response rate was 41% (271 questionnaires). The results show that climate for well-being positively influences social exchange relationships, which are in turn associated with enhanced ward commitment and reduced strain. Climate for well-being negatively influences evaluations of economic exchange, which are in turn negatively related to ward commitment. This study shows that nurses use the information available in their immediate work environment to evaluate their exchange relationship with the organization. Second, the findings point towards the importance of economic and social exchange relationships as a mechanism between climate for well-being on the one hand and affective ward commitment and job strain on the other hand.


Relative Stabilities of Transition States Determine Diastereocontrol in Sulfur Ylide Additions onto Chiral N-Sulfinyl Imines.
Additions of methylphenylsulfonium methylide onto chiral non-racemic N-sulfinyl imines (R'-SO-N=CH-R, R'=t-butyl, R=protected diol), followed by ring closure, yield terminal aziridines with high diastereoselectivity. Control reactions have established that both N- and C- iminyl substituents impact product preference, and when properly matched, one addition product is selected almost exclusively. Using solution-phase density functional computational methods, minima and transition state searches have been performed to reveal the structural origins of the diastereoselectivity. Our computational findings indicate that ring closure is fast and irreversible, and consequently, the relative energies of the transition states for the competing Re/Si addition steps determine the product diastereomeric ratios. Analysis of addition transition state structures reveals the causes of selectivity as arising from the N- and C- iminyl substituents, and we identify the S (R) configuration of the N-sulfinyl sulfur atom as the dominant director of Si (Re) addition. The control attributed to the sulfur configuration is tied to an important favorable internal interaction between the sulfinyl oxygen and the iminyl hydrogen. The protected diol acts as a secondary director, owing to steric/electrostatic interactions with the approaching ylide.


Analysis of brain edema in RHAPSODY.
Cerebral edema is a secondary complication of acute ischemic stroke, but its time course and imaging markers are not fully understood. Recently, net water uptake (NWU) has been proposed as a novel marker of edema. Studying the RHAPSODY trial cohort, we sought to characterize the time course of edema and test the hypothesis that NWU provides distinct information when added to traditional markers of cerebral edema after stroke by examining its association with other markers. A total of 65 patients had measurable supratentorial ischemic lesions. Patients underwent head computed tomography (CT), brain magnetic resonance imaging (MRI) scans, or both at the baseline visit and after 2, 7, 30, and 90 days following enrollment. CT and MRI scans were used to measure four imaging markers of edema: midline shift (MLS), hemisphere volume ratio (HVR), cerebrospinal fluid (CSF) volume, and NWU using semi-quantitative threshold analysis. Trajectories of the markers were summarized, as available. Correlations of the markers of edema were computed and the markers compared by clinical outcome. Regression models were used to examine the effect of 3K3A-activated protein C (APC) treatment. Two measures of mass effect, MLS and HVR, could be measured on all imaging modalities, and had values available across all time points. Accordingly, mass effect reached a maximum level by day 7, normalized by day 30, and then reversed by day 90 for both measures. In the first 2 days after stroke, the change in CSF volume was associated with MLS (ρ = -0.57, p = 0.0001) and HVR (ρ = -0.66, p < 0.0001). In contrast, the change in NWU was not associated with the other imaging markers (all p ⩾ 0.49). While being directionally consistent, we did not observe a difference in the edema markers by clinical outcome. In addition, baseline stroke volume was associated with all markers (MLS (p < 0.001), HVR (p < 0.001), change in CSF volume (p = 0.003)) with the exception of NWU (p = 0.5). Exploratory analysis did not reveal a difference in cerebral edema markers by treatment arm. Existing cerebral edema imaging markers potentially describe two distinct processes, including lesional water concentration (i.e. NWU) and mass effect (MLS, HVR, and CSF volume). These two types of imaging markers may represent distinct aspects of cerebral edema, which could be useful for future trials targeting this process.


Comprehensive morphologic and functional imaging of heart transplant patients: first experience with dynamic perfusion CT.
We aimed to assess the diagnostic performance of a combined protocol with coronary computed tomography angiography (CCTA) and stress CT perfusion imaging (CTP) in heart transplant patients for comprehensive morphological and functional imaging. In this prospective study, 13 patients undergoing routine follow-up 8±6 years after heart transplantation underwent CCTA and dynamic adenosine stress CTP using a third-generation dual-source CT scanner, cardiac magnetic resonance (MR) adenosine stress perfusion imaging at 1.5 T, and catheter coronary angiography. In CCTA stenoses >50% luminal diameter narrowing were noted. Myocardial perfusion deficits were documented in CTP and MR. Quantitative myocardial blood flow (MBF) was calculated with CTP. Left ventricular ejection fraction was determined on cardiac MR cine images. Radiation doses of CT were determined. One of the 13 patients had to be excluded because of severe motion artifacts. CCTA identified three patients with stenosis >50%, which were confirmed with catheter coronary angiography. CTP showed four patients with stress-induced myocardial hypoperfusion, which were confirmed by MR stress perfusion imaging. Quantitative analysis of global MBF showed lower mean values as compared to known reference values (MBF under stress 125.5 ± 34.5 ml/100 ml/min). Average left ventricular ejection fraction was preserved (56 ± 5%). In heart transplant patients, a comprehensive CT protocol for the assessment of morphology and function including CCTA and CTP showed good concordance to results from MR perfusion imaging and catheter coronary angiography. • Stress CT perfusion imaging enables the detection of myocardial ischemia • CT myocardial perfusion imaging can be combined with coronary computed tomography angiography • Combining perfusion and coronary CT imaging is accurate in heart transplant patients • CT myocardial perfusion imaging can be performed at a reasonable radiation dose.


What is the optimum strategy for managing dyspepsia?
The demand for upper gastrointestinal endoscopy is increasing. The main impetus has been to detect gastric cancer at a treatable stage. Gastric cancer is rare in the young, but endoscopy is still performed in this age group. The rationale is to detect significant pathology such as peptic ulcer disease. Endoscopy is expensive and resources are limited, so alternative strategies to investigate young dyspeptics is desirable. This paper reviews the strategies available for investigating young patients with dyspepsia. These include symptom questionnaires, empirical anti-secretory therapy, screening for Helicobacter pylori and endoscoping those that are positive, screening for H. pylori, and treating those that are positive or prescribing empirical H. pylori eradication therapy. We have found screening for H. pylori and treating those infected has reduced endoscopy in the young by 34% in our unit and may be the most cost-effective method of managing dyspepsia in those at low risk of underlying upper gastrointestinal malignancy.


European S2k Guideline on Chronic Pruritus.
Pruritus is a frequent symptom in medicine. Population-based studies show that every 5th person in the general population has suffered from chronic pruritus at least once in the lifetime with a 12-month incidence of 7%. In patient populations its frequency is much higher depending on the underlying cause, ranging from around 25% in haemodialysis patients to 100% in skin diseases such as urticaria and atopic dermatitis (AD). Pruritus may be the result of a dermatological or non-dermatological disease. Especially in non-diseased skin it may be caused by systemic, neurological or psychiatric diseases, as well as being a side effect of medications. In a number of cases chronic pruritus may be of multifactorial origin. Pruritus needs a precise diagnostic work-up. Management of chronic pruritus comprises treatment of the underlying disease and topical treatment modalities, including symptomatic antipruritic treatment, ultraviolet phototherapy and systemic treatment. Treating chronic pruritus needs to be targeted, multimodal and performed in a step-wise procedure requiring an interdisciplinary approach. We present the updated and consensus based (S2k) European guideline on chronic pruritus by a team of European pruritus experts from different disciplines. This version is an updated version of the guideline that was published in 2012 and updated in 2014 (www.euroderm.org).


