Tacrolimus and sirolimus in capillary dried blood spots allows for remote monitoring

Therapeutic drug monitoring of tacrolimus and sirolimus plays a significant role in the clinical follow‐up of transplant patients receiving IMS therapy. Success of transplant and favorable patient outcome relies on maintaining adequate therapeutic drug levels. The purpose of this research is to assess the clinical utility of remote collection of DBS for immunosuppressant monitoring and compare the IMS level in paired collections of venous whole blood and DBS. Sirolimus and tacrolimus levels were clinically correlated in capillary blood collected from a finger poke with venous whole blood from pediatric, post‐transplant patients. The participants took the dried blood spot card home with them with a pre‐addressed, postage‐paid envelope and mailed it back to the laboratory. Overall, a small but statistically significant negative bias was observed (?0.6 ng/mL, p = 0.0011). A chart review was performed to assess whether clinical management would have changed, and none of the cases revealed a clinically significant change. Sirolimus in DBS also correlated with venous levels. Overall, a small but statistically negative bias was observed (?0.8 ng/mL, p = 0.029). In summary, analysis of IMS levels in DBS is possible, and the difference noted between capillary and venous blood is within the clinically acceptable limits.     

Association between synthetic cannabinoid use and depressive symptomology: Analysis of a US national survey of high-school seniors

Introduction: Synthetic cannabinoid (SC) use among adolescents in the US is a major public health concern. SCs are considered by many teens to be a safe alternative to cannabis; however, little is known about the association between its use and depressive symptomology (DS). This study aims to examine the association between SC use and DS in US high-school seniors.

Methods: Data from the 2011–2014 Monitoring the Future (MTF) survey for high-school seniors was analyzed (N = 9,272). Multinomial logistic regression analysis was used to examine the association between SC use (any use, ≤6 or >6 times in the last 12 months) and DS (low, medium, or high).

Results: Approximately 8% of high-school seniors reported SC use in the last 12 months and 24% reported high levels of DS. Multinomial logistic regression analyses showed that in the unadjusted model and the model that controlled for sociodemographic factors, a significant association between SC use and DS was observed. However, upon controlling for other substance use, the association became markedly attenuated and lost its statistical significance.

Conclusions: SC use was not associated with DS in high-school seniors. Future longitudinal studies are needed to further examine the relationship.     

Needleless emulsion electrospinning for the regulated delivery of susceptible proteins

In the present work, we developed a novel needleless emulsion electrospinning technique that improves the production rate of the core/shell production process. The nanofibres are based on poly‐ε‐caprolactone (PCL) as a continuous phase combined with a droplet phase based on Pluronic F‐68 (PF‐68). The PCL‐PF‐68 nanofibres show a time‐regulated release of active molecules. Needleless emulsion electrospinning was used to encapsulate a diverse set of compounds to the core phase [i.e. 5‐(4,6‐dichlorotriazinyl) aminofluorescein ‐PF‐68, horseradish peroxidase, Tetramethylrhodamine‐dextran, insulin growth factor‐I, transforming growth factor‐β and basic fibroblast growth factor]. In addition, the PF‐68 facilitates the preservation of the bioactivity of delivered proteins. The system's potential was highlighted by an improvement in the metabolic activity and proliferation of mesenchymal stem cells. The developed system has the potential to deliver susceptible molecules in tissue‐engineering applications.     

Bivariate phase-rectified signal averaging for assessment of spontaneous baroreflex sensitivity: normalization of the results

