The jugular approach for leadless pacing: A novel and safe alternative.

AIMS: To evaluate safety of leadless pacemaker implantation through the internal jugular vein in a larger cohort with longer follow-up. Moreover, feasibility of non-apical pacing as well as relation between pacing site and QRS duration were assessed. METHODS: Eighty Two consecutive patients, who received a leadless pacemaker though the internal jugular vein, were included. Electrical parameters were measured at regular follow-up and any complications were registered. Paced QRS interval was compared for three pacing sites, RVOT, RV mid septum, and RV apical septum. RESULTS: In all patients, the leadless pacemaker was implanted successfully. In 69 patients, the device was implanted in a non-apical position. In 71% of cases, the device could be deployed at first attempt. The median fluoroscopy time was 4.4 min (range 0.9-51) The paced QRS interval was significantly narrower for non-apical pacing sites compared to apical pacing si 156  vs. 179 ms. p = .04, respectively. During mean follow-up of 16 months (range 0-43 months), electrical parameters remained stable. Two complications occurred, which could be resolved during the implant procedure. There were no access site related complications. CONCLUSION: The jugular approach for leadless pacemaker implantation is feasible and may avoid vascular complications. It facilitates non-apical positioning of leadless pacemakers leading to a narrower paced QRS interval. The jugular approach allows for immediate post procedural ambulation.

Chitosan Nanoparticles Functionalized Viscose Fabrics as Potentially Durable Antibacterial Medical Textiles.

This research proposed two pretreatments of viscose fabrics: oxidation with 2,2,6,6-tetramethylpiperidine-1-oxy radical (TEMPO) and coating with TEMPO-oxidized cellulose nanofibrils (TOCN), to introduce functional groups (COOH and CHO) suitable for irreversible binding of chitosan nanoparticles without and with embedded zinc (NCS and NCS + Zn, respectively) and consequently achieving washing durable antibacterial properties of the chitosan nanoparticles functionalized fabrics. The characterizations of pretreated and chitosan nanoparticles functionalized fabrics were performed by FTIR and XPS spectroscopy, elemental analysis, inductively coupled plasma optical emission spectrometry, zeta potential measurements, scanning electron microscopy, determination of COOH and CHO groups content, and antimicrobial activity under dynamic contact conditions. Influence of pretreatments on NCS and NCS + Zn adsorption, chemical, electrokinetic, and antibacterial properties as well as morphology, and washing durability of NCS and NCS + Zn functionalized fabrics were studied and compared. Washing durability was evaluated through changes in the chitosan and zinc content, zeta potential, and antibacterial activity after 1, 3, and 5 washing cycles. Pretreatments improved washing durability of antibacterial properties of chitosan nanoparticles functionalized fabrics. The NCS and NCS + Zn functionalized pretreated fabrics preserved antibacterial activity against S. aureus after five washing cycles, while antibacterial activity against E. coli was preserved only after one washing cycle in the case NCS + Zn functionalized pretreated viscose fabrics.

Faecal microbiota transplantation halts progression of human new-onset type 1 diabetes in a randomised controlled trial.

OBJECTIVE: Type 1 diabetes (T1D) is characterised by islet autoimmunity and beta cell destruction. A gut microbiota-immunological interplay is involved in the pathophysiology of T1D. We studied microbiota-mediated effects on disease progression in patients with type 1 diabetes using faecal microbiota transplantation (FMT). DESIGN: Patients with recent-onset (<6 weeks) T1D (18-30 years of age) were randomised into two groups to receive three autologous or allogenic (healthy donor) FMTs over a period of 4 months. Our primary endpoint was preservation of stimulated C peptide release assessed by mixed-meal tests during 12 months. Secondary outcome parameters were changes in glycaemic control, fasting plasma metabolites, T cell autoimmunity, small intestinal gene expression profile and intestinal microbiota composition. RESULTS: Stimulated C peptide levels were significantly preserved in the autologous FMT group (n=10 subjects) compared with healthy donor FMT group (n=10 subjects) at 12 months. Small intestinal Prevotella was inversely related to residual beta cell function (r=-0.55, p=0.02), whereas plasma metabolites 1-arachidonoyl-GPC and 1-myristoyl-2-arachidonoyl-GPC levels linearly correlated with residual beta cell preservation (rho=0.56, p=0.01 and rho=0.46, p=0.042, respectively). Finally, baseline CD4 +CXCR3+T cell counts, levels of small intestinal Desulfovibrio piger and CCL22 and CCL5 gene expression in duodenal biopsies predicted preserved beta cell function following FMT irrespective of donor characteristics. CONCLUSION: FMT halts decline in endogenous insulin production in recently diagnosed patients with T1D in 12 months after disease onset. Several microbiota-derived plasma metabolites and bacterial strains were linked to preserved residual beta cell function. This study provides insight into the role of the intestinal gut microbiome in T1D. TRIAL REGISTRATION NUMBER: NTR3697.

