Double-blind trial of solid lipid Boswellia serrata particles (SLBSP) vs. standardized Boswellia serrata gum extract (BSE) for osteoarthritis of knee.

Objectives The present study was planned to investigate the efficacy of SLBSP vs. standardized BSE for symptomatic knee osteoarthritis (OA) treatment. Methods It was a prospective, randomized, double-blind, double-dummy, placebo-controlled, and single-centre clinical trial for symptomatic osteoarthritis of knee. Subjects were randomized to receive SLBSP capsule+BSE Placebo or BSE tablet+SLBSP placebo for two months. Patients were allowed to take rescue analgesics (Acelofenac 100 mg). Improvement in pain and function was assessed utilizing WOMAC, VAS. Level of CTX-II in urine and serum levels of inflammatory cytokines including IL-2, IL-4, IL-6, TNF-α, and IFN-γ was measured initially and at end of treatment. Results and conclusions Western Ontario and McMaster Universities osteoarthritis index (WOMAC) and Visual Analog Scale score improved markedly in SLBSP as well as in BSE arm (p < 0.05). Difference in VAS and WOMAC scores between the two arms was not statistically significant. Most significant effect was observed in the need for rescue analgesics. SLBSP caused marked lowering of pro-inflammatory cytokines levels whereas a several fold increase was noted in the BSE arm (p < 0.05). Both groups showed marked improvement in pain, SLBSP being superior to BSE with respect to reducing the need for rescue analgesics in addition to modulating inflammatory cytokines.

Enterococcus faecalis persistence in pediatric patients treated with antibiotic prophylaxis for recurrent urinary tract infections.

AIM: Enterococcus faecalis is one of the most common causes of recurrent urinary tract infection (RUTI), yet enterococcal pathogenesis is poorly understood. Our aims were to identify the prevalence of enterococci in RUTI patients and characterize the enterococcal response to nitrofurantoin and trimethoprim-sulfamethoxazole. MATERIALS & METHODS: We studied pediatric patients receiving antibiotic prophylaxis and those only under clinical observation for 12 months (n = 39). We then assessed the response of uropathogenic E. faecalis to nitrofurantoin and trimethoprim-sulfamethoxazole. RESULTS: Enterococci were isolated from almost half of patients and exposure of Enterococcus to nitrofurantoin increased virulence properties; this did not correlate with increased expression of virulence factors. CONCLUSION: Our results demonstrate that antibiotic prophylaxis may not be suitable for treatment of enterococcal RUTI (NCT02357758).

Cisplatin-induced renal inflammation is ameliorated by cilastatin nephroprotection.

BACKGROUND: Cisplatin is a potent chemotherapeutic drug whose nephrotoxic effect is a major complication and a dose-limiting factor for antitumoral therapy. There is much evidence that inflammation contributes to the pathogenesis of cisplatin-induced nephrotoxicity. We found that cilastatin, a renal dehydropeptidase-I inhibitor, has protective effects in vitro and in vivo against cisplatin-induced renal damage by inhibiting apoptosis and oxidation. Here, we investigated the potential use of cilastatin to protect against cisplatin-induced kidney injury and inflammation in rats. METHODS: Male Wistar rats were divided into four groups: control, cilastatin-control, cisplatin and cilastatin-cisplatin. Nephrotoxicity was assessed 5 days after administration of cisplatin based on blood urea nitrogen, creatinine, glomerular filtration rate (GFR), kidney injury molecule (KIM)-1 and renal morphology. Inflammation was measured using the electrophoretic mobility shift assay, immunohistochemical studies and evaluation of inflammatory mediators. RESULTS: Compared with the control rats, cisplatin-administered rats were affected by significant proximal tubule damage, decreased GFR, increased production of inflammatory mediators and elevations in urea, creatinine and tissue KIM-1 levels. Cilastatin prevented these changes in renal function and ameliorated histological damage in cisplatin-administered animals. Cilastatin also reduced pro-inflammatory cytokine levels, activation of nuclear factor-κB and CD68-positive cell concentrations. CONCLUSIONS: Cilastatin reduces cisplatin-induced nephrotoxicity, which is associated with decreased inflammation in vivo. Although the exact role of decreased inflammation in nephroprotection has not been fully elucidated, treatment with cilastatin could be a novel strategy for the prevention of cisplatin-induced acute kidney injury.

