Beneficial carry-over effects of chronic at-home genital nerve stimulation on incontinence in individuals with spinal cord injury: A pragmatic trial.

BACKGROUND: Genital nerve stimulation (GNS) is a promising, but under-researched, alternative treatment for neurogenic detrusor overactivity (NDO) in those with spinal cord injury (SCI). OBJECTIVES: To investigate the urodynamic, quality-of-life (QOL) and carry-over effects of GNS when applied at home for 2 weeks by participants with incomplete SCI and NDO during activities of daily living. METHODS: Seven men and 1 woman participated in this 1-month protocol study. Urodynamic and QOL data were gathered during week 1 (baseline measurements), followed by 2 weeks of daily GNS at home using a portable device. GNS was applied either on-demand or thrice daily, depending on the individual's sensation. At week 4, post-stimulation tests were repeated to record any carry-over effect from the GNS. Participants maintained voiding diaries throughout the study. Assessments were carried out at the end of each protocol period in a randomized order. Clinical procedures were conducted at Taipei Medical University Hospital (Taipei, Taiwan). RESULTS: Everyone completed the study but only 7 of the 8 participants completed their voiding diary. Two weeks after GNS, average cystometric bladder capacity was increased by 30 % compared to baseline (P< 0.05). A 1-week carry-over effect was demonstrated as this capacity remained, on average, 35 % greater than baseline in week 4 after GNS was stopped (P< 0.05). Incontinence frequency significantly decreased by the end of week 3 (P< 0.05) but no significant improvements were recorded for either detrusor pressure or bladder compliance. CONCLUSIONS: Chronic at-home GNS improved cystometric bladder capacity and reduced urinary incontinence for individuals with incomplete SCI and NDO. A carry-over effect of 1 week was observed following GNS treatment. The use of portable GNS treatment that can be applied by the individual at home merits further investigation as alternative treatment for NDO in those with SCI.

A time-course study of urodynamic analyses in rat models with dopaminergic depletion induced through unilateral and bilateral 6-hydroxydopamine injections.

BACKGROUND: Bladder dysfunction is a common non-motor disorder in Parkinson's disease (PD). This study attempted to determine the bladder dysfunction with disease progression in the PD rat model produced from unilateral/bilateral injections of 6-hydroxydopamine (6-OHDA). METHODS: Cystometrographic (CMG) and external urethral sphincter electromyographic (EUS-EMG) measurements were scheduled in a time-course manner to determine the disease timing, onset, and severity. Animals were allotted into normal control, unilateral, bilateral 6-OHDA injected groups and subjected to scheduled CMG, EUS-EMG analyses at weeks 1, 2, and 4. RESULTS: The urodynamic results concluded that voiding efficiency (VE) was reduced in both unilateral and bilateral PD rats at all-time points. VE had decreased from 57 ± 11% to 31 ± 7% in unilateral PD rats and in bilateral PD rats, a decreased VE of 20 ± 6% was observed compared to control and unilateral PD rats. The EMG results in unilateral PD rats indicated declines in bursting period (BP) (3.78-2.94 s), active period (AP) (93.38-88.75 ms), and silent period (SP) (161.62-114.30 ms). A sudden reduction was noticed in BP (3.62-2.82 s), AP (92.21-86.01 ms), and SP (128.61-60.16 ms) of bilateral PD rats than in control and unilateral PD rats. Histological evidence exhibited a progressive dopaminergic neurons (DA) depletion in the substantia nigra (SN) region in 6-OHDA lesioned rats. CONCLUSION: The experimental outcomes strongly implied that significant variations in bladder function and VE decline were due to the depletion of DA neurons in the SN region of the brain.

Sacubitril Valsartan Enhances Cardiac Function and Alleviates Myocardial Infarction in Rats through a SUV39H1/SPP1 Axis.

