chondroitin-sulfates and Urinary-Tract-Infections

chondroitin-sulfates has been researched along with Urinary-Tract-Infections* in 16 studies

Reviews

2 review(s) available for chondroitin-sulfates and Urinary-Tract-Infections

ArticleYear
Novel Key Ingredients in Urinary Tract Health-The Role of D-mannose, Chondroitin Sulphate, Hyaluronic Acid, and
    Nutrients, 2023, Aug-14, Volume: 15, Issue:16

    Urinary tract infections represent a common and significant health concern worldwide. The high rate of recurrence and the increasing antibiotic resistance of uropathogens are further worsening the current scenario. Nevertheless, novel key ingredients such as D-mannose, chondroitin sulphate, hyaluronic acid, and

    Topics: Acetylcysteine; Chondroitin Sulfates; Humans; Hyaluronic Acid; Mannose; Urinary Tract; Urinary Tract Infections

2023
Intravesical hyaluronic acid and chondroitin sulfate for recurrent urinary tract infections: systematic review and meta-analysis.
    International urogynecology journal, 2018, Volume: 29, Issue:7

    The objective was to assess the efficacy of intravesical hyaluronic acid (HA) and chondroitin sulfate (CS), alone or in combination, for recurrent urinary tract infections (RUTIs) in adult female patients using a systematic review and meta-analysis.. English-language articles were obtained from the MEDLINE, Embase, and Cochrane databases through November 2016, by manual searching and cross-referencing. Randomized and nonrandomized trials of adult female patients with a documented history of RUTIs who received HA, CS or HA plus CS were included. The random effects model was applied to all pooled analyses. Risk of bias was assessed for individual studies and across studies.. Two randomized (n = 85) and six nonrandomized (n = 715) studies met the inclusion criteria. These studies assessed HA ± CS; studies of CS alone were not identified in the search. HA ± CS decreased the UTI rate per patient-year (pooled mean difference [MD] -2.56; 95% confidence interval [CI] -3.86, -1.26; p < 0.001) and increased the time to first UTI recurrence (pooled MD 130.05 days; 95% CI 5.84, 254.26; p = 0.04). There was heterogeneity in most outcomes considered, and publication bias in many studies. The standard of trial reporting was low. The patient population size, and the number of studies included, were small.. HA ± CS appears to reduce the rate of UTI and increase the time to recurrence in women with RUTI. As randomized controlled studies are available only for HA plus CS, the quality of evidence is higher for the combination than for HA alone.

    Topics: Administration, Intravesical; Adult; Chondroitin Sulfates; Female; Humans; Hyaluronic Acid; Treatment Outcome; Urinary Tract Infections

2018

Trials

2 trial(s) available for chondroitin-sulfates and Urinary-Tract-Infections

ArticleYear
Efficacy of an orally administered combination of hyaluronic acid, chondroitin sulfate, curcumin and quercetin for the prevention of recurrent urinary tract infections in postmenopausal women.
    European journal of obstetrics, gynecology, and reproductive biology, 2016, Volume: 207

    To assess whether the orally administered combination of hyaluronic acid (HA), chondroitin sulfate (CS), curcumin and quercetin could be effective in preventing recurrent cystitis in postmenopausal women and whether its efficacy was conditioned by the concurrent use of local estrogen therapy.. This was a prospective evaluation of 145 postmenopausal women consecutively recruited from the database of three different investigators. All women should have mild-to-moderate urogenital atrophy and a history of recurrent urinary tract infections (≥2 episodes within 6 months or ≥3 episodes within 12 months documented by positive urine cultures) during the last year. Patients were assigned to three different therapeutic regimens: the first group was treated only with vaginal estrogens, the second group only with HA, CS, curcumin and quercetin per os, and the third group was treated with HA, CS, curcumin and quercetin associated with local estrogens. We evaluated the number of patients with <2 infective episodes in the 6-month follow-up and <3 episodes in the 12-month follow-up (main aim definition) and the reduction of related symptoms through a Visual Analog Scale (VAS) and the Pelvic Pain and Urgency/Frequency (PUF) patient symptom scale. Student's t-test and chi-squared test were used for data analysis as appropriate.. At 6-month follow up, the main aim rate was 8%, 11.1% and 25% in the three groups, respectively (p<0.05 compared to baseline only in group 3). Although the reduction in the number of recurrent episodes became significant in all groups at 1 year follow-up, the main aim rate was almost double in women receiving both local estrogens and oral therapy (group 3) compared to those receiving single treatments. The improvement of related symptoms was significant in all groups at 12-month follow-up.. In postmenopausal women, the combination of HA, CS, curcumin and quercetin per os was effective in preventing recurrent urinary tract infections, especially if administered with vaginal estrogen therapy.

