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Allo-HSCT with CCR5 Delta 32/Delta 32 donor cells is the only curative HIV-1 intervention. We investigated the impact of allo-HSCT on the viral reservoir in PBMCs and post-mortem tissue in two patients. IciS-05 and IciS-11 both received a CCR5 Delta 32/Delta 32 allo-HSCT. Before allo-HSCT, ultrasensitive HIV-1 RNA quantification; HIV-1-DNA quantification; co-receptor tropism analysis; deep-sequencing and viral characterization in PBMCs and bone marrow; and post-allo-HSCT, ultrasensitive RNA and HIV-1-DNA quantification were performed. Proviral quantification, deep sequencing, and viral characterization were done in post-mortem tissue samples. Both patients harbored subtype B CCR5-tropic HIV-1 as determined genotypically and functionally by virus culture. Pre-allo-HSCT, HIV-1-DNA could be detected in both patients in bone marrow, PBMCs, and T-cell subsets. Chimerism correlated with detectable HIV-1-DNA LTR copies in cells and tissues. Post-mortem analysis of IciS-05 revealed proviral DNA in all tissue biopsies, but not in PBMCs. In patient IciS-11, who was transplanted twice, no HIV-1-DNA could be detected in PBMCs at the time of death, whereas HIV-1-DNA was detectable in the lymph node. In conclusion, shortly after CCR5 Delta 32/Delta 32, allo-HSCT HIV-1-DNA became undetectable in PBMCs. However, HIV-1-DNA variants identical to those present before transplantation persisted in post-mortem-obtained tissues, indicating that these tissues play an important role as viral reservoirs.

Among candidate treatment options for COVID-19, propolis, produced by honey bees from bioactive plant exudates, has shown potential against viral targets and has demonstrated immunoregulatory properties. We conducted a randomized, controlled, open-label, single center trial, with a standardized propolis product (EPP-AF) on hospitalized adult COVID-19 patients. Patients received standard care plus propolis at an oral dose of 400mg/day (n=40) or 800mg/day (n=42) for seven days, or standard care alone (n=42). Standard care included all necessary interventions, as determined by the attending physician. The primary end point was the time to clinical improvement defined as the length of hospital stay or oxygen therapy dependency. Secondary outcomes included acute kidney injury and need for intensive care or vasoactive drugs. Time in the hospital after intervention was significantly shortened in both propolis groups compared to the controls; median 7 days with 400mg/day and 6 days with 800mg/day, versus 12 days for standard care alone. Propolis did not significantly affect the need for oxygen supplementation. With the higher dose, significantly fewer patients developed acute kidney injury than in the controls (2 versus 10 of 42 patients). Propolis as an adjunct treatment was safe and reduced hospitalization time. The registration number for this clinical trial is: NCT04480593 (20/07/2020).

Contains fulltext : 220023.pdf (Publisher’s version ) (Open Access) BACKGROUND: Tofacitinib is a Janus kinase inhibitor approved for the treatment of ulcerative colitis (UC). AIM: To evaluate effectiveness, safety and use of tofacitinib in daily practice. METHODS: UC patients initiating tofacitinib were prospectively enrolled in 15 hospitals in the Netherlands. Corticosteroid-free clinical remission (short clinical colitis activity index [SCCAI] ≤2), biochemical remission (faecal calprotectin level ≤250 µg/g), combined corticosteroid-free clinical and biochemical remission, predictors of remission, safety outcomes, treatment dose and effect on lipids were determined at weeks 12 and 24. Endoscopic outcomes were evaluated in centres with routine endoscopic evaluation. RESULTS: In total, 123 UC patients (95% anti-TNF, 62% vedolizumab and 3% ustekinumab experienced) were followed for a median duration of 24 weeks (interquartile range 12-26). The proportion of patients in corticosteroid-free clinical, biochemical, and combined corticosteroid-free clinical and biochemical remission rate at week 24 was 29% (n: 22/77), 25% (n: 14/57), and 19% (n: 11/57) respectively. Endoscopic remission (Mayo = 0) was achieved in 21% of patients at week 12 (n: 7/33). Prior vedolizumab exposure was associated with reduced clinical remission (odds ratio 0.33, 95% confidence interval [CI] 0.11-0.94). At week 24, 33% (n: 14/42) of patients still on tofacitinib treatment used 10 mg twice daily. In total, 33 tofacitinib-related adverse events (89 per 100 patient years) occurred, 7 (6% of total cohort) resulted in discontinuation. Cholesterol, HDL and LDL levels increased during induction treatment by 18% (95% CI 9-26), 18% (95% CI 8-28) and 21% (95% CI 14-39) respectively. CONCLUSION: Tofacitinib is an effective treatment for UC after anti-TNF and vedolizumab failure. However, a relatively high rate of adverse events was observed resulting in discontinuation in 6% of patients.

