Concomitant Detrusor and External Urethral Sphincter Botulinum Toxin-A Injections in Male Spinal Cord Injury Patients with Detrusor Overactivity and Detrusor Sphincter Dyssynergia.

OBJECTIVE: To investigate the effects of concomitant injections of botulinum toxin-A (BoNT-A) into the detrusor and external urethral sphincter muscles in suprasacral spinal cord injured patients with detrusor overactivity and detrusor sphincter dyssynergia. DESIGN: An open treatment trial with pre- and posttreatment evaluations. SUBJECTS: Male suprasacral spinal cord injury patients (n = 20) with neurogenic detrusor overactivity and detrusor sphincter dyssynergia who emptied their bladder by reflex voiding and were unwilling to increase the frequency of intermittent catheterization. METHODS: Cystoscopic guidance of 200 U BoNT-A injections into the detrusor muscle and 100 U into external urethral sphincter muscles were applied. The urodynamic parameters, voiding diaries and quality of life scores using Urinary Distress Inventory, Short Form (UDI-6) and Incontinence Impact Questionnaire, Short Form (IIQ-7) were compared. RESULTS: All participants experienced a significant mean reduction in maximal detrusor pressure and maximal urethral pressure profile, and a mean significant increase in maximal cystometric bladder capacity 12 weeks after concomitant injections. Bladder diaries demonstrated persistently increased spontaneous voided volume, but no increase in post-void residual ratio, daily clean intermittent catheterization (CIC) frequency and diaper pad use from baseline to 24 weeks. UDI-6 scores were significantly improved at 4 and 12 weeks and IIQ-7 scores improved only at 12 weeks. CONCLUSION: Concomitant detrusor and external urethral sphincter BoNT-A injections may decrease detrusor and urethral pressure without increasing postvoid residual ratio and diaper pad use. For spinal cord injury patients with neurogenic detrusor overactivity and detrusor sphincter dyssynergia who are unwilling, or for whom it is inconvenient, to increase CIC frequency and who want to preserve spontaneous voiding, this treatment may provide an optional alternative.

Inhibitory effects of phenolic glycosides from Trollius chinensis Bunge on α-glucosidase: inhibition kinetics and mechanisms.

Two undescribed phenolic glycosides, trochinenols B and C (1 and2), together with four known analogues (3-6), were isolated from the functional tea Trollius chinensis Bunge and their α-glucosidase inhibitory kinetics and mechanisms were investigated. It was found that 1 inhibited α-glucosidase in a noncompetitive manner with an IC50 value of 25.96 µM, while 3 showed a notable inhibitory effect against α-glucosidase in an uncompetitive manner with an IC50 value of 3.14 µM. Analysis of synchronous fluorescence and circular dichroism spectroscopy indicated that the binding of 1 to α-glucosidase led to the rearrangement and conformational alteration of the α-glucosidase enzyme. Furthermore, molecular docking indicated that 1 had a high affinity close to the active site pocket of α-glucosidase and indirectly inhibited the catalytic activity of the enzyme. However, 3 was bound to the entrance part of the active center of α-glucosidase and could hinder the release of the substrate as well as the catalytic reaction product, eventually suppressing the catalytic activity of α-glucosidase.

Experience of sorafenib treatment in differentiated thyroid cancer from Taiwan.

BACKGROUND: Sorafenib has been shown to prolong the progression free survival (PFS) of advanced radioiodine (RAI) refractory differentiated thyroid cancer (DTC) and has been approved by the FDA as the result of the phase III DECISION trial. Sorafenib has been reimbursed for the treatment of RAI refractory DTC in Taiwan since Jan 2017. High percentage of adverse events (AE) was noted in DECISION trial. We conducted a study to show the real-world experience of sorafenib in Taiwan. METHODS: We retrospectively collected the clinical data, including dose, AE, and PFS of sorafenib, of the DTC patients who received sorafenib treatment in National Cheng Kung University Hospital and China Medical University Hospital by chart review from 2012 to 2018. RESULTS: Thirty-six advanced DTC patients with progression were included in this study. The starting dose of sorafenib in most patients was 200 mg twice daily and the mean daily maintenance dose was 433 mg. Five patients had partial response (13.9%) and 28 patients had stable disease (77.8%). The median PFS was 17.3 months (95% confidence interval: 11.9-33.6 months). Daily maintenance dose ≥ 600 mg was associated with better PFS (median PFS, not reached). The most common toxicity of sorafenib was hand foot skin reaction (69%), followed by diarrhea (42%), and skin rash (33%). Most of the toxicities were grade I/II. CONCLUSION: Higher maintenance dose of sorafenib is associated with longer PFS while starting from half dose is feasible to minimize the incidence of high grade toxicities in the real-world use of sorafenib.