Intravesical Bacillus Calmette Guerin Combined with a Cancer Vaccine Increases Local T-Cell Responses in Non-muscle-Invasive Bladder Cancer Patients.

PURPOSE: Treatments with cancer vaccines may be delivered as combination therapies for better efficacy. Addition of intravesical immunostimulation with bacteria promotes vaccine-specific T cells in the bladder and tumor-regression in murine bladder cancer models. Here, we determined whether an adjuvanted cancer vaccine can be safely administered with concomitant standard intravesical Bacillus-Calmette-Guérin (BCG) therapy and how vaccine-specific immune responses may be modulated in patients with non-muscle-invasive bladder cancer (NMIBC). EXPERIMENTAL DESIGN: In a nonrandomized phase I open-label exploratory study, 24 NMIBC patients, apportioned in three groups, received 5 injections of a subunit cancer vaccine (recMAGE-A3 protein+AS15) alone or in two combinations of intravesical BCG-instillations. Safety profiles were compared between the three treatment groups, considering single vaccine injections or BCG instillations and concomitant interventions. Immune responses in blood and urine were compared between treatment groups and upon BCG instillations. RESULTS: The mild adverse events (AE) experienced by all the patients were similar to AE previously reported for this vaccine and standard BCG treatment. AEs were not increased by the double interventions, suggesting that BCG did not exacerbate the AE caused by the MAGE-A3 vaccine and vice-versa. All patients seroconverted after MAGE-A3 vaccination. In half of the patients, vaccine-specific T cells were induced in blood, irrespective of BCG treatment. Interestingly, such T cells were only detected in urine upon BCG-induced T-cell infiltration. CONCLUSIONS: Cancer vaccines, including strong adjuvants, can be safely combined with intravesical BCG therapy. The increase of vaccine-specific T cells in the bladder upon BCG provides proof-of-principle evidence that cancer vaccines with local immunostimulation may be beneficial. Clin Cancer Res; 23(3); 717-25. ©2016 AACR.

[Bone and Nutrition. Effect of isoflavones on bone health].

Effects of isoflavones on bone health in postmenopausal women are expected, since it shows weak estrogenic activity. In the observational study in Asia, association between intake of soy foods or isoflavone and bone mineral density and fracture prevention has been observed. In the meta-analysis of intervention trials of isoflavone in 60 years or less of postmenopausal women, 75 mg by day about 6 months to 1 year intervention of isoflavones induced suppression of significant decline of bone resorption markers in the urine was observed. On the other hand, intended for Westerners women in the study intervened isoflavones with calcium and vitamin D simultaneously, it is not observed effectiveness of isoflavones on the bone. Such a difference might be due to diversity in the individual metabolic capacity for isoflavones as well as the effects of presence or absence of other co-interventions nutrients.

Urinary cytokines in patients treated with intravesical mitomycin-C with and without hyperthermia.

OBJECTIVES: To explore whether urinary cytokine and chemokine (CK) levels differed between cold mitomycin-C (cold-MMC)-treated patients and chemohyperthermia (C-HT)-treated patients, to shed light on the possible molecular mechanisms that might explain the superior outcome of C-HT. Furthermore, CK-differences were explored between C-HT responders and C-HT non-responders. METHODS: Twelve NMIBC patients were included. Nine received six-weekly C-HT, and three received four-weekly cold-MMC instillations. Urine was collected on 8-12 time points before and after every treatment. MDC, IL-2, IL-6, IL-8, IP-10, MCP-1 and RANTES were determined by Luminex(®)-analysis. RESULTS: Elevated urinary CK levels were observed in both groups after treatment. In general, CK-peaks were lower in the cold-MMC group in comparison with levels in the C-HT group. Significant higher MCP-1 and IL-6 levels were observed in C-HT-treated patients. Additionally, significant cumulative effects were observed for IP-10 and IL-2. However, IP-10 and IL-2 levels did not significantly differ between treatments. MDC levels after the first week of treatment were significantly higher in the C-HT responders compared with the non-responders. CONCLUSION: MMC treatment leads to elevated urinary CK levels with significantly higher MCP-1 and IL-6 levels in C-HT-treated patients. Increased MDC levels after the first C-HT instillation appear to be related to good clinical outcome and might be of additional value to personalize treatment. Studies involving more patients and longer follow-up are needed to substantiate this observation.

