Photoelectrocatalytic CO2 Reduction to Formate Using a BiVO4/ZIF-8 Heterojunction.

Converting CO2 into high-value chemical fuels through green photoelectrocatalytic reaction path is considered as a potential strategy to solve energy and environmental problems. In this work, BiVO4/ZIF-8 heterojunctions are prepared by in-situ synthesis of ZIF-8 nanocrystals with unique pore structure on the surface of BiVO4. The experimental results show that the silkworm pupa-like BiVO4 is successfully combined with porous ZIF-8, and the introduction of ZIF-8 can provide more sites for CO2 capture. The optimal composite ratio of 4 : 1-BiVO4/ZIF-8 exhibits excellent CO2 reduction activity and the lowest electrochemical transport resistance. In the electrocatalytic system, the formate Faraday efficiency of 4 : 1-BiVO4/ZIF-8 at -1.0 V vs. RHE is 82.60 %. Furthermore, in the photoelectrocatalytic system, the Faraday efficiency increases to 91.24 % at -0.9 V vs. RHE, which is 10.8 times higher than the pristine BiVO4. The results show that photoelectric synergism can not only reduce energy consumption, but also improve the Faraday efficiency of formate. In addition, the current density did not decrease during 34 h electrolysis, showing long-term stability. This work highlights the importance of the construction of heterojunction to improve the performance of photoelectrocatalytic CO2 reduction.

Insights into the Enhanced Bioavailability of Per- and Polyfluoroalkyl Substances in Food Caused by Chronic Inflammatory Bowel Disease.

Understanding the bioavailability of per- and polyfluoroalkyl substances (PFAS) in food is essential for accurate human health risk assessment. Given the rising incidence of inflammatory bowel disease (IBD), this study aimed to investigate the impacts of IBD on the bioavailability of PFAS in food using mice models. The relative bioavailability (RBA) of PFAS was the highest in the chronic IBD mice (64.3-144%), followed by the healthy (60.8-133%) and acute IBD mice (41.5-121%), suggesting that chronic IBD enhanced the PFAS exposure risk. In vitro tests showed that the intestinal micelle stability increased as a result of reduced content of short-chain fatty acids, thus promoting the PFAS bioaccessibility in the digestive fluid of chronic IBD. Additionally, increased pathogenic and decreased beneficial bacteria in the gut of IBD groups facilitated the intestinal permeability, thus enhancing PFAS absorption. These together explained the higher RBA of PFAS in the chronic IBD. However, remarkably lower enzymatic activities suggested severely impaired digestive ability in the acute IBD, which facilitated the excretion of PFAS from feces, thus lowering the RBA. Conversely, PFAS exposure might exacerbate IBD by changing the gut microbiota structures. This study hints that individuals with chronic intestinal inflammation might have higher PFAS exposure risk than the healthy population.

Circulation pattern and genetic variation of rhinovirus infection among hospitalized children on Hainan Island, before and after the dynamic zero-COVID policy, from 2021 to 2023.

Throughout the COVID-19 pandemic, rhinovirus (RV) remained notable persistence, maintaining its presence while other seasonal respiratory viruses were largely suppressed by pandemic restrictions during national lockdowns. This research explores the epidemiological dynamics of RV infections among pediatric populations on Hainan Island, China, specifically focusing on the impact before and after the zero-COVID policy was lifted. From January 2021 to December 2023, 19 680 samples were collected from pediatric patients hospitalized with acute lower respiratory tract infections (ARTIs) at the Hainan Maternal and Child Health Hospital. The infection of RV was detected by tNGS. RV species and subtypes were identified in 32 RV-positive samples representing diverse time points by analyzing the VP4/VP2 partial regions. Among the 19 680 pediatric inpatients with ARTIs analyzed, 21.55% were found to be positive for RV infection, with notable peaks observed in April 2021 and November 2022. A gradual annual decline in RV infections was observed, alongside a seasonal pattern of higher prevalence during the colder months. The highest proportion of RV infections was observed in the 0-1-year age group. Phylogenetic analysis on 32 samples indicated a trend from RV-A to RV-C in 2022. This observation suggests potential evolving dynamics within the RV species although further studies are needed due to the limited sample size. The research emphasizes the necessity for ongoing surveillance and targeted management, particularly for populations highly susceptible to severe illnesses caused by RV infections.