Tumor Priming by SMO Inhibition Enhances Antibody Delivery and Efficacy in a Pancreatic Ductal Adenocarcinoma Model.
Despite frequent overexpression of numerous growth factor receptors by pancreatic ductal adenocarcinomas (PDAC), such as EGFR, therapeutic antibodies have not proven effective. Desmoplasia, hypovascularity, and hypoperfusion create a functional drug delivery barrier that contributes to treatment resistance. Drug combinations that target tumor/stroma interactions could enhance tumor deposition of therapeutic antibodies, although clinical trials have yet to support this strategy. We hypothesize that macromolecular or nanoparticulate therapeutic agents may best exploit stroma-targeting "tumor priming" strategies, based on the fundamental principles of the Enhanced Permeability and Retention phenomenon. Therefore, we investigated the molecular and pharmacologic tumor responses to NVP-LDE225, an SMO inhibitor of sonic hedgehog signaling (sHHI), of patient-derived xenograft models that recapitulate the desmoplasia and drug delivery barrier properties of PDAC. Short-term sHHI exposure mediated dose- and time-dependent changes in tumor microvessel patency, extracellular matrix architecture, and interstitial pressure, which waned with prolonged sHHI exposure, and increased nanoparticulate permeability probe deposition in multiple PDAC patient-derived xenograft isolates. During sHHI-mediated priming, deposition and intratumor distribution of both a nontargeted mAb and a mAb targeting EGFR, cetuximab, were enhanced. Sequencing the sHH inhibitor with cetuximab administration resulted in marked tumor growth inhibition compared with cetuximab alone. These studies suggest that PDAC drug delivery barriers confound efforts to employ mAb against targets in PDAC, and that short-term, intermittent exposure to stromal modulators can increase tumor cell exposure to therapeutic antibodies, improving their efficacy, and potentially minimize adverse effects that may accompany longer-term, continuous sHHI treatment.


A Socioecological Predication Model of Posttraumatic Stress Disorder in Low-Income, High-Risk Prenatal Native Hawaiian/Pacific Islander Women.
Only recently has perinatal posttraumatic stress disorder (PTSD) been researched in any depth; however, the causes and consequences of this serious illness remain unclear. Most commonly, childbirth trauma and interpersonal violence have been reported as contributing factors. However, not all Native Hawaiian/Pacific Islander (NHPI) women who experience these events experience PTSD. The factors affecting PTSD are many and complex, intertwining individual, family, and community contexts. Using a socioecological framework, 3 levels of contextual variables were incorporated in this study (individual, family, and social/community). The purpose of this study was to determine the socioecological predictors associated with prenatal PTSD among NHPI. A case-control design was used to collect retrospective data about socioecological variables from medical record data. The sample was low-income, high-risk NHPI women receiving perinatal health care at a rural community health center in Hawaii who screened positive (n = 55) or negative (n = 91) for PTSD. Hierarchical logistic regression was conducted to determine socioecological predictors of positive PTSD screening. Although the majority of women (66.4%) experienced some form of interpersonal violence, a constellation of significant predictor variables from all 3 levels of the model were identified: depression (individual level), lack of family support and family stress (family level), and violence (social/community level). Each of the predictor variables has been identified by other researchers as significantly affecting perinatal PTSD. However, it is because these variables occur together that a more complex picture emerges, suggesting the importance of considering multiple variables in context when identifying and caring for these women. Although additional research is needed, it is possible that the significant predictor variables could be useful in identifying women who are at higher risk for PTSD in other similar populations.


Platelet Rich Plasma for Chronic Synovitis Treatment in Patients with Haemophilia.
Haemophilic synovitis is caused by chronic accumulation of blood in the joint. Conservative treatment is insufficient to solve this pathology. Platelet-rich plasma (PRP) has a high concentration of growth factors (GFs) that play a key role in regulation and stimulation of healing processes. The aim of this study was to describe the effect of PRP injection in chronic synovitis of the joints in patients with haemophilia (PWH). Nineteen patients with 28 joints were treated at our centre in Buenos Aires, Argentina between December 2014 and December 2015. Eighteen were Haemophilia type A (17 severe, one mild) and one was type B severe. Mean age was 26 years old. Chronic synovitis was present in two ankles, seven elbows and 19 knee joints. All affected joints were evaluated for range of motion (ROM), perimeter, Haemophilia Joint Health Score (HJHS), number of bleedings episodes and Visual Analogue Scale (VAS). Evaluations were before treatment and 3 and 6 months after treatment. A mean volume of 4 mL of PRP was injected into the joint cavity. The statistical analysis before and after treatments revealed a statistically significant (P < 0.001) decrease in the HJHS score. Decrease in joint bleeding episodes was also statistically significant (P < 0.001). All patients reported pain relief and VAS scores were statistically significant (P < 0.001). Joint perimeter also showed a statistically significant difference (P < 0.001). No complications were observed in any of the patients, either during blood collection or during PRP injection, even for inhibitor patients. Platelet-rich plasma is a useful, safe, and inexpensive treatment for chronic haemophilic synovitis.


Recurrent Hepatitis in Two Iranian Children: A Novel (Q166R) Mutation in EIF2AK3 Leading to Wolcott-Rallison Syndrome.
Early-onset diabetes, liver dysfunction, growth retardation, spondyloepiphyseal dysplasia, and tendency to skeletal fractures due to osteopenia are characteristics of Wolcott-Rallison syndrome (WRS). Eukaryotic translation initiation factor 2α kinase (EIF2AK3) is the only known gene, which is responsible for this rare autosomal recessive disorder. Here, we report two siblings a girl and a boy with diabetes mellitus (DM) who presented in one and two months of age respectively. Recurrent self-limiting hepatitis developed later, and severe hepatic failure resulted in death of the first child. The second child visited was a 7.75 year old boy who had spondyloepiphyseal dysplasia and subclinical hypothyroidism besides DM and recurrent hepatitis. We suggested WRS for this patient, and it was confirmed by identification of a novel homozygous missense mutation (Q166R) in exon 3 of the EIF2AK3 gene. The aim of this report is to remind the possibility of WRS in isolated neonatal diabetes; while, the other clinical manifestations of this syndrome including its major symptom of recurrent hepatitis may appear later.


Macrophage Colony Stimulating Factor Derived from CD4+ T Cells Contributes to Control of a Blood-Borne Infection.
Dynamic regulation of leukocyte population size and activation state is crucial for an effective immune response. In malaria, Plasmodium parasites elicit robust host expansion of macrophages and monocytes, but the underlying mechanisms remain unclear. Here we show that myeloid expansion during P. chabaudi infection is dependent upon both CD4+ T cells and the cytokine Macrophage Colony Stimulating Factor (MCSF). Single-cell RNA-Seq analysis on antigen-experienced T cells revealed robust expression of Csf1, the gene encoding MCSF, in a sub-population of CD4+ T cells with distinct transcriptional and surface phenotypes. Selective deletion of Csf1 in CD4+ cells during P. chabaudi infection diminished proliferation and activation of certain myeloid subsets, most notably lymph node-resident CD169+ macrophages, and resulted in increased parasite burden and impaired recovery of infected mice. Depletion of CD169+ macrophages during infection also led to increased parasitemia and significant host mortality, confirming a previously unappreciated role for these cells in control of P. chabaudi. This work establishes the CD4+ T cell as a physiologically relevant source of MCSF in vivo; probes the complexity of the CD4+ T cell response during type 1 infection; and delineates a novel mechanism by which T helper cells regulate myeloid cells to limit growth of a blood-borne intracellular pathogen.