Pyuria and Post-Operation Urinary Tract Infection after Diode Laser Vaporesection of the Prostate.

Background: Monopolar transurethral resection of prostate (m-TURP) remains the gold standard for benign prostate obstruction (BPO). Recently developed laser surgical technique provides fewer peri-operative complications with equivalent outcomes. Diode laser vaporesection (DiLRP) offers better hemostasis, shorter catheterization duration, and shorter hospital stay, however, deep thermal penetration might cause prolonged prostatic urethra inflammation and subsequent complications. We conducted a retrospective study to compare the pyuria duration and post-operative urinary tract infection sequelae (POUTIs) between DiLRP and m-TURP. Methods: From July 2011 to September 2015, we retrieved medical records for patients with lower urinary tract symptoms resulting from prostate obstruction who underwent m-TURP and DiLRP. Demographic characteristics were recorded from a computerized database. The duration of pyuria after operation was compared by Kaplan-Meier analysis and risk factors were evaluated by Cox regression analysis. Results: One hundred twelve patients underwent DiLRP and 81 underwent m-TURP performed by the same surgeon during the same period. The mean age of the patients was 72 ± 7.3 years in the DiLRP group and 70 ± 7.6 years in the m-TURP group (p = 0.069). There was a higher percentage of anticoagulant used in the DiLRP group than in the m-TURP group (18.5% vs. 7.4%, p = 0.028). Operation time was longer but post-operative normal saline irrigation interval was shorter in DiLRP compared with m-TURP, respectively (62.8 ± 20.6 vs. 47.4 ± 22.1 minutes, p < 0.001; 2.1 ± 0.3 vs. 2.5 ± 0.9 days, p < 0.001). The post-operative infections were statistically significantly higher in the DiLRP group, including epididymitis (10.2% vs. 1.2%, p = 0.013) and POUTIs-related hospitalization (8.3% vs. 1.2%, p=0.031).The DiLRP resulted in longer pyuria period (16 vs. 12 weeks, p = 0.0014), with factors including operative method by DiLRP (hazard ratio [HR]: 1.828, p = 0.003) and age (HR: 0.665, p = 0.040). Conclusions: According to our study, DiLRP associated with more POUTIs is possibly caused by a longer pyuria period. Further larger prospective studies are necessary for the evaluation of the association between post-operative pyuria and POUTIs.

[Aconite cake-separated moxibustion for knee osteoarthritis with kidney-marrow deficiency].

OBJECTIVE: To observe the effects among aconite cake-separated moxibustion, moxibustion and acupuncture for knee osteoarthritis (KOA) with kidney-marrow deficiency and to explore the feasibility of cake-separated moxibustion as a home remedy solution. METHODS: Ninety patients were randomized into an aconite cake-separated moxibustion group, a moxibustion group and an acupuncture group, 30 cases in each one. The acupoints in the three groups were Neixiyan (EX-LE 4), Dubi (ST 35) in the affected side, and bilateral Xuehai (SP 10), Liangqiu (ST 34), Heding (EX-LE 2), Shenshu (BL 23) and Zusanli (ST 36). All the treatment was given for 3 sessions, 10 days as a session with 2 to 3 days between 2 sessions, and once a day. The first 2 courses of aconite cake-separated moxibustion was applied in the hospital and the other 1 session was used at home guided by officer physician. Symptoms and physical signs classification score and life quality scores were recorded before and after treatment and 6 months after treatment, including walking pain, knee pain in stoop and squat, knee discomfort in stair activity and daily discomfort. The effects were evaluated. RESULTS: The symptoms and physical signs classification scores in the three groups after treatment and at follow-up were lower than those before treatment (P<0.01, P<0.05), and the scores in the aconite cake-separated moxibustion group were better than those in the moxibustion group and acupuncture group (all P<0.01). The scores of walking pain, knee pain in stoop and squat, knee discomfort in stair activity and daily discomfort were lower in the three groups after treatment and 6 months after treatment (P<0.01, P<0.05), and the scores of walking pain and daily discomfort in the aconite cake-separated moxibustion group were lower than those in the moxibustion group and acupuncture group (P<0.01, P<0.05). After treatments, the cured and markedly effective rate in the aconite cake-separated moxibustion group was 63.3% (19/30); that in the moxibustion group was 50.0% (15/30) and one in the acupuncture group was 43.3% (13/30). The cured and markedly effective rate of aconite cake-separated moxibustion group was more promising than those in the other two groups (both P<0.05). At follow-up, the cured and markedly effective rate in the aconite cake-separated moxibustion group was 56.7% (17/30), which was better than 36.7% (11/30) in the moxibustion group and 40.0% (12/30) in the acupuncture group (both P<0.05). CONCLUSION: Aconite cake-separated moxibustion can be used for KOA patients with kidney-marrow deficiency, which can improve patients' life quality and is better than moxibustion and acupuncture. The method is feasible as a home remedy solution.

