Low-dose smoking resumption in ex-smokers with refractory ulcerative colitis

Background and aimUlcerative colitis (UC) is primarily a disease of non-smokers. Ex-smokers may have a more refractory disease course and anecdotal evidence in non-controlled clinical trials have suggested that smoking resumption, or the administration of nicotine, may ameliorate signs and symptoms of UC in ex-smokers. We report outcomes of ex-smokers with refractory UC who resumed low-dose cigarette smoking.Methods17 ex-smokers with refractory UC were identified. Clinical remission was defined as a disease activity index score of 0.ResultsTwo out of 17 patients refused the recommendation to resume smoking. Of the 15 patients who resumed smoking, the mean daily number of cigarettes was 8.6. Fourteen out of those 15 patients who resumed smoking were able to maintain prolonged clinical remission off steroids. One out of the 15 patients failed to improve and required oral steroids. Another patient was compelled to quit smoking since he became addicted. His disease flared after maintaining a prolonged remission of 3 years and he eventually underwent surgery. Three out of these 15 patients switched from cigarettes smoking to nicotine compounds and continued to maintain remission.ConclusionResumption of low dose smoking in a selected group of ex-smokers with refractory UC may ameliorate signs and symptoms. Quality of life, medication side effects, and smoking risk factors should all be considered and discussed with patients. Smokers should be meticulously followed for compliance with “low-dose” regimen and all associated smoking risks.     

Inflammatory bowel disease and smoking: a review of epidemiology, pathophysiology, and therapeutic implications

The relationship between smoking behavior and inflammatory bowel disease (IBD) is complex. While Crohn's disease (CD) is associated with smoking and smoking has detrimental effects on the clinical course of the disease, ulcerative colitis (UC) is largely a disease of nonsmokers and former smokers. Furthermore, cigarette smoking may even result in a beneficial influence on the course of ulcerative colitis. The potential mechanisms involved in this dual relationship include changes in humoral and cellular immunity, cytokine and eicosanoid levels, gut motility, permeability, and blood flow, colonic mucus, and oxygen free radicals. Nicotine is assumed to be the active moiety. The differential therapeutic consequences comprise the cessation of smoking in CD and, so far, clinical trials using nicotine in different forms of application for UC. In this article, we review the relationship between cigarette smoking and IBD, considering epidemiological, pathogenetic, and clinical aspects.     

Effect of smoking on inflammatory bowel disease： Is it disease or organ specific？

Smoking is an important environmental factor in inflammatory bowel disease （IBD） with differing effects in ulcerative colitis （UC） and Crohn＇s disease （CD）. Never smoking and formerly smoking increase the risk of UC, whereas smoking exacerbates the course of CD. The potential mechanisms involved in this dual relationship are yet unknown. A reasonable assumption is that smoking has different effects on the small and large intestine. This assumption is based on animal and human studies that show that the effects of smoking/nicotine on CD and UC depend on the site of inflammation and not on the type of disease.     

In siblings with similar genetic susceptibility for inflammatory bowel disease,smokers tend to develop Crohn's disease and non-smokers develop ulcerative colitis

BACKGROUND AND AIMS: Smoking tobacco has opposite effects on the different forms of inflammatory bowel disease (IBD). It predisposes to the development of Crohn's disease (CD) yet is associated with a reduced incidence of ulcerative colitis (UC). We have studied sib pairs discordant for both smoking and IBD phenotype (UC or CD) to investigate whether smoking determines the type of IBD that develops in individuals with very similar genetic susceptibility. PATIENTS: Smoking habits and disease characteristics were analysed in 242 IBD pedigrees (658 patients). Within this group there were 339 affected sibling pairs of whom 89 were discordant for smoking when diagnosed. RESULTS: Smoking at diagnosis was associated with development of CD (odds ratio (OR) 3.55; 95% confidence limits 2.50-5.02; p<0.001) in all of the familial patients, with increases when analysed for ileocaecal disease, fibrostenosis, and intestinal resection. Smokers were also protected from UC (OR 0.28; 0.2-0.4; p<0.001). Of 89 sibling pairs discordant for smoking at diagnosis, 23 were also discordant for disease type-in 21 of these, CD occurred in the smoker and UC in the non-smoker (OR 10.5; 2.6-92; p<0.0001). CONCLUSIONS: Smoking is a strong environmental risk factor for Crohn's disease and increases the likelihood of needing surgery. However, sib pairs who are discordant for both smoking and IBD type almost always show CD in the smoker and UC in the non-smoker, and so in some cases tobacco consumption acts on IBD genetic predisposition to shift the phenotype from UC towards CD. The explanation of part of the apparent "protective" effect of smoking on sporadic UC may be that the form of IBD that develops in a proportion of smokers is not UC but CD.     