Determination of cyclic adenosine phosphate and protein content in dormant chlamydospore and nondormant chlamydospore of Arthrobotrys flagrans.

Arthrobotrys flagrans, a nematode-eating fungus, is an effective component of animal parasitic nematode biocontrol agents. In the dried formulation, the majority of spores are in an endogenous dormant state. This study focuses on dormant chlamydospore and nondormant chlamydospore of A. flagrans to investigate the differences in cyclic adenosine monophosphate (cAMP) and protein content between the two types of spores. cAMP and soluble proteins were extracted from the nondormant chlamydospore and dormant chlamydospore of two isolates of A. flagrans. The cAMP Direct Immunoassay Kit and Bradford protein concentration assay kit (Coomassie brilliant blue method) were used to detect the cAMP and protein content in two types of spores. Results showed that the content of cAMP in dormant spores of both isolates was significantly higher than that in nondormant spores (p < 0.05). The protein content of dormant spores in DH055 bacteria was significantly higher than that of nondormant spores (p < 0.05). In addition, the protein content of dormant spores of the SDH035 strain was slightly higher than that of nondormant spores, but the difference was not significant (p > 0.05). The results obtained in this study provide evidence for the biochemical mechanism of chlamydospore dormancy or the germination of the nematophagous fungus A. flagrans.

Microstructure characterization of different types of chlamydospores in Arthrobotrys flagrans.

The morphological and structural differences of different types of chlamydospore of Arthrobotrys flagrans, a nematophagous fungus, were studied under light microscope and electron microscope to provide a reference for the biological control of parasitic nematodiasis. In this study, A. flagrans isolate F088 dormant chlamydospore and nondormant chlamydospore were selected as the research objects. The structural differences of these spores were observed by optical microscopy through lactol cotton blue, Trypan blue, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) staining. FunXite -1, 4',6-diamidino-2-phenylindole, and calcofluor white staining were used to observe the metabolic activity, cell wall, and nucleus differences of the two types of spores under fluorescence microscope. Ultrastructure of the two kinds of spores was observed using scanning electron microscope (SEM) and transmission electron microscope (TEM). Since lacto phenol cotton blue, trypan blue staining cannot distinguish dormant spores from dead spores, MTT assay was performed. Fluorescence microscopy observation showed that the cytoplasmic metabolic activity of nondormant spores was stronger than that of dormant spores. The nucleus of dormant spores was bright blue, and their fluorescence was stronger than that of nondormant spores. The cell wall of nondormant spores produced stronger yellow-green fluorescence than that of dormant spores. Ultrastructural observation showed that there were globular protuberances on the surface of the two types of spores but with no significant difference between them. The inner wall of dormant spore possesses a thick zona pellucida with high electron density which was significantly thicker than that of nondormant spores, and their cytoplasm is also changed. In this study, the microstructure characteristics of dormant and nondormant chlamydospores of A. flagrans fungi were preliminarily clarified, suggesting that the state of cell wall and intracellular materials were changed after spores entered to dormancy.

Exploring Route-Specific Pharmacokinetics of PFAS in Mice by Coupling in Vivo Tests and Physiologically Based Toxicokinetic Models.

BACKGROUND: Oral ingestion, inhalation, and skin contact are important exposure routes for humans to uptake per- and polyfluoroalkyl substances (PFAS). However, nasal and dermal exposure to PFAS remains unclear, and accurately predicting internal body burden of PFAS in humans via multiple exposure pathways is urgently required. OBJECTIVES: We aimed to develop multiple physiologically based toxicokinetic (PBTK) models to unveil the route-specific pharmacokinetics and bioavailability of PFAS via respective oral, nasal, and dermal exposure pathways using a mouse model and sought to predict the internal concentrations in various tissues through multiple exposure routes and extrapolate it to humans. METHODS: Mice were administered the mixed solution of perfluorohexane sulfonate, perfluorooctane sulfonate, and perfluorooctanoic acid through oral, nasal, and dermal exposure separately or jointly. The time-dependent concentrations of PFAS in plasma and tissues were determined to calibrate and validate the individual and combined PBTK models, which were applied in single- and repeated-dose scenarios. RESULTS: The developed route-specific PBTK models successfully simulated the tissue concentrations of PFAS in mice following single or joint exposure routes as well as long-term repeated dose scenarios. The time to peak concentration of PFAS in plasma via dermal exposure was much longer (34.1-83.0 h) than that via nasal exposure (0.960 h). The bioavailability of PFAS via oral exposure was the highest (73.2%-98.0%), followed by nasal (33.9%-66.8%) and dermal exposure (4.59%-7.80%). This model was extrapolated to predict internal levels in human under real environment. DISCUSSION: Based on these data, we predict the following: PFAS were absorbed quickly via nasal exposure, whereas a distinct hysteresis effect was observed for dermal exposure. Almost all the PFAS to which mice were exposed via gastrointestinal route were absorbed into plasma, which exhibited the highest bioavailability. Exhalation clearance greatly depressed the bioavailability of PFAS via nasal exposure, whereas the lowest bioavailability in dermal exposure was because of the interception of PFAS within the skin layers. https://doi.org/10.1289/EHP11969.

