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Objectives This study sought to evaluate the correlation between His bundle (HB) pacing (HBP) implantation characteristics, lead-tip location, and association of intraprocedural His record...

Background: Changes in Ca2+ regulation have been implicated in various pathologies such as coronary artery disease and metabolic syndrome (MetS), thereby potentiating these diseases. Our lab has shown that MetS decreases voltage-gated Ca2+ channel (VGCC) activity and sarcoplasmic reticulum (SR) Ca2+ release in coronary smooth muscle cells and increases coronary artery disease in Ossabaw miniature swine. Furthermore, decreased SIRT1 enzyme function can impair Ca2+ signaling and increase coronary disease and MetS. We hypothesized that impaired SIRT1 and MetS would decrease VGCC function and SR calcium store. Methods: CRISPR/Cas9 methods delivered a leucine to proline point mutation in SIRT1 (SIRT1L100P) into the Ossabaw swine genome to compare to wild type (WT), mimicking the naturally occurring mutation in humans which decreases SIRT1 activity. Four treatment groups of juvenile swine were based on genotype and diet: WT Lean, SIRT1 Lean, WT MetS, and SIRT1 MetS. Lean swine were fed normal chow and MetS were fed a hypercaloric, atherogenic diet for 7 months. The left anterior descending coronary artery was harvested and enzymatically digested to obtain cells. Fluorescence microscopy measured the Ca2+ indicator fura-2 in single cells. Depolarization of cells with perfusion of 80 mM K+ was used to elicit Ca2+ influx through VGCC. Caffeine (5 mM) exposure activated the Ca2+ release channel (ryanodine receptor) on the SR. Results: MetS was confirmed by increased body weight, impaired glucose tolerance, hyperinsulinemia, and hypercholesterolemia. Coronary atherosclerosis was shown by angiography, intravascular ultrasound, and gross imaging. A two-way analysis of variance revealed statistically significant overall effects of genotype (p=0.02), diet (p

The influence of the crystallization temperature and the pressure on the crystallization kinetics, structure and compression strength of γ-polypropylene was investigated. Samples were produced in a custom-made high-pressure crystallization cell and characterized by differential scanning calorimetry (DSC), wide angle X-ray scattering (WAXS) and transmission electron microscopy (TEM). It could be shown that the strength is mainly affected by the mean lamellar thickness. The strength of γ-PP is at least 40% higher than α-PP at the same mean lamellar thickness. This confirms the hypothesis that the arrangement of non-parallel chains restricts the number of possible slip systems so that almost no mobile dislocations are generated. The mode of nucleation is only slightly affected by the crystallization pressure. The Avrami coefficient is n = 2.5 ± 0.1 at the beginning of crystallization and largely independent of pressure.

This study sought to evaluate the correlation between His bundle (HB) pacing (HBP) implantation characteristics, lead-tip location, and association of intraprocedural His recordings with approximated HB anatomic landmarks using computed tomography (CT) imaging.HBP continues to grow in clinical practice due to offering true physiological pacing. However, a clear understanding of HB anatomy and the lead-tip location's influence on pacing characteristics is lacking.The IMAGE-HBP study (Imaging Study of Lead Implant for His Bundle Pacing) was a prospective, multicenter study designed to assess implantation characteristics of the SelectSecure Model 3830 lead placed at the HB, evaluate protocol-specified HBP success (His recording present on electrogram and HBP threshold ≤2.5 V at 1 ms), and correlation between lead-tip location by CT imaging and HBP characteristics as well as lead-related complications through 12 months.Sixty-nine patients underwent a lead implantation attempt at the HB. Of these, 61 patients (88%) had a lead successfully implanted at the HB, and 52 patients (75%) met the pre-specified definition of successful HBP. In 51 patients with CT imaging, 11 leads (22%) were placed in the atrial aspect of the HB region (36% selective HBP), and 40 leads (78%) were placed in the ventricular aspect (28% selective HBP). Four of the 51 patients had P-wave oversensing, all with leads in the atrium. Freedom from lead-related complication at 12 months was 93%.Successful HBP could be achieved at lead-tip locations in the atrium or ventricle but is preferable in the ventricle to eliminate risk of oversensing. The IMAGE-HBP study offers better insight into approximated HB anatomic landmarks, lead-tip location, and correlation with pacing characteristics. (Imaging Study of Lead Implant for His Bundle Pacing [IMAGE-HBP]; NCT03294317).

Introduction: Administrative data can aid in study and intervention design, incorporating hard-to-reach individuals who may otherwise be poorly represented. We aim to use administrative health data to examine emergency department visits by people experiencing homelessness and explore the application of this data for planning interventions. Methods: We conducted a serial cross-sectional study examining emergency department use by people experiencing homelessness and non-homeless individuals in the Niagara region of Ontario, Canada. The study period included administrative health data from April 1st, 2010 to March 31st, 2018. Outcomes included number of visits, number of unique patients; group proportions of Canadian Triage and Acuity Scale (CTAS) scores; time spent in emergency; and time to see an MD. Descriptive statistics were generated, and t-tests were performed for point estimates and a Mann-Whitney U test for distributional measures. Results: Our data included 1,486,699 emergency department visits. The number of unique people experiencing homelessness ranged from 91 in 2010 to 344 in 2017, trending higher over the study period compared to non-homeless patients. The rate of visits increased from 1.7 to 2.8 per person. People experiencing homelessness tend to present later in the day and with higher overall acuity as compared to the general population. Time in emergency department and time to see an MD were greater among people experiencing homelessness. Conclusion: Administrative health data allows researchers to enhance interventions and models of care to improve services for vulnerable populations. Given the challenging fiscal realities of research, our study provides insights to more effectively target interventions for vulnerable populations.