Background Previous evidence suggests that slower gait speed is longitudinally associated with cognitive impairment, dementia and falls in older adults. Despite this, the longitudinal relationship between gait speed, cognition and falls in those with a diagnosis of dementia remains poorly explored. We sought to assess this longitudinal relationship in a cohort of older adults with mild to-moderate Alzheimer Disease (AD). Methods Analysis of data from NILVAD, an 18-month randomised-controlled trial of Nilvadipine in mild to moderate AD. We examined: (i) the cross-sectional (baseline) association between slow gait speed and cognitive function, (ii) the relationship between baseline slow gait speed and cognitive function at 18 months (Alzheimer Disease Assessment Scale, Cognitive Subsection: ADAS-Cog), (iii) the relationship between baseline cognitive function and incident slow gait speed at 18 months and finally (iv) the relationship of baseline slow gait speed and incident falls over the study period. Results Overall, one-tenth (10.03%, N = 37/369) of participants with mild-to-moderate AD met criteria for slow gait speed at baseline and a further 14.09% (N = 52/369) developed incident slow gait speed at 18 months. At baseline, there was a significant association between poorer cognition and slow gait speed (OR 1.05, 95% CI 1.01–1.09, p = 0.025). Whilst there was no association between baseline slow gait speed and change in ADAS-Cog score at 18 months, a greater cognitive severity at baseline predicted incident slow gait speed over 18 months (OR 1.04, 1.01–1.08, p = 0.011). Further, slow gait speed at baseline was associated with a significant risk of incident falls over the study period, which persisted after covariate adjustment (IRR 3.48, 2.05–5.92, p Conclusions Poorer baseline cognition was associated with both baseline and incident slow gait speed. Slow gait speed was associated with a significantly increased risk of falls over the study period. Our study adds further evidence to the complex relationship between gait and cognition in this vulnerable group and highlights increased falls risk in older adults with AD and slow gait speed. Trial registration Secondary analysis of the NILVAD trial (Clincaltrials.gov NCT02017340; EudraCT number 2012–002764-27). First registered: 20/12/2013.

BackgroundTissue inflammation in inflammatory bowel diseases (IBD) is associated with a decrease in local pH. The gene encoding G-protein-coupled receptor 65 (GPR65) has recently been reported to be a genetic risk factor for IBD. In response to extracellular acidification, proton activation of GPR65 stimulates cAMP and Rho signalling pathways. We aimed to analyse the clinical and functional relevance of the GPR65 associated single nucleotide polymorphism (SNP) rs8005161.Methods1138 individuals from a mixed cohort of IBD patients and healthy volunteers were genotyped for SNPs associated with GPR65 (rs8005161, rs3742704) and galactosylceramidase (rs1805078) by Taqman SNP assays. 2300 patients from the Swiss IBD Cohort Study (SIBDC) were genotyped for rs8005161 by mass spectrometry based SNP genotyping. IBD patients from the SIBDC carrying rs8005161 TT, CT, CC and non-IBD controls (CC) were recruited for functional studies. Human CD14+ cells were isolated from blood samples and subjected to an extracellular acidic pH shift, cAMP accumulation and RhoA activation were measured.ResultsIn our mixed cohort, but not in SIBDC patients, the minor variant rs8005161 was significantly associated with UC. In SIBDC patients, we observed a consistent trend in increased disease severity in patients carrying the rs8005161-TT and rs8005161-CT alleles. No significant differences were observed in the pH associated activation of cAMP production between IBD (TT, CT, WT/CC) and non-IBD (WT/CC) genotype carriers upon an acidic extracellular pH shift. However, we observed significantly impaired RhoA activation after an extracellular acidic pH shift in IBD patients, irrespective of the rs8005161 allele.ConclusionsThe T allele of rs8005161 might confer a more severe disease course in IBD patients. Human monocytes from IBD patients showed impaired pH associated RhoA activation upon an acidic pH shift.

