In reversed-phase liquid chromatography (RP-LC), the retention of cationic analytes such as basic drugs is known to be enhanced by the presence of chaotropic additives in the mobile phase. In this ...study, the chaotropic effect of triflate anion was evaluated. Four cationic drugs were chromatographed on a C18 column, comparing retention obtained between triflate, perchlorate, and trifluoroacetate mobile phase additives in the range from 5 to 30 mM. It was found that triflate exhibited very similar chaotropic effect to perchlorate. Retention factors afforded by triflate were typically within 5% of the corresponding perchlorate values throughout the entire concentration range studied. It was also found through dynamic vapor sorption studies that sodium triflate monohydrate salt was a more stable crystalline solid than the sodium perchlorate monohydrate salt with regard to hygroscopicity, showing good stability in the range of 10-70% relative humidity compared to sodium perchlorate monohydrate which was stable only within the range of approximately 20-40% relative humidity. The better physical stability and handling properties of the sodium triflate monohydrate salt suggests it may be an attractive alternative to sodium perchlorate monohydrate salt as a chaotropic additive in RP-LC analysis of pharmaceuticals.
The human gastrointestinal tract is inhabited by the largest microbial community within the human body consisting of trillions of microbes called gut microbiota. The normal flora is the site of many ...physiological functions such as enhancing the host immunity, participating in the nutrient absorption and protecting the body against pathogenic microorganisms. Numerous investigations showed a bidirectional interplay between gut microbiota and many organs within the human body such as the intestines, the lungs, the brain, and the skin. Large body of evidence demonstrated, more than a decade ago, that the gut microbial alteration is a key factor in the pathogenesis of many local and systemic disorders. In this regard, a deep understanding of the mechanisms involved in the gut microbial symbiosis/dysbiosis is crucial for the clinical and health field. We review the most recent studies on the involvement of gut microbiota in the pathogenesis of many diseases. We also elaborate the different strategies used to manipulate the gut microbiota in the prevention and treatment of disorders. The future of medicine is strongly related to the quality of our microbiota. Targeting microbiota dysbiosis will be a huge challenge.
Alloimmune risk stratification in renal transplantation has lacked the necessary prognostic biomarkers to personalize recipient care or optimize clinical trials. HLA molecular mismatch improves ...precision compared to traditional antigen mismatch but has not been studied in detail at the individual molecule level. This study evaluated 664 renal transplant recipients and correlated HLA-DR/DQ single molecule eplet mismatch with serologic, histologic, and clinical outcomes. Compared to traditional HLA-DR/DQ whole antigen mismatch, HLA-DR/DQ single molecule eplet mismatch improved the correlation with de novo donor-specific antibody development (area under the curve 0.54 vs 0.84) and allowed recipients to be stratified into low, intermediate, and high alloimmune risk categories. These risk categories were significantly correlated with primary alloimmune events including Banff ≥1A T cell–mediated rejection (P = .0006), HLA-DR/DQ de novo donor-specific antibody development (P < .0001), antibody-mediated rejection (P < .0001), as well as all-cause graft loss (P = .0012) and each of these correlations persisted in multivariate models. Thus, HLA-DR/DQ single molecule eplet mismatch may represent a precise, reproducible, and widely available prognostic biomarker that can be applied to tailor immunosuppression or design clinical trials based on individual patient risk.
Despite more than two decades of use, the optimal maintenance dose of tacrolimus for kidney transplant recipients is unknown. We hypothesized that HLA class II
donor-specific antibody (
DSA) ...development correlates with tacrolimus trough levels and the recipient's individualized alloimmune risk determined by HLA-DR/DQ epitope mismatch. A cohort of 596 renal transplant recipients with 50,011 serial tacrolimus trough levels had HLA-DR/DQ eplet mismatch determined using HLAMatchmaker software. We analyzed the frequency of tacrolimus trough levels below a series of thresholds <6 ng/ml and the mean tacrolimus levels before
DSA development in the context of HLA-DR/DQ eplet mismatch. HLA-DR/DQ eplet mismatch was a significant multivariate predictor of
DSA development. Recipients treated with a cyclosporin regimen had a 2.7-fold higher incidence of
DSA development than recipients on a tacrolimus regimen. Recipients treated with tacrolimus who developed HLA-DR/DQ
DSA had a higher proportion of tacrolimus trough levels <5 ng/ml, which continued to be significant after adjustment for HLA-DR/DQ eplet mismatch. Mean tacrolimus trough levels in the 6 months before
DSA development were significantly lower than the levels >6 months before
DSA development in the same patients. Recipients with a high-risk HLA eplet mismatch score were less likely to tolerate low tacrolimus levels without developing
DSA. We conclude that HLA-DR/DQ eplet mismatch and tacrolimus trough levels are independent predictors of
DSA development. Recipients with high HLA alloimmune risk should not target tacrolimus levels <5 ng/ml unless essential, and monitoring for
DSA may be advisable in this setting.