Background Frequent right ventricular pacing causes ventricular dyssynchrony and adverse outcomes. His bundle pacing (HBP) offers a physiological alternative. HBP electrical performance characteristics with cardiac conduction system abnormalities are not well established. Purpose To compare HBP implant procedure related parameters in patients with abnormal atrioventricular (AV) conduction versus those with intact AV conduction. Methods Patients prospectively enrolled in the IMAGE-HBP study undergoing implant attempt with a SelectSecure 3830 lead placed at the putative His-bundle location were included in the analysis. Patients were divided into groups based on AV conduction status. Implant characteristics and electrical performance of the pacemaker were tabulated and compared between the two groups with formal statistical tests. Results Among 60 patients (age 74.7 years old and 60% male), 29 patients (48%) had abnormal AV conduction at or below the AV node (18 with AV block of which 5 also had bundle branch block (BBB), 6 with SND and BBB, and 5 with AV node ablation). The remaining 31 patients (52%) had intact AV conduction. Procedure times were not significantly different between the groups (P=0.26). Selective HBP was achieved in 20.7% of abnormal AV conduction patients and 45.2% of intact AV conduction patients (P=0.06); the remaining patients had non-selective HBP. There were no differences detected in pacing characteristics at implant and paced QRS durations by AV conduction status. Patient with intact AV conduction (N=31) Patients with abnormal AV conduction at or below AV node (N=29) Procedure time in minutes (mean ± SD, Median, IQR) 99±38; 87 [43, 180] 108±32; 108 [65, 182] Fluoroscopy time in minutes (mean ± SD, Median, IQR) 15±12; 11 [3, 50] 16±9; 13 [4, 36] Number of fixation attempts 3.0±2.2 2.2±2.0 sHBP PCT N=14 N=6 V at 0.5ms 1.8±0.9 1.7±1.2 V at 1.0ms 1.6±1.2 1.2±0.8 nsHBP PCT N=17 N=22 V at 0.5ms 2.2±1.9 1.7±1.3 V at 1.0ms 1.5±1.1 1.3±1.1 His signal recorded, number 30 (96.8%) 28 (96.6%) H-QRS interval, ms 46±7 48±13 His Injury of Current, N (%) 23 (74.2%) 18 (62.1%) Baseline Intrinsic QRS, ms 96±16 107±22 Paced QRS duration, ms (from HBP at 1.0ms) 119±23 121±19 Conclusions Selective and non-selective HBP are achievable in bradycardic patients with abnormal and intact AV conduction, including those with BBB. There were no major differences in HBP implant parameters between patients with abnormal AV conduction and those with intact AV conduction.

Introduction: Understanding how homeless patients interact with healthcare systems can be challenging. The nature of the population is such that identifying and following these persons can be severely limited by data. Previous studies have used survey data which relies on self-reporting and selected samples such as those persons admitted to homeless shelters (Gray et al. 2011). Other studies have been able to leverage administrative data but only for selected local geographic areas (Somers et al. 2016, Tompkins et al 2003). It is possible that the current literature has not examined a large proportion of homeless persons and their healthcare use. This is concerning because this population can have higher associated medical costs and greater medical resource utilization especially with regards to psychiatric and emergency department (ED) resources (Tulloch et al. 2012, Forchuk et al, 2015). Methods: Administrative health data (2010 to 2017) is used to analyze ambulatory care records for homeless individuals in Ontario, Canada. Uniquely, we are able to use ED contacts as a way of identifying homeless migrations from region to region within Ontario. Using a network analysis we identify high impact ED nodes and discrete hospital networks where homeless patients congregate. We are also able to more fully characterize this population's demographics, health issues, and disposition from the ED. Results: We provide a more complete understanding of migration patterns for homeless individuals, across Ontario and their concomitant ED use and hospitalizations. The three most frequented regions in Ontario (n = 640,897) were Toronto Central (35.96%), Hamilton Niagara Halimand Brant (8.9%) and Champlain (7.84%). In subsequent visits, the majority of patients presented to different EDs, however a subgroup who always presented to the same site was present. Over the 7 year period, migration between visits occurred most often between urban areas, and increased as a whole. Conclusion: The results of the study allow for the enhancement care coordination for vulnerable populations and enhance the availability and delivery of services for sub-groups of homelessness whose care needs may differ based on migration patterns. Services can be coordinated between jurisdictions for homeless individuals, and appropriate referrals can be made across the health care system. Further evidence is provided for a novel method of mapping migration among the homeless and its associations and effects on ED use.

Introduction: Wait time predictions have become more common in emergency departments in Canada. These estimate the wait times a patient faces to see providers and they are usually provided in an accessible way such as through an online interface. One purpose of these trackers is to improve ED system efficiency. Patients can self-triage to alternative care such as their primary care physician, defer care until a later time or could move from oversubscribed to undersubscribed EDs. However, these mechanisms could also be abused. If providers can artificially influence the wait time this may provide a possible lever to change patients flows to an ED. I investigate whether there is evidence suggestive of manipulation of online wait time trackers at an ED system in Ontario. Methods: Inputs into the wait time prediction algorithm, like patient volumes are taken from the ED EMR. This is the most likely place where staff can manipulate the wait time tracker by retaining patients in the EMR system even after they are discharged. I examine two sets of data to assess whether the online tracker displays differences in patient volumes from “true” data. The first is scraped data of patient volumes from the wait times website. The second are the accurate patient volumes from administrative data which includes when a physician discharged patients from the ED. I compare values of the true patient volumes to the online values and plot distributions of these differences. I also employ measures of accuracy such as mean square error and root mean square error to provide a value of how accurate the online data is compared to the true data. I examine these by ED and over time. Results: There are differences between the number of patients that are posted online and those in the administrative data. The distributions of these differences are skewed towards positive values suggesting that the online data more often overcounts rather than undercounts patients. Measures of accuracy increase during times when EDs are congested but do not decrease when EDs become less congested. This inaccuracy persists for a period after EDs cease to be busy. Conclusion: ED wait time trackers have the potential to be manipulated. When staff have incentive to reduce patient volumes, online data becomes more inaccurate relative to true data. This suggests that wait time trackers may have unintended consequences and that the information that they provide may not be entirely accurate.