The effect of reducing and other agents on the motility of Treponema pallidum in an acellular culture medium.
The maintenance of Treponema pallidum motility was investigated in an acellular medium based on T. pallidum immobilization test medium. The acellular medium contained cysteine, glutathione, thioglycollate and dithiothreitol as reducing agents and had a redox potential of -275 +/- 25 mV at pH 7.3. In an atomosphere containing 3% O2, motile treponemes survived four times longer when calf serum and bovine serum albumin were added to the medium. The selective omission of glutathione and, particularly, thioglycollate prolonged the survival of motile treponemes almost fivefold. In addition, stored medium, in which thioglycollate had become inactive, sustained motile treponemes for longer than did freshly prepared medium. Thus, thioglycollate is toxic for the organisms. It may be omitted from the medium because low redox potentials can be achieved without it.


The hydroperoxyl radical scavenging activity of sulfuretin: insights from theory.
Sulfuretin (SFR), which is isolated from Rhus verniciflua, Toxicodendron vernicifluum, Dahlia, Bidens tripartite and Dipterx lacunifera, is one of the most important natural flavonoids. This compound is known to have numerous biological activities; among these, the antioxidant activity has not been thoroughly studied yet. In this study, the hydroperoxyl scavenging activity of SFR was examined by using density functional theory calculations. SFR is predicted to be an excellent HOO• scavenger in water at pH = 7.40 with k overall = 4.75 × 107 M-1 s-1, principally due to an increase in the activity of the anionic form following the single-electron transfer mechanism. Consistently, the activity of the neutral form is more prominent in the non-polar environment with k overall = 1.79 × 104 M-1 s-1 following the formal hydrogen transfer mechanism. Thus, it is predicted that SFR exhibits better HOO• antiradical activity than typical antioxidants such as resveratrol, ascorbic acid or Trolox in the lipid medium. The hydroperoxyl radical scavenging of SFR in the aqueous solution is approximately 530 times faster than that of Trolox and similar to ascorbic acid or resveratrol. This suggests that SFR is a promising radical scavenger in physiological environments.


Uncovering the potential of private providers' involvement in health to strengthen comprehensive health systems: a discussion paper.
Health systems strengthening (HSS) is being increasingly recognized as a strategic cross-cutting issue in all World Health Organization (WHO) work. Health systems comprise six building blocks: service delivery; medical products, vaccines and technologies; health workforce; health systems financing; health information system; and leadership and governance. Public-private mix (PPM) approaches or partnerships consist of initiatives aimed at increasing collaboration and improving the relationships between public-public, public-private and private-private health providers. An important component of PPM is the clear distribution of tasks between the different providers involved in the provision of health care. In practice, most PPM initiatives are disease-specific and are often related to the health service delivery block mentioned above. Although there is widespread consensus that PPM initiatives are typically of an HSS nature, efforts to make explicit the links between PPM and health systems building blocks are rather uncommon. The present paper aims to identify - in order to facilitate operationalization - potential aspects linking PPM to health systems building blocks, using a few experiences from tuberculosis control and beyond. The paper targets policymakers, donors and health systems scientists and ends with a call for more aware and innovative leadership, for increased support of PPM initiatives covering various building blocks, and for more operational research.


19F nuclear magnetic resonance analysis of the carbamate reaction of alpha-fluoro-beta-alanine (FBAL), the major catabolite of fluoropyrimidines. Application to FBAL carbamate determination in body fluids of patients treated with 5'-deoxy-5-fluorouridine.
alpha-Fluoro-beta-alanine (FBAL), the major catabolite of the antineoplastic fluoropyrimidines, is an amino acid which is in equilibrium with its carbamate derivative in weakly alkaline aqueous solutions containing carbonate. In both water and control biological fluids (urine, plasma) spiked with FBAL (and sodium bicarbonate, in some cases), 19F NMR was used: (i) to determine the pH range over which FBAL carbamate is present (pH greater than or equal to 7), the maximum concentration formed occurring around pH 9, (ii) to show that the amino group of FBAL interacts very slowly with a non-protein plasma component to form a compound X, unstable in acid medium. The presumed structure of X is RCONHCH2CHFCOOH, with R different from an alkyl group but still unidentified. The behavior of FBAL in urine and plasma of rats treated with FBAL or 5'-deoxy-5-fluorouridine (5'-dFUrd), a prodrug of 5-fluorouracil, and from patients treated with 5'-dFUrd was investigated. FBAL carbamate was not present in acid medium and was therefore absent in acidic human urine. However, it was found in alkaline rat urine. FBAL carbamate was found in plasma along with the compound X. The 19F NMR spectra of FBAL and derivatives are complex since alpha-fluoro-beta-ureido-propionic acid, the precursor of FBAL in the catabolic pathway of antineoplastic fluoropyrimidines, produces a signal overlapping that of FBAL carbamate, and very close to that of compound X.(ABSTRACT TRUNCATED AT 250 WORDS)


The age of the Taklimakan Desert.
The Taklimakan Desert is located in the foreland basin of the Tibetan Plateau. We report here the results of stratigraphic investigations of a 1626-meter-thick sequence with interbedded wind-blown silt from the southern marginal Taklimakan Desert. Because the studied section is located downwind of the desert, the eolian silt accumulation is closely linked to desert formation. Our new evidence indicates that shifting sand dunes prevailed in the Tarim Basin by at least 5.3 million years ago, as they do today. We attribute this event to late Cenozoic climatic deterioration, as well as to changes in atmospheric circulation induced by Tibetan Plateau uplift.


Vegetal Undercurrents-Obscured Riverine Dynamics of Plant Debris.
Much attention has been focused on fine-grained sediments carried as suspended load in rivers due to their potential to transport, disperse, and preserve organic carbon (OC), while the transfer and fate of OC associated with coarser-grained sediments in fluvial systems have been less extensively studied. Here, sedimentological, geochemical, and biomolecular characteristics of sediments from river depth profiles reveal distinct hydrodynamic behavior for different pools of OC within the Mackenzie River system. Higher radiocarbon (14C) contents, low N/OC ratios, and elevated plant-derived biomarker loadings suggest a systematic transport of submerged vascular plant debris above the active riverbed in large channels both upstream of and within the delta. Subzero temperatures hinder OC degradation promoting the accumulation and waterlogging of plant detritus within the watershed. Once entrained into a channel, sustained flow strength and buoyancy prevent plant debris from settling and keep it suspended in the water column above the riverbed. Helical flow motions within meandering river segments concentrate lithogenic and organic debris near the inner river bends forming a sediment-laden plume. Moving offshore, we observe a lack of discrete, particulate OC in continental shelf sediments, suggesting preferential trapping of coarse debris within deltaic and neritic environments. The delivery of waterlogged plant detritus transport and high sediment loads during the spring flood may reduce oxygen exposure times and microbial decomposition, leading to enhanced sequestration of biospheric OC. Undercurrents enriched in coarse, relatively fresh plant fragments appear to be reoccurring features, highlighting a poorly understood yet significant mechanism operating within the terrestrial carbon cycle.