Superconducting coplanar waveguide resonators that can operate in strong magnetic fields are important tools for a variety of high frequency superconducting devices. Magnetic fields degrade resonator performance by creating Abrikosov vortices that cause resistive losses and frequency fluctuations, or suppressing superconductivity entirely. To mitigate these effects we investigate lithographically defined artificial defects in resonators fabricated from NbTiN superconducting films. We show that by controlling the vortex dynamics the quality factor of resonators in perpendicular magnetic fields can be greatly enhanced. Coupled with the restriction of the device geometry to enhance the superconductors critical field, we demonstrate stable resonances that retain quality factors $\simeq 10^5$ at the single photon power level in perpendicular magnetic fields up to $B_\perp \simeq$ 20 mT and parallel magnetic fields up to $B_\parallel \simeq$ 6 T. We demonstrate the effectiveness of this technique for hybrid systems by integrating an InSb nanowire into a field resilient superconducting resonator, and use it to perform fast charge readout of a gate defined double quantum dot at $B_\parallel =$ 1 T., Comment: 8 pages, 6 figures

Contains fulltext : 182657.pdf (Publisher’s version ) (Open Access) BACKGROUND: Leucopenia is a common side effect in patients treated with thiopurines. Variants in the thiopurine S-methyltransferase (TPMT) gene are the best-known risk factor, but only explain up to 25% of leucopenia cases. AIM: To identify the clinical risk factors for thiopurine-induced leucopenia in patients without a common TPMT variant, and explore if these patients are at increased risk for infections. METHODS: Post hoc analysis of the Thiopurine response Optimisation by Pharmacogenetic testing in Inflammatory bowel disease Clinics (TOPIC) trial. For this analysis, patients without a variant in TPMT (*2, *3A or*3C) were included. Uni- and multivariate Cox-proportional hazard models were used to identify risk factors for leucopenia and infections. Leucopenia was defined as a white blood cell (WBC) count

We study the index of refraction of an ultracold bosonic gas in the dilute regime. Using phase-contrast imaging with light detuned from resonance by several tens of linewidths, we image a single cloud of ultracold atoms for 100 consecutive shots, which enables the study of the scattering rate as a function of temperature and density using only a single cloud. We observe that the scattering rate is increased below the critical temperature for Bose-Einstein condensation by a factor of 3 compared to the single-atom scattering rate. We show that current atom-light interaction models to second order of the density show a similar increase, where the magnitude of the effect depends on the model that is used to calculate the pair-correlation function. This confirms that the effect of quantum statistics on the index of refraction is dominant in this regime.

In Germany, discussions on the fees for statutory sickness insurance for ambulatory surgery has, in the last few years, become almost a symbol of dispute for the German health services. Outpatient surgeons complain about the fact that the fees do not cover their services. They see innovation severely threatened by bureaucracy, profitability by planned economy, rights by reasons of State, aggravated by the 'reform' attempts of the Greens and Socialist coalition Federal Government. On the other hand their opponents complain about the money mindedness of the doctors. Intentional panic or real disaster? The fundamental consideration to clarify this question is based on a comparison of the German statutory medical insurance fees and private fees with our neighbours. In Europe an economic area with similar prices for goods, services and wages, even 'outpatient operations' services with comparable cost rates should be paid for at a corresponding level. Any discrepancies would give cause to look for an explanation by analysing the historic development of fees and the question of a fair comparison between operations and the non-operative services.

Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci. © 2013 Beaudoin et al., 0, SCOPUS: ar.j, info:eu-repo/semantics/published

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Infection with Yersinia enterocolitica leads to a self-limiting disease, but in a small number of cases a protracted course can develop. The host genetic factors contributing to the advancement of the disease to the chronic phase are not known. We describe a patient suffering from an abdominal inflammatory mass due to chronic yersiniosis. Functional assays revealed defects in the recognition of flagellin by Toll-like receptor 5 (TLR5) and of muramyl dipeptide by NOD2, leading to a defective inflammatory response to Yersinia enterocolitica. Genetic sequencing showed that the patient was compound heterozygous for five different mutations in TLR5, while being homozygous for the 3020insC NOD2 mutation. In conclusion, we describe a patient in whom specific defects in the TLR5 and NOD2 recognition pathways led to chronic yersiniosis.

