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The liver has been proposed as an important “immune organ” of the body, as it is critically involved in a variety of specific and unique immune tasks. It contains a huge resident immune cell repertoire, which determines the balance between tolerance and inflammation in the hepatic microenvironment. Liver-resident immune cells, populating the sinusoids and the space of Disse, include professional antigen-presenting cells, myeloid cells, as well as innate and adaptive lymphoid cell populations. Machine perfusion (MP) has emerged as an innovative technology to preserve organsex vivowhile testing for organ quality and function prior to transplantation. As for the liver, hypothermic and normothermic MP techniques have successfully been implemented in clinically routine, especially for the use of marginal donor livers. Although there is evidence that ischemia reperfusion injury-associated inflammation is reduced in machine-perfused livers, little is known whether MP impacts the quantity, activation state and function of the hepatic immune-cell repertoire, and how this affects the inflammatory milieu during MP. At this point, it remains even speculative if liver-resident immune cells primarily exert a pro-inflammatory and hence destructive effect on machine-perfused organs, or in part may be essential to induce liver regeneration and counteract liver damage. This review discusses the role of hepatic immune cell subtypes during inflammatory conditions and ischemia reperfusion injury in the context of liver transplantation. We further highlight the possible impact of MP on the modification of the immune cell repertoire and its potential for future applications and immune modulation of the liver.

Background Atrial fibrillation (AF) is common, often without symptoms, and is an independent risk factor for mortality, stroke and heart failure. It is unknown if screening asymptomatic individuals for AF can improve clinical outcomes. Methods mSToPS was a pragmatic, direct-to-participant trial that randomized individuals from a single US-wide health plan to either immediate or delayed screening using a continuous-recording ECG patch to be worn for two weeks and 2 occasions, ~3 months apart, to potentially detect undiagnosed AF. The 3-year outcomes component of the trial was designed to compare clinical outcomes in the combined cohort of 1718 individuals who underwent monitoring and 3371 matched observational controls. The prespecified primary outcome was the time to first event of the combined endpoint of death, stroke, systemic embolism, or myocardial infarction among individuals with a new AF diagnosis, which was hypothesized to be the same in the two cohorts but was not realized. Results Over the 3 years following the initiation of screening (mean follow-up 29 months), AF was newly diagnosed in 11.4% (n = 196) of screened participants versus 7.7% (n = 261) of observational controls (p Conclusions At 3 years, screening for AF was associated with a lower rate of clinical events and improved outcomes relative to a matched cohort, although the influence of earlier diagnosis of AF via screening on this finding is unclear. These observational data, including the high event rate surrounding a new clinical diagnosis of AF, support the need for randomized trials to determine whether screening for AF will yield a meaningful protection from strokes and other clinical events. Trail registration The mHealth Screening To Prevent Strokes (mSToPS) Trial is registered on ClinicalTrials.gov with the identifier NCT02506244.

To identify groups of heterogeneous HbAThe study comprised 6355 adults with newly diagnosed Type 2 diabetes (55% men, median age 62 years, baseline BMI 31 kg/mFour distinct longitudinal HbAFour subgroups with distinct HbA

Toll-like receptor 2 (TLR2) recognizes bacterial derived- and synthetic-lipopeptides after dimerization with TLR1 or TLR6. Hyper-activation of TLR2 has been described in several inflammatory diseases and the discovery of inhibitors of its pro-inflammatory activity represent potential starting points to develop therapeutics in such pathologies. We designed peptides derived from the TLR2 sequence comprising amino acid residues involved in ligand binding (Pam3CSK4) or heterodimerization (TLR2/TLR1) as pointed out by structural data.2 We identified several peptides (P13, P13(LL), P16, P16(LL)) which inhibited TLR2/1 signaling in HEK293-TLR2 cells (MAPK activation and NF-kB activity). Moreover, P13L and P16L decreased TNFα release in human primary PBMCs and mouse macrophages. The peptides were selective for TLR2/1 as they did not inhibit the activity of other TLRs tested. P13L and P16L inhibited the internalization of Pam3CSK4 fluorescently labeled in macrophages and the heterodimerization of TLR2 with TLR1 as demonstrated by immunoprecipitation studies. Our data demonstrate that peptides derived from the region comprising the leucine-rich repeats (LRR) 11 and 13 in the extracellular domain of TLR2 are good starting points to develop more potent anti-inflammatory peptides with TLR2 inhibitory activity.