Exposure to Blue Light Reduces Melanopsin Expression in Intrinsically Photoreceptive Retinal Ganglion Cells and Damages the Inner Retina in Rats.
The purpose of this study was to investigative the effects of blue light on intrinsically photoreceptive retinal ganglion cells (ipRGCs). Brown Norway rats were used. Nine rats were continuously exposed to blue light (light emitting diodes [LEDs]: 463 nm; 1000 lx) for 2 days (acute exposure [AE]); 9 rats were exposed to 12 hours of blue light and 12 hours of darkness for 10 days (long-term exposure [LTE]); 6 control rats were exposed to 12 hours of white fluorescent light (1000 lx) and 12 hours of darkness for 10 days. Whole-mount retinas were immunolabelled with melanopsin antibodies; melanopsin-positive (MP) ipRGC somas and processes were counted and measured with Neuron J. To detect apoptosis, retinal cryo-sections were stained with terminal deoxynucleotidyl transferase dUTP nick-end labeling. Ultra-thin sections were visualized with transmission electron microscopy. The number of MP ipRGC somas was significantly lower in retinas from AE and LTE rats than in those from control rats (P < 0.001 and = 0.002, respectively). The mean length of MP areas of processes was significantly lower in AE rats (P < 0.001). AE rats had severe retinal damage and massive apoptosis in the outer nuclear layer; their mitochondria were damaged in the axons and dendrites of the nerve fiber layer and the inner plexiform layer. Retinal ganglion cells (RGCs) in AE rats appeared to have reduced amounts of free ribosomes and rough endoplasmic reticulum. AE to blue light reduces melanopsin expression and damages RGCs, likely including ipRGCs. Changes in the axons and dendrites of RGCs suggest possible disruption of intraretinal and extraretinal signal transmission.


Hepatitis C virus NS3/4A protease.
Despite an urgent medical need, a broadly effective anti-viral therapy for the treatment of infections with hepatitis C viruses (HCVs) has yet to be developed. One of the approaches to anti-HCV drug discovery is the design and development of specific small molecule drugs to inhibit the proteolytic processing of the HCV polyprotein. This proteolytic processing is catalyzed by a chymotrypsin-like serine protease which is located in the N-terminal region of non-structural protein 3 (NS3). This protease domain forms a tight, non-covalent complex with NS4A, a 54 amino acid activator of NS3 protease. The C-terminal two-thirds of the NS3 protein contain a helicase and a nucleic acid-stimulated nucleoside triphosphatase (NTPase) activities which are probably involved in viral replication. This review will focus on the structure and function of the serine protease activity of NS3/4A and the development of inhibitors of this activity.


Predicted effect of circadian clock modulation of NHE3 of a proximal tubule cell on sodium transport.
Major renal functions such as renal blood flow, glomerular filtration rate, and urinary excretion are known to exhibit circadian oscillations. However, the underlying mechanisms that govern these variations have yet to be fully elucidated. To better understand the impact of the circadian clock on renal solute and water transport, we have developed a computational model of the renal circadian clock and coupled that model to an epithelial transport model of the proximal convoluted cell of the rat kidney. The activity of the Na+-H+ exchanger 3 (NHE3) is assumed to be regulated by changes in transcription of the NHE3 mRNA due to regulation by circadian clock proteins. The model predicts the rhythmic oscillations in NHE3 activity, which gives rise to significant daily fluctuations in Na+ and water transport of the proximal tubule cell. Additionally, the model predicts that 1) mutation in period 2 (Per2) or cryptochrome 1 (Cry1) preserves the circadian rhythm and modestly raises Na+ reabsorption; 2) mutation in Bmal1 or CLOCK eliminates the circadian rhythm and modestly lowers Na+ reabsorption; 3) mutation in Rev-Erb or ROR-related orphan receptor (Ror) has minimal impact on the circadian oscillations. The model represents the first step in building a tool set aimed at increasing our understanding of how the molecular clock affects renal ion transport and renal function, which likely has important implications for kidney disease.


Long-Term Effect of Serial Infections with H13 and H16 Low-Pathogenic Avian Influenza Viruses in Black-Headed Gulls.
Infections of domestic and wild birds with low-pathogenic avian influenza viruses (LPAIVs) have been associated with protective immunity to subsequent infection. However, the degree and duration of immunity in wild birds from previous LPAIV infection, by the same or a different subtype, are poorly understood. Therefore, we inoculated H13N2 (A/black-headed gull/Netherlands/7/2009) and H16N3 (A/black-headed gull/Netherlands/26/2009) LPAIVs into black-headed gulls (Chroicocephalus ridibundus), their natural host species, and measured the long-term immune response and protection against one or two reinfections over a period of >1 year. This is the typical interval between LPAIV epizootics in wild birds. Reinfection with the same virus resulted in progressively less virus excretion, with complete abrogation of virus excretion after two infections for H13 but not H16. However, reinfection with the other virus affected neither the level nor duration of virus excretion. Virus excretion by immunologically naive birds did not differ in total levels of excreted H13 or H16 virus between first- and second-year birds, but the duration of H13 excretion was shorter for second-year birds. Furthermore, serum antibody levels did not correlate with protection against LPAIV infection. LPAIV-infected gulls showed no clinical signs of disease. These results imply that the epidemiological cycles of H13 and H16 in black-headed gulls are relatively independent from each other and depend mainly on infection of first-year birds. Low-pathogenic avian influenza viruses (LPAIVs) circulate mainly in wild water birds but are occasionally transmitted to other species, including humans, where they cause subclinical to fatal disease. To date, the effect of LPAIV-specific immunity on the epidemiology of LPAIV in wild birds is poorly understood. In this study, we investigated the effect of H13 and H16 LPAIV infection in black-headed gulls on susceptibility and virus excretion of subsequent infection with the same or the other virus within the same breeding season and between breeding seasons. These are the only two LPAIV hemagglutinin subtypes predominating in this species. The findings suggest that H13 and H16 LPAIV cycles in black-headed gull populations are independent of each other, indicate the importance of first-year birds in LPAIV epidemiology, and emphasize the need for alternatives to avian influenza virus (AIV)-specific serum antibodies as evidence of past LPAIV infection and correlates of protection against LPAIV infection in wild birds.


Associated change in plantar temperature and sweating after transthoracic endoscopic T2-3 sympathectomy for palmar hyperhidrosis.
Transthoracic endoscopic T2-3 sympathectomy is currently the treatment of choice for palmar hyperhidrosis. Compensatory sweating of the face, trunk, thigh, and sole of the foot was found in more than 50% of patients who underwent this procedure. The authors conducted this study to investigate the associated intraoperative changes in plantar skin temperature and postoperative plantar sweating. One hundred patients with palmar hyperhidrosis underwent bilateral transthoracic endoscopic T2-3 sympathectomy. There were 60 female and 40 male patients who ranged in age from 13 to 40 years (mean age 21.6 years). Characteristics studied included changes in palmar and plantar skin temperature measured intraoperatively, as well as pre- and postoperative changes in plantar sweating and sympathetic skin responses (SSRs). In 59 patients (59%) elevation of plantar temperature was demonstrated at the end of the surgical procedure. In this group, plantar sweating was found to be exacerbated in three patients (5%); plantar sweating was improved in 52 patients (88.1%); and no change was demonstrated in four patients (6.8%). In the other group of patients in whom no temperature change occurred, increased plantar sweating was demonstrated in three patients (7.3%); plantar sweating was improved in 20 patients (48.8%); and no change was shown in 18 patients (43.9%). The difference between temperature and sweating change was significant (p = 0.001). Compared with the presympathectomy rate, the rate of absent SSR also significantly increased after sympathectomy: from 20 to 76% after electrical stimulation and 36 to 64% after deep inspiration stimulation, respectively (p < 0.05). In contrast to compensatory sweating in other parts of the body after T2-3 sympathetomy, improvement: in plantar sweating was shown in 72% and worsened symptoms in 6% of patients. The intraoperative plantar skin temperature change and perioperative SSR demonstrated a correlation between these changes.