Bioaccessibility of per- and polyfluoroalkyl substances in food and dust: Implication for more accurate risk assessment.

Humans are exposed to per- and polyfluoroalkyl substances (PFASs) mainly through oral exposure route, while little is known about their bioaccessibility (BC) in oral matrices. Here, the BC of 13 PFASs in simulated vegetable (VFs) and animal foods (AFs) as well as indoor dust was investigated using a physiology-based extraction test. The BC of PFASs in the AFs (78.5 ± 13.6 %) was distinctly higher than that in the VFs (60.6 ± 13.4 %), because high-saturated and long-chain fatty acids in the animal fat favored formation of more stable micelles. The BC of most long-chain PFASs was positively correlated with the protein content while negatively correlated with the carbohydrate content in the foods. The BC of polyfluoroalkyl phosphate diesters was negatively correlated with the lipid content. The BC of the very long-chain PFASs in the foods was 2.42-6.02 times higher than that in the dust, which might be attributed to their strong sequestration in dust. With the increase in bile salt concentration, the BC of PFASs in food increased and then remained constant, which was related to the changes in fatty acids and stability of the formed micelles. Comparing with the previous results obtained from animal study, the BC obtained in this study has the potential to predict PFAS bioavailability in food.

Novel Insight into the Mechanisms of Neurotoxicity Induced by 6:6 PFPiA through Disturbing the Gut-Brain Axis.

As alternatives to traditional per- and polyfluoroalkyl substances, perfluoroalkyl phosphonic acids (PFPiAs) are frequently detected in aquatic environments, but the neurotoxic effects and underlying mechanisms remain unclear. In this study, male zebrafish were exposed to 6:6 PFPiA (1 and 10 nM) for 28 days, which exhibited anxiety-like symptoms. Gut microbiome results indicated that 6:6 PFPiA significantly increased the abundance of Gram-negative bacteria, leading to enhanced levels of lipopolysaccharide (LPS) and inflammation in the gut. The LPS was delivered to the brain through the gut-brain axis (GBA), damaged the blood-brain barrier (BBB), stimulated neuroinflammation, and caused apoptosis as well as neural injury in the brain. This mechanism was verified by the fact that antibiotics reduced the LPS levels in the gut and brain, accompanied by reduced inflammatory responses and anxiety-like behavior. The BBB damage also resulted in the enhanced accumulation of 6:6 PFPiA in the brain, where it might bind strongly with and activate aryl hydrocarbon receptor (AhR) to induce brain inflammation directly. Additionally, as the fish received treatment with an inhibitor of AhR, the inflammation response and anxiety-like behavior decreased distinctly. This study sheds light on the new mechanisms of neurotoxicity-induced 6:6 PFPiA due to the interruption on GBA.

Occurrence of perfluoroalkyl substances in the environment compartments near a mega fluorochemical industry: Implication of specific behaviors and emission estimation.