Effect of a sports drink based on highly-branched cyclic dextrin on cytokine responses to exhaustive endurance exercise.

BACKGROUND: Aim of the present study was to compare the effects of highly branched cyclic dextrin (HBCD) drink with a glucose-based control drink on immunoendocrine responses to endurance exercise. METHODS: Using a randomized, double-blind placebo-controlled cross-over design, seven male triathletes participated in two duathlon races separated by one month, consisting of 5 km of running, 40 km of cycling and 5 km of running. In the first race, four athletes consumed the HBCD-based drink and three athletes consumed the glucose-based drink. In the second race, three athletes consumed the HBCD-based drink and four athletes consumed the glucose-based drink. We collected blood and urine samples before and after the races to analyze leukocyte count and concentrations of hormones and cytokines. RESULTS: Lymphocyte and neutrophil counts increased significantly after exercise in both trials (P<0.05), but were not significantly different between the trials. Plasma noradrenalin concentration increased significantly (P<0.05) during exercise in the glucose trial, but not in the HBCD trial. Plasma concentrations of interleukin (IL)-8 and IL-10 increased significantly during exercise in both trials (P<0.05) but were not significantly different between the trials. Post-race urinary IL-8, IL-10 and IL-12p40 concentrations were significantly lower in the HBCD trial compared with the glucose trial (P<0.05), although the plasma concentrations of these cytokines were not significantly different between both trials. CONCLUSION: These results suggest that the HBCD-based drink may attenuate the stress hormone response, and reduce the urinary cytokine levels following exhaustive exercise.

The effect of garlic powder on human urinary cytokine excretion.

PURPOSE: To evaluate the effects of orally administered dehydrated garlic powder on cytokine excretion in the urinary tract. MATERIALS AND METHODS: A total of 60 healthy volunteers, randomized into 3 groups, were given a single oral dose of 1 g or 3 g of dehydrated garlic powder or placebo. Urine samples were obtained 6.0 and 24.0 h after garlic intake and assayed for interleukin-8 (IL-8), interleukin- 12 (IL-12), tumor necrosis factor-alpha (TNF-α), diallyl disulfide (DADS) and diallyl sulfide (DAS). RESULTS: Significant increases in IL-12 levels over baseline were noted in urine samples obtained after oral intake of 1 g and 3 g of garlic powder (P < .001). In the 1 g and 3 g garlic powder treatment groups, time-dependent variations in IL-12 levels over the study period were significantly different from the placebo group (P < .001). In both garlic treatment groups, urinary levels of IL-8 and TNF-α were not significantly different from baseline and placebo levels (P > .017). DADS and DAS were not detected in the urine samples at any time after garlic powder intake. CONCLUSION: Oral intake of doses of garlic traditionally used for daily supplementation increases urinary levels of IL-12, which is a potent stimulator of T helper cell 1 (Th-1) immune responses. This observation encourages further studies investigating the immunostimulatory role of garlic in the urinary tract.

[Comparative estimation of efficacy of the immunecorrecting combined three- level cytokino- and ozonotherapy in complex treatment of extended peritonitis].