    Topics: Aging; Anti-Infective Agents, Urinary; Antioxidants; Atrophic Vaginitis; Chondroitin Sulfates; Combined Modality Therapy; Curcumin; Dietary Supplements; Disease Resistance; Estriol; Estrogen Replacement Therapy; Estrogens; Female; Humans; Hyaluronic Acid; Middle Aged; Postmenopause; Quercetin; Secondary Prevention; Severity of Illness Index; Urinary Tract Infections; Vaginal Creams, Foams, and Jellies

2016
Prevention of recurrent urinary tract infections by intravesical administration of hyaluronic acid and chondroitin sulphate: a placebo-controlled randomised trial.
    European urology, 2011, Volume: 59, Issue:4

    Urinary tract infection (UTI) is a prevalent condition in women during their lifetime with a high rate of recurrence within 3-6 mo.. Our aim was to investigate the efficacy and tolerability of the intravesical administration of combined hyaluronic acid (HA) and chondroitin sulphate (CS) in female patients with a history of recurrent UTI.. We conducted a prospective, randomised, double-blind, placebo-controlled study comparing the intravesical instillation of HA-CS with placebo in women with recurrent UTI.. Participants were randomised to receive 50 ml of sterile sodium HA 1.6% and CS 2.0% solution (IALURIL(®)) weekly for 4 wk and then monthly for 5 mo.. The primary end point of the study was defined as the mean number of UTI per patient per year. Participants were evaluated addressing UTI status/urinary symptoms and with a general health-related quality-of-life (QoL) questionnaire at baseline and after 3, 6, 9, and 12 mo.. In the intention-to-treat analysis, 57 women were randomly allocated to HA-CS (n=28) or placebo (n=29). The UTI rate per patient per year at the end of the study (12 mo) (mean±SD: -86.6%±47.6 vs -9.6%±24.6; mean difference: 77%; 95% confidence interval, 72.3-80.8; p=0.0002) and the mean time to UTI recurrence (52.7±33.4 vs 185.2±78.7 d; p<0.001) were significantly reduced after treatment with HA-CS compared with placebo. Overall urinary symptoms and QoL measured by questionnaires significantly improved compared with placebo (Pelvic Pain and Urgency/Frequency questionnaire symptom score: 14.53±4.32 vs 9.88±6.77; p=0.004; SF-36 QoL score: 78.6±6.44 vs 53.1±4.72; p<0.001). No serious adverse event was reported.. Compared with placebo, HA-CS intravesical instillations significantly reduced UTI rate without severe side effects while improving symptoms and QoL over a 12-mo period in patients with recurrent UTI.. ISRCTN 76354426.

    Topics: Administration, Intravesical; Adult; Chondroitin Sulfates; Cystitis; Drug Therapy, Combination; Female; Humans; Hyaluronic Acid; Kaplan-Meier Estimate; Middle Aged; Placebos; Quality of Life; Secondary Prevention; Treatment Outcome; Urinary Tract Infections; Viscosupplements

2011

Other Studies

12 other study(ies) available for chondroitin-sulfates and Urinary-Tract-Infections

ArticleYear
Intravesical hyaluronic acid with chondroitin sulphate to prevent urinary tract infection after spinal cord injury.
    The journal of spinal cord medicine, 2023, Volume: 46, Issue:5