With the stringent restrictions on long-chain per- and polyfluoroalkyl substances (PFASs), ether-PFASs are being widely used as alternatives. We estimated that the mega fluorochemical industrial park (FIP) in Shandong, China, had emitted a maximum of 5040 kg and 1026 kg of hexafluoropropylene oxides (HFPOs), and 7560 kg and 1890 kg of perfluorooctanoic acid (PFOA) to water and air during 2021. In the surface water, groundwater, outdoor dust, soil, tree leaf and bark collected in the vicinity of the FIP, PFOA was predominant, followed by HFPOs. The much higher percentage of HFPO dimer acid (HFPO-DA) in groundwater than in surface water verified that this compound was more mobile in porous media. The strong correlations between the main PFASs in outdoor dust and surface soil suggested that the soil PFASs were mainly derived from air deposition, particularly for HFPO trimer acid (HFPO-TA), which has a stronger binding affinity with particles than PFOA. High percentage of the hydroxylated product of 6:2 polyfluorinated ether sulfonic acid was observed in groundwater, implying reductive dechlorination might occur in groundwater. Strong correlations between PFASs in outdoor dust and those in tree leaf and bark magnified that tree could serve as a sampler to effectively monitor airborne PFASs. This study provides the first line of information about the discharge, transport, and fate of novel ether-PFASs in the multiple environmental media near a point source.

Novel insights into the mediating roles of cluster of differentiation 36 in transmembrane transport and tissue partition of per- and polyfluoroalkyl substances in mice.

Transmembrane transport is important for bioaccumulation of per- and polyfluoroalkyl substances (PFASs) in organisms, but has not yet been well understood. Here, the roles of cluster of differentiation 36 (CD36) in accumulation of PFASs were investigated. CD36 was overexpressed in Escherichia coli to get CD36-BL21 strain, and the binding affinities of 20 PFASs with CD36 were determined by microscale thermophoresis, which grew up to 17.5 µM with increasing carbon chain length. Consequently, the accumulation of most PFASs was remarkably promoted in CD36-BL21 in comparison to the wild strain, and the enhancement was proportional to their binding affinities with CD36 (r = -0.96). However, this effect was depressed greatly as CD36 was inhibited by sulfo-N-succinimidyl oleate (SSO). Additionally, as the mice received SSO pretreatment before they were exposed to perfluorododecanoic acid, its accumulation in the tissues rich in CD36, such as liver, was suppressed, but increased by 1.1 times in the serum. These indicated that CD36 played critical roles in the transmembrane transport and tissue partition of PFASs in organisms. The developed relationship between liver-blood partition of PFASs and their binding affinities with intracellular proteins was distinctly improved by incorporating that with CD36 (r = -0.97).

Insights into the Competitive Mechanisms of Per- and Polyfluoroalkyl Substances Partition in Liver and Blood.

Some per- and polyfluoroalkyl substances (PFASs) tend to be accumulated in liver and cause hepatotoxicity. However, the difficulty to directly measure liver concentrations of PFASs in humans hampers our understanding of their hepatotoxicity and mechanisms of action. We investigated the partitioning of 11 PFASs between liver and blood in male CD-1 mice. Although accumulation of the perfluoroalkanesulfonic acids (PFSAs) in mice serum was higher than their carboxylic acids (PFCAs) counterparts as expected, the liver-blood partition coefficients (RL/S) of PFSAs were lower than the PFCAs RL/S, implying a competition between liver and blood. The in vitro experiments further indicated that the partitioning was dominantly determined by their competitive binding between human liver fatty acid binding protein (hL-FABP) and serum albumin (HSA). The binding affinities (Kd) of PFASs to both proteins were measured. The correlations between the RL/S and log Kd (hL-FABP)/log Kd (HSA) were stronger than those with log Kd (hL-FABP) alone, magnifying that the partitioning was dominantly controlled by competitive binding between hL-FABP and HSA. Therefore, the liver concentrations of the selected PFASs in humans could be predicted from the available serum concentrations, which is important for assessing their hepatotoxicity.

Mechanisms Underlying the Impacts of Lipids on the Diverse Bioavailability of Per- and Polyfluoroalkyl Substances in Foods.

Food is a major source of human exposure to per- and polyfluoroalkyl substances (PFASs), yet little is known about their bioavailability in food matrices. Here, the relative bioavailability (RBA) of PFASs in foods was determined using an in vivo mouse model. Pork, which had the highest lipid content, exhibited the greatest effect on bioavailability by increasing the RBAs of perfluoroalkyl acids (PFAAs) while reducing those of fluorotelomer phosphate diesters (diPAPs). During intestinal digestion of lipids, the bioaccessibility of PFAAs increased due to their greater partition into the stable mixed micelles. However, diPAPs were more likely to partition into the undigested oil phase due to their strong hydrophobicity. Both in vitro incubation and molecular docking results indicated that the PFAAs exhibited stronger binding affinities with mouse blood chylomicrons (CMs) than with diPAPs. Collectively, both lipid digestion in the intestine and the carrier effect of CMs played important roles in modulating the bioavailability of PFASs in food. More attention should be given to further evaluating the health risks of PFASs associated with the intake of high-lipid foods.