Introduction: People experiencing homelessness have complex psychiatric and medical presentations, and have poor access to primary care. Thus, emergency departments (EDs) often become their main point of healthcare contact. Using routinely collected administrative data from EDs, we examine the ED utilization, health and reasons for presentations of people experiencing homelessness.. Methods: All routinely collected administrative health data from EDs located within Ontario, Canada from 2010-2017 were analyzed. Individuals experiencing homelessness were identified by a marker that was adopted in 2009 replacing their recorded postal code with an XX designation. Outcomes include number of unique patients, number of visits and repeat visits, CTAS scores, ambulance utilization, and type of ICD-10 presentation. Results: 640,897 visits to the ED over 10 years were made by 39,525 unique individuals experiencing homelessness. A visit to an ED by a homeless patient resulted in repeat presentation on the same day 5% of the time. The median repeat presentation to an ED was 14 days. In people experiencing homelessness, the most prevalent category of presentations were primary mental health diagnoses, accounting for 34.8% of visits (n = 223,392). Under mental health conditions, psychoactive substance use presentations made up more than 54% of the presentations (n = 121,112). Alcohol was by far the most common cause of substance use/induced disorders (n = 84,805). Conclusion: Applications of administrative data presents a novel method of measuring health and healthcare outcomes for marginalized populations. We found people experiencing homelessness are presenting to ED more frequently in Ontario, with significant mental health and addiction problems. Our study identifies several important health vulnerabilities within the population, which may serve as potential targets for future interventions.

Introduction: Despite the visibility of the homeless population, there is limited data on the information of this patient population. Point-in-time counts and survey data from selected samples (such as those admitted to emergency shelter) have primarily been used. This literature suggests that this hard-to-reach population has high rates of presentation at emergency departments (EDs), and as such, EDs often become their main point of contact for health and social services. Leveraging this fact and administrative data we construct a crude census of homeless persons within Ontario. We further examine demographic characteristics of patients experiencing homelessness, and compare this data to findings from previous literature. Methods: All routinely collected administrative health data from EDs located within Ontario, Canada from 2010-2017 were analyzed to examine patient characteristics. Individuals experiencing homelessness were identified by a marker that was adopted in 2009 replacing their recorded postal code with an XX designation. s. Aggregating by LHIN, date and week of year, we examine the overall number of patients experiencing homelessness and number by LHIN location and seasonality. Demographic outcomes examined include age and sex. Results: 640,897 visits to the ED over 7 years were made by 39,525 unique individuals experiencing homelessness. Number of ED visits has steadily increased over 10 years in all of Ontario, despite decline in shelter use for individuals. Presentations were concentrated in large urban centres like Toronto, Ottawa and Hamilton. Fewer presentations occur in the spring and summer months and rise in the winter. Male patients presented older and in greater numbers than female patients. The modal female age of presentation is in the 20-24 age category. The modal male age of presentation is in the 25-29 age category. Older male patients were more likely to have multiple presentations. Conclusion: The utilization of administrative health data offers a novel, cost-effective method to measure demographic characteristics of people experiencing homelessness. Identifying characteristics of homeless patients through this method allows for a more complete understanding of the characteristics of a hard-to-reach population, which will allow policy makers to develop appropriate services for this sub-group. Furthermore, through analysis of trends of demographics over time, changes in the homeless population can be tracked in real-time to allow for coordination and implementation of services in a time-sensitive manner.

Dass Leistungssport bis hin zur Teilnahme an Olympischen Spielen auch mit Diabetes moglich ist, beweisen viele Profisportler. Der Sport hat neben dem Erfolg zusatzlich positiven Einfluss auf die psychosoziale Entwicklung Jugendlicher und geht mit einer Reduktion diabetischer Folgeerkrankungen einher. Direkte Auswirkungen sind eine gesteigerte Insulinsensitivitat und eine geringere Insulinresistenz. Die jeweilige Insulintherapie hangt von der Disziplin, der korperlichen Konstitution und der personlichen Praferenz ab. Unterstutzend kann ein CGM-System (CGM: kontinuierliches Glukosemonitoring) die Blutzuckereinstellung erleichtern und einen wirksamen Schutz v. a. auch vor nachtlichen Hypoglykamien bieten. Ein strukturierter Ablaufplan von Plasmaglukosekontrollen, Kohlenhydrataufnahme und Insulinanpassung fur Trainings- und Wettkampftage hilft, sowohl Fehler zu vermeiden als auch den Erfolg des Vorgehens zu analysieren. Die Erfahrungen aus dem Profisport sollen dazu beitragen, dass Amateursportler mit Diabetes ohne Einschrankungen aktiv sein konnen.