Poly[diaqua-μ(2)-oxalato-di-μ(4)-terephthalato-dilutetium(III)].
In the title compound, [Lu(2)(C(8)H(4)O(4))(2)(C(2)O(4))(H(2)O)(2)](n), the Lu(3+) cations are each coordinated by eight O atoms of four terephthalate anions, one oxalate anion and one aqua ligand to complete a distorted square-anti-prismatic geometry. They are bridged by the terephthalate ligands, generating a three-dimensional framework, which is further stabilized by the oxalate ligands. The terephthalate ions and oxalate ions are all located on centers of inversion.


A New Late Miocene Odobenid (Mammalia: Carnivora) from Hokkaido, Japan Suggests Rapid Diversification of Basal Miocene Odobenids.
The modern walrus, Odobenus rosmarus, is specialized and only extant member of the family Odobenidae. They were much more diversified in the past, and at least 16 genera and 20 species of fossil walruses have been known. Although their diversity increased in the late Miocene and Pliocene (around 8-2 Million years ago), older records are poorly known. A new genus and species of archaic odobenid, Archaeodobenus akamatsui, gen. et sp. nov. from the late Miocene (ca. 10.0-9.5 Ma) top of the Ichibangawa Formation, Hokkaido, northern Japan, suggests rapid diversification of basal Miocene walruses. Archaeodobenus akamatsui is the contemporaneous Pseudotaria muramotoi from the same formation, but they are distinguishable from each other in size and shape of the occipital condyle, foramen magnum and mastoid process of the cranium, and other postcranial features. Based on our phylogenetic analysis, A. akamatsui might have split from P. muramotoi at the late Miocene in the western North Pacific. This rapid diversification of the archaic odobenids occurred with a combination of marine regression and transgression, which provided geological isolation among the common ancestors of extinct odobenids.


Influence of CRHR1 Polymorphisms and Childhood Abuse on Suicide Attempts in Affective Disorders: A GxE Approach.
Background: Previous studies have shown that the hypothalamus-pituitary-adrenal-axis (HPA-axis) is closely involved in the development of affective disorders. Given that early life events are also linked to dysregulation of the same system, there might be an association between childhood adversities and suicidal behavior in affective disorders, moderated by HPA-axis genes. We aimed to investigate a potential association between childhood trauma and previous suicide attempts in affective disorder patients, moderated by variants of the corticotropin-releasing hormone receptor 1 (CRHR1) gene. Methods: The current pilot study is part of an ongoing study on suicidal behavior in affective disorders (VieSAD). Two hundred fifty eight Caucasian affective disorder patients were assessed at the Department of Psychiatry and Psychotherapy of the Medical University Vienna and the Karl Landsteiner University for Health and Science. An assemblage of psychiatric interviews was performed (e.g., SCAN, HAMD, SBQ-R, CTQ) and DNA samples of peripheral blood cells were genotyped with TaqMan® SNP Genotyping Assays (rs7209436, rs4792887, rs110402, rs242924, and rs242939). Results: Neither genetic, nor haplotypic associations between CRHR1 polymorphisms and previous suicide attempts could be established for the present sample. Using a binary logistic regression model, significant gene-environment-interactions were found for the single nucleotide polymorphisms (SNPs) rs7209436 and rs110402, reflecting the impact of childhood trauma and CRHR1 polymorphisms on previous suicide attempts. Limitations: A larger sample size will be required to ultimately elucidate the link between childhood trauma and the HPA axis in suicidal behavior. Conclusion: This pilot study presents promising gene-environment-interaction findings in affective disorder patients with a history of suicide attempts.


Vascular Remodeling Is a Crucial Event in the Early Phase of Hepatocarcinogenesis in Rodent Models for Liver Tumorigenesis.
The investigation of hepatocarcinogenesis is a major field of interest in oncology research and rodent models are commonly used to unravel the pathophysiology of onset and progression of hepatocellular carcinoma. HCC is a highly vascularized tumor and vascular remodeling is one of the hallmarks of tumor progression. To date, only a few detailed data exist about the vasculature and vascular remodeling in rodent models used for hepatocarcinogenesis. In this study, the vasculature of HCC and the preneoplastic foci of alteration (FCA) of different mouse models with varying genetic backgrounds were comprehensively characterized by using immunohistochemistry (CD31, Collagen IV, αSMA, Desmin and LYVE1) and RNA in situ hybridization (VEGF-A). Computational image analysis was performed to evaluate selected parameters including microvessel density, pericyte coverage, vessel size, intratumoral vessel distribution and architecture using the Aperio ImageScope and Definiens software programs. HCC presented with a significantly lower number of vessels, but larger vessel size and increased coverage, leading to a higher degree of maturation, whereas FCA lesions presented with a higher microvessel density and a higher amount of smaller but more immature vessels. Our results clearly demonstrate that vascular remodeling is present and crucial in early stages of experimental hepatocarcinogenesis. In addition, our detailed characterization provides a strong basis for further angiogenesis studies in these experimental models.


Effectiveness of continuing medical education.
Despite the broad range of continuing medical education (CME) offerings aimed at educating practicing physicians through the provision of up-to-date clinical information, physicians commonly overuse, under-use, and misuse therapeutic and diagnostic interventions. It has been suggested that the ineffective nature of CME either accounts for the discrepancy between evidence and practice or at a minimum contributes to this gap. Understanding what CME tools and techniques are most effective in disseminating and retaining medical knowledge is critical to improving CME and thus diminishing the gap between evidence and practice. The purpose of this review was to comprehensively and systematically synthesize evidence regarding the effectiveness of CME and differing instructional designs in terms of knowledge, attitudes, skills, practice behavior, and clinical practice outcomes. We formulated specific questions with input from external experts and representatives of the Agency for Healthcare Research and Quality (AHRQ) and the American College of Chest Physicians (ACCP) which nominated this topic. We systematically searched the literature using specific eligibility criteria, hand searching of selected journals, and electronic databases including: MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, The Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Database of Abstracts of Reviews of Effects (DARE), PsycINFO, and the Educational Resource Information Center (ERIC). Two independent reviewers conducted title scans, abstract reviews, and then full article reviews to identify eligible articles. Each eligible article underwent double review for data abstraction and assessment of study quality. Of the 68,000 citations identified by literature searching, 136 articles and 9 systematic reviews ultimately met our eligibility criteria. The overall quality of the literature was low and consequently firm conclusions were not possible. Despite this, the literature overall supported the concept that CME was effective, at least to some degree, in achieving and maintaining the objectives studied, including knowledge (22 of 28 studies), attitudes (22 of 26), skills (12 of 15), practice behavior (61 of 105), and clinical practice outcomes (14 of 33). Common themes included that live media was more effective than print, multimedia was more effective than single media interventions, and multiple exposures were more effective than a single exposure. The number of articles that addressed internal and/or external characteristics of CME activities was too small and the studies too heterogeneous to determine if any of these are crucial for CME success. Evidence was limited on the reliability and validity of the tools that have been used to assess CME effectiveness. Based on previous reviews, the evidence indicates that simulation methods in medical education are effective in the dissemination of psychomotor and procedural skills. Despite the low quality of the evidence, CME appears to be effective at the acquisition and retention of knowledge, attitudes, skills, behaviors and clinical outcomes. More research is needed to determine with any degree of certainty which types of media, techniques, and exposure volumes as well as what internal and external audience characteristics are associated with improvements in outcomes.