    Prevention of urinary tract infection (UTI) after spinal cord injury is an important goal. Intravesical hyaluronic acid with chondroitin sulphate (HA+CS) has been effective in preventing UTI in other settings. We aimed to demonstrate safety and feasibility of a standard treatment course of 7 intravesical HA+CS instillations over 12 weeks, in patients with acute (Arm A) and chronic (Arm B) spinal cord injury (SCI).. Follow-up of adverse events, quality of life bladder management difficulty (BMD) and bladder complication (BC). Of 33 and 14 individuals screened, 2 and 8 participants were recruited to the study for Arm A and Arm B respectively. Of the 10 participants, 8 completed all 7 instillations. HA+CS commonly caused cloudy urine with urinary sediment which was mild and short-lived. In Arm B, a mean reduction in BMD and BC T-scores was observed from baseline (57.3 and 54.4 respectively), of 6.8 and 4.3 at 12 weeks and 1.6 and 2.8 at 24 weeks, respectively. Four participants with a history of frequent UTI in the prior 12 months did not have UTI in the 24 weeks of the study.. HA+CS was well tolerated. Recruitment was more difficult in early acute SCI; participants with chronic SCI were highly motivated to reduce UTI and manage self-administration without difficulty. Larger case-control or randomized controlled trials in patients with neurogenic bladder from SCI are warranted.. ClinicalTrials.gov identifier: NCT03945110.

    Topics: Chondroitin Sulfates; Humans; Hyaluronic Acid; Quality of Life; Spinal Cord Injuries; Urinary Tract Infections

2023
Urinary Glycosaminoglycans Are Associated with Recurrent UTI and Urobiome Ecology in Postmenopausal Women.
    ACS infectious diseases, 2023, 04-14, Volume: 9, Issue:4

    Glycosaminoglycans (GAGs) are linear, negatively charged polysaccharides composed of repeating disaccharide units of uronic acid and amino sugars. The luminal surface of the bladder epithelium is coated with a GAG layer. These urothelial GAGs are thought to provide a protective barrier and serve as a potential interaction site with the urinary microbiome (urobiome). Previous studies have profiled urinary GAG composition in mixed cohorts, but the urinary GAG composition in postmenopausal women remains undefined. To investigate the relationship between GAGs and recurrent urinary tract infection (rUTI), we profiled urinary GAGs in a controlled cohort of postmenopausal women. We found that chondroitin sulfate (CS) is the major urinary GAG in postmenopausal women and that urinary CS was elevated in women with active rUTI. We also associated urinary GAGs with urobiome composition and identified bacterial species that significantly associated with urinary GAG concentration.

    Topics: Chondroitin Sulfates; Female; Glycosaminoglycans; Heparin; Humans; Postmenopause; Urinary Tract Infections

2023
The efficacy and safety of intravesical chondroitin sulphate solution in recurrent urinary tract infections.
    BMC urology, 2022, Nov-23, Volume: 22, Issue:1

    Urinary tract infections are among the most common indications for antibiotic therapy. The emergence of resistant uropathogens indicates the need for treatment alternatives. Replenishment of the glycosaminoglycan layer of the bladder, achieved by intravesical instillation of e.g. chondroitin sulphate (CS), is described to be a cornerstone in the therapy of cystitis. To retrospectively evaluate the efficacy of a therapy with 0.2% CS in patients suffering recurrent urinary tract infections (rUTI) in comparison to a treatment with low-dose long-term antibiotics (LDLTAB) and a combination of both.. A total of 151 patients with recurrent UTI who underwent intravesical therapy at Diaconesse hospital in Leiden, The Netherlands were included. 50 patients had been treated with CS, 51 patients had received LDLTAB, and 50 patients had received a combination therapy (LDLTABCS). Data recorded for baseline, after 6, and 12 months of treatment were evaluated. Descriptive statistics were calculated. Exploratory comparisons between groups and within groups were performed by using one-tailed and paired t-tests. Patients filled in a standardized quality of life questionnaire (EQ-5D).. We found a statistically significant reduction of number of infections from 7.10 ± 0.50 SEM to 0.45 ± 0.07 SEM after 12 months therapy with CS compared to 12 months therapy with LDLTAB (from 7.04 ± 0.47 SEM to 1.8 ± 0.15 SEM). The number of visits to the urologist significantly decreased in the CS group from 7.46 ± 0.80 SEM to 1.28 ± 0.11 SEM and from 4.10 ± 0.29 SEM to 1.35 ± 0.11 SEM in the LDLTABCS group. In addition, a significant increase in Quality of life (QoL) was seen in the CS-group (from 58.2 ± 0.82 SEM to 80.43 ± 0.82 SEM) and in the LDLTABCS group (from 62.4 ± 0.97 SEM to 76.73 ± 1.06 SEM). There was no improvement in QoL with LDLTAB (from 58.24 ± 1.08 SEM to 58.96 ± 1.19 SEM). Evaluation's evidence is limited due to its retrospective character.. Retrospective analysis of data from patients that underwent therapy for rUTIs confirms the safety and efficacy of CS and indicate a superiority to antibiotic treatment of rUTIs.