Three cases of de novo acute B-cell lymphoblastic leukemia are presented, all with an unusual phenotype, involvement of translocation t(14;18) and additional chromosomal abnormalities, including translocation t(8;14) and deletion of chromosome 9. In contrast to normal FAB-L2 or FAB-L3 acute lymphoblastic leukemia (ALL), these leukemias did not express cytoplasmatic and membranous immunoglobulin. The combination of translocation t(14;18) and additional chromosomal events on the other chromosome 14 account for the lack of immunoglobulin expression. In one case a low grade follicular lymphoma was found next to a high grade Burkitt type ALL. The translocation t(14;18) takes place as a mistake in the VDJH joining in pre-B cells in the bone marrow. It is proposed that some cases of de novo ALL may arise as a blast crisis induced by genetic events, secondary to the primary t(14;18) translocation. This type of ALL seems to have a poor prognosis.

A spontaneously growing EBV-negative B-cell line (DoHH2) was established from the pleural fluid cells of a 60-year-old man with centroblastic/centrocytic non-Hodgkin's lymphoma, that had transformed into an immunoblastic lymphoma. The pleural fluid cells and the DoHH2 cells expressed IgG lambda, were reactive with CD10 and CD19 monoclonal antibodies, and showed by cytogenetic analysis 48,XY, +7, +del(12)(q24), t(14;18)(q32;q21). Southern blot analysis of mini-satellite DNA patterns, and of rearrangements of the immunoglobulin genes and bcl-2, confirmed that the cell line was derived from the patient's clonal lymphoma cells. Direct nucleotide sequence analysis on polymerase chain reaction (PCR) products of the t(14;18) junction revealed an identical sequence for the JH-bcl-2 junction at JH6 and in the major breakpoint region of bcl-2 in both the original tumor cells and the DoHH2 cell line. The cell line was valuable as a standard quantification control for PCR analysis of the t(14;18) breakpoint. Titration experiments demonstrated the detection of up to one tumor cell in 10(5) normal blood lymphocytes.

It was investigated whether the decrease of platelet count, which occurs during open heart surgery with the use of the heart-lung machine (HLM), is a result of platelet adhesion and/or aggregation. PGE1 in concentrations of 100, 10 and 5 ng/ml, respectively, inhibited platelet decrease in human heparinized blood circulating in the HLM in vitro. It is concluded that under the conditions used the adhesion/aggregation process is involved and that platelet aggregates are circulating. The relation to platelet function, organ impairment by micro-embolization and the function of filters in the HLM in cardiopulmonary bypass are discussed.

B-CELL lymphomas are considered to represent "frozen" stages in the maturation of normal B cells. However, progression to a more malignant histologic form is frequently observed in low-grade lymphomas.1 Cytogenetic studies have shown that sub-clones can develop during the course of the disease, identifiable by a cascade of multiple recurrent chromosomal abnormalities.2 , 3 In follicular lymphoma, for example, these abnormalities may be superimposed on translocation t(14;18)(q32;q21), which is found as a marker in about 85 percent of cases and involves the putative oncogene bcl-2.4 Although several of these aberrations could be correlated with histologic progression, development of leukemia, or a poor . . .

Large cell lymphomas (LCLs) are heterogeneous in morphology, clinical presentation, and behavior. We studied 52 de novo LCLs of B-cell type for rearrangements of the bcl-2 and c-myc oncogenes by Southern blot analysis and related these data to the primary site of presentation, stage, and cytomorphology. Thirteen tumors had comigrating rearrangements of JH and bcl-2, indicative of a t(14;18). Far more primary nodal lymphomas than extranodal lymphomas carried a t(14;18) (40% v less than 5%). Additionally, almost all lymphomas with a t(14;18) versus 41% of the tumors without a bcl-2 rearrangement presented with lymphadenopathy. c-myc rearrangements were seen in 35% of the extranodal lymphomas and 5% of the nodal lymphomas. No differences were observed in bone marrow involvement and staging according to Ann Arbor. bcl-2 rearrangements were found in 50% of the LCLs with cleaved nuclei, whereas c-myc rearrangements were relatively frequent (25%) in the noncleaved subtype. Our data support the hypothesis that primary nodal and extranodal lymphomas have a different genetic origin.