Using Virtual Visits to Care for Primary Care Patients With COVID-19 Symptoms.
Examine use of office resources by primary care patients who were initially evaluated through telehealth, telephone, or in-person encounters. Retrospective electronic health record review on patients seen in March 2020 for evaluation of potential COVID-19 symptoms, to assess the total number of interactions with physicians and office staff. Of 202 patients, 89 (44%) had initial telehealth, 55 (27%) telephone, and 52 (26%) in-person encounters. Patients initially evaluated through telehealth, telephone, and in-person encounters had a mean of 6.1 (S.D. = 3.7), 5.2 (S.D. = 3.6), and 4.5 (S.D. = 3.0) total interactions with the office, respectively (P = .03), and 9%, 12.7%, and 19.2%, respectively, had a subsequent in-person or emergency department visit (P = .22). Multivariable analysis showed no differences in number of office interactions based on initial visit type; older patients (95% CI = 0.00-0.07) and those with subjective fevers (95% CI = 1.01-3.01) or shortness of breath (95% CI = 0.23-2.28) had more interactions with the office. Primary care providers used virtual visits to care for most patients presenting with potential COVID-19 symptoms, with many patients choosing telephone over telehealth visits. Virtual visits can successfully limit patient exposure to other people, and consideration could be given to increasing its use for patients with potential symptoms of COVID-19.


The occurrence of Aeromonas in drinking water, tap water and the porsuk river.
The occurrence of Aeromonas spp. in the Porsuk River, public drinking water and tap water in the City of Eskisehir (Turkey) was monitored. Fresh water samples were collected from several sampling sites during a period of one year. Total 102 typical colonies of Aeromonas spp. were submitted to biochemical tests for species differentiation and of 60 isolates were confirmed by biochemical tests. Further identifications of isolates were carried out first with the VITEK system (BioMe˜rieux) and then selected isolates from different phenotypes (VITEK types) were identified using the DuPont Qualicon RiboPrinter® system. Aeromonas spp. was detected only in the samples from the Porsuk River. According to the results obtained with the VITEK system, our isolates were 13% Aeromonas hydrophila, 37% Aeromonas caviae, 35% Pseudomonas putida, and 15% Pseudomonas acidovorans. In addition Pseudomonas sp., Pseudomonas maltophila, Aeromonas salmonicida, Aeromonas hydrophila, and Aeromonas media species were determined using the RiboPrinter® system. The samples taken from the Porsuk River were found to contain very diverse Aeromonas populations that can pose a risk for the residents of the city. On the other hand, drinking water and tap water of the City are free from Aeromonas pathogens and seem to be reliable water sources for the community.


[Epizootic hepatitis A among African green monkeys kept in a vivarium].
The results of observations on the pattern of spread of hepatitis A virus and immune response to it in African green monkeys (Cercopithecus aethiops) kept in the animal house are presented. The infection in the monkeys was found to be characterized by all virological, serological, and biochemical parameters inherent in hepatitis A virus. The results indicated that hepatitis A in monkeys may run both asymptomatic and clinically manifest course, and the spread of infection in the animal house sequentially involves most seronegative animals into the epidemic process.


The site-specific recombinase encoded by pinD in Shigella dysenteriae is due to the presence of a defective Mu prophage.
The DNA inversion systems are made up of an invertible DNA segment and a site-specific recombinase gene. Five systems are known in prokaryotes: the Salmonella typhimurium H segment and hin gene (H-hin), phage Mu G-gin, phage P1 C-cin, Escherichia coli e14 P-pin, and Shigella sonnei B-pinB systems. In this report a site-specific recombinase (pinD) gene of Shigella dysenteriae was cloned and sequenced. pinD mediated inversion of five known segments at the same extent in E. coli. Although one inv sequence was identified, no invertible region was detected in a cloned fragment. The predicted amino acid sequences of PinD and three ORFs showed high homology to those of Gin and its flanking gene products. An ORF homologous to Mom of Mu conserved a functional activity to modify intracellular plasmid DNA. Southern analysis showed that the cloned fragment contains two homologous regions corresponding to the left and right ends of the Mu genome. Together these results indicated that the pinD gene in S. dysenteriae is derived from a Mu-like prophage.


Strategy and Methodology in the Synthesis of Multicomponent Molecular Solids: The Quest for Higher Cocrystals.
Crystal engineering is the art and science of making crystals by design. Crystallization is inherently a purifying phenomenon. Bringing together more than one organic compound into the same crystal always needs deliberate action. Cocrystals are important because they offer a route to the controlled modulation of crystal properties. The route to cocrystal synthesis was opened up with the heterosynthon concept, which considers the complementary recognition of chemical groups from different molecules. Using this concept, binary cocrystals of enormous variety have been generated, even as crystal engineering has evolved into a form of solid-state supramolecular synthesis. Introducing a third component (a component is somewhat arbitrarily defined as an organic substance that is a solid at room temperature, mostly with the idea of excluding solvates) in a stoichiometric manner requires substantially greater effort and a careful balance of intermolecular interactions-their strengths, directional properties, and distance falloff characteristics. The first systematic ternary cocrystal synthesis was reported around 15 years ago. Drawing in a fourth component in stoichiometric amounts is exceedingly difficult, and we reported such syntheses in 2016. To date, a limited number of ternary cocrystals have been realized (around 120 in all, with a half from our group) and an even smaller number of quaternary cocrystals (around 30, all from our group, barring one). It is impressive that our experiments largely yielded the intended higher cocrystal (three- or four-component) with very small traces of contaminating binaries and pure compounds. A fifth or sixth component may be brought into the solid in the manner of a solid solution in that these components are situated at one of the sites of the quaternary cocrystal. To date, five components have not been included stoichiometrically within the same crystal. This is still an open challenge. The merit in synthesizing (higher) cocrystals is that one can systematically engineer property modularity: Each component is associated with a distinct property. This is important in the pharmaceutical industry, where each component can, in principle, confer a different, desirable property-drug action, solubility, or permeability. However, difficult synthetic targets are also addressed in chemistry simply because they are there. The intellectual satisfaction in making something that is very difficult to make renders the enterprise worthwhile in itself, and new chemistry usually gets uncovered in the process. The development of synthetic organic chemistry can undoubtedly be credited to various reliable methods for chemical transformations, and many difficult total syntheses were achieved by employing these methods over two centuries of research. In contrast, supramolecular synthesis (of multicomponent cocrystals and other assemblies) is in no way at a similar level of sophistication because the subject is still relatively young. Our group and others have reported the synthesis of many higher cocrystals with reliable, reproducible, and robust design strategies. There is a general perception that the isolation of some of these cocrystals is a matter of luck! The crux of this Account is that far from being a serendipitous matter, higher cocrystals may only be made with a judicious combination of strategy and methodology-the essence of synthesis.