Hypothesis about mechanisms through which nicotine might exert its effect on the interdependence of inflammation and gut barrier function in ulcerative colitis

Ulcerative colitis (UC) is characterized by impairment of the epithelial barrier and the formation of ulcer-type lesions, which result in local leaks and generalized alterations of mucosal tight junctions. Ultimately, this results in increased basal permeability. Although disruption of the epithelial barrier in the gut is a hallmark of inflammatory bowel disease and intestinal infections, it remains unclear whether barrier breakdown is an initiating event of UC or rather a consequence of an underlying inflammation, evidenced by increased production of proinflammatory cytokines. UC is less common in smokers, suggesting that the nicotine in cigarettes may ameliorate disease severity. The mechanism behind this therapeutic effect is still not fully understood, and indeed it remains unclear if nicotine is the true protective agent in cigarettes. Nicotine is metabolized in the body into a variety of metabolites and can also be degraded to form various breakdown products. It is possible these metabolites or degradation products may be the true protective or curative agents. A greater understanding of the pharmacodynamics and kinetics of nicotine in relation to the immune system and enhanced knowledge of gut permeability defects in UC are required to establish the exact protective nature of nicotine and its metabolites in UC. This review suggests possible hypotheses for the protective mechanism of nicotine in UC, highlighting the relationship between gut permeability and inflammation, and indicates where in the pathogenesis of the disease nicotine may mediate its effect.     

Do clinical factors help to predict disease course in inflammatory bowel disease?

While therapeutic strategies able to change the natural history of the disease are developing,it is of major importance to have available predictive factors for aggressive disease to try and target these therapeutic strategies.Clinical predictors have probably been the most broadly studied.In both Crohn's disease(CD) and ulcerative colitis(UC),age at diagnosis,disease location and smoking habit are currently the strongest predictors of disease course.A younger age at onset is associated with more aggressive...     

Reduced nicotine content cigarettes: effects on toxicant exposure,dependence and cessation

Aims To examine the effects of reduced nicotine cigarettes on smoking behavior, toxicant exposure, dependence and abstinence. Design Randomized, parallel arm, semi‐blinded study. Setting University of Minnesota Tobacco Use Research Center. Interventions Six weeks of: (i) 0.05 mg nicotine yield cigarettes; (ii) 0.3 mg nicotine yield cigarettes; or (iii) 4 mg nicotine lozenge; 6 weeks of follow‐up. Measurements Compensatory smoking behavior, biomarkers of exposure, tobacco dependence, tobacco withdrawal and abstinence rate. Findings Unlike the 0.3 mg cigarettes, 0.05 mg cigarettes were not associated with compensatory smoking behaviors. Furthermore, the 0.05 mg cigarettes and nicotine lozenge were associated with reduced carcinogen exposure, nicotine dependence and product withdrawal scores. The 0.05 mg cigarette was associated with greater relief of withdrawal from usual brand cigarettes than the nicotine lozenge. The 0.05 mg cigarette led to a significantly higher rate of cessation than the 0.3 mg cigarette and a similar rate as nicotine lozenge. Conclusion The 0.05 mg nicotine yield cigarettes may be a tobacco product that can facilitate cessation; however, future research is clearly needed to support these preliminary findings.     