In general, a genetic predisposition to a tumour disease such as gastric cancer is postulated in patients with cancer at an unusually early age or when several relatives are affected. A clear definition of hereditary gastric cancer is lacking. Two types of families may be distinguished: kindreds with gastric cancer only (site-specific), and kindreds with gastric as well as colorectal cancer, representing the hereditary non-polyposis colon cancer (HNPCC) syndrome. A genetic predisposition is presumed in young patients with a diffuse type of gastric cancer, in contrast to the intestinal type which is associated with atrophic gastritis and older age. A variety of genetic abnormalities in tumour tissue have been described, e.g. mutations in genes involved in DNA repair. Helicobacter pylori plays an important role in the aetiology, but the interaction with genetic factors is unknown.

This dissertation studied the risks and risk factors of Breast Implant Associated Anaplastic Large Cell T-cell Lymphoma (BIA-ALCL). This is a rare type of lymphoma that occurs in the fluid or capsule surrounding a breast prosthesis. In the study, the authors highlight how many women in the Netherlands have a breast prosthesis (1 in 30) and what the risk is of BIA-ALCL: by the time a woman with a breast prosthesis reaches the age of 75, the risk is 1 in 7,000. This study also confirms the great importance of breast prosthesis registries for monitoring insights into prosthesis-related complications. In addition, genetic research has shown that BIA-ALCL shows specific DNA changes, and thus distinguishes itself as a new disease entity. The researchers call for better quality international research to identify the origins and risk factors.

Policy makers support substitution of aircraft services by High Speed Train (HST) services, mainly due to growing congestion at major airports and the skies between them and the potential for environmental benefits. This substitution is usually promoted through competition between the modalities.

Chlamydia psittaci is variably associated with ocular adnexal MALT lymphoma in different geographical regions Infectious agents play a critical role in MALT lymphoma development. Studies from Italy showed Chlamydia psittaci infection in 87% of ocular adnexal MALT lymphomas and complete or partial regression of the lymphoma after C psittaci eradication in four of nine cases. However, C. psittaci was not demonstrated in ocular adnexal MALT lymphomas from the USA. This study was thus designed to investigate further the role of C psittaci, and other infectious agents commonly associated with chronic eye disease, in the development of ocular adnexal MALT lymphoma. The presence of C psittaci, C trachomatis, C pneumoniae, herpes simplex virus 1 and 2 (HSV1, HSV2), and adenovirus 8 and 19 (ADV8, ADV19) was assessed separately by polymerase chain reaction in 142 ocular adnexal MALT lymphomas, 53 non-marginal zone lymphomas, and 51 ocular adnexal biopsies without a lymphoproliferative disorder (LPD), from six geographical regions. C psittaci was detected at similar low frequencies in non-LPD and non-marginal zone lymphoma groups from different geographical regions (0-14%). Overall, the prevalence of C psittaci was significantly higher in MALT lymphomas (22%) than in non-LPD (10%, p = 0.042) and non-marginal zone lymphoma cases (9%, p = 0.033). However, the prevalence of C. psittaci infection in MALT lymphoma showed marked variation among the six geographical regions examined, being most frequent in Germany (47%), followed by the East Coast of the USA (35%) and the Netherlands (29%), but relatively low in Italy (13%), the UK (12%), and Southern China (11%). No significant differences in the detection of C. pneumoniae, C trachomatis, HSV1, HSV2, ADV8, and ADV19 were found between lymphomas and controls from different geographical regions. In conclusion, our results show that C psittaci, but not C. pneumoniae, C. trachomatis, HSV1, HSV2, ADV8 or ADV19, is associated with ocular adnexal MALT lymphoma and that this association is variable in different geographical areas. Copyright (c) 2006 Pathological Society of Great Britain and Ireland.