    Topics: Anti-Bacterial Agents; Chondroitin Sulfates; Cystitis; Humans; Quality of Life; Retrospective Studies; Urinary Tract Infections

2022
Intravesical instillation of hyaluronic acid and chondroitin sulfate for recurrent urinary tract infections.
    Actas urologicas espanolas, 2020, Volume: 44, Issue:8

    Topics: Adjuvants, Immunologic; Administration, Intravesical; Chondroitin Sulfates; Humans; Hyaluronic Acid; Urinary Tract Infections

2020
[Recurrent urinary tract infections: prevention of recurrence with intravesical instillations of chondroitin sulfate and hyaluronic acid.]
    Archivos espanoles de urologia, 2017, Volume: 70, Issue:2

    The aim of our study is to demonstrate that intravesical administration of the association chondroitin sulfate (CS) and hyaluronic acid (HA), according to our treatment schedule, is a benefit for women with recurrent urinary tract infections (RUTI), not only from a clinical point of view, but also reducing recurrences.. This is a study of 28 women diagnosed with RUTI, with a positive culture, and compatible symptoms;frethey underwent treatment according to the protocol of intravesical instillations of the combination CS 2%-1 gr + HA 1.6%-800 mg. To evaluate the effectiveness of the treatment, symptoms improvement, reduction of the number of episodes of urinary tract infection and quality of life were considered.. In our series, we can observe an improvement of the quality of life assessed by PG-I, 66% after 12 months. It was seen that 55.6% of the patient's urine cultures became negative, while 44.4% had episodes of urinary infection, but with lower baseline symptoms intensity.. Patients included in the protocol of instillation improved significantly their quality of life; in addition, to a considerable extent new urinary infections were not presented, being milder when they presented.

    Topics: Administration, Intravesical; Adult; Aged; Aged, 80 and over; Chondroitin Sulfates; Drug Therapy, Combination; Female; Humans; Hyaluronic Acid; Middle Aged; Quality of Life; Recurrence; Urinary Tract Infections

2017
Intravesical administration of combined hyaluronic acid (HA) and chondroitin sulfate (CS) for the treatment of female recurrent urinary tract infections: a European multicentre nested case-control study.
    BMJ open, 2016, Mar-31, Volume: 6, Issue:3

    To compare the clinical effectiveness of the intravesical administration of combined hyaluronic acid and chondroitin sulfate (HA+CS) versus current standard management in adult women with recurrent urinary tract infections (RUTIs).. A European Union-based multicentre, retrospective nested case-control study.. 276 adult women treated for RUTIs starting from 2009 to 2013.. Patients treated with either intravesical administration of HA+CS or standard of care (antimicrobial/immunoactive prophylaxis/probiotics/cranberry).. The primary outcome was occurrence of bacteriologically confirmed recurrence within 12 months. Secondary outcomes were time to recurrence, total number of recurrences, health-related quality of life and healthcare resource consumption. Crude and adjusted results for unbalanced characteristics are presented.. 181 patients treated with HA+CS and 95 patients treated with standard of care from 7 centres were included. The crude and adjusted ORs (95% CI) for the primary end point were 0.77 (0.46 to 1.28) and 0.51 (0.27 to 0.96), respectively. However, no evidence of improvement in terms of total number of recurrences (incidence rate ratio (95% CI), 0.99 (0.69 to 1.43)) or time to first recurrence was seen (HR (95% CI), 0.99 (0.61 to 1.61)). The benefit of intravesical HA+CS therapy improves when the number of instillations is ≥ 5.. Our results show that bladder instillations of combined HA+CS reduce the risk of bacteriologically confirmed recurrences compared with the current standard management of RUTIs. Total incidence rates and hazard rates were instead non-significantly different between the 2 groups after adjusting for unbalanced factors. In contrast to what happens with antibiotic prophylaxis, the effectiveness of the HA+CS reinstatement therapy improves over time.. NCT02016118.