BackgroundPreviously proposed technique for assessment of spontaneous baroreflex sensitivity (BRS) based on bivariate phase-rectified signal averaging measures averaged R-R interval (RRI) changes triggered by beat-to-beat increases in systolic blood pressure (SBP). In this study, we investigate a normalized version of the method that relates the averaged RRI changes to the triggering blood pressure changes, thus providing the results in measurement units comparable with existing literature.MethodsData of previously reported prospective observational study were used. In each of 146 heart failure patients presenting with sinus rhythm, 10-minute recordings of electrocardiogram and arterial and blood pressures were obtained in the supine resting position. The averaged RRI increases initiated by beat-to-beat SBP increases were measured (original BRS result in milliseconds) and normalized for the averaged beat-to-beat SBP increases (normalized BRS result in milliseconds per millimeters of mercury). Both results were compared in terms of predicting all-cause mortality during a mean follow-up of 2.7 ± 1.1 years when 42 patients (28.8%) died.ResultsBoth types of results were highly correlated (r = 0.938, P < .001) and led to similarly strong separation of high- and low-risk groups. The receiver operator characteristics of both indices were well within the 95% confidence intervals of each other, and the areas under the characteristics were practically identical: 71.1% (95% confidence interval, 60.7%-80.9%) for original BRS and 69.7% (58.9%-79.2%) for normalized BRS.ConclusionThe results might question the concept of a linear relationship between the SBP changes and RRI changes. The phase-rectified signal averaging–based assessment of BRS may be used with equal legitimacy in the nonnormalized and normalized forms; the normalized form provides results in conventional measurement units.     

Managing the underestimated risk of statin-associated myopathy

In clinical practice 5-10% of patients receiving statins develop myopathy, a side effect that had been systematically underestimated in the randomized controlled trials with statins. The most common manifestation of myopathy is muscle pain (usually symmetrical, involving proximal muscles) without creatinine kinase (CK) elevation or less frequently with mild CK elevation. Clinically significant rhabdomyolysis (muscle symptoms with CK elevation >10 times the upper limit of normal and with creatinine elevation) is extremely rare. Myopathy complicates the use of all statins (class effect) and is dose-dependent. The pathophysiologic mechanism of statin-associated myopathy is unknown and probably multifactorial. The risk of statin-associated myopathy can be minimized by identifying vulnerable patients (i.e. patients with impaired renal or liver function, advanced age, hypothyroidism, etc.) and/or by eliminating-avoiding statin interactions with specific drugs (cytochrome P-450 3A4 inhibitors, gemfibrozil, etc.). In symptomatic patients, the severity of symptoms, the magnitude of CK elevation and the risk/benefit ratio of statin continuation should be considered before statin treatment is discontinued. Potential strategies are the use of the same statin at a lower dose and if symptoms recur the initiation of fluvastatin XL 80 mg daily or rosuvastatin intermittently in low dose (5-10mg), combined usually with ezetimibe 10mg daily. Failure of these approaches necessitates the use of non-statin lipid lowering drugs (ezetimibe, colesevelam). In order to provide evidence based recommendations for the appropriate management of statin-intolerant patients we need randomized clinical trials directly comparing the myopathic potential of different lipid-lowering medications at comparable doses.     

Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21

The 40-fold increase in childhood megakaryocyte-erythroid and B-cell leukemia in Down syndrome implicates trisomy 21 (T21) in perturbing fetal hematopoiesis. Here, we show that compared with primary disomic controls, primary T21 fetal liver (FL) hematopoietic stem cells (HSC) and megakaryocyte-erythroid progenitors are markedly increased, whereas granulocyte-macrophage progenitors are reduced. Commensurately, HSC and megakaryocyte-erythroid progenitors show higher clonogenicity, with increased megakaryocyte, megakaryocyte-erythroid, and replatable blast colonies. Biased megakaryocyte-erythroid–primed gene expression was detected as early as the HSC compartment. In lymphopoiesis, T21 FL lymphoid-primed multipotential progenitors and early lymphoid progenitor numbers are maintained, but there was a 10-fold reduction in committed PreproB-lymphoid progenitors and the functional B-cell potential of HSC and early lymphoid progenitor is severely impaired, in tandem with reduced early lymphoid gene expression. The same pattern was seen in all T21 FL samples and no samples had GATA1 mutations. Therefore, T21 itself causes multiple distinct defects in FL myelo- and lymphopoiesis.     

The role of autoimmunity in gastroenterology

Crohn's disease (CD) is an immune-mediated chronic intestinal disorder thought to be the result of an aggressive immune response to a subset of enteric bacteria in a genetically predisposed host. Numerous environmental factors are apparently involved in disease pathogenesis. Impaired ability of CD patients to control the gut microflora is associated with defects in the production of some antibacterial compounds (cryptdins) by epithelial cells. In addition, there are the defects in cytoplasmic NOD-like receptors which are sensing intracellularly localized bacteria in CD patients. These defects together with the failure to induce autophagy lead to lack of bacterial clearance and subsequently to mucosal immunopathology.