Meta-Analysis of Effects of Voluntary Slow Breathing Exercises for Control of Heart Rate and Blood Pressure in Patients With Cardiovascular Diseases.

Rising heart rate (HR) and elevated blood pressure (BP) cause a greater frequency of cardiovascular events. Many patients cannot maintain target HR and BP using pharmacological therapies. To evaluate the effectiveness of voluntary slow breathing exercises in reducing resting HR and BP, we searched Embase (1974 to April 2016), PubMed (1966 to April 2016), the Cochrane Central Register of Controlled Trials (issue 4, April 2016), and PEDro (www.pedro.org.au; 1999 to April 2016). The primary outcome was the mean change in HR at rest. Secondary outcomes included changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) as well as compliance with the breathing training. Finally, we included 6 studies consisting of 269 subjects. Practice of the breathing exercises resulted in statistically significant HR reduction (mean difference: -1.72 beats/min, 95% CI -2.70 to -0.75). Reductions were seen in SBP (mean difference: -6.36 mm Hg, 95% CI -10.32 to -2.39) and DBP (mean difference: -6.39 mm Hg, 95% CI -7.30 to -5.49) compared with the controls. Trial durations ranged from 2 weeks to 6 months. In conclusion, the existing evidence from randomized controlled trails demonstrates that short-term voluntary slow breathing exercises can reduce resting HR, SBP, and DBP for patients with cardiovascular diseases.

Green Tea Polyphenol Epigallocatechin-3-gallate Suppresses Toll-like Receptor 4 Expression via Up-regulation of E3 Ubiquitin-protein Ligase RNF216.

Toll-like receptor 4 (TLR4) plays an essential role in innate immunity through inflammatory cytokine induction. Recent studies demonstrated that the abnormal activation of TLR4 has a pivotal role in obesity-induced inflammation, which is associated with several diseases, including hyperinsulinemia, hypertriglyceridemia, and cardiovascular disease. Here we demonstrate that (-)-epigallocatechin-3-O-gallate, a natural agonist of the 67-kDa laminin receptor (67LR), suppressed TLR4 expression through E3 ubiquitin-protein ring finger protein 216 (RNF216) up-regulation. Our data indicate cyclic GMP mediates 67LR agonist-dependent RNF216 up-regulation. Moreover, we show that the highly absorbent 67LR agonist (-)-epigallocatechin-3-O-(3-O-methyl)-gallate (EGCG3″Me) significantly attenuated TLR4 expression in the adipose tissue. EGCG3″Me completely inhibited the high-fat/high-sucrose (HF/HS)-induced up-regulation of tumor necrosis factor α in adipose tissue and serum monocyte chemoattractant protein-1 increase. Furthermore, this agonist intake prevented HF/HS-induced hyperinsulinemia and hypertriglyceridemia. Taken together, 67LR presents an attractive target for the relief of obesity-induced inflammation.

Oligomer formation of a tea polyphenol, EGCG, on its sensing molecule 67 kDa laminin receptor.

Green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) has been attributed to the activation of its cell surface sensing receptor 67 kDa laminin receptor (67LR). However, the action of EGCG to activate 67LR remains unknown. Here we show that EGCG undergoes oligomer formation on its surface receptor 67LR.

Green tea polyphenol epigallocatechin-O-gallate induces cell death by acid sphingomyelinase activation in chronic myeloid leukemia cells.

An epidemiological study showed that green tea consumption is associated with a reduced risk of hematopoietic malignancy. The major green tea polyphenol epigallocatechin­3-O-gallate (EGCG) is reported to have anticancer effects. Chronic myeloid leukemia (CML) is a major hematopoietic malignancy characterized by expansion of myeloid cells. In the present study, we showed EGCG-induced acid sphingomyelinase (ASM) activation and lipid raft clustering in CML cells. The ASM inhibitor desipramine significantly reduced EGCG-induced cell death. Protein kinase Cδ is a well­known kinase that plays an important role in ASM activation. We observed EGCG-induced phosphorylation of protein kinase Cδ at Ser664. Importantly, EGCG-induced ASM activation was significantly reduced by pretreatment of CML cells with the soluble guanylate cyclase inhibitor NS2028, suggesting that EGCG induced ASM activation through the cyclic guanosine monophosphate (cGMP)-dependent pathway. Indeed, pharmacological inhibition of a cGMP-negative regulator enhanced the anti-CML effect of EGCG. These results indicate that EGCG-induced cell death via the cGMP/ASM pathway in CML cells.