Bis zu 4 % aller Neugeborenen in Mitteleuropa kommen mit einer kongenitalen Huftdysplasie (KHD) auf die Welt, die somit die haufigste angeborene Erkrankung des Bewegungsapparats ist. Im Rahmen der hier vorgestellten retrospektiven Erhebung wurden die Therapieergebnisse von Neugeborenen mit KHD Typ D, III oder IV nach Graf nachuntersucht, die mit einer Pavlik-Bandage behandelt wurden und deren Therapiebeginn innerhalb der ersten 12 Lebenswochen lag. Beurteilt wurden Zusammenhange zwischen dem Zeitpunkt des Therapiebeginns bzw. dem Ausgangsbefund nach Graf und dem erzielten sonographischen Ergebnis sowie den Rontgenbildern nach einem und 2 Jahren. Es wurden ausbleibende Repositionen durch die Pavlik-Bandage und Nebenwirkungen ausgewertet sowie deren Relevanz beurteilt, insbesondere in Bezug auf die avaskulare Huftkopfnekrose. Es wurden alle Neugeborenen ermittelt, die von 2010 bis 2012 in unserer Klinik aufgrund einer KHD mit einer Pavlik-Bandage behandlungspflichtig waren. Es konnten insgesamt 62 Patienten mit insgesamt 79 pathologischen Huften ermittelt werden. Um den Einfluss des Therapiebeginns auf das Ergebnis zu evaluieren, wurden die Kinder in 3 Gruppen eingeteilt: Gruppe I: Erstuntersuchung und Beginn der Pavlik-Bandagenbehandlung innerhalb der ersten 10 Lebenstage (U1 und U2), Gruppe II ab 11. Lebenstag bis 4. Lebenswoche, Gruppe III ab der 4. Lebenswoche (U3 und spater). Klinische und sonographische Nachuntersuchungen wurden befundabhangig durchschnittlich nach 1, 3 und 6 Monaten durchgefuhrt. Weiterhin erfolgten klinische und radiologische Kontrolluntersuchungen nach dem 1. und 2. Lebensjahr sowie befundabhangige weitere Nachuntersuchungen. Eine ausbleibende Reposition durch die Pavlik-Bandage trat in der Gruppe I in einem Fall (2,2 %), in Gruppe II in einem Fall (7,1 %) und in Gruppe III in 2 Fallen (10 %) auf. Bei Huften vom Typ D und Typ III traten ausbleibende Repositionen jeweils in einem Fall (3,3 %) und bei Typ IV in 2 Fallen (10,5 %) auf. Huftkopfnekrosen wurden in Gruppe I in 2 Fallen (4,4 %), in Gruppe II mit 0 % und in Gruppe III in einem Fall (5 %) nachgewiesen. Initial handelte es sich bei allen Patienten mit einer Huftkopfnekrose um Typ-IV-Huften. Alle Nekrosen waren zu den Verlaufskontrollen nach spatestens 2 Jahren nicht mehr nachweisbar. Zusammenfassend zeigt die Untersuchung, dass auch bei spaterem Therapiebeginn sehr gute Ergebnisse erzielt werden konnen; allerdings steigen die Raten von ausbleibenden Repositionen und Huftkopfnekrosen an. Ein Huftultraschallscreening zur U3 scheint somit ausreichend, wobei sich insbesondere bei Risikogruppen ein zusatzliches Screening bis zur U2 empfiehlt, was bei normalen Befunden jedoch eine erneute Evaluation zur U3 nicht ersetzt.

The growth hormone (GH)/insulin-like growth factor (Igf) endocrine axis regulates somatic growth in the face of changing environmental conditions. In actinopterygian fishes, food availability is a key modulator of the somatotropic axis, with lower food intake generally depressing liver Igf1 release to diminish growth. Igf1 signaling, however, also involves several distinct IGF binding proteins (Igfbps), and the functional roles of many of these Igfbps in affecting growth during shifting food availability remain uncertain. Here, we tested how complete food deprivation (fasting) affected gene transcription for paralogs of all six types of Igfbps in the liver and fast-twitch skeletal muscle of cabezon (Scorpaenichthys marmoratus), a nearshore marine fish important for recreational fisheries in the eastern North Pacific Ocean. Juvenile cabezon were maintained as either fed (6% mass food⋅g fish wet mass-1⋅d-1) or fasted for 14 d. Fasted fish exhibited a lower body condition (K), a depressed mass-specific growth rate (SGR), and reduced plasma concentrations of Igf1. In the liver, fasting reduced the relative abundance of gene transcripts encoding Igfbps igfbp2a and igfbp2b, while significantly elevating mRNA levels for igfbp1a, igfbp1b, igfbp3b, and igfbp4. Fasting also reduced hepatic mRNA levels of GH receptor-1 (ghr1) - but not GH receptor-2 (ghr2) - supporting the idea that changes in liver sensitivity to GH may underlie the decline in plasma Igf1 during food deprivation. In skeletal muscle, fasting downregulated gene transcripts encoding igf1, igfbp2b, igfbp5b, and igfbp6b, while also upregulating mRNAs for igf2 and ghr2. These data demonstrate isoform-specific regulation of Igfbps in liver and skeletal muscle in cabezon experiencing food deprivation and reinforce the idea that the repertoire of duplicated Igfbp genes that evolved in actinopterygian fishes supports a diverse scope of endocrine and paracrine functions.

We have demonstrated direct nanoscale transfer printing (nTP) of PdAu lines from a hard mold onto a hard substrate at room temperature without employing any flexible buffer layers or organic adhesion promoters or release agent layers. PdAu was evaporated onto the mold surface, and a Ti layer was deposited on top of the PdAu layer. By pressing the mold against a Si/SiO2 substrate, the PdAu/Ti sandwich structure was directly transferred onto the SiO2 surface. The molds used in these experiments were GaAs/AlGaAs sandwich structures fabricated by molecular beam epitaxy that we cleaved and selectively etched afterwards in order to generate 3-D grating structures with nanometer resolution on their edges. We fabricated positive multiline molds with different aspect ratios, linewidths between 15 and 100 nm, and spacings between lines ranging from 5 to 70 nm. We also fabricated negative single-line molds with a positive supporting structure comprising a single 16-nm-wide groove feature. The experiments revealed that direct hard-on-hard transfer of nanoscale structures from a mold onto a substrate can be used to fabricate PdAu gaps with widths down to 9 nm. We also performed electronic measurements on transfer patterns and demonstrated that transferred structures can be used as electrodes, which are electrically isolated by these gaps. Since isolation characteristics of gaps improved with decreasing gap length, we partitioned longer gap segments into multiple shorter ones by focused ion beam lithography and conventional optical lithography in combination with wet chemical or plasma etching of the mold or the substrate, respectively. In this paper, we give a detailed description of all technological aspects of the developed direct nTP technique, including mold preparation, patterning efficiency, short reduction techniques, and yield.

Serologische Tests zur Immunglobulin-G4-(IgG4-) Bestimmung gegen Nahrungsmittel werden weiterhin fur die Diagnose einer nahrungsmittelbedingten Uberempfindlichkeit beworben. Da viele Patienten ohne diagnostische Bestatigung eines kausalen Zusammenhanges davon uberzeugt sind, dass ihre Symptome mit der Nahrungsmittelzufuhr zusammenhangen, stellen Tests auf nahrungsmittelspezifisches IgG4 einen wachsenden Markt dar. Die Bestimmung von IgG4 im Blut gegen verschiedene Nahrungsmittel wird anhand eines umfangreichen Screenings auf Hunderte von Nahrungsmitteln mit Enzymimmunoassays (EIA) und Radioallergosor-benttests (RAST) bei Kleinkindern, Jugendlichen und Erwachsenen durchgefuhrt.