Sacubitril valsartan (lcz696) has been demonstrated as a substitute for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for the treatment of heart failure. This research is aimed at examining the effects of lcz696 and its target molecules on myocardial infarction (MI). A rat model of MI was induced by left anterior descending artery ligation and treated with lcz696. Lcz696 treatment significantly reduced cardiac injury and heart failure, restored the left ventricular fractional shortening and ejection fraction, and reduced oxidative stress and inflammatory responses in rat myocardium. By analyzing the heart failure-related GSE47495 dataset and performing gene ontology (GO) functional enrichment analysis, we obtained histone lysine methyltransferase SUV39H1 and secreted phosphoprotein 1 (SPP1) as two molecules implicated in the oxidative stress and inflammation processes. An elevation of SUV39H1 whereas a decline of SPP1 were detected in cardiac tissues after lcz696 treatment. Enrichments of SUV39H1 and H3K9me3 at the SPP1 promoter were identified by chromatin immunoprecipitation assay. SUV39H1 catalyzed H3K9me3 modification to suppress the expression of SPP1. Preconditioning of SUV39H1 silencing blocked the protective roles of lcz696, but SPP1 silencing alleviated the myocardial injury. In conclusion, this study demonstrates that lcz696 enhances cardiac function and alleviates MI in rats through a SUV39H1/SPP1 axis.

Risk of incident active tuberculosis disease in patients treated with non-steroidal anti-inflammatory drugs: a population-based study.

BACKGROUND: Mycobacterium tuberculosis (TB) is one of the world's most devastating public health threats. Our goal is to evaluate whether the use of non-steroidal anti-inflammatory drugs (NSAIDs) affect the risk of new incident active TB disease. METHODS: We conducted a nested case-control analysis by using a 1 million longitudinally followed cohort, from Taiwan's national health insurance research database. Effects of NSAIDs on active TB were estimated by conditional logistic regression and adjusted using a TB-specific disease risk score (DRS). NSAIDs exposures were defined as having a prescription record of NSAIDs ≧ 7 days that ended between 31 and 90 days prior to the index date. RESULTS: A total of 123,419 users of traditional NSAIDs, 16,392 users of cyclooxygenase-2 selective inhibitor (Coxibs), and 4706 incident cases of active TB were identified. Compared with nonusers, use of traditional NSAIDs was associated with an increased risk of TB in the unadjusted analysis ([RR], 1.39; 95% [CI], 1.24 - 1.57 and DRS adjusted analysis ([ARR], 1.30; 95% [CI], 1.15- 1.47). However, use of Coxibs was not associated with a significant increase in the risk of TB after DRS adjustment ([ARR], 1.23; 95% [CI], 0.89 - 1.70). CONCLUSIONS: In this large population-based study, we found that subjects using traditional NSAIDs were associated with increased risk for active TB. We did not find evidence for a causative mechanism between traditional NSAIDs and TB, and more research is required to verify whether the association between traditional NSAIDs and TB is causal, or simply reflects an increased use of anti-inflammatory drugs in the early phases of TB onset.

Resveratrol attenuates ICAM-1 expression and monocyte adhesiveness to TNF-α-treated endothelial cells: evidence for an anti-inflammatory cascade mediated by the miR-221/222/AMPK/p38/NF-κB pathway.

Resveratrol, an edible polyphenolic phytoalexin, improves endothelial dysfunction and attenuates inflammation. However, the mechanisms have not been thoroughly elucidated. Therefore, we investigated the molecular basis of the effects of resveratrol on TNF-α-induced ICAM-1 expression in HUVECs. The resveratrol treatment significantly attenuated the TNF-α-induced ICAM-1 expression. The inhibition of p38 phosphorylation mediated the reduction in ICAM-1 expression caused by resveratrol. Resveratrol also decreased TNF-α-induced IκB phosphorylation and the phosphorylation, acetylation, and translocation of NF-κB p65. Moreover, resveratrol induced the AMPK phosphorylation and the SIRT1 expression in TNF-α-treated HUVECs. Furthermore, TNF-α significantly suppressed miR-221/-222 expression, which was reversed by resveratrol. miR-221/-222 overexpression decreased p38/NF-κB and ICAM-1 expression, which resulted in reduced monocyte adhesion to TNF-α-treated ECs. In a mouse model of acute TNF-α-induced inflammation, resveratrol effectively attenuated ICAM-1 expression in the aortic ECs of TNF-α-treated wild-type mice. These beneficial effects of resveratrol were lost in miR-221/222 knockout mice. Our data showed that resveratrol counteracted the TNF-α-mediated reduction in miR-221/222 expression and decreased the TNF-α-induced activation of p38 MAPK and NF-κB, thereby suppressing ICAM-1 expression and monocyte adhesion. Collectively, our results show that resveratrol attenuates endothelial inflammation by reducing ICAM-1 expression and that the protective effect was mediated partly through the miR-221/222/AMPK/p38/NF-κB pathway.