Impact of environmental and dietary factors on the course of inflammatory bowel disease

Besides their possible effects on the development of inflammatory bowel disease (IBD), some environmental factors can modulate the clinical course of both ulcerative colitis (UC) and Crohn's disease (CD). This review is mainly devoted to describing the current knowledge of the impact of some of these factors on the outcome of IBD, with special emphasis on smoking and diet. Although the impact of smoking on the susceptibility to develop CD and UC is firmly established, its influence on the clinical course of both diseases is still debatable. In CD, active smoking is a risk factor for postoperative recurrence. Beyond this clinical setting, smoking cessation seems to be advantageous in those CD patients who were smokers at disease diagnosis, while smoking resumption may be of benefit in ex-smokers with resistant UC. The role of dietary habits on the development of IBD is far from being well established. Also, food intolerances are very frequent, but usually inconsistent among IBD patients, and therefore no general dietary recommendations can be made in these patients. In general, IBD patients should eat a diet as varied as possible. Regarding the possible therapeutic role of some dietary components in IBD, lessons should be drawn from the investigation of the primary therapeutic effect of enteral nutrition in CD. Low-fat diets seem to be particularly useful. Also, some lipid sources, such as olive oil, medium-chain triglycerides, and perhaps omega-3 fatty acids, might have a therapeutic effect. Fermentable fiber may have a role in preventing relapses in inactive UC.     

Meta-analysis of the role of oral contraceptive agents in inflammatory bowel disease.

Numerous epidemiological studies have been performed to determine factors that might contribute to the development of inflammatory bowel disease. Although the role of oral contraceptive agents in Crohn's disease (CD) and ulcerative colitis (UC) have been assessed, most studies were of small sample size and characterised by low statistical precision. A meta-analysis was performed to increase the statistical power and to investigate the association between the use of oral contraceptives and the development of CD and UC. The study was based on a search of a Medline database from 1975 to October 1993 and a review of reference lists from published articles, reviews, symposia proceedings, and abstracts from major gastrointestinal meetings. All studies specifically designed to evaluate this association were selected. The combined results of nine studies--two cohort studies (30,379 unexposed and 30,673 exposed patients) and seven case-control studies (482 CD, 237 UC, and 3198 controls)--which satisfied our selection criteria were evaluated. The pooled relative risk (adjusted for smoking) associated with oral contraceptive use was 1.44 (1.12, 1.86) for CD and 1.29 (0.94, 1.77) for UC. These results suggest modest associations between the use of oral contraceptives and the development of CD and UC. As these associations are weak, non-causal explanations for the findings cannot be eliminated.     

Cigarette smoking as a risk factor for atherosclerosis and renal disease: Novel pathogenic insights

Cigarette smoking is the major cause of preventable morbidity and mortality in the United States. It is a major risk factor for atherosclerotic vascular disease and recently was identified as an important risk factor in the progression of chronic kidney disease. Several compounds in cigarette smoke, including nicotine and reactive aldehydes (eg, acrolein), have been implicated as mediators of endothelial dysfunction and atherosclerosis in smokers. In addition, studies have demonstrated that nicotine induces endothelial dysfunction in humans and accelerates atherosclerosis in animals. Large clinical trials have suggested that cigarette smoking is a risk factor for progression of chronic kidney disease in diabetics and nondiabetics, and in polycystic kidney disease, lupus nephritis, and IgA nephropathy. Recent studies suggest that nicotine has powerful mitogenic effects and induces extracellular matrix production in human mesangial cells via reactive oxygen species generation. These effects of nicotine may play a major role in the pathogenic mechanisms that mediate the deleterious effects of smoking in renal disease.     

Clinical status of ulcerative colitis in patients who smoke

Objectives: Ulcerative colitis (UC) is largely a disease of nonsmokers. There are few patients who are current smokers, but we have identified a group and reviewed their clinical status, disease activity, and nicotine exposure to examine whether they remain well controlled while smoking.
Methods: Fifty-one patients from three centers with verified UC were reviewed.
Results: Thirty of the group were men; mean age 50 yr, with a mean age of onset of 37 yr. Twenty-two patients had proctosigmoid disease, 12 involvement of left colon, and 17 total colitis. All were current smokers; 41 were cigarette smokers averaging 17 daily. At the onset of colitis 30 were nonsmokers, 25 of them were ex-smokers and 19 developed colitis within 2 yr of stopping smoking. Twenty-eight believed smoking improved disease activity and none felt smoking had a detrimental effect on their UC. Eleven were receiving no medication for UC, 40 were receiving 5-ASA (5-aminosalicylic acid) preparations, and only two took oral steroids. All were in clinical remission, with the exception of one patient; mean St. Marks score was 1.5, out of a possible total of 22. Sigmoidoscopic grades were inactive in all patients except three. Histological assessment showed significant activity in only five. Median serum nicotine was 8 ng/ml (range, 0.4–24.4), median serum cotinine 180 ng/ml (range, 20–453), with corresponding salivary cotinine of 255 ng/ml (range, 34–683). Median rise in nicotine 2 min after a cigarette in 35 patients was 12.1 ng/ml (range, 0.4–44).
Conclusions: Because most current smokers with UC have inactive disease, smoking may contribute to the clinical remission in these patients.     