Clinical and genetic correlates of islet-autoimmune signatures in juvenile-onset type 1 diabetes.

AIMS/HYPOTHESIS: Heterogeneity in individuals with type 1 diabetes has become more generally appreciated, but has not yet been extensively and systematically characterised. Here, we aimed to characterise type 1 diabetes heterogeneity by creating immunological, genetic and clinical profiles for individuals with juvenile-onset type 1 diabetes in a cross-sectional study. METHODS: Participants were HLA-genotyped to determine HLA-DR-DQ risk, and SNP-genotyped to generate a non-HLA genetic risk score (GRS) based on 93 type 1 diabetes-associated SNP variants outside the MHC region. Islet autoimmunity was assessed as T cell proliferation upon stimulation with the beta cell antigens GAD65, islet antigen-2 (IA-2), preproinsulin (PPI) and defective ribosomal product of the insulin gene (INS-DRIP). Clinical parameters were collected retrospectively. RESULTS: Of 80 individuals, 67 had proliferation responses to one or more islet antigens, with vast differences in the extent of proliferation. Based on the multitude and amplitude of the proliferation responses, individuals were clustered into non-, intermediate and high responders. High responders could not be characterised entirely by enrichment for the highest risk HLA-DR3-DQ2/DR4-DQ8 genotype. However, high responders did have a significantly higher non-HLA GRS. Clinically, high T cell responses to beta cell antigens did not reflect in worsened glycaemic control, increased complications, development of associated autoimmunity or younger age at disease onset. The number of beta cell antigens that an individual responded to increased with disease duration, pointing to chronic islet autoimmunity and epitope spreading. CONCLUSIONS/INTERPRETATION: Collectively, these data provide new insights into type 1 diabetes disease heterogeneity and highlight the importance of stratifying patients on the basis of their genetic and autoimmune signatures for immunotherapy and personalised disease management.

Influence of Different Pretreatments on the Antibacterial Properties of Chitosan Functionalized Viscose Fabric: TEMPO Oxidation and Coating with TEMPO Oxidized Cellulose Nanofibrils.

The main objective of this study was to obtain chitosan functionalized viscose fabric with improved antibacterial properties and washing durability. In this regard carboxyl and aldehyde groups, as binding points for irreversible chitosan attachment into/onto viscose fabric, were introduced by two different pretreatments: 2,2,6,6-tetramethylpiperidine-1-oxy radical (TEMPO) oxidation and coating with TEMPO oxidized cellulose nanofibrils (TOCN). The Fourier transform infrared spectroscopy, elemental analysis, zeta potential measurements, scanning electron microscopy, breaking strength and antibacterial testing were used to evaluate the influence of these pretreatments on chitosan binding, but also on chemical, electrokinetic, morphological, mechanical and antibacterial properties of pretreated and chitosan functionalized viscose fabrics. Washing durability of chitosan functionalized viscose was monitored through changes in the chitosan content, electrokinetic and antibacterial properties after multiple washing. TOCN coating improves mechanical properties of fabric, while TEMPO oxidation deteriorates them. The results show that both pretreatments improve chitosan adsorption and thus antibacterial properties, which are highly durable to washing. After five washings, the chitosan functionalized pretreated viscose fabrics preserve their antibacterial activity against Staphylococcus aureus, while antibacterial activity against Escherichia coli was lost. TOCN coated and chitosan functionalized viscose fabric is a high value-added product with simultaneously improved antibacterial and mechanical properties, which may find application as medical textiles.