The results of surgical treatment of 211 patients, suffering extended peritonitis (EP) of various etiology, were analyzed. The peritonitis severity was graded in accordance to Mannheim's index of peritonitis (MIP). The patients were divided on two groups. In 60 patients (group of comparison) the basic treatment was conducted, without immunocorrection. The patients of the main group were divided on three subgroups. To the patients of the first subgroup (43) 400 ml of ozonated isotonic solution (OIS) of sodium chloride was infused intravenously additionally in the contents of basic therapy, as well as peritoneal-enteral detoxication using OIS was conducted. In a second subgroup a regional intraabdominal endolymphatic ozonotherapy (OTH) was conducted to 57 patients with OIS and peritoneal-enteral sanation using medical ozone. In the 3d subgroup in 51 patients additionally were applied intravenous infusion of OIS and peritoneal-enteral sanation with medical ozone. To these patients cytokinotherapy was conducted, when splenopid was applied intravenously, intraperitoneally and enterally simultaneously. The indices of the T- and B-immunity links, phagocytic activity of neutrophils, including phagocytic index, phagocytic number, the completeness of phagocytosis index, as well as the content of the tumor necrosis factor alpha (TNF-alpha), gamma-interferon (IFN-gamma) and interleukins (IL) - IL-1, IL-2, IL-4, IL-6, IL-10 were estimated in the blood serum in dynamics. The combined staged three-level (systemic, intraperitoneal and enteral) application of natural cytokins and medical ozone have promoted mutual potentiating of their action, significant efficacy of the immunemodulating therapy in comparison with such systemic and local OTH.

Improvement by phytotherapeutic agent of detrusor overactivity, down-regulation of pharmacological receptors and urinary cytokines in rats with cyclophosphamide induced cystitis.

PURPOSE: We characterized pharmacological effects of the phytotherapeutic agent Eviprostat® on urodynamic parameters, bladder muscarinic and purinergic receptors, and urinary cytokines in rats with cyclophosphamide induced cystitis. MATERIALS AND METHODS: Urodynamic parameters in cyclophosphamide (150 mg/kg intraperitoneally) treated rats were measured by a cystometric method. Muscarinic and purinergic receptors in the bladder and other tissues were measured by radioreceptor assays using [N-methyl-(3)H]scopolamine methyl chloride and [(3)H]αß-MeATP, respectively. The urinary cytokines interleukin-1ß, 6 and 17 were measured with enzyme-linked immunoassay kits. Eviprostat (36 mg/kg per day twice daily for 7 days) was orally administered. RESULTS: On cystometry the micturition interval and micturition volume were significantly decreased in cyclophosphamide vs sham treated rats, while micturition frequency, basal pressure and post-void residual urine volume were significantly increased. Repeat oral administration of Eviprostat in cyclophosphamide treated rats significantly increased the micturition interval and micturition volume, and decreased micturition frequency, basal pressure and post-void residual urine volume. The maximal number of binding sites for [N-methyl-(3)H]scopolamine methyl chloride and [(3)H]αß-MeATP was significantly decreased in the bladder of cyclophosphamide vs sham treated rats. Such decreases were significantly attenuated by repeat Eviprostat treatment. Increased urinary cytokine levels in cyclophosphamide treated rats were also effectively attenuated by Eviprostat. CONCLUSIONS: Repeat Eviprostat treatment significantly improved detrusor overactivity, down-regulated the expression of bladder pharmacological receptors and increased urinary cytokine levels in rats with cyclophosphamide induced cystitis. Therefore, Eviprostat may be a pharmacologically useful phytotherapeutic agent for cystitis.

Effect of a phytotherapeutic agent, Eviprostat®, on prostatic and urinary cytokines/chemokines in a rat model of nonbacterial prostatitis.

BACKGROUND: Chronic inflammation in the prostate has recently been recognized as an important component of the symptom progression of benign prostatic hyperplasia. The objective of this study was to evaluate a range of cytokines/chemokines in prostate tissue and urine to identify markers of prostate inflammation in a prostatitis model and to investigate the effect of a phytotherapeutic agent, Eviprostat®, on these markers. METHODS: Ten-month-old male Wistar rats were divided into four groups. Nonbacterial prostatitis (NBP) was experimentally induced in groups 2-4 by castration followed by daily subcutaneous injection of 17ß-estradiol for 30 days. Control rats were fed a standard diet, while animals in the Eviprostat groups were fed a diet containing 0.05 or 0.1% Eviprostat for 30 days. The levels of cytokines/chemokines in prostate tissue on the 31st day and in urine collected the day before castration and the day before removal of the prostate were determined. RESULTS: Experimentally induced NBP increased the prostatic levels of the cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α). The levels of the chemokines CCL2/monocyte chemoattractant protein-1 (MCP-1), CCL3/macrophage inflammatory protein-1α (MIP-1α), CXCL1/CINC-1, CXCL3/CINC-2, and CXCL5/LIX were elevated in both prostate and urine. Eviprostat significantly suppressed the increases in prostate IL-1ß, TNF-α and CCL3/MIP-1α and prostatic and urinary CCL2/MCP-1 and CXCL1/CINC-1. CONCLUSIONS: Chemokines, including CCL2/MCP-1 and CXCL1/CINC-1, were elevated in the prostate and urine of NBP rats, and Eviprostat potently suppressed the increases in CCL2/MCP-1 and CXCL1/CINC-1. These chemokines are therefore candidate diagnostic biomarkers for nonbacterial chronic prostatic inflammation.