The World Health Organisation and other food safety authorities recognise food allergy as a significant public health concern due to the high prevalence and potential severity of the condition and the impact it has on the quality of life and economy. A public health perspective focuses on risk management at the societal level rather than precautions taken by individuals. Allergen lists were originally drawn up on the basis of a combination of prevalence and severity information, but data to document inclusion were limited. Since then the number of allergenic foods for which reactions have been well documented has grown considerably. Yet, most of them are of limited significance to public health. To address food allergy issues from the point of view of risk management, an expert group appointed by the Food Allergy Task Force of the International Life Sciences Institute ILSI Europe reviewed the criteria. We propose a revised set of criteria together with a framework which can be used to help decide which allergenic foods are of sufficient public health importance to be included in allergen lists. Criteria include clinical issues (diagnosis, potency of allergen, severity of reactions), population elements (prevalence, exposure) and modulating factors (food processing). In the framework, data providing evidence for these criteria are weighted according to quality, using a ranking derived from evidence-based medicine. The advantage of this approach is that it makes explicit each of the considerations, thereby rendering the whole process more transparent for all stakeholders.

Serological tests for immunoglobulin G4 (IgG4) against foods are persistently promoted for the diagnosis of food-induced hypersensitivity. Since many patients believe that their symptoms are related to food ingestion without diagnostic confirmation of a causal relationship, tests for food-specific IgG4 represent a growing market. Testing for blood IgG4 against different foods is performed with large-scale screening for hundreds of food items by enzyme-linked immunosorbent assay-type and radioallergosorbent-type assays in young children, adolescents and adults. However, many serum samples show positive IgG4 results without corresponding clinical symptoms. These findings, combined with the lack of convincing evidence for histamine-releasing properties of IgG4 in humans, and lack of any controlled studies on the diagnostic value of IgG4 testing in food allergy, do not provide any basis for the hypothesis that food-specific IgG4 should be attributed with an effector role in food hypersensitivity. In contrast to the disputed beliefs, IgG4 against foods indicates that the organism has been repeatedly exposed to food components, recognized as foreign proteins by the immune system. Its presence should not be considered as a factor which induces hypersensitivity, but rather as an indicator for immunological tolerance, linked to the activity of regulatory T cells. In conclusion, food-specific IgG4 does not indicate (imminent) food allergy or intolerance, but rather a physiological response of the immune system after exposition to food components. Therefore, testing of IgG4 to foods is considered as irrelevant for the laboratory work-up of food allergy or intolerance and should not be performed in case of food-related complaints.

The therapeutic effect of metronidazole, alone or in combination with the basic treatment schedule of corticosteroids, salazosulphapyridine or dietary formula was analysed retrospectively for 34 patients with active Crohn's disease who had previously been treated without success on the basic schedule. Clinical remission was achieved in all ten patients with highly florid Crohn's disease but no fistulae, regardless of whether metronidazole was given alone or in combination with the basic treatment regimen. Complete closure of the fistulae was achieved in 12 or 24 patients with fistulae, while marked regression of fistulae secretion occurred in a further five. It is concluded that metronidazole is of value particularly in cases resistant to basic treatment or with fistulae.

Pancreatic neuroendocrine tumors (PNETs) are heterogeneous neoplasms which represent only 2% of all pancreatic neoplasms by incidence, but 10% by prevalence. Genetic risk factors could have an important role in the disease aetiology, however only a small number of case control studies have been performed yet. To further our knowledge, we genotyped 13 SNPs belonging to the pleiotropic CDKN2A/B gene region in 320 PNET cases and 4436 controls, the largest study on the disease so far. We observed a statistically significant association between the homozygotes for the minor allele of the rs2518719 SNP and an increased risk of developing PNET (ORhom = 2.08, 95% CI 1.05-4.11, p = 0.035). This SNP is in linkage disequilibrium with another polymorphic variant associated with increased risk of several cancer types. In silico analysis suggested that the SNP could alter the sequence recognized by the Neuron-Restrictive Silencer Factor (NRSF), whose deregulation has been associated with the development of several tumors. The mechanistic link between the allele and the disease has not been completely clarified yet but the epidemiologic evidences that link the DNA region to increased cancer risk are convincing. In conclusion, our results suggest rs2518719 as a pleiotropic CDKN2A variant associated with the risk of developing PNETs. © 2016 The Author(s).

Up to 4% of all neonates in Central Europe are born with congenital hip dysplasia (CHD), the most common congenital disease of the musculoskeletal system. However, in this retrospective analysis the outcomes of infants with CHD (type D, III or IV according to Graf) have been considered, with Pavlik therapy starting within the first 12 weeks of life. Connections between the start of therapy or the first finding according to Graf`s classification and the ultrasound result achieved, as well as the X-rays taken after 1 and 2 years, were evaluated. No repositioning under Pavlik treatment or side effects and their relevance have been evaluated, especially with regard to avascular necrosis (AVN) of the femoral head.All infants treated using Pavlik treatment for CHD between 2010 and 2012 in our clinic were determined. A total of 62 patients with 79 pathological hips were included. The infants were classified into three groups to evaluate the influence of the start of therapy on the result: group I with the first investigation and start of treatment within the first 10 days of life, group II between the 11th day and the end of week 3, group III within preventive general examinations (U3) after the 4th week. Clinical examinations and the usual ultrasound scans were performed at an average of 1, 3, and 6 months. Furthermore, after 1 and 2 years clinical and radiological investigations were carried out, as well as further examinations depending on the findings.A failure of repositioning of the Pavlik treatment occurred in group I in 1 case (2.2%), in group II in 1 case (7.1%), and in group III in 2 cases (10%). This occurs in hips type D and type III in 1 case each (3.3%) and type IV in 2 cases (10.5%). Maturation disorders of the hips were found in 1 case (2.2%) in group I, 1 case (7.1%) in group II, and 3 cases (15%) in group III. Avascular necrosis of the femoral head was proven in 2 cases (4.4%) in group I, 0% in group II, and in 1 case (5%) in group III. All patients initially had femoral head necrosis of Graf type IV . All necrosis and maturation disorders were no longer visible on subsequent examinations after 2 years at the most.In summary, the study shows that even with a late treatment start (U3) good results could be achieved, but with a rising number of repositioning failures and femoral necroses. Ultrasound screening on U3 seems to be sufficient; however, for high-risk groups an additional screening in the first week of life should be performed, which does not replace a second evaluation at U3 if there are normal findings.