Nicotine induced haemodynamic changes during cigarette smoking and nicotine gum chewing: a placebo controlled study in young healthy volunteers

Because cigarette smoking is a definite risk for the development of cardiovascular disease and nicotine induced vasoconstriction may be a possible pathogenetic factor the haemodynamic effects of smoking cigarettes with high or low nicotine content were compared with those induced by chewing nicotine gum in a placebo controlled, crossover study in six healthy volunteers. The three stimuli induced similar increases in heart rate (about 20%) and systolic blood pressure (about 7%) and a decrease in digital blood flow. Although the mean haemodynamic changes parallelled the mean plasma nicotine concentration increases, no correlation was found between them when the individual values were considered. It is concluded that the nicotine induced haemodynamic changes probably occur as a result of the (local) release of vasoactive mediators such as adrenaline or noradrenaline after a threshold plasma nicotine concentration has been reached. Such a threshold may explain the large interindividual variability in susceptibility to smoking induced cardiovascular diseases.     

Smoking cessation, but not smoking reduction, reduces plasma homocysteine levels.

BACKGROUND: Cigarette smoking has been associated with increased plasma homocysteine levels. Although hyperhomocysteinemia may mediate some of the adverse cardiovascular consequences of smoking cigarettes, the effects of smoking cessation and smoking reduction on homocysteine levels have not been evaluated previously. HYPOTHESIS: The purpose of this study was to determine the effects of smoking cessation and smoking reduction on plasma homocysteine levels. METHODS: Fifty-one healthy subjects who smoked 35.9 +/- 6.4 cigarettes daily were randomized to continue smoking, reduce smoking to 4-8 cigarettes daily, or to stop smoking. A nicotine inhaler and individualized counseling were provided as aids to smoking cessation. RESULTS: In subjects who quit smoking, homocysteine levels decreased by 11.6%, from 8.58 +/- 2.31 to 7.53 +/- 2.26 micromol/l (p = 0.013). Significant changes in homocysteine levels were not observed in subjects who reduced smoking or continued to smoke. CONCLUSION: A "harm reduction" strategy of reducing cigarette use may not be sufficient for reducing the vascular risk associated with smoking cigarettes.     

Association of a single nucleotide polymorphism in neuronal acetylcholine receptor subunit alpha 5 (CHRNA5) with smoking status and with 'pleasurable buzz' during early experimentation with smoking

AIMS: To extend the previously identified association between a single nucleotide polymorphism (SNP) in neuronal acetylcholine receptor subunit alpha-5 (CHRNA5) and nicotine dependence to current smoking and initial smoking-experience phenotypes. DESIGN, SETTING, PARTICIPANTS: Case-control association study with a community-based sample, comprising 363 Caucasians and 72 African Americans (203 cases, 232 controls). MEASUREMENTS: Cases had smoked > or = five cigarettes/day for > or = 5 years and had smoked at their current rate for the past 6 months. Controls had smoked between one and 100 cigarettes in their life-time, but never regularly. Participants also rated, retrospectively, pleasurable and displeasurable sensations experienced when they first smoked. We tested for associations between smoking phenotypes and the top 25 SNPs tested for association with nicotine dependence in a previous study. FINDINGS: A non-synonymous coding SNP in CHRNA5, rs16969968, was associated with case status [odds ratio (OR) = 1.5, P = 0.01] and, in Caucasians, with experiencing a pleasurable rush or buzz during the first cigarette (OR = 1.6, P = 0.01); these sensations were associated highly with current smoking (OR = 8.2, P = 0.0001). CONCLUSIONS: We replicated the observation that the minor allele of rs16969968 affects smoking behavior, and extended these findings to sensitivity to smoking effects upon experimentation. While the ability to test genetic associations was limited by sample size, the polymorphism in the CHRNA5 subunit was shown to be associated significantly with enhanced pleasurable responses to initial cigarettes in regular smokers in an a priori test. The findings suggest that phenotypes related to subjective experiences upon smoking experimentation may mediate the development of nicotine dependence.     