Cardiovascular disease remains the leading cause of death and disease worldwide. As demands on an already resource-constrained healthcare system intensify, disease prevention in the future will likely depend on out-of-office monitoring of cardiovascular risk factors. Mobile health tracking devices that can track blood pressure and heart rate, in addition to new cardiac vital signs, such as physical activity level and pulse wave velocity (PWV), offer a promising solution. An initial barrier is the development of accurate and easily-scalable platforms. In this study, we made a customized smartphone app and used mobile health devices to track PWV, blood pressure, heart rate, physical activity, sleep duration, and multiple lifestyle risk factors in ≈250 adults for 17 continual weeks. Eligible participants were identified by a company database and then were consented and enrolled using only a smartphone app, without any special training given. Study participants reported high overall satisfaction, and 73% of participants were able to measure blood pressure and PWV

Background Emergent therapies in anticancer vaccination use Toll-like receptors (TLRs) agonists as dendritic cell (DC) vaccine adjuvants. DCs from the patient are isolated, stimulated with TLR agonists and tumor antigens ex vivo and then infused back into the patient. Although some TLR ligands have been tested in clinical trials, novel TLR agonists with improved immunomodulatory properties are essential to optimize treatment success. We report on the discovery of small-molecule TLR2 agonists, with favorable properties as synthetic adjuvants. Methods We performed a shape- and featured-based similarity virtual screening against a commercially available compound library. The selected virtual hits were experimentally tested in TLR2-reporter cells and their activity in phagocytes and DCs was characterized. A binding model of the compounds to TLR2 (docking studies) was proposed. Results Through a virtual screening approach against a library of three million compounds four virtual hits (AG1, AG2, AG3, AG4) were found to synergistically augment the NF-kB activation induced by the lipopeptide ligand Pam 3 CSK 4 in luciferase reporter assays using HEK293-TLR2 cells. Biacore experiments indicated that AG1–AG4 are ago-allosteric modulators of TLR2 and AG2 bound TLR2 with high affinity (K D 0.8 μM). The compounds induced TNF-α production in human peripheral blood mononuclear cells (PBMCs) and they activated DCs as indicated by IL-12 production and upregulation of CD83/CD86. Conclusions Following a combined in silico / in vitro approach we have discovered TLR2-agonists (AG1–AG4) that activate human and mouse immune cells. General significance We introduce four novel TLR2 ago-allosteric modulators that stimulate myeloid cell activity and constitute promising candidates as synthetic adjuvants.

A wide range of personal wireless health-related sensor devices are being developed with hope of improving health management. Factors related to effective user engagement, however, are not well-known. We sought to identify factors associated with consistent long-term use of the Scanadu Scout multi-parameter vital sign monitor among individuals who invested in the device through a crowd-funding campaign. Email invitations to join the study were sent to 4525 crowd-funding participants from the US. Those completing a baseline survey were sent a device with follow-up surveys at 3, 12, and 18 months. Of 3872 participants receiving a device, 3473 used it during Week 1, decreasing to 1633 (47 percent) in Week 2. Median time from first use of the device to last use was 17 weeks (IQR: 5-51 weeks) and median uses per week was 1.0 (IQR: 0.6-2.0). Consistent long-term use (defined as remaining in the study at least 26 weeks with at least 3 recordings per week during at least 80% of weeks) was associated with older age, not having children in the household, and frequent use of other medical devices. In the subset of participants answering the 12-month survey (n = 1222), consistent long-term users were more likely to consider the device easy to use and to share results with a healthcare provider. Thirty percent of this subset overall reported improved diet or exercise habits and 25 percent considered medication changes in response to device results. The study shows that even among investors in a device, frequency of device usage fell off rapidly. Understanding how to improve the value of information from personal health-related sensors will be critical to their successful implementation in care.

