Validation of donor fraction cell-free DNA with biopsy-proven cardiac allograft rejection in children and adults

ObjectivesDonor-specific cell-free DNA shows promise as a noninvasive marker for allograft rejection, but as yet has not been validated in both adult and pediatric recipients. The study objective was to validate donor fraction cell-free DNA as a noninvasive test to assess for risk of acute cellular rejection and antibody-mediated rejection after heart transplantation in pediatric and adult recipients.MethodsPediatric and adult heart transplant recipients were enrolled from 7 participating sites and followed for 12 months or more with plasma samples collected immediately before all endomyocardial biopsies. Donor fraction cell-free DNA was extracted, and quantitative genotyping was performed. Blinded donor fraction cell-free DNA and clinical data were analyzed and compared with a previously determined threshold of 0.14%. Sensitivity, specificity, negative predictive value, positive predictive value, and receiver operating characteristic curves were calculated.ResultsA total of 987 samples from 144 subjects were collected. After applying predefined clinical and technical exclusions, 745 samples from 130 subjects produced 54 rejection samples associated with the composite outcome of acute cellular rejection grade 2R or greater and pathologic antibody-mediated rejection 2 or greater and 323 healthy samples. For all participants, donor fraction cell-free DNA at a threshold of 0.14% had a sensitivity of 67%, a specificity of 79%, a positive predictive value of 34%, and a negative predictive value of 94% with an area under the curve of 0.78 for detecting rejection. When analyzed independently, these results held true for both pediatric and adult cohorts at the same threshold of 0.14% (negative predictive value 92% and 95%, respectively).ConclusionsDonor fraction cell-free DNA at a threshold of 0.14% can be used to assess for risk of rejection after heart transplantation in both pediatric and adult patients with excellent negative predictive value.     

Evidence-based pathogenesis and treatment of ulcerative colitis: A causal role for colonic epithelial hydrogen peroxide

In this comprehensive evidence-based analysis of ulcerative colitis (UC), a causal role is identified for colonic epithelial hydrogen peroxide (H₂O₂) in both the pathogenesis and relapse of this debilitating inflammatory bowel disease. Studies have shown that H₂O₂ production is significantly increased in the non-inflamed colonic epithelium of individuals with UC. H₂O₂ is a powerful neutrophilic chemotactic agent that can diffuse through colonic epithelial cell membranes creating an interstitial chemotactic molecular “trail” that attracts adjacent intravascular neutrophils into the colonic epithelium leading to mucosal inflammation and UC. A novel therapy aimed at removing the inappropriate H₂O₂ mediated chemotactic signal has been highly effective in achieving complete histologic resolution of colitis in patients experiencing refractory disease with at least one (biopsy-proven) histologic remission lasting 14 years to date. The evidence implies that therapeutic intervention to prevent the re-establishment of a pathologic H₂O₂ mediated chemotactic signaling gradient will indefinitely preclude neutrophilic migration into the colonic epithelium constituting a functional cure for this disease. Cumulative data indicate that individuals with UC have normal immune systems and current treatment guidelines calling for the suppression of the immune response based on the belief that UC is caused by an underlying immune dysfunction are not supported by the evidence and may cause serious adverse effects. It is the aim of this paper to present experimental and clinical evidence that identifies H₂O₂ produced by the colonic epithelium as the causal agent in the pathogenesis of UC. A detailed explanation of a novel therapeutic intervention to normalize colonic H₂O₂, its rationale, components, and formulation is also provided.     

细菌与病毒感染的鉴别

急性感染早期准确鉴别细菌和病毒感染一直是临床面临的挑战,随着临床各种检验、检测技术的快速发展、长足进步,越来越多的病原学、人体基因学、分子生物学指标用于鉴别细菌与病毒感染。未来将有更多的检测指标采用床旁即时检测方式便于临床应用;将有更精准、丰富的生物医学信息平台和更高效的医院信息系统,进行多指标综合分析,提供更精准的病原诊断,有助于最佳临床实践的实施。     

Brain maturation in the first 3 months of life,measured by electroencephalogram: A comparison between preterm and term-born infants