Leadless pacing: Going for the jugular.

BACKGROUND: Leadless pacing is generally performed from a femoral approach. However, the femoral route is not always available. Until now, data regarding implantation using a jugular approach other than a single-case report were lacking. METHODS: The case records of all patients who underwent internal jugular venous (IJV) leadless pacemaker implantation (Micra, Medtronic, Dublin, Ireland) at our center were analyzed retrospectively. RESULTS: Nineteen patients underwent IJV leadless pacemaker implantation, nine females, mean age of 77.5 ±9.6  years; permanent atrial fibrillation in all patients with normal left ventricular ejection fraction. Implant indication was atrioventricular conduction disturbance in 10, pre-AV node ablation in seven, and replacement of a conventional VVI pacemaker in two (infection in one and lead malfunction in the other). The device was positioned at the superior septum in seven patients, apicoseptal in seven patients, and midseptal in five patients. In 12 patients, a sufficient device position was obtained at the first attempt, in three at the second, in one at the third, in one at the fourth, and in two at the sixth attempt. The mean pacing threshold was 0.56 ± 0.39V at 0.24-ms pulse width, sensed amplitude was 9.1 ± 3.2 mV, mean fluoroscopy duration was 3.1 ± 1.6 min. There were no vascular or other complications. At follow-up, electrical parameters remained stable in 18 of 19 patients. CONCLUSION: Although experience is minimal, we suggest that the IJV approach is safe and may be considered in patients where the femoral approach is contraindicated.

Vitamin D controls the capacity of human dendritic cells to induce functional regulatory T cells by regulation of glucose metabolism.

Tolerogenic dendritic cells (tolDCs) instruct regulatory T cells (Tregs) to dampen autoimmunity. Active vitamin D3 (1α,25-dihydroxyvitamin D3; 1α,25(OH)2D3) imprints human monocyte-derived DCs with tolerogenic properties by reprogramming their glucose metabolism. Here we identify the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) as a critical checkpoint and direct transcriptional target of 1α,25(OH)2D3 in determining the tolDC profile. Using tracer metabolomics, we show that PFKFB4 activity is essential for glucose metabolism, especially for glucose oxidation, which is elevated upon 1α,25(OH)2D3 exposure. Pharmacological inhibition of PFKFB4 reversed the 1α,25(OH)2D3-mediated shift in metabolism, DC profile and function, as determined by expression of inhibitory surface markers and secretion of regulatory cytokines and factors. Moreover, PFKFB4 inhibition in 1α,25(OH)2D3-treated DCs blocked their hallmark capacity to induce suppressive Tregs. This work demonstrates that alterations in the bioenergetic metabolism of immune cells are central to the immunomodulatory effects induced by 1α,25(OH)2D3.

Melancholic and atypical major depression--connection between cytokines, psychopathology and treatment.

BACKGROUND AND PURPOSE: Growing scientific evidence indicates that there is a correlation between depression and alternations in the immune system. The main aim of the study was to investigate serum levels of Interleukin-6 (IL-6) and Tumour Necrosis Factor-alpha (TNF-α) in melancholic and atypical depressive patients during acute exacerbations of illness, compared to healthy subjects. The secondary aim was to explore a possible association between cytokine levels and clinical characteristics, as well as total duration of prior antidepressant treatment. METHOD: We measured serum levels of IL-6 and TNF-α in 47 patients suffering from major depressive disorder (MDD) (29 melancholic and 18 atypical) in exacerbation of illness, compared to 39 healthy controls, matched by sex, body mass index (BMI) and smoking habits. Serum levels of IL-6 and TNF-α were measured by enzyme-linked immunosorbent assay (ELISA). The severity of psychopathology was assessed using the Hamilton Depression Rating Scale (HDRS). RESULTS: IL-6 was significantly elevated in melancholic depressive patients (MDD-M) compared to healthy controls, while no difference was found between the patients with atypical depression (MDD-A) and the healthy group. Lower TNF-α serum level was found both in melancholic and in patients with atypical depression, compared with healthy subjects. We detected a positive correlation between cytokine levels in atypical, but not in melancholic subjects. Sex, age, smoking habits and BMI were not associated to cytokine levels in neither group. Clinical parameters (duration of illness, current episode, age of onset) were related to cytokine levels in atypical depression, while the duration of lifetime exposure to antidepressant treatment correlated to IL-6 serum levels in both melancholic and atypical depression. CONCLUSION: Our results suggest that the difference in pro-inflammatory cytokine levels could reflect a biological difference between melancholic and atypical depression. A positive correlation between the cytokines (TNF-α and IL-6) observed in depressive patients with atypical features, might be influenced by chronic course of illness, while IL-6 elevation could represent a state indicator for acute exacerbation, especially in melancholic patients. Total duration of antidepressant treatment could be a relevant factor influencing the immune status of patients who suffer either from melancholic or atypical depression.