The default response to protein antigens in the intestine is the induction of systemic and local hyporesponsiveness, ensuring the prevention of coeliac disease and food allergies. Interest is increasing in the role of dietary manipulation and probiotics in treating allergic and other diseases, but less is known about how these regimens might influence systemic and local immune responses. This paper addresses the mechanisms at the interface of innate and adaptive immunity that determine how the body responds to orally administered proteins and how local bacteria modify these.This paper discusses evidence that dendritic cells in the intestinal mucosa are the critical cells that take up dietary proteins and migrate to the draining mesenteric lymph node, where they induce regulatory CD4 T-cell differentiation. The properties of tolerized T cells are discussed and it is proposed that the gut microenvironment maintains homeostasis by conditioning dendritic cells to remain in a quiescent state. Inhibitory signalling by commensal bacteria possibly contributes to this process.A regulatory network controls how dietary antigens are taken up and presented to T lymphocytes by specialized antigen-presenting cells. Elucidating their nature and how they are influenced by external factors such as probiotics may help develop novel therapies for allergy and help understand diseases such as coeliac disease.

MHC class II-positive late endosomes of enterocytes are thought to be involved in antigen presentation to CD4(+) T cells. In contrast to enterocytes of BALB/c mice, severe combined immunodeficiency (SCID) enterocytes lack MHC class II expression and fail to transport internalized ovalbumin (OVA) into late endosomes. IFN-gamma is known to induce MHC class II in enterocytes and antigen targeting to late endosomes in macrophages. In this study, we investigated the influence of IFN-gamma and MHC class II on the processes of antigen traffic in enterocytes. Subcellular targeting of OVA and MHC class II expression within enterocytes were examined in SCID, IFN-gamma-treated SCID, BALB/c and C57BL/6 MHC class II knockout (KO) mice after a single feed with OVA. Sorting of OVA into late endosomes was found in enterocytes from BALB/c, C57BL/6 KO and IFN-gamma-stimulated SCID mice, but not from untreated SCID mice. MHC class II expression was restricted to enterocytes of IFN-gamma-treated SCID and BALB/c mice, present at basolateral membranes and within endosomal compartments. These enterocytes further revealed colocalization of class II antigens and OVA in endosomes. We suggest that antigen trafficking into late endosomes of enterocytes is mediated by IFN-gamma and occurs in the absence of MHC class II.

Human milk is thought by many authorities to be preferable to formula as a source of nutrients for infants. Some of the benefits may stem from its high concentration of unbound oligosaccharides (5-10 g/L). These sugars have structural similarities to selectin ligands, known to mediate important cell–cell interactions in the immune system. Platelet-neutrophil complexes (PNC) exist in healthy individuals but have been implicated in disease states. Formation of these complexes requires selectins and as such, could be influenced by human milk oligosaccharides (HMO). Here, we investigate this possibility by examining the effect of HMO on the formation of PNC and activation of associated neutrophils. We collected blood from 10 healthy volunteers, activated platelets with adenosine 5′-diphosphate, and added HMO, oligosaccharide standards, or phosphate-buffered saline as a control. We determined the influence of HMO on PNC formation and adjacent neutrophil activation with fluorescein-activated cell sorter analysis after labeling with antibodies for the platelet marker CD42a and the neutrophil activation marker CD11b. Within physiologically achievable concentrations (6.25-125 μg/mL), an acidic HMO fraction reduced PNC formation up to 20%, which was similar to the effect seen with high concentrations of sialyl-Lewis x. Associated neutrophils showed a dose-dependent decrease in β 2 integrin expression, up to 30%, at high but physiological concentrations. The neutral HMO fraction had no effect. These results support the hypothesis that acidic HMO serve as anti-inflammatory components of human milk and thus, contribute to the lower incidence of inflammatory diseases such as necrotizing enterocolitis in breast-fed versus formula-fed infants.

The structure of the NASICON-like phase Li2.5V2(PO4)3 has been determined by X-ray and neutron powder diffraction, demonstrating that it crystallizes in the space group P21/n (a = 8.5539(4) A; b = 8.6099(4) A; c = 11.9825(5) A; β = 90.002(7)°). Combined studies using 6,7Li MAS NMR, EPR, and ac impedance spectroscopy show that this pseudo-orthorhombic lattice represents a room-temperature analogue of the high-temperature orthorhombic phase γ-Li3Sc2(PO4)3. Lithium disorder over partially vacant sites leads to enhanced ion mobility. EPR spectroscopy confirms the presence of localized V4+ in the lattice, whose short-range order with V3+ gives rise to five resolvable Li shifts in the 6,7Li MAS NMR spectrum. These shifts can be rationalized by consideration of the Fermi-contact interactions arising from the difference between V3+ and V4+ coupling in the three lithium sites.

SUMMARYMost studies investigating the induction of oral tolerance (OT) use purified proteins such as ovalbumin (OVA), bovine serum albumin (BSA) and beta-lactoglobulin (β-LG). Little information is available regarding the induction of OT to a protein mixture, e.g. cow's milk. In this study we compared the regulatory mechanisms induced after the oral administration of a whey protein concentrate (WP) derived from cow's milk following immunization with two different adjuvants, complete Freund's adjuvant (CFA) and alum. OVA was used as a control antigen. Animals were given a single feed of these proteins at an equivalent dose of 1 mg/g body weight before they were immunized seven days later with the antigen in Freund's adjuvant or alum. Delayed type hypersensitivity (DTH) responses were suppressed by both a feed of WP and OVA after immunization with CFA. However, only OVA feeding suppressed antigen specific IgG responses. In an attempt to investigate whether WP would tolerize the more susceptible IgE responses, alum immunization replaced CFA as the adjuvant used for systemic immunizations. WP, after a single feed, significantly primed for DTH and IgE responses indicating oral sensitization to WP. In contrast, OVA suppressed DTH, IgE and IgG responses. Antigen specific proliferation of mononuclear cells was suppressed in mice fed OVA, but primed in those fed with WP. In addition cells taken from sensitized mice fed WP up-regulated levels of specific interleukin (IL) -4, -10 and -12 in vitro whereas these cytokines were suppressed in cultures from tolerant WP fed mice. Global suppression was obtained in cultures from tolerant OVA fed mice. TGF-β was not detected in draining PLN cell cultures of either tolerant or sensitized mice. These data suggest that a whey protein mixture induces divergent responses following immunization with either CFA or alum despite being fed at an identical dose. We suggest that that the choice of the adjuvant may determine the immunoregulatory outcome and this is also reflected by the systemic cytokine profile.