    Topics: Administration, Intravesical; Adult; Aged; Case-Control Studies; Chondroitin Sulfates; Databases, Factual; Drug Therapy, Combination; Europe; Female; Humans; Hyaluronic Acid; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Quality of Life; Recurrence; Retrospective Studies; Treatment Outcome; Urinary Tract Infections

2016
Is intravesical instillation of hyaluronic acid and chondroitin sulfate useful in preventing recurrent bacterial cystitis? A multicenter case control analysis.
    Taiwanese journal of obstetrics & gynecology, 2015, Volume: 54, Issue:5

    Urinary tract infections (UTIs) are common in the female population and, over a lifetime, about half of women have at least one episode of UTI requiring antibiotic therapy. The aim of the current study was to compare two different strategies for preventing recurrent bacterial cystitis: intravesical instillation of hyaluronic acid (HA) plus chondroitin sulfate (CS), and antibiotic prophylaxis with sulfamethoxazole plus trimethoprim.. This was a retrospective review of two different cohorts of women affected by recurrent bacterial cystitis. Cases (experimental group) were women who received intravesical instillations of a sterile solution of high concentration of HA + CS in 50 mL water with calcium chloride every week during the 1(st) month and then once monthly for 4 months. The control group included women who received traditional therapy for recurrent cystitis based on daily antibiotic prophylaxis using sulfamethoxazole 200 mg plus trimethoprim 40 mg for 6 weeks.. Ninety-eight and 76 patients were treated with experimental and control treatments, respectively. At 12 months after treatment, 69 and 109 UTIs were detected in the experimental and control groups, respectively. The proportion of patients free from UTIs was significantly higher in the experimental than in the control group (36.7% vs. 21.0%; p = 0.03). Experimental treatment was well tolerated and none of the patients stopped it.. The intravesical instillation of HA + CS is more effective than long-term antibiotic prophylaxis for preventing recurrent bacterial cystitis.

    Topics: Adjuvants, Immunologic; Administration, Intravesical; Adult; Chondroitin Sulfates; Cystitis; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hyaluronic Acid; Instillation, Drug; Recurrence; Retrospective Studies; Urinalysis; Urinary Tract Infections

2015
In vitro studies on the role of glycosaminoglycans in crystallization intensity during infectious urinary stones formation.
    APMIS : acta pathologica, microbiologica, et immunologica Scandinavica, 2014, Volume: 122, Issue:6

    Proteus mirabilis cause urinary tract infections which are recurrent and can lead to formation of urinary calculi. Both bacterial and the host factors are involved in the development of urolithiasis. To determine the impact of glycosaminoglycans (GAGs) in the formation of P. mirabilis-induced urinary stones, we investigated the in vitro crystallization, aggregation and adhesion of crystals in the presence of GAGs naturally appearing in urine. Crystallization experiments were performed in synthetic urine infected with P. mirabilis in the presence of: hyaluronic acid (HA), heparan sulfate (HS), chondroitin sulfate A, B and C (ChSA, ChSB, ChSC). The intensity of crystallization and aggregation were established by counting particles and phase-contrast microscopy. To analyze the adhesion of crystals, we used normal urothelium and (45)Ca isotope-labeled crystals. In the presence of ChSC, both the size of the crystals formed and their number were higher compared with the control. GAGs increased crystals adhesion to the cells, but only for ChSA this effect was significant. Chondroitin sulfates, which accelerate the first stages of infection-induced stones formation, may play an important role in the pathogenesis of infectious urolithiasis.

    Topics: Adhesiveness; Apatites; Cell Line; Chondroitin Sulfates; Crystallization; Dermatan Sulfate; Glycosaminoglycans; Heparitin Sulfate; Host-Pathogen Interactions; Humans; Hyaluronic Acid; Magnesium Compounds; Microscopy, Phase-Contrast; Models, Biological; Phosphates; Proteus Infections; Proteus mirabilis; Struvite; Urinary Calculi; Urinary Tract Infections; Urothelium; Virulence

2014
Morphological changes of bladder mucosa in patients who underwent instillation with combined sodium hyaluronic acid-chondroitin sulphate (Ialuril®).
    Urologia internationalis, 2013, Volume: 91, Issue:1