Does procalcitonin, C-reactive protein, or interleukin-6 test have a role in the diagnosis of severe infection in patients with febrile neutropenia? A systematic review and meta-analysis.

PURPOSE: The study aims to determine the usefulness of procalcitonin (PCT) and other blood markers for identification of bacterial infection among patients with febrile neutropenia (FN). METHODS: The Medline, EMBASE, and Cochrane databases were searched for articles from 1966 to December 2012. We performed a search to identify articles that examined the diagnostic accuracy of PCT in patients with FN. Statistical analyses (fixed- or random-effect models) were conducted to summarize and calculate the sensitivity, specificity, likelihood ratios, and 95 % confidence intervals (CIs). RESULTS: Twenty-seven studies were included (1960 febrile episodes) for PCT analysis, 13 (1712 febrile episodes) for C-reactive protein (CRP) analysis, and five (314 febrile episodes) for interleukin (IL)-6 analysis. Increased PCT levels (odds ratio [OR] 11.5; 95 % CI 7.6 to 17.3), raised CRP levels (3.3; 2.7 to 4.2), and raised IL-6 levels (10.0; 5.5 to 18.0) were significantly associated with bacterial infection. Overall positive likelihood ratio was 5.49 (4.04-7.45) for PCT, 1.82 (1.42-2.33) for CRP, and 3.68 (2.41-5.60) for IL-6. Overall negative likelihood ratio was 0.40 (0.31-0.51) for PCT, 0.40 (0.26-0.61) for CRP, and 0.33 (0.23-0.46) for IL-6. CONCLUSIONS: Of the three potentially useful markers, PCT had the best positive likelihood ratio and can be used to confirm the diagnosis of bacterial infections in patients with FN. Due to unacceptably high negative likelihood ratio, medical decision for stopping antibiotics based on PCT alone in this high-risk population may not be possible.

Real-time electrochemical recording of dopamine release under optogenetic stimulation.

Dopaminergic PC12 cells can synthesize and release dopamine, providing a good cellular model for investigating dopamine regulation. Optogenetic stimulation of channelrhodopsin-2 provides high spatial and temporal precision for selective stimulation as a powerful neuromodulation tool for neuroscience studies. The aim of this study is to measure dopamine release from dopaminergic PC12 cells under optogenetic stimulation using electrochemical recording of self-assembled monolayers modified microelectrode with amperometric measurement in real time. The activation of PC12 cells under various optogenetic stimulation schemes are characterized by measuring single-cell Ca(2+) imaging. After 10 seconds of optogenetic stimulation, the evoked intracellular Ca(2+) level and dopamine current of channelrhodopsin-2-transfected PC12 cells were 1.6- and 3.5-fold higher than those of the control cells. The optogenetic stimulation effects on Ca(2+) influx and dopamine release were 81% and 63% inhibition by using a Ca(2+) channel antagonist Nifedipine. The results indicate that optogenetic stimulation can evoke voltage-gated Ca(2+) channel-dependent dopamine exocytosis from PC12 cells in a cell specific, temporally precise and dose-dependent manner. This proposed dopamine recording system can be developed to be a good cell model for dopamine regulation and drug screening in vitro, or dopaminergic cell implantation therapy in vivo using optogenetic stimulation in a precise and convenient way.