Genetic variants of glutathione S-transferases μ, θ, and π display no susceptibility to inflammatory bowel disease in the Danish population

Abstract

Introduction. A combination of genetic predisposition and interactions with environmental factors are believed to be responsible for disease phenotype and disease progression in inflammatory bowel diseases. The harmful effect of smoking and other environmental factors is believed to be highly dependent on the activity of detoxification enzymes. The aims of the study were to examine possible associations between the detoxifying glutathione S-transferases (GSTs) family μ, θ and π gene variants and inflammatory bowel disease, and secondly to examine a potential genotype–genotype interaction between these variants. Genotype–disease phenotype associations and a possible interaction between genotype and cigarette smoking were also assessed. Methods. Three hundred and eighty-eight patients with Crohn's disease (CD), 565 patients with ulcerative colitis (UC) and 796 healthy Danish controls were included in the study. Genomic DNA was used for genotyping of the GST genes using PCR or real-time PCR. Results. No associations were found between GST genotypes and inflammatory bowel diseases. Neither did a combination of the GST genotypes reveal any associations. No genotype–disease phenotype associations were found. Smoking was positively associated with CD and negatively associated with UC. An interaction between smoking and GSTM1*0 genotype was found for UC, where the GSTM1*0 genotype appear to strengthen the protective effect of smoking on disease susceptibility. Conclusion. The GST genotypes do not seem to be important in susceptibility of inflammatory bowel disease in the Danish population. Nor did we find convincing evidence of associations between GST genotype and phenotypic features of inflammatory bowel diseases.     

The relationship between heritability and smoking habits in Crohn's disease. Italian Cooperative Study Group

OBJECTIVE: In Crohn's disease (CD), the relationship between genetic predisposition and smoking has not been well defined. The aim of this study was to compare the smoking habits at the time of the diagnosis of CD patients having familial occurrence of inflammatory bowel disease (IBD) with those of some control groups. METHODS: In a multicenter study, 136 CD patients with a relative with IBD, 272 healthy controls matched for sex and age, 500 CD patients without familial occurrence of IBD, and 84 ulcerative colitis patients (UC) with familial occurrence of IBD were personally interviewed about their smoking habits. In addition, data for 35 healthy siblings of patients with familial CD were collected by interviewing the patients' relatives. RESULTS: The prevalence of smokers was found significantly higher in CD patients with a family history for IBD than in healthy controls and in familial UC patients (OR 2.28 CI 1.5-3.48 and OR 5.81 CI 3.15-10.75, respectively). No significant difference was found either in the percentage of smokers or in the number of cigarettes smoked per day between familial and sporadic CD patients. Among all siblings of CD patients, 72% of affected siblings and 34% of healthy siblings were smokers, concordant with their relatives. CONCLUSIONS: In CD patients with familial occurrence of IBD, the percentage of smokers is elevated. It is possible that in a genetically predisposed population, smoking could be an important environmental factor in determining CD or expressing this disease instead of UC.     

Environmental factors in inflammatory bowel disease: a co-twin control study of a Swedish-Danish twin population

BACKGROUND: Genetics and environmental factors are implicated in the etiology of inflammatory bowel disease (IBD). We studied environmental factors in a population-based Swedish-Danish twin cohort using the co-twin control method. SUBJECTS AND METHODS: A questionnaire was sent to 317 twin pairs regarding markers of exposures in the following areas: infections/colonization and diet as well as smoking, appendectomy, and oral contraceptives. Odds ratios (OR) were calculated by conditional logistic regression. When confounding appeared plausible, multivariate conditional logistic regression was added. The questions were also divided into topic groups, and adjustment was made for multiple testing within each of the groups. RESULTS: The response rate to the questionnaire was 83%. In consideration of the study design, only discordant pairs were included (Crohn's disease [CD], n = 102; ulcerative colitis [UC], n = 125). Recurrent gastrointestinal infections were associated with both UC (OR, 8.0; 95% confidence interval [CI], 1.0-64) and CD (OR, 5.5; 95% CI, 1.2-25). Hospitalization for gastrointestinal infections was associated with CD (OR, 12; 95% CI, 1.6-92). Smoking was inversely associated with UC (OR, 0.4; 95% CI, 0.2-0.9) and associated with CD (OR, 2.9; 95% CI, 1.2-7.1). CONCLUSIONS: The observed associations indicate that markers of possible infectious events may influence the risk of IBD. Some of these effects might be mediated by long-term changes in gut flora or alterations in reactivity to the flora. The influence of smoking in IBD was confirmed.     