    To investigate what changes are endoscopically evident after glycosaminoglycans (GAGs) therapy by hyaluronic acid (HA) and chondroitin sulphate (CS) (Ialuril®) in female patients affected by bladder pain syndrome(BPS)/ interstitial cystitis (IC) or recurrent urinary tract infections (rUTIs).. 21 female patients over 18 years affected by rUTIs or BPS/IC received intravesical instillation of HA and CS (4 weekly instillations followed by 2 instillations every 2 weeks and 2 instillation monthly). Post-treatment evaluation included cystoscopy and patient assessment of improvement in symptoms and satisfaction on a visual analogue scale (VAS) from 0 to 10.. The post-treatment endoscopy showed a positive effect on bladder mucosa morphology. In 2 cases, treatment did not change endoscopic findings and clinical symptoms. In the other patients, when macroscopic features of the bladder mucosa normalized, the clinical picture improved.. GAGs therapy by HA and CS (Ialuril) improves the morphology of bladder mucosa in patients with rUTI or BPS/IC.

    Topics: Adult; Aged; Chondroitin Sulfates; Cystitis; Cystitis, Interstitial; Cystoscopy; Drug Combinations; Endoscopy; Female; Glycosaminoglycans; Humans; Hyaluronic Acid; Middle Aged; Mucous Membrane; Urinary Bladder; Urinary Bladder Diseases; Urinary Tract Infections; Urothelium

2013
Adhesion blockers: a paradigm shift in the treatment of urinary tract infections.
    European urology, 2012, Volume: 62, Issue:2

    Topics: Chondroitin Sulfates; Drug Therapy, Combination; Female; Humans; Hyaluronic Acid; Mucous Membrane; Quality of Life; Randomized Controlled Trials as Topic; Urinary Bladder; Urinary Tract Infections

2012
Intravesical hyaluronic acid and chondroitin sulfate alone and in combination for urinary tract infection: assessment of protective effects in a rat model.
    International journal of urology : official journal of the Japanese Urological Association, 2012, Volume: 19, Issue:12

    To determine the protective effects of hyaluronic acid and chondroitin sulfate in treating urinary tract infections in a rat model.. A total of 28 rats, which were induced with urinary tract infections through intravesical administration of Escherichia coli, were included in the study. By random selection, they were equally divided into four groups as control (no treatment), hyaluronic acid, chondroitin sulfate and hyaluronic acid + chondroitin sulfate. Bacteriological cultures of the urine and bladder tissue samples were carried out, and the data for each group were statistically compared.. In the urine cultures, there were significant differences in median bacterial growth rates in hyaluronic acid (5 × 10(3) cfu/mL) and chondroitin sulfate (1 × 10(4) cfu/mL) groups relative to the control group (5 × 10(4) cfu/mL). However, a significantly lower rate of bacterial colony growth was observed in the hyaluronic acid + chondroitin sulfate group (8 × 10(2) cfu/mL; P < 0.05). In the bladder tissues, statistically significant decreases in median bacterial growth rates were detected in the hyaluronic acid and hyaluronic acid + chondroitin sulfate groups (both 0 cfu/mg tissue; P < 0.05). Also, transitional epithelium damage decreased in the treatment groups. However, this effect was prominent in hyaluronic acid + chondroitin sulfate group.. Our experimental findings show that the hyaluronic acid + chondroitin sulfate combination has a potential benefit in reducing the bacterial load in urine and the thickness of the transitional epithelium.

    Topics: Adjuvants, Immunologic; Administration, Intravesical; Analysis of Variance; Animals; Chondroitin Sulfates; Colony Count, Microbial; Drug Therapy, Combination; Escherichia coli; Escherichia coli Infections; Female; Hyaluronic Acid; Rats; Rats, Sprague-Dawley; Statistics, Nonparametric; Urinary Bladder; Urinary Tract Infections; Urine; Urothelium

2012
Editorial comment to intravesical hyaluronic acid and chondroitin sulfate alone and in combination for urinary tract infection: assessment of protective effects in a rat model.
    International journal of urology : official journal of the Japanese Urological Association, 2012, Volume: 19, Issue:12

    Topics: Adjuvants, Immunologic; Animals; Chondroitin Sulfates; Escherichia coli; Escherichia coli Infections; Female; Hyaluronic Acid; Urinary Tract Infections

2012