Insights into the impacts of dissolved organic matter of different origins on bioaccumulation and translocation of per- and polyfluoroalkyl substances (PFASs) in wheat.

Per- and polyfluoroalkyl substances (PFASs) have been found to be widely present in soil. Dissolved organic matter (DOM) in soil are supposed to greatly affect the bioavailability of PFASs in soil. Herein, hydroponic experiments were conducted to understand the impacts of two kinds of typical DOM, bovine serum albumin (BSA) and humic acid (HA), on the uptake and translocation of legacy PFASs and their emerging alternatives, perfluorooctane sulfonic acid (PFOS), perfluorooctane acid (PFOA), perfluorohexane sulfonic (PFHxS) and 6:2 chlorinated polyfluoroalkyl ether sulfonate (6:2 Cl-PFESA) in wheat (Triticum aestivum L.). The results indicated that both HA and BSA significantly inhibited the bioaccumulation and translocation of PFASs in the roots and shoots of wheat, and the impacts of BSA were greater than HA. This difference was explained by the greater binding affinities of the four PFASs with BSA than with HA, as evidenced by the equilibrium dialysis and isothermal titration calorimetry (ITC) analyses. It was noting that inhibition impacts of the BSA-HA mixture (1:1) were lower than BSA alone. The results of Fourier transform infrared (FT-IR) spectroscopy and excitation-emission matrix (EEM) fluorescence spectroscopy suggested that HA could bind with the fluorescent tryptophan residues in BSA greatly, competing the binding sites with PFASs and forming a cover on the surface of BSA. As a result, the binding of PFASs with BSA-HA complex was much lower than that with BSA, but close to HA. The results of this study shed light on the impacts of DOM in soil on the bioaccumulation and translocation of PFASs in plants.

Psychometric properties of the Chinese version of the attitude towards the prevention of incontinence-associated dermatitis (C-APrIAD) among Chinese nurses.

AIM: Nurses' attitude is a significant determinant of incontinence-associated dermatitis (IAD) prevention, and a positive attitude may benefit quality improvement projects. This research aimed to translate the attitude towards the prevention of incontinence-associated dermatitis instrument (C-APrIAD) into Chinese and test the reliability and validity among Chinese nurses. METHODS: The C-APrIAD was translated into Chinese using a standard procedure of backward-forward translation and cross-cultural adaption. Totally 170 nurses were recruited through the convenience sampling method from three tertiary hospitals in Tianjin, Shandong, and Heilongjiang province of China. Reliability (internal consistency, stability) and validity (content validity, structure validity, and convergent validity), were assessed. Convergent Validity was evaluated by correlation with the General Self-Efficacy Scale (GSES). RESULTS: Of the 170 completed questionnaires, 158 (93%) were suitable for analysis. The item-total correlation coefficients ranged from 0.39 to 0.80. The content validity of C-APrIAD was 0.96. A factor analysis indicated the construct of a 14-item instrument in a four factors solution: (1) beliefs about the impact of IAD on patients, (2) beliefs about team responsibility to prevent IAD, (3) beliefs about personal responsibility to prevent IAD, and (4) beliefs about the effectiveness of IAD prevention products and procedures. The correlation coefficient between the GSES and C-APrIAD was 0.49 (P < 0.01). For the total instrument, the Cronbach's α coefficient was 0.87 and the test-retest reliability was 0.99. CONCLUSION: The C-APrIAD is reliable and valid. The C-APrIAD may benefit nursing research as well as clinical practice to optimize interventions to improve IAD prevention.

Mechanisms for tissue-specific accumulation and phase I/II transformation of 6:2 fluorotelomer phosphate diester in earthworm (M. guillelmi).