Importance Opportunistic screening for atrial fibrillation (AF) is recommended, and improved methods of early identification could allow for the initiation of appropriate therapies to prevent the adverse health outcomes associated with AF. Objective To determine the effect of a self-applied wearable electrocardiogram (ECG) patch in detecting AF and the clinical consequences associated with such a detection strategy. Design, Setting, and Participants A direct-to-participant randomized clinical trial and prospective matched observational cohort study were conducted among members of a large national health plan. Recruitment began November 17, 2015, and was completed on October 4, 2016, and 1-year claims-based follow-up concluded in January 2018. For the clinical trial, 2659 individuals were randomized to active home-based monitoring to start immediately or delayed by 4 months. For the observational study, 2 deidentified age-, sex- and CHA 2 DS 2 -VASc–matched controls were selected for each actively monitored individual. Interventions The actively monitored cohort wore a self-applied continuous ECG monitoring patch at home during routine activities for up to 4 weeks, initiated either immediately after enrolling (n = 1364) or delayed for 4 months after enrollment (n = 1291). Main Outcomes and Measures The primary end point was the incidence of a new diagnosis of AF at 4 months among those randomized to immediate monitoring vs delayed monitoring. A secondary end point was new AF diagnosis at 1 year in the combined actively monitored groups vs matched observational controls. Other outcomes included new prescriptions for anticoagulants and health care utilization (outpatient cardiology visits, primary care visits, or AF-related emergency department visits and hospitalizations) at 1 year. Results The randomized groups included 2659 participants (mean [SD] age, 72.4 [7.3] years; 38.6% women), of whom 1738 (65.4%) completed active monitoring. The observational study comprised 5214 (mean [SD] age, 73.7 [7.0] years; 40.5% women; median CHA 2 DS 2 -VASc score, 3.0), including 1738 actively monitored individuals from the randomized trial and 3476 matched controls. In the randomized study, new AF was identified by 4 months in 3.9% (53/1366) of the immediate group vs 0.9% (12/1293) in the delayed group (absolute difference, 3.0% [95% CI, 1.8%-4.1%]). At 1 year, AF was newly diagnosed in 109 monitored (6.7 per 100 person-years) and 81 unmonitored (2.6 per 100 person-years; difference, 4.1 [95% CI, 3.9-4.2]) individuals. Active monitoring was associated with increased initiation of anticoagulants (5.7 vs 3.7 per 100 person-years; difference, 2.0 [95% CI, 1.9-2.2]), outpatient cardiology visits (33.5 vs 26.0 per 100 person-years; difference, 7.5 [95% CI, 7.2-7.9), and primary care visits (83.5 vs 82.6 per 100 person-years; difference, 0.9 [95% CI, 0.4-1.5]). There was no difference in AF-related emergency department visits and hospitalizations (1.3 vs 1.4 per 100 person-years; difference, 0.1 [95% CI, −0.1 to 0]). Conclusions and Relevance Among individuals at high risk for AF, immediate monitoring with a home-based wearable ECG sensor patch, compared with delayed monitoring, resulted in a higher rate of AF diagnosis after 4 months. Monitored individuals, compared with nonmonitored controls, had higher rates of AF diagnosis, greater initiation of anticoagulants, but also increased health care resource utilization at 1 year. Trial Registration ClinicalTrials.gov Identifier:NCT02506244

Efficient methods for screening populations for undiagnosed atrial fibrillation (AF) are needed to reduce its associated mortality, morbidity, and costs. The use of digital technologies, including wearable sensors and large health record data sets allowing for targeted outreach toward individuals at increased risk for AF, might allow for unprecedented opportunities for effective, economical screening. The trial's primary objective is to determine, in a real-world setting, whether using wearable sensors in a risk-targeted screening population can diagnose asymptomatic AF more effectively than routine care. Additional key objectives include (1) exploring 2 rhythm-monitoring strategies-electrocardiogram-based and exploratory pulse wave-based-for detection of new AF, and (2) comparing long-term clinical and resource outcomes among groups. In all, 2,100 Aetna members will be randomized 1:1 to either immediate or delayed monitoring, in which a wearable patch will capture a single-lead electrocardiogram during the first and last 2 weeks of a 4-month period beginning immediately or 4 months after enrollment, respectively. An observational, risk factor-matched control group (n = 4,000) will be developed from members who did not receive an invitation to participate. The primary end point is the incidence of new AF in the immediate- vs delayed-monitoring arms at the end of the 4-month monitoring period. Additional efficacy and safety end points will be captured at 1 and 3 years. The results of this digital medicine trial might benefit a substantial proportion of the population by helping identify and refine screening methods for undiagnosed AF.

Beneficial microbes enter the food supply primarily through fermented foods (largely milks) and addition of probiotics. Fermented milks are a significant component of the diet of some geographical regions, including Europe. The fermentation process serves to preserve safety, nutritional quality and palatability of milk. In addition, the microbes associated with fermented milks and probiotics are associated with human health benefits. However, in the area of health claims only one claim for beneficial microbes has been approved in the European Union, that is for yoghurt to improve lactose tolerance. We searched for health messages that include probiotics or fermented milks in nutrition guidelines and recommendations in thirteen countries of the EU plus Switzerland. Such messages are allowed when they are made by non-commercial government bodies. Our analysis revealed that five EU member states have national nutrition guidelines or recommendations that include either probiotics or fermented milks with live bacteria. This supports that some EU member states recognise health benefits associated with consumption of live microbes, even if commercial marketing claims are not authorised. Harmonisation between recommendations and approved health-claims would benefit consumers and public health.