Metabolic profiling-based data-mining for an effective chemical combination to induce apoptosis of cancer cells.

Green tea extract (GTE) induces apoptosis of cancer cells without adversely affecting normal cells. Several clinical trials reported that GTE was well tolerated and had potential anti-cancer efficacy. Epigallocatechin-3-O-gallate (EGCG) is the primary compound responsible for the anti-cancer effect of GTE; however, the effect of EGCG alone is limited. To identify GTE compounds capable of potentiating EGCG bioactivity, we performed metabolic profiling of 43 green tea cultivar panels by liquid chromatography-mass spectrometry (LC-MS). Here, we revealed the polyphenol eriodictyol significantly potentiated apoptosis induction by EGCG in vitro and in a mouse tumour model by amplifying EGCG-induced activation of the 67-kDa laminin receptor (67LR)/protein kinase B/endothelial nitric oxide synthase/protein kinase C delta/acid sphingomyelinase signalling pathway. Our results show that metabolic profiling is an effective chemical-mining approach for identifying botanical drugs with therapeutic potential against multiple myeloma. Metabolic profiling-based data mining could be an efficient strategy for screening additional bioactive compounds and identifying effective chemical combinations.

CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice.

UNLABELLED: Sorafenib, a broad tyrosine kinase inhibitor, is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC) but provides limited survival benefits. Recently, immunotherapy has emerged as a promising treatment strategy, but its role remains unclear in HCCs, which are associated with decreased cytotoxic CD8(+) T-lymphocyte infiltration in both murine and human tumors. Moreover, in mouse models after sorafenib treatment intratumoral hypoxia is increased and may fuel evasive resistance. Using orthotopic HCC models, we now show that increased hypoxia after sorafenib treatment promotes immunosuppression, characterized by increased intratumoral expression of the immune checkpoint inhibitor programmed death ligand-1 and accumulation of T-regulatory cells and M2-type macrophages. We also show that the recruitment of immunosuppressive cells is mediated in part by hypoxia-induced up-regulation of stromal cell-derived 1 alpha. Inhibition of the stromal cell-derived 1 alpha receptor (C-X-C receptor type 4 or CXCR4) using AMD3100 prevented the polarization toward an immunosuppressive microenvironment after sorafenib treatment, inhibited tumor growth, reduced lung metastasis, and improved survival. However, the combination of AMD3100 and sorafenib did not significantly change cytotoxic CD8(+) T-lymphocyte infiltration into HCC tumors and did not modify their activation status. In separate experiments, antibody blockade of the programmed death ligand-1 receptor programmed death receptor-1 (PD-1) showed antitumor effects in treatment-naive tumors in orthotopic (grafted and genetically engineered) models of HCC. However, anti-PD-1 antibody treatment had additional antitumor activity only when combined with sorafenib and AMD3100 and not when combined with sorafenib alone. CONCLUSION: Anti-PD-1 treatment can boost antitumor immune responses in HCC models; when used in combination with sorafenib, anti-PD-1 immunotherapy shows efficacy only with concomitant targeting of the hypoxic and immunosuppressive microenvironment with agents such as CXCR4 inhibitors.

A study of renal function influence by integrating cloud-based manometers and physician order entry systems.

BACKGROUND: No evidence exists from randomized trials to support using cloud-based manometers integrated with available physician order entry systems for tracking patient blood pressure (BP) to assist in the control of renal function deterioration. We investigated how integrating cloud-based manometers with physician order entry systems benefits our outpatient chronic kidney disease patients compared with typical BP tracking systems. METHODS: We randomly assigned 36 chronic kidney disease patients to use cloud-based manometers integrated with physician order entry systems or typical BP recording sheets, and followed the patients for 6 months. The composite outcome was that the patients saw improvement both in BP and renal function. RESULTS: We compared the systolic and diastolic BP (SBP and DBP), and renal function of our patients at 0 months, 3 months, and 6 months after using the integrated manometers and typical BP monitoring sheets. Nighttime SBP and DBP were significantly lower in the study group compared with the control group. Serum creatinine level in the study group improved significantly compared with the control group after the end of Month 6 (2.83 ± 2.0 vs. 4.38 ± 3.0, p = 0.018). Proteinuria improved nonsignificantly in Month 6 in the study group compared with the control group (1.05 ± 0.9 vs. 1.90 ± 1.3, p = 0.09). Both SBP and DBP during the nighttime hours improved significantly in the study group compared with the baseline. CONCLUSION: In pre-end-stage renal disease patients, regularly monitoring BP by integrating cloud-based manometers appears to result in a significant decrease in creatinine and improvement in nighttime BP control. Estimated glomerular filtration rate and proteinuria were found to be improved nonsignificantly, and thus, larger population and longer follow-up studies may be needed.