Eine fehlende klinische Reaktion der Mukosa auf Nahrungsantigene uberwiegt in der Mehrheit der Bevolkerung. Zusatzlich bestehen klinische und experimentelle Beweise fur eine orale Toleranz beim Menschen. Der Zeitpunkt der Antigen- bzw. Nahrungszufuhr ist ein wichtiger Faktor in der Entwicklung einer Nahrungsmittelallergie. Die Induktion einer Toleranz wird oft als Th2-vermittelte Reaktion angesehen, die auf der einen Seite vor schadlichen mukosalen Immunreaktionen schutzt, auf der anderen Seite jedoch zu uberschiesenden Abwehrreaktionen bei anfalligen Individuen beitragt. Die primaren Mechanismen der Toleranz schliesen T-Zell-Zerstorung, Anergie, Suppression, "Ignoranz" und Apoptose ein. Th1-zellvermittelte verzogerte Hypersensitivitatsreaktionen, die an der Pathogenese von autoimmunen und gastrointestinalen Entzundungen beteiligt sind, sind besonders stark unterdruckt.

The Mid-Atlantic Integrated Assessment (MAIA-Estuaries) evaluated ecological conditions in US Mid-Atlantic estuaries during the summers of 1997 and 1998. Over 800 probability-based stations were monitored in four main estuarine systems––Chesapeake Bay, the Delaware Estuary, Maryland and Virginian coastal bays, and the Albemarle–Pamlico Estuarine System. Twelve smaller estuaries within the four main systems were also assessed to establish variance at the local scale. A subset of the MAIA-Estuaries data is used here to estimate the extent of eutrophication, sediment contamination, and benthic degradation in mid-Atlantic estuaries. An Environmental Report Card and Index of Environmental Integrity summarize conditions in individual estuaries, the four estuarine systems, and the entire MAIA region. Roughly 20–50% of the region showed signs of eutrophication (high nutrients, excessive production of organic matter, poor water clarity, or depleted dissolved oxygen), 30% had contaminated sediments, and 37% had degraded benthic communities. Compared with the Environmental Monitoring and Assessment Program (EMAP)-Virginian Province study in 1990–1993, larger fractions of Chesapeake Bay (17%) and Delaware River (32%) had increased metals or organics in sediments.

Summary Aim : To study the efficacy of three pantoprazole-based triple therapy regimens for the eradication of Helicobacter pylori infection and gastric ulcer healing. Methods : In an open, multi-centre, randomized study, 519 H. pylori-positive patients with active gastric ulcer were randomized to receive pantoprazole (40 mg) (P) and two of three antibiotics: clarithromycin (500 mg) (C), metronidazole (500 mg) (M) or amoxicillin (1000 mg) (A). Triple therapy (PAC, PCM, PAM) was administered twice daily for 7 days, followed by pantoprazole until the ulcer had healed. Antrum and corpus biopsies were taken to determine the pattern of gastritis, to assess the H. pylori status and to determine the strain susceptibility to antibiotics, and from the ulcer margins and base to exclude malignancy. Scores based on the Sydney system were used to categorize the gastritis phenotypically. Results : The H. pylori eradication rates for the per protocol (intention-to-treat) analysis were 89% (67%) for PAC, 83% (68%) for PCM and 76% (60%) for PAM, with a significant difference between PAC and PAM. Healing rates after 4 weeks were 91% for PAM, 90% for PCM and 88% for PAC (per protocol analysis). The eradication rates were lower in patients in whom strains resistant to any antibiotic used in the triple therapies were detected. Successful eradication [odds ratio, 5.2 (3.3; 8.3)] and the ulcer size (

We previously demonstrated that the major ecto-nucleoside triphosphate phosphohydrolase in the chicken liver membranes is an ecto-ATP-diphosphohydrolase (ecto- ATPDase) [Caldwell, C., Davis, M.D. & Knowles, A.F. (1999) Arch. Biochem. Biophys. 362, 46-58]. Enzymatic properties of the liver membrane ecto-ATPDase are similar to those of the chicken oviduct ecto-ATPDase that we have previously purified and cloned. Using antibody developed against the latter, we have purified the chicken liver ecto-ATPDase to homogeneity. The purified enzyme is a glycoprotein with a molecular mass of 85 kDa and a specific activity of approximately 1000 U.mg protein-1. Although slightly larger than the 80-kDa oviduct enzyme, the two ecto-ATPDases are nearly identical with respect to their enzymatic properties and mass of the deglycosylated proteins. The primary sequence of the liver ecto-ATPDase deduced from its cDNA obtained by RT-PCR cloning also shows only minor differences from that of the oviduct ecto-ATPDase. Immunochemical staining demonstrates the distribution of the ecto-ATPDase in the bile canaliculi of the chicken liver. HeLa cells transfected with the chicken liver ecto-ATPDase cDNA express an ecto-nucleotidase activity with characteristics similar to the enzyme in its native membranes, most significant of these is stimulation of the ATPDase activity by detergents, which inhibits other members of the ecto- nucleoside triphosphate diphosphohydrolase (E-NTPDase) family. The stimulation of the expressed liver ecto-ATPDase by detergents indicates that this property is intrinsic to the enzyme protein, and cannot be attributed to the lipid environment of the native membranes. The molecular identification and expression of a liver ecto-ATPDase, reported here for the first time, will facilitate future investigations into the differences between structure and function of the different E-NTPDases, existence of liver ecto-ATPDase isoforms in different species, its alteration in pathogenic conditions, and its physiological function.