Our aim was to prospectively assess the antibiotic resistance rates in
strains in Europe in 2018 and to study the link between antibiotic consumption in the community and
resistance levels in the ...different countries.
The proportion of primary antibiotic resistance cases of
and their corresponding risk factors were investigated in 24 centres from 18 European countries according to a standardised protocol. Data on antibiotic consumption in the community were collected for the period 2008-2017. The link between antibiotic consumption and resistance data was assessed using generalised linear mixed models. The model with the best fit was selected by means of the Akaike Information Criterion.
resistance rates for the 1211 adult patients included were 21.4% for clarithromycin, 15.8% for levofloxacin and 38.9% for metronidazole and were significantly higher in Central/Western and Southern than in the Northern European countries.The best model fit was obtained for the Poisson distribution using 2013 consumption data. A significant association was found between
clarithromycin resistance and consumption in the community of macrolides (p=0.0003) and intermediate-acting macrolides (p=0.005), and between levofloxacin resistance and consumption of quinolones (p=0.0002) and second-generation quinolones (p=0.0003).
This study confirms the positive correlation between macrolide and quinolone consumption in the community and corresponding
resistance in European countries. Hence,
treatment with clarithromycin and levofloxacin should not be started without susceptibility testing in most European countries.
In recent years, novel strategies to control insects have been based on protease inhibitors (PIs). In this regard, molecular docking and molecular dynamics simulations have been extensively used to ...investigate insect gut proteases and the interactions of PIs for the development of resistance against insects. We, herein, report an in silico study of (disodium 5′-inosinate and petunidin 3-glucoside), (calcium 5′-guanylate and chlorogenic acid), chlorogenic acid alone, (kaempferol-3,7-di-O-glucoside with hyperoside and delphinidin 3-glucoside), and (myricetin 3′-glucoside and hyperoside) as potential inhibitors of acetylcholinesterase receptors, actin, α-tubulin, arginine kinase, and histone receptor III subtypes, respectively. The study demonstrated that the inhibitors are capable of forming stable complexes with the corresponding proteins while also showing great potential for inhibitory activity in the proposed protein-inhibitor combinations.
De novo DSA (dnDSA) after renal transplantation has been shown to correlate with antibody-mediated rejection and allograft loss. However, the lack of proven interventions and the time and cost ...associated with annual screening for dnDSA are difficult to justify for all recipients. We studied a well-characterized consecutive cohort (n=949) with over fifteen years of prospective dnDSA surveillance to identify risk factors that would help institute a resource-responsible surveillance strategy. Younger recipient age and HLA-DR/DQ molecular mismatch were independent predictors of dnDSA development. Combining both risk factors into Recipient Age Molecular Mismatch (RAMM) categories we found that 52% of recipients could be categorized as low-risk for dnDSA development (median subclinical dnDSA-free survival at 5 and 10 years 98% and 97%). After adjustment, multivariate correlates of dnDSA development included tacrolimus versus cyclosporin maintenance immunosuppression (HR 0.37, 95%CI 0.2-0.6, p<0.0001), and RAMM category intermediate versus low (HR 2.48, 95%CI 1.5-4.2, p=0.0007), high versus intermediate (HR 2.56, 95%CI 1.6-4.2, p=0.0002), and high versus low (HR 6.36, 95%CI 3.7-10.8, p<0.00001). When combined, recipient age and HLA-DR/DQ molecular mismatch provide a novel data-driven approach to reduce testing by >50% while selecting those most likely to benefit from dnDSA surveillance.
The prevalence and long‐term impact of T cell–mediated rejection (TCMR) is poorly defined in the modern era of tacrolimus/mycophenolate‐based maintenance therapy. This observational study evaluated ...775 kidney transplant recipients with serial histology and correlated TCMR events with the risk of graft loss. After a ~30% incidence of a first Banff Borderline or greater TCMR detected on for‐cause (17%) or surveillance (13%) biopsies, persistent (37.4%) or subsequent (26.3%) TCMR occurred in 64% of recipients on follow‐up biopsies. Alloimmune risk categories based on the HLA‐DR/DQ single molecule eplet molecular mismatch correlated with the number of TCMR events (p = .002) and Banff TCMR grade (p = .007). Both a first and second TCMR event correlated with death‐censored and all‐cause graft loss when adjusted for baseline covariates and other significant time‐dependent covariates such as DGF and ABMR. Therefore, a substantial portion of kidney transplant recipients, especially those with intermediate and high HLA‐DR/DQ molecular mismatch scores, remain under‐immunosuppressed, which in turn identifies the need for novel agents that can more effectively prevent or treat TCMR.
Histologic follow‐up after T cell‐mediated rejection demonstrates that persistent and subsequent events are common and associate with death‐censored and all‐cause graft loss after adjusting for other time‐dependent covariates. Helanterä comments on page 681.
PDF