While laparoscopic cholecystectomy is widely accepted for therapy of cholecystolithiasis, controversy still exists concerning the management of common bile duct stones. Besides preoperative endoscopic papillotomy followed by laparoscopic cholecystectomy and open common bile duct surgery, management of common bile duct stones can be conducted by laparoscopy, if respective experience is available.During laparoscopic cholecystectomy a cholangiography via the cystic duct is routinely performed. If bile duct stones are detected they are retrieved via the cystic duct or via incision of the common bile duct by insertion of a Fogarty catheter or Dormia basket. Exclusion criteria against simultaneous laparoscopic management include suspicion of malignancy, severe pancreatitis, or cholangitis.From November 1991 to March 2002, 200 patients primarily underwent laparoscopic therapy of bile duct stones. Retrieval was performed via cystic duct and common bile duct incision in 115 and 85 cases, respectively. Complete removal was achieved in 91%; complication rate and mortality was 7% and 0.5%, respectively. During the same period primary endoscopic papillotomy was necessary in 40 patients because of the above contraindications.When correct indications and surgical expertise are observed, simultaneous laparoscopic management of common bile duct stones represents a safe and minimally invasive alternative to a two-procedure approach.

To identify signal-transduction pathways induced by glial cell-derived neurotrophic factor (GDNF) in corneal epithelial cells and to characterize its effect on cell migration.Expression of GDNF receptor (GFR) alpha-1 in human corneal epithelium was detected by RT-PCR and Western blot analysis. Expression and phosphorylation of Ret, activation of focal adhesion kinase (FAK) and mitogen-associated protein kinase (MAPK) signaling pathways, and phosphorylation of paxillin by GDNF were investigated by immunoprecipitation and Western blot analysis in primary human corneal epithelial cells and a corneal epithelial cell line. The tyrosine kinase inhibitor herbimycin A and Ras farnesyltransferase inhibitor manumycin were used to specifically inhibit GDNF-induced signaling pathways. In vitro wound-healing assays and modified Boyden chamber analysis were performed to investigate the effect of GDNF on epithelial cell migration.Expression of GFRalpha-1 was detected in normal and transformed human corneal epithelium. GDNF induced tyrosine phosphorylation of Ret. Furthermore, tyrosine phosphorylation of FAK and phosphotyrosine kinase (Pyk) 2; serine phosphorylation of c-Raf, MEK1, and Elk 1; and tyrosine-threonine phosphorylation of Erk-1 and -2 were time-dependently activated in the presence of GDNF. Tyrosine phosphorylation of paxillin was also induced by GDNF. Migration of corneal epithelial cells was significantly stimulated by GDNF. Herbimycin A strongly inhibited the activation of Ret, FAK, c-Raf, and Erk-1 and -2; the phosphorylation of paxillin; and corneal epithelial cell migration. More specifically, the Ras inhibitor manumycin inhibited phosphorylation of c-Raf, MEK 1, Erk-1 and -2, and Elk 1, but not that of FAK.Corneal epithelial cells express receptors specific for GDNF that are used by GDNF to induce intracellular signaling. FAK and MAPK pathways seem to be activated by GDNF to modulate gene transcription and cell migration. FAK seems to be an upstream regulator of the MAPK cascade for GDNF signal transduction. As an inducer of FAK-dependent corneal epithelial migration, GDNF may play an important role in corneal regeneration and wound healing.

Endoscopic subfascial dissection of perforating veins (ESDP) represents a new additional technique for treatment of greater saphenous system varicosities. We present a modification of ESDP, entitled endoscopic subfascial insufflation-dissection of perforating veins (ESIDP). In ESIDP CO2-insufflation induced enlargement of subfascial space (subfascial pneumocave) facilitates identification and dissection of perforating veins. From 1.1.1998 to 1.7.2000, 150 procedures of ESIDP have been conducted in 127 patients (90 females, 37 males). Identification of incompetent perforating and superficial veins and assessment of deep veins were performed preoperatively using duplex sonography. In addition to a description of the surgical technique, we present an overview about indications for ESIDP and possible ESIDP-related postoperative complications.