Saireito and saikosaponin D prevent urinary protein excretion via glucocorticoid receptor in adrenalectomized WKY rats with heterologous-phase anti-GBM nephritis.

AIMS: In order to clarify the antinephritic mechanisms of saireito, the glucocorticoid receptor agonistic effect of saireito was evaluated in adrenalectomized rats with anti-glomerular basement membrane (anti-GBM) nephritis. METHODS: Rats with anti-GBM nephritis were subjected to adrenalectomy to exclude the effects of endogenous steroid hormones to investigate effects of saireito on the nephritis. The suppressive effects of saireito and saikosaponin D on the production of cytokines were investigated in vitro andin vivo. RESULTS: Administration of saireito or saikosaponin D significantly suppressed the increase of urinary protein excretion and histopathological changes in adrenalectomized nephritic rats. Coadministration of saireito or saikosaponin D and RU-38486, a glucocorticoid receptor antagonist, did not suppress the increase of urinary protein excretion. Saikosaponin D inhibited the glucocorticoid receptor binding of [(3)H]dexamethasone in anin vitro assay (IC(50) ratio 5.8 micromol/l). The IC(50) values of saikosaponin D for the release of IL-2 and IL-10 were 13.4 and 12.3 micromol/l, respectively. Administration of saireito and saikosaponin D prevented an increase in IL-2 levels in the renal cortex of anti-GBM nephritic rats. CONCLUSION: These results suggest that the antinephritic effects of saireito may be partly attributable to an agonistic action on the glucocorticoid receptor by saikosaponin D, a component of saireito.

Cell salvage alters the systemic inflammatory response after off-pump coronary artery bypass grafting surgery.

BACKGROUND: Retransfused cardiotomy suction blood contains elevated inflammatory markers and is a bypass independent source of inflammatory mediators. We hypothesized that, during off-pump coronary artery bypass (OPCAB) grafting surgery, avoiding retransfusion of unwashed cardiotomy suction blood would beneficially alter both urinary and plasma cytokine concentrations and be renoprotective. METHODS: Thirty-seven OPCAB surgery patients were randomly allocated to control (retransfusion of unwashed shed blood) and treatment (retransfusion of washed shed blood or discarding of unwashed blood) groups. Over 72 hours we measured plasma (tumor necrosis factor-alpha [TNF-alpha], interleukin-8, interleukin-6, interleukin-10, TNF soluble receptor-2, and interleukin-1 receptor antagonist) and urinary TNF soluble receptor-2 and interleukin-1 receptor antagonist and markers of renal injury and dysfunction (N-acetyl beta D glucosaminidase and alpha1-microglobulin). RESULTS: We demonstrated elevated proinflammatory cytokines in cardiotomy suction blood, which were effectively eliminated by cell salvage. After retransfusion, in comparison with controls, the treatment group had reduced plasma TNF soluble receptor-2. As compared with controls, treatment group patients also demonstrated significantly reduced levels of the urinary anti-inflammatory cytokine TNF soluble receptor-2. There were no between group differences in markers of renal injury or dysfunction. CONCLUSIONS: We have demonstrated that the management of shed mediastinal blood alters perioperative, systemic, plasma and urinary cytokine homeostasis at OPCAB surgery but does not impact on subclinical renal injury or dysfunction in this low risk group of patients.