ObjectivePreterm infants are at risk for altered brain maturation resulting in neurodevelopmental impairments. Topographical analysis of high-density electroencephalogram during sleep matches underlying brain maturation. Using such an EEG mapping approach could identify preterm infants at risk early in life.Methods20 preterm (gestational age < 32 weeks) and 20 term-born infants (gestational age > 37 weeks) were recorded by 18-channel daytime sleep-EEG at term age (GA 40 weeks for preterm and 2–3 days after birth for term infants) and 3 months (corrected age for preterm infants).ResultsPreterm infant’s power spectrum at term age is immature, leveling off with term infants at 3 months of age. Topographical distribution of maximal power density however, reveals qualitative differences between the groups until 3 months of age. Preterm infants exhibit more temporal than central activation at term age and more occipital than central activation at 3 months of age. Moreover, being less mature at term age predicts being less mature at 3 months of age.ConclusionTopographical analysis of sleep EEG reveals changes in brain maturation between term and preterm infants early in life.SignificanceIn future, automated analysis tools using topographical power distribution could help identify preterm infants at risk early in life.     

An evaluation of the reliability of the foot-tapping test in a healthy sample

The foot-tapping test (FTT) can be used to assess upper motor neuron dysfunction in clinical populations. However, relatively little is known regarding the reliability or normative values of the FTT in either healthy or clinical populations. Although several different FTT methods have been used, no study to date has demonstrated the reliability or validity of FTT by comparing it across several different counting methods in healthy persons. This unfortunately limits its usefulness in medicine and research.ObjectiveThis study sought to examine the reliability and validity of the FTT in healthy individuals to determine its usefulness and to make recommendations for its implementation in clinical populations. Furthermore, the concurrent validity and reliability of using a force plate as an objective measure of foot-taps was considered.DesignThirty-eight healthy individuals had their foot-tapping assessed using Live, Force Plate, and Video Counting methods over four separate visits.MethodsParticipants were seated as per previous FTT recommendations and asked to tap their foot in 10-second intervals while the number of taps was counted via Live, Video, and Force Plate counters. This was done with both legs, with shoes ON and OFF, and repeated over four separate visits.ResultsDespite significant differences between repeat trials for Force Plate and Video Counts (∼2 foot-taps, p < 0.01), test-retest reliability was high for all three methods (Pearson’s R > 0.90). Dominant foot trials were higher (∼2 foot-taps, p < 0.05) than Non-dominant for all three counts. When performed with shoes ON, counts were higher (∼2 foot-taps, p < 0.05) than OFF for the Live and Force Plate counts. Reliability between visits was high (ICC > 0.80) and only the Video count was significantly lower for Visit 1 (p < 0.01).ConclusionsGiven findings, the authors suggest using a Force Plate counting method and have compiled a list of suggestions for future implementation of the FTT.     

PI3K/AKT pathway mediates the antidepressant- and anxiolytic-like roles of hydrogen sulfide in streptozotocin-induced diabetic rats via promoting hippocampal neurogenesis

We have previously demonstrated that hydrogen sulfide (H₂S), the third endogenous gasotransmitter, ameliorates the depression- and anxiety-like behaviors in diabetic rats, but the underlying mechanism remains unclear. The present was aimed to investigate whether the hippocampal phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway mediates H₂S-ameliorated depression- and anxiety-like behaviors in diabetic rats by improving the hippocampal neurogenesis. The depression-like behaviors were examined by Tail suspension test (TST), the anxiety-like behaviors were examined by Elevated plus maze test (EPM), and the locomotor activity was detected by Open Field Test (OFT). The expressions of doublecortin (DCX), neuron-specific nuclear protein (NeuN), glial fibrillary acidic protein (GFAP), p-AKT, and AKT in the hippocampus were determined by Western blot analysis. Results showed that NaHS, a donor of exogenous H₂S, not only activated the hippocampal PI3K/AKT pathway, as evidenced by the increase of phosphorylated AKT, but also favorably reversed streptozotocin (STZ)-disturbed hippocampal neurogenesis, as evidenced by the increases in the expressions of DCX and NeuN as well as the decrease in the expression of GFAP in the hippocampus of STZ-induced diabetic rats. Furthermore, inhibited PI3K/AKT pathway by LY294002 significantly abolished H₂S-exerted the improvement of hippocampal neurogenesis and the antidepressant- and anxiolytic-like effects in the STZ-induced diabetic rats. Taken together, these results uncover that the activation of hippocampal PI3K/AKT pathway plays an important role to restore hippocampal neurogenesis and subsequently to mediate the antidepressant- and anxiolytic-like roles of H₂S in STZ-induced diabetic rats and enhance our understanding of the robustness of H₂S as a therapeutic strategy for treatment of depression in diabetes mellitus.