Females with XY gonadal dysgenesis are sterile, due to degeneration of the initially present ovaries into nonfunctional streak gonads. Some of these sex-reversal cases can be attributed to mutation or deletion of the SRY gene. We now describe an SRY-deleted 47,XXY female who has one son and two daughters, and one of her daughters has the same 47,XXY karyotype. PCR and FISH analysis revealed that the mother carries a structurally altered Y chromosome that most likely resulted from an aberrant X-Y interchange between the closely related genomic regions surrounding the gene pair PRKX and PRKY on Xp22.3 and Yp11.2, respectively. As a consequence, Yp material, including SRY, has been replaced by terminal Xp sequences up to the PRKX gene. The fertility of the XXY mother can be attributed to the presence of the additional X chromosome that is missing in XY gonadal dysgenesis females. To our knowledge, this is the first human XXY female described who is fertile.

Dendritic cells (DC) are professional antigen-presenting cells specialized in the initiation of primary immune responses. We were interested to know whether mature DC can be grown in vitro from peripheral blood mononuclear cells (PBMC) of patients with chronic myelogenous leukemia (CML), and whether they carry the Philadelphia (Ph) translocation. Using a method recently described, DC were generated from PBMC precursors of 12 patients with CML using GM-CSF, IL-4, and monocyte-conditioned medium. DC exhibited the typical morphology with thin cytoplasmatic processes and expressed high levels of MHC class II, CD86, and CD83 typical for mature DC. After sorting with the monoclonal antibody CD83, a cell population of more than 95% CD83 positive cells was obtained. The presence of the Ph translocation was analyzed in these cells, in PBMC, lymphoblastoid cell lines (LCL), and in phytohemagglutinin (PHA)-induced T blasts from the same patients by fluorescence in situ hybridization (FISH). In contrast to all other cells analyzed, the vast majority of DC (95.9 +/- 0.7%) displayed the Ph translocation, irrespective of disease stage or therapy. PBMC were predominantly positive for the Ph chromosome (67.6 +/- 7.3%), whereas only 11.4 +/- 1% of the B cells and 4.4 +/- 1.1% of the PHA blasts carried the Ph translocation. Using such leukemic DC as antigen-presenting cells, a primary CML-directed cytotoxic immune response in vitro was obtained, as shown by the specific recognition of Ph chromosome positive cells. We conclude that DC can be generated from blood progenitors of CML patients in vitro and exhibit, to a large extent, the Ph translocation. Such DC, which in a preliminary experiment have been able to induce a primary CML-directed cytotoxic immune response in vitro, might be ideal candidates for adoptive immunotherapy either by direct transfer of DC for in vivo generation of a T-cell response or by in vitro generation of CML-specific cytotoxic autologous or HLA-matched normal T-cell clones for use in vivo.

This is a case report on a 66-year old woman who suffered from chronic polyarthritis for 15 years and developed a sicca syndrome pattern for 2 years. 2 years later epithelioid cell granulomas were found from a submandibular lymph node as well as from a suspicious area at the epiglottis and the mucosa of the upper lip. Moreover, there was a chronic keratoconjunctivitis and discrete lung involvement. The sarcoidosis on the lip and at the epiglottis disappeared, and lung involvement and conjunctivitis improved under corticosteroid therapy. In spite of above therapy, the sicca syndrome pattern and the rheumatic complaints (osteoporosis) persisted.

On the basis of a casuistics the diagnosis, the differential diagnosis and the expert opinion of allergic multiple reactions (bronchial asthma, allergic alveolitis, sarcoidosis) are discussed.

Heart rate dynamics in response to active orthostasis of 10 min duration were examined in 48 patients with mitral stenosis and compared with the mean and diastolic pulmonary artery pressure. Classification of the characteristics of the heart rate was done according Drischel and co-workers (1963) using amplitude and time values. In contrast to healthy subjects, in patients with mitral stenosis the best regulatory behavior was observed in type B with lower pulmonary artery pressure, the least favorable regulatory dynamics being predominant in type A with higher pulmonary artery pressure. From a functional diagnostic point of view, regulatory efficiency can be graded on the following descending scale: (1) the best regulatory behavior in type B; (2) a decrease in the amplitude values in type B; (3) transition of the dynamics to type A; and (4) prolongation of the time values in type A. The pathophysiological mechanisms are changes in the sensitivity of dilatation receptors in the intrathoracic low-pressure system and of the carotid baroreceptors.