Green tea extract containing a highly absorbent catechin prevents diet-induced lipid metabolism disorder.

We investigated the effects of extracts of Benifuuki (a tea cultivar that contains methylated catechins such as epigallocatechin-3-O-(3-O-methyl) gallate (EGCG3"Me)) in mice fed a high-fat/high-sucrose (HF/HS) diet. This tea cultivar was then compared with an extract of Yabukita (a popular tea cultivar that lacks methylated catechins). For 6 weeks, C57BL/6J mice were fed either HF/HS diet with or without tea extracts from tea cultivars, which contained almost identical ingredients except for methylated catechins (i.e., Yabukita (0.2% and 1%) or Benifuuki (0.2% and 1%) extract powders). Supplementation with Benifuuki 0.2% markedly lowered plasma levels of TG and NEFAs compared with mice supplemented with Yabukita 0.2%. The diet containing Benifuuki 1% decreased adipose tissue weights, liver TG, and expression of lipogenic genes in the liver. These results suggested that Benifuuki had much greater lipid-lowering effects than Yabukita. Taken together, these data suggest that methylated catechins direct the strong lipid-lowering activity of Benifuuki.

Green tea polyphenol EGCG induces lipid-raft clustering and apoptotic cell death by activating protein kinase Cδ and acid sphingomyelinase through a 67 kDa laminin receptor in multiple myeloma cells.

EGCG [(-)-epigallocatechin-3-O-gallate], the major polyphenol of green tea, has cancer chemopreventive and chemotherapeutic activities. EGCG selectively inhibits cell growth and induces apoptosis in cancer cells without adversely affecting normal cells; however, the underlying molecular mechanism in vivo is unclear. In the present study, we show that EGCG-induced apoptotic activity is attributed to a lipid-raft clustering mediated through 67LR (67 kDa laminin receptor) that is significantly elevated in MM (multiple myeloma) cells relative to normal peripheral blood mononuclear cells, and that aSMase (acid sphingomyelinase) is critical for the lipid-raft clustering and the apoptotic cell death induced by EGCG. We also found that EGCG induces aSMase translocation to the plasma membrane and PKCδ (protein kinase Cδ) phosphorylation at Ser664, which was necessary for aSMase/ceramide signalling via 67LR. Additionally, orally administered EGCG activated PKCδ and aSMase in a murine MM xenograft model. These results elucidate a novel cell-death pathway triggered by EGCG for the specific killing of MM cells.

[Study on the feasibility for judging the lifting-thrusting manipulation of acupuncture by using "quality control figure" measurement].

OBJECTIVE: To explore the feasibility of judgment of the lifting-thrusting acupuncture manipulation by using "quality control figure" measurement, so as to provide a possible reference for demonstration in acupuncture teaching and scientific research. METHODS: A total of 13 high-professional title acupuncturists and teachers and 100 college students participated in the present study. The so-called "quality control figures" of lifting-thrusting acupuncture skill were established by collecting operation data from 13 acupuncturists and teachers with an "Acupuncture Manipulation Parameter Detector System". A total of 100 college students who have learnt acupuncture and massage learnings were asked to perform the same acupuncture manipulation after training, followed by giving a mark with conventional manipulation method and "quality control figure" method (scores), respectively. In addition, the correlation between these two scoring methods was analyzed. RESULTS: The average score of conventional scoring of lifting-thrusting manipulation was (81.03 +/- 18.40) points and that of "quality control figure" scoring was (80.60 +/- 7.48) points in those college students after training. No significant difference was found between these two scoring methods (P > 0.05). But a positive correlation was found between them (r = 0.6943, P < 0.01), suggesting a positive feasibility for judging the lifting-thrusting acupuncture manipulation with "quality control figure" measurement. CONCLUSION: A positive correlation exists between the conventional scoring and "quality control figure" scoring for lifting-thrusting acupuncture manipulation, suggesting a feasibility in judging this acupuncture manipulation with "quality control figure" measurement.