Estrategias de reducción de riesgos en tabaquismo: ¿oportunidad o amenaza?

The smoking control policies recommended by the World Health Organisation have achieved a slight decrease in smoking prevalence in the developed countries, although associated mortality is still very high. The use of tobacco products other than cigarettes and even medicinal nicotine (known as nicotine replacement therapy (NRT)) has been proposed as a risk reduction strategy. Among the tobacco products with less individual risk than cigarettes would be any type of tobacco without smoke (smokeless) with a low content in nitrosamines and modified cigarettes; both forms included under the PREP (Potentially Reduced Exposure Products) concept. The idea would be to promote these products among those who cannot quit smoking or wish to reduce their risk without giving up nicotine intake. The possible effects of risk reduction strategies, including PREP, on the decreased prevalence and morbidity and mortality are reviewed, and the possible implications that this measure could have in our country are analysed. Tobacco control measures in Spain are recent and still insufficient. Therefore, the current priority in Spain is the development of policies of control that have shown to more than effective. The marketing and advertising of new tobacco products, even with reduced potential risk, seems more a serious threat than an opportunity for the development of smoking control policies.     

The role of smoking as a risk factor in inflammatory bowel diseases: single center study in Korea]

BACKGROUND/AIMS: Cigarette smoking is the most significant environmental factor identified in inflammatory bowel disease (IBD). Smoking has a beneficial effect on ulcerative colitis (UC) patients. In contrast, Crohn's disease (CD) is associated with smoking, and a detrimental effect of smoking on the course of CD has been demonstrated. The aim of this study was to explore the prevalence in smoking in CD and UC at the time of diagnosis compared with the general population in a single center study. METHODS: Prevalence of smoking at the time of IBD diagnosis were compared between CD and UC patients in Kyung-Hee Medical Center with healthy general population at age-, gender-, and time period-adjusted rates. We investigated the smoking status of IBD patients at the time of diagnosis by telephone interview. There were 178 IBD patients (98 UC patients and 80 CD patients) between January 1995 and December 2004. RESULTS: The male to female ratio in CD and UC were 2:1 and 1:1.4, respectively. The onset of age was 28.2 years and 38.8 years, respectively. The prevalence of smoking was significantly lower in CD and UC patients than in the general population (CD; odds ratio 0.21, 95% confidence interval 0.12-0.41, p<0.001, UC; odds ratio 0.06, 95% confidence interval 0.03-0.14, p<0.001). After statistical adjustment for gender and age at the diagnosis of IBD, the odds ratio of a current smoker diagnosed as UC was 73% lower than that of CD (adjusted odds ratio 0.27, 95% confidence interval 0.12-0.59, p<0.001). In contrast, being a former smoker showed a risk of approximate 1.27-fold higher likelihood of having UC diagnosis (adjusted odds ratio 1.27, confidence interval 0.41-3.95, p=0.68). CONCLUSIONS: Cigarette smoking is protective against developing UC at any age, but is not associated with the development of CD in Korean population. Former smoking is not the high risk factor in developing UC.     

Effects of current cigarette smoking on clinical course of Crohn's disease and ulcerative colitis

Cigarette smoking worsens Crohn's disease (CD) but ameliorates ulcerative colitis (UC). In Israel, where there is no epidemiological association of smoking with CD, we examined the effects of current smoking on the course of CD and UC. Patients at nine public hospitals completed a questionnaire detailing their smoking history, disease course and treatments; subjects altering their smoking habit after the onset of disease were excluded. Sixty-four smokers and 144 nonsmokers had CD, and 34 smokers and 158 nonsmokers had UC. No differences were found between CD smokers and nonsmokers for hospitalizations, operations, and requirement for corticosteroid and immunosuppressive treatment. By contrast, UC smokers had less extensive disease than nonsmokers (P < 0.02) and fewer hospitalizations (P = 0.01) and operations (P = 0.025). Our results agree with a minority of studies showing no adverse effect of smoking on the course of CD, and confirm the protective effect of smoking in UC.