Haemostatic abnormalities in treatment-naïve patients with Type 1 Gaucher's disease.

There is a paucity of data on the effects of enzyme replacement therapy (ERT) on the coagulation abnormalities and platelet function of patients with Gaucher's disease (GDPs) and much of this data are controversial. This study investigates the haemostatic parameters in treatment-naïve GDPs and the effects of ERT. 31 Serbian treatment-naïve type 1 GDPs (M/F 17/14; median age 49 years, splenectomized 9/31) were studied. The complete blood count, prothrombin time (PT), activated partial tromboplastin time (aPTT) and coagulation factors were measured using the standard methods. Platelet aggregation was assessed with a whole-blood aggregometer. Splenic volumes were assessed using computer tomography. Twenty-one patients were treated with ERT (Imiglucerase). The haemostatic parameters were assessed after 6, 12 and 24 months (ERT(6, 12, 24)). Initially bleeding episodes were registered in 10/31 GDPs. Median platelet count was 108 × 10(9)/L; 22/31 GDPs were thrombocytopenic. The PT and aPTT values were abnormal in 16/31 and 13/31 GDPs, respectively. Platelet aggregation abnormalities were recorded in 19/31GDPs. Median platelet aggregation was reduced in response to adenosine-diphosphate 5 µmol/L (ADP(5) 0.46) and collagen 5 µmol/L (Col(5) 0.47). Splenic volume inversely correlated with the platelet count and a reduced response to arachidonic acid (AA), Col(5) and ADP(5) (p < 0.05). The splenectomized GDPs had a significantly lower platelet aggregation to Col(10) (p < 0.05). Bleeding GDPs had a significantly lower platelet count, higher chitotriosidase levels and a greater splenic volume compared to non-bleeding patients (p < 0.01). ERT: The number of bleeding GDPs had significantly decreased by ERT(6) (1/10; p < 0.01). The platelet count had significantly increased by ERT(6) (ERT(6) 180 × 10(9)/L, p < 0.01). The PT increased significantly from ERT(0) to ERT(24) (PT(0) 65%, PT(24) 81%; p < 0.05). The von Willebrand factor had increased significantly by ERT(6) and ERT(24) (ERT(0) 56%, ERT(6) 70%, ERT(12) 70%, ERT(24) 86%; p < 0.01). The number of GDPs with abnormal platelet aggregation had decreased significantly by ERT(6) (10/19; p < 0.05). Platelet aggregation on ADP(10) and AA significantly increased by ERT(6) (ADP(10): ERT(0) 0.75, ERT(6) 0.8 p < 0.01; AA: ERT(0) 0.7, ERT(6) 0.8 p < 0.05). In conclusion, platelet dysfunction and coagulation abnormalities were found in a considerable number of our GDPs. The absence of severe bleeding episodes suggests that the haemostatic system is sufficiently balanced and therefore the exact mechanism of the etiology of these abnormalities need to be fully clarified. ERT resulted in the cessation of bleeding and marked increase in platelet count, PT, vWF and platelet aggregation.

Increase of ventricular output inducing ventricular afterpotential sensing and ventricular safety pacing in a biventricular implanted cardioverter defibrillator.

Programming maximum right ventricular output in a patient with a biventricular implanted cardioverter defibrillator resulted in ventricular oversensing and ventricular safety pacing in the same cardiac cycle.