Immune response of rat spleen cells to a carcinogen and to vaccination with anti-p53 polyclonal antibodies.
The tumor-suppressive effects of rabbit anti-p53 antibodies on chemically induced rat colon cancer were demonstrated previously (Cancer J, 10:116-120, 1997). In this communication, the spleen's role in the immune response of rats to cancer and vaccination was evaluated histologically and immunohistochemically. The following groups of rats were studied: a) control non treated rats; b) tumor-free non vaccinated rats treated with a carcinogen; c) tumor-bearing non vaccinated rats; d) tumor-free vaccinated rats exposed to a carcinogen; e) tumor-bearing vaccinated rats. Exposure to a carcinogen (group 2) caused the appearance of the proliferative and apoptotic changes associated with immune response. They included abundant blast transformation of CD20-positive B lymphocytes, expansion of germinal centers and of periarterial sheaths (CD3-positive T cells), an increase in the number of plasma cells, mitotic and apoptotic cells in the follicles, and in CD25 IL2-depending T cells. The presence of colon tumors (group 3) caused insufficiency of the splenic lymphoid system: blast transformation was weaker, the white pulp area decreased and its devastation was reflected in fewer lymphoid cells. There were less plasma cells in the red pulp, while the number of dendritic cells, CD25+ T cells, macrophages and neutrophils increased sharply, suggesting a compensatory reaction to the severe antigenic effects. Similar, but stronger changes, occurred in tumor-free vaccinated rats (group 4). In tumor-bearing vaccinated rats (group 5), the rate of proliferation change was higher than in group 3, probably as a result of a weaker splenic insufficiency. A strong correlation was found between the number of mitotic, apoptotic or dendritic cells, tumorigenesis and vaccination. A sharp increase in the number of dendritic cells in vaccinated tumor-bearing rats suggests that these cells participate in the host's reaction to tumorigenesis. We conclude that vaccination with anti-p53 polyclonal antibodies activates lymph components of the spleen.


Consumer Attitudes towards Local and Organic Food with Upcycled Ingredients: An Italian Case Study for Olive Leaves.
Food made with upcycled ingredients has received considerable attention in very recent years as a result of the need to both reduce waste and increase food nutritional properties. However, consumer acceptance of these novel foods is fundamental to their market uptake. This paper aims to assess the likelihood of the acceptance of food obtained from upcycled ingredients of olive oil productions and its association with some relevant recent consumption trends, such as organic food consumption and attention to food origin. In addition, particular attention is given to age group behaviors to appraise the differences between generations. Results suggest that, despite the negative influence of food technophobia, a core of sustainability-minded consumers seems to emerge that is interested in organic or local products, that could also favor the uptake of these novel food made with upcycled ingredients in the market. Results suggest that developing organic or "local" food products with upcycled ingredients can increase the probability of consumer acceptance.


Measuring violence against children: The adequacy of the International Society for the Prevention of Child Abuse and Neglect (ISPCAN) child abuse screening tool - Child version in 9 Balkan countries.
Violence against children is a global public health concern. Researchers are increasingly using self-report measures of physical, psychological, and sexual violence and neglect for population-based surveys. The current gold-standard measure, the 45-item ISPCAN Child Abuse Screening Tool has been used across the world. This study assesses its adequacy for measuring abuse across countries. Multiple group confirmatory factor analyses were used to assess the configural, metric and scalar invariance of the measure across nine Balkan countries. Data were collected using a three-stage stratified random sampling frame of 42,194 school-attending children in three grades (aged 11,13 and 16 years) from schools in Albania, Bosnia and Herzegovina, Bulgaria, Croatia, Greece, North Macedonia, Romania, Serbia, and Turkey. Children completed the ICAST-C, which measures children's exposure to physical, psychological, and sexual violence, neglect and witnessing household violence in the past year and across the lifespan. The analyses show partial scalar invariance for the ICAST-C constructs children's exposure to physical and psychological violence, neglect and witnessing household violence across the nine countries and partial scalar invariance for the constructs of children's exposure to physical, psychological and sexual violence, neglect and witnessing household violence across eight countries (Turkey did not measure sexual violence). The ICAST-C can be used to validly compare levels of physical, psychological, and sexual violence, neglect and witnessing violence in school-aged children across countries. It can also be used to validly compare the relations between these forms of violence and their covariates, predictors, and outcomes across countries.


Thiol/Disulfide Balance in Patients with Familial Hypercholesterolemia.
Herein, we investigated the balance of thiol/disulfide, with the hypothesis that the balance between disulfides and thiols, which are natural antioxidants, might be disrupted in patients with familial hypercholesterolemia, which eventually leads to endothelial damage. In this study, we evaluated 51 patients diagnosed with familial hypercholesterolemia and 81 healthy subjects. Blood samples were taken from the patients after a minimum of 12 hours of fasting; samples were immediately centrifuged, stored in Eppendorf tubes, and preserved at -80°C. This study found that thiol levels are significantly lower in patients with familial hypercholesterolemia, whereas disulfide levels are higher (independent of age, gender, and body mass index). This means that in such patients, the thiol/disulfide balance changes in favour of disulfide. In this study, we found that the thiol/disulfide balance in patients with familial hypercholesterolemia is disrupted in favour of disulfide.


[Role of interoceptive afferentation in the activities of the cortical portion of the visual analyzer].
The experiments on diplacin-immobilized rats showed that stimulation of gastric and rectal mechanoreceptors caused noticeable changes in the control and light-induced impulse activity of neurons of the optic cortex (field 17). The predominant pattern of cell reactions were tonic changes of impulsation. They included both stimulatory and inhibitory effects. The latter occurred mostly as a result of stimulation of gastric mechanoreceptors. Changes in the evoked activity of those neurons involved most frequently enhancement or inhibition of responses, contrasting and stabilization of short-latent responses, and their masking with neuronal noise. The paper discusses the functional importance of the above changes in the control and evoked activities of neurons of the optic cortex during interoceptive effects as well as possible central pathways of their realization in the optic cortex.


A single nucleotide polymorphism in MGEA5 encoding O-GlcNAc-selective N-acetyl-beta-D glucosaminidase is associated with type 2 diabetes in Mexican Americans.
Excess O-glycosylation of proteins by O-linked beta-N-acetylglucosamine (O-GlcNAc) may be involved in the pathogenesis of type 2 diabetes. The enzyme O-GlcNAc-selective N-acetyl-beta-d glucosaminidase (O-GlcNAcase) encoded by MGEA5 on 10q24.1-q24.3 reverses this modification by catalyzing the removal of O-GlcNAc. We have previously reported the linkage of type 2 diabetes and age at diabetes onset to an overlapping region on chromosome 10q in the San Antonio Family Diabetes Study (SAFADS). In this study, we investigated menangioma-expressed antigen-5 (MGEA5) as a positional candidate gene. Twenty-four single nucleotide polymorphisms (SNPs), identified by sequencing 44 SAFADS subjects, were genotyped in 436 individuals from 27 families whose data were used in the original linkage report. Association tests indicated significant association of a novel SNP with the traits diabetes (P = 0.0128, relative risk = 2.77) and age at diabetes onset (P = 0.0017). The associated SNP is located in intron 10, which contains an alternate stop codon and may lead to decreased expression of the 130-kDa isoform, the isoform predicted to contain the O-GlcNAcase activity. We investigated whether this variant was responsible for the original linkage signal. The variance attributed to this SNP accounted for approximately 25% of the logarithm of odds. These results suggest that this variant within the MGEA5 gene may increase diabetes risk in Mexican Americans.