We describe a patient with frequent, symptomatic, and drug-refractory premature ventricular contractions (PVCs) with a right bundle branch block, inferior axis morphology suggestive of a left ventricular outflow tract (LVOT) origin. Successful ablation of the PVCs was performed from the left coronary cusp of the aortic valve. We discuss our patient and review the literature regarding patients with ventricular arrhythmias arising from the coronary cusps, with special emphasis on the use of the electrocardiogram to aid localization of the focus.

We have investigated the mechanism underlying the surface conductivity observed for synthetic diamond(001) samples. It is found that (1) the surface conductivity depends on the pressure of the surrounding gas atmosphere, (2) the temperature dependence can be described as being due to a thermally activated process and (3) a chromogeneous WO3 cathode turns color from transparent to blue and gas bubbles develop underneath the cathode if an electrical dc current is passed through such an arrangement. In contrast, the complementary WO3 anode neither changed color nor were gas bubbles observed. One concludes that hydrogen develops at the negatively biased WO3-diamond interface, recombining to gaseous H2. However, most of the hydrogen invades the WO3 cathode coloring it blue, thereby clearly indicating the involvement of protons. Though the conductivity crucially depends on temperature, time and history of a sample, the resistances of various and even differently prepared diamond specimens covering eleven orders of magnitude can be scaled onto one master curve reflecting a thermally activated behavior. Taken together, we propose that the mechanism of the diamond(001) surface conductivity as observed under ambient conditions is at least partly due to proton conduction.

Cylindrical diamond columns of 15 nm height and 10 nm diameter have been prepared on a diamond(100) substrate by exploiting the self-organization of metal-loaded diblock copolymers. For this purpose, chemomechanically polished substrates of synthetic (high pressure high temperature) diamond exhibiting extremely low roughness (typical root-mean-square roughness 60 pm) were covered by a monolayer of gold-loaded inverse polystyrene-block-poly(2-vinylpyridine) micelles which self-organize in an hexagonal order on the substrate. After burning off the blockcopolymer in an oxygen plasma, the resulting Au nanoparticles act as a mask during further etching the diamond substrate in this plasma. As a result, Au-capped diamond columns are formed with an approximate size of the former gold particles. After removing the Au caps by evaporation at 1100 °C in ultrahigh vacuum, an array of diamond nanocolumns is obtained. As a consequence of this preparation process, the columns form an hexagonal lattice with a separation of 85 nm reflecting the arrangement of the self-organized micelles. The successive states of sample preparation were characterized by atomic force microscopy, Rutherford backscattering, and in situ scanning tunneling microscopy.

The evolution of management of ventricular arrhythmia has occurred largely as a result of randomized, controlled clinical trials. 14,17 The Cardiac Arrhythmia Suppression Trial was pivotal in changing the approach to arrhythmia investigation. First, the study of treatments for ventricular arrhythmias should include a placebo arm whenever feasible and ethical. In comparing two therapies, one of which is subsequently proven to be superior to the other, it is incorrect to assume that the inferior therapy provides outcomes similar to no therapy. The superior therapy may be similar to no therapy, whereas the inferior therapy may be detrimental. Similarly, the superior therapy may provide outcomes only slightly better than no therapy, whereas the inferior therapy may provide slightly worse outcomes (Fig. 1). 39 Second, total mortality rate is the most important endpoint, because many patients at risk of developing ventricular arrhythmias have competing risks for death, and the classification of death in clinical trials is fraught with inaccuracies. 33 Applying the results of clinical trials to everyday practice in an appropriate manner can be as difficult as conducting clinical trials themselves. One must remember that a certain treatment that has proven benefit in a specific patient population may not necessarily be beneficial if applied to a more general population. The applicability of many otherwise well-conducted studies has been diminished by the narrowly focused populations of patients studied. This is particularly relevant in the treatment of ventricular arrhythmias. Studying patients at high risk of recurrent ventricular arrhythmias is important, but the overall impact on arrhythmia prevention is low (Fig. 2). 38 Arrhythmia trials have studied progressively broader patient populations. This article summarizes the results of large clinical trials in the management of ventricular arrhythmias and attempts to provide guidelines for applying their results to everyday clinical practice.

PMOS devices with and without nitrogen implant into the gate electrode before doping with boron and with nitridation of the gate oxide were manufactured. The influence of nitrogen on the penetration of boron ions into the substrate through ultra-thin gate oxides was investigated by electrical and SIMS measurements. Boron diffusion can be effectively prevented by high nitrogen concentrations located immediately above the gate oxide and within the polysilicon gate electrode.

The evolution of the surface morphology of a diamond (100) surface has been investigated as induced by low-energy (1.2–1.5 keV) Ar+-ion bombardment at grazing incidence and fluences in the range 1016–1017 cm−2. Identical bombardments were applied to three different initial stages of the diamond surface: (1) a chemomechanically polished ultra-smooth surface, (2) a surface as in (1) that was roughened by exposure to an intense hydrogen plasma and showing a brick-wall pattern, and (3) a smooth surface carrying hexagonally arranged columns of size 10 nm×10 nm at an average separation of 85 nm. Depending on the starting condition of the sample surface, its morphology develops very differently under ion bombardment. The ultra-smooth surface with a root-mean-square (RMS) roughness of 0.1 nmrms does not change its roughness significantly. The nanocolumns of the nanostructured surface can be removed efficiently and the surface approaches the roughness of an ultra-smooth surface. However, the roughness of the plasma-treated surface, which exhibited a starting value of 4.5 nmrms, could not be reduced significantly by the bombardment, and the formation of characteristic needles accompanied by laguna-like patterns was observed. We discuss our results in terms of (1) simple geometry, (2) an enhanced sputter yield for structures comparable to or smaller than the penetration depth of the ions, and (3) the evolution of a characteristic spatial wavelength according to the non-linear Kardar–Parisi–Zhang theory.