Polyfluoroalkyl phosphate esters (PAPs) are high production volume surfactants used in the food contact paper and packaging industries. They are prone to partition to soil due to their strong hydrophobicity and may biotransform into recalcitrant perfluoroalkyl carboxylic acids (PFCAs); little is known about their fate and behaviors in terrestrial organisms. Here, geophagous earthworms (M. guillelmi) were exposed to 6:2 fluorotelomer phosphate diester (6:2 diPAP)-contaminated soil to examine tissue-specific accumulation and biotransformation. 6:2 diPAP quickly accumulated in M. guillelmi with the highest biota-soil-accumulation factor (BSAF) in the gut, followed by the organs, skin, and body fluid. The total amount of 6:2 diPAP accumulated in the skin was the highest due to its high mass content. These results indicated that skin absorption and gut processes were two major pathways for earthworms to accumulate 6:2 diPAP from soil. In vitro desorption experiments indicated that the gut digestion fluid greatly promoted the desorption of 6:2 diPAP from the soil and enhanced its bioavailability. Degradation of 6:2 diPAP in the soil was stimulated when the earthworm appeared. In contrast to the soil, a more extensive transformation occurred in the earthworm. Perfluorohexanoic acid (PFHxA) was the primary phase Ⅰ product, followed by perfluoropentyl propanoic acid (FPePA), perfluoropentanoic acid (PFPeA), 2-perfluorohexyl ethanoic acid (FHEA), and perfluoroheptanoic acid (PFHpA), which confirmed the occurrence of α- and ß-oxidation in earthworms. For the first time, a new phase II product, namely, a 6:2 fluorotelomer alcohol sulfate conjugate, was identified in earthworms at unexpectedly high levels, which might be the primary way earthworms eliminate 6:2 diPAP. Both in vivo and in vitro experiments suggested that 6:2 diPAP experienced faster and more extensive biotransformation in the gut than in the organs. This work sheds light on the bioaccumulation and biotransformation of 6:2 diPAP in terrestrial invertebrates, providing strong evidence of indirect sources of PFCAs in the environment.

Effects of dance therapy on cognitive and mood symptoms in people with Parkinson's disease: A systematic review and meta-analysis.

OBJECTIVE: To investigate whether the dance therapy was more beneficial than non-dance therapy on cognitive and mood symptoms in patients with Parkinson's disease (PD). METHODS: MEDLINE, CINAHL, Embase and the Cochrane Central Register of Controlled Trials were searched from inception to December 11, 2018. Risk of bias for the included trials was assessed using criteria in the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Seven randomized controlled trials were identified on cognitive and mood symptoms in patients with PD. There were significant differences in favor of dance in executive function (WMD = 1.17, 95% CI:0.39 to 1.95, P = 0.003; I2 = 0%, P = 0.45), but not in outcomes of global cognitive function, depression and apathy. CONCLUSIONS: Dance therapy is beneficial in improving executive function for adults with PD. However, there are no positive effects were founded on global cognitive function, depression and apathy for PD.

[Clinical study on electroacupuncture combined with acupoint sticking therapy for treatment of chronic ulcerative colitis].

OBJECTIVE: To compare the clinical efficacy on chronic ulcerative colitis between electroacupuncture (EA) combined with acupoint sticking therapy (AST) and western medicine. METHODS: Ninety cases were randomly divided into EA + AST group and western medication group, 45 cases in each one. In EA + AST group, (1) Zhongwan (CV 12), Tianshu (ST 25), Guanyuan (CV 4), Qihai (CV 6) and (2) Shangjuxu (ST 37), Pishu (BL 20), Dachangshu (BL 25), Zusanli (ST 36) were selected for EA and AST by turns. In western medication group, Mesalazine was administered orally. Clinical symptom evaluation and colonoscopic examination were conducted respectively before and after treatment, and the differences in efficacy were compared. RESULTS: In EA + AST group, the total effective rate of clinical symptoms was 91.1% (41/45) and the total effective rate of the colonoscopic improvements in mucosal lesions was 84.4% (38/45), which were all superior to those (73.3%, 33/45; 66.7%, 30/45) in medication group (both P < 0.05). CONCLUSION: The combination of electroacupuncture and acupoint sticking therapy can improve in clinical symptoms and colonoscopic mucosal lesions significantly in the patients with ulcerative colitis and the efficacy of it is superior to that of Mesalazine.