Patient involvement in own rehabilitation after early discharge.
A European Union Commission report in 2015 concluded that the concept of patient involvement refers specially to the right of patients to have a central position in the healthcare process (EU Commission 2012, http://ec.europa.eu/public_opinion/archives/quali/ql_5937_patient_en.pdf). Recent research suggests that patient involvement after hip replacement is a very effective strategy in older adults with regard to improving walking ability and reducing pain and thereby lessening loss of physical, mental and social aspects of the quality of life. The growing number of older adults all over the world will increase the need for hip surgery. Older adults' involvement in own rehabilitation improves their health and quality of life after hip replacement. To involve and coach older adults with a hip replacement to self-care after early discharge in transition between hospital and home. Empirical data were collected by carrying out three randomised clinical trials (RCT) focusing on self-rated health and involvement of patients undergoing total hip replacement in three Danish orthopaedic clinics. Based on power calculation, 260 patients (mean age 67.5 years) were invited to participate. In this third study in 2010-2013, patients were randomised to either an intervention group or a control group. Randomised clinical trials (RCT). Questionnaire SF-36 a generic tool measuring patients' self-rated health status and quality of life. All patients filled out SF-36 before surgery and again 3, 6, 9 and 12 months after surgery. Patients in the intervention group had an additional follow-up 1, 3 and 7 weeks after discharge by nurses from orthopaedic clinic in hospital. The nurses used a semi-structured interview guide as intervention model to coach, counsel and involve patients to improve their self-care and planned rehabilitation after hip replacement. Older adults benefit through involvement based on an intervention model of expectations, measurement of self-rated health and quality of life. The results of the randomised trials one and two documented that patients' self-rated health status in the intervention group reached their habitual level 3 months after hip replacement vs. 9 months in the control group. Since our working hypothesis 'patient involvement in own rehabilitation improves health and quality of life after hip replacement' was found valid, our ambition is now based on results from this third study to contribute to further research and development within patient involvement. To follow new evidence-based research, results concluded that walking ability is very necessary in order to increase physical activity to benefit the health of older adults and prevent disease.


A Customized Next-Generation Sequencing-Based Panel to Identify Novel Genetic Variants in Dementing Disorders: A Pilot Study.
The advancements in the next-generation sequencing (NGS) techniques have allowed for rapid, efficient, and cost-time-effective genetic variant detection. However, in both clinical practice and research setting, sequencing is still often limited to the use of gene panels clinically targeted on the genes underlying the disease of interest. We performed a neurogenetic study through an ad hoc NGS-based custom sequencing gene panel in order to screen 16 genes in 8 patients with different types of degenerative cognitive disorders (Alzheimer's disease, mild cognitive impairment, frontotemporal dementia, and dementia associated with Parkinson's disease). The study protocol was based on previous evidence showing a high sensitivity and specificity of the technique even when the panel is limited to some hotspot exons. We found variants of the TREM2 and APP genes in three patients; these have been previously identified as pathogenic or likely pathogenic and, therefore, considered "disease causing." In the remaining subjects, the pathogenicity was evaluated according to the guidelines of the American College of Medical Genetics (ACMG). In one patient, the p.R205W variant in the CHMP2B gene was found to be likely pathogenic of the disease. A variant in the CSF1R and SERPINI1 genes found in two patients was classified as benign, whereas the other two (in the GRN and APP genes) were classified as likely pathogenic according to the ACMG. Notwithstanding the preliminary value of this study, some rare genetic variants with a probable disease association were detected. Although future application of NGS-based sensors and further replication of these experimental data are needed, this approach seems to offer promising translational perspectives in the diagnosis and management of a wide range of neurodegenerative disorders.


Epigallocatechin-3-gallate and epicatechin-3-gallate from green tea decrease plasma non-transferrin bound iron and erythrocyte oxidative stress.
Beta-thalassemia patients suffer from secondary iron overload caused by increased iron absorption and multiple blood transfusions. Excessive iron catalyzes free-radical formation, causing oxidative tissue damage. Non-transferrin bound iron (NTBI) detected in thalassemic plasma is highly toxic and chelatable. Desferrioxamine and deferiprone are used to treat the iron overload, but many side effects are found. Epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) in green tea (GT) show strong antioxidant properties. We separated the EGCG and ECG from GT extract using an HPLC, and examined their iron-binding and free-radical scavenging activities. They bound Fe(3+) rapidly to form a complex with a predominant absorption at 560 nm. EGCG and ECG bound chemical Fe(3+) and chelated the NTBI in a time- and dose dependent manner. They also decreased oxidative stress in iron-treated erythrocytes. In conclusion, EGCG and ECG could be natural iron chelators that efficiently decrease the levels of NTBI and free radicals in iron overload.


[3-dimensional representation of transient evoked otoacoustic emissions].
A new method for the transformation of TEOAE signals into 3-dimensional diagrams is presented. The special transformation algorithm is based on a latency related frequency analysis of the cochlear response. The analysis and presentation are implemented in a C-programme. In a first clinical study 390 TEOAE signals from ears with and without hearing impairment were evaluated. For normal hearing the 3-dimensional diagram of TEOAE-signals is characterised by a typical wave form: with increasing frequency the latency of the cochlear response decrease. In the case of hearing loss there is an overall tendency to increasing wave latencies in comparison to normal hearing. An additional wave in the 3-dimensional diagrams of ears with tinnitus was observed. This characteristic is interpreted as an indicator of cochlea dysfunction. The 3-dimensional diagram promises to give a new aspect in the clinical interpretation of click-evoked otoacoustic emissions.


Channel initiation and the problem of landscape scale.
Since the 1940s it has been proposed that landscape dissection into distinct valleys is limited by a threshold of channelization that sets a finite scale to the landscape. This threshold is equal to the hillslope length that is just shorter than that necessary to support a channel head. A field study supports this hypothesis by showing that an empirically defined topographic threshold associated with channel head locations also defines the border between essentially smooth, undissected hillslopes and the valley bottoms to which they drain. This finding contradicts assertions that landscapes are scale-independent and suggests that landscape response to changes in climate or land use depends on the corresponding changes in the threshold of channelization.


A Probabilistic Method for Image Enhancement With Simultaneous Illumination and Reflectance Estimation.
In this paper, a new probabilistic method for image enhancement is presented based on a simultaneous estimation of illumination and reflectance in the linear domain. We show that the linear domain model can better represent prior information for better estimation of reflectance and illumination than the logarithmic domain. A maximum a posteriori (MAP) formulation is employed with priors of both illumination and reflectance. To estimate illumination and reflectance effectively, an alternating direction method of multipliers is adopted to solve the MAP problem. The experimental results show the satisfactory performance of the proposed method to obtain reflectance and illumination with visually pleasing enhanced results and a promising convergence rate. Compared with other testing methods, the proposed method yields comparable or better results on both subjective and objective assessments.