[Elafin-expressing probiotic Escherichia coli Nissle 1917 protects against experimental colitis].

Objective: To construct the gene modified probiotic Escherichia coli nissle1917 (EcN) which can express human Elafin protein and to explore its protective effect on the acute colitis in mice. Methods: The recombinant plasmid with human Elafin gene was constructed and then transferred to EcN. Western blot results confirmed that the engineered probiotic expressed Elafin successfully in vitro. C57/BL6J mouse was used in this study and were randomly divided into 4 groups according to different treatment: PBS gavage (PBS group); DSS administrated (DSS group); DSS administrated with wild-type EcN (EcN-WT) gavage (EcN-WT group); DSS administrated with EcN-Elafin gavage (EcN-Elafin group). Body weight and disease activity index (DAI) were measured every day. The length of mice colons in each group were measured after euthanasia. The degree of inflammation of intestinal mucosa in each group was measured through histopathological scoring. The proportion of neutrophils and macrophages infiltrated into colon lamina propria was detected by flow cytometry. The protein expression levels of pro-inflammatory cytokines TNF-α, IL-6 and chemokine CXCL-1 in colonic tissue were quantified by enzyme-linked immunosorbent assay. Results: Elafin protein could be detected in the supernatant of EcN-Elafin culture medium and EcN-Elafin homogenates. Compared with DSS group, the weight loss and DAI score of EcN-Elafin group and EcN-WT group were both significantly improved. The colon length of EcN-Elafin group was significantly longer than that of DSS group. The histological score of colitis in EcN-Elafin group was significantly lower than that in DSS group (5.3±2.3 vs 9.3±1.4, P<0.05). In EcN-Elafin group, the proportion of neutrophils[(8.65±1.49)% vs (17.60±2.16)%, P<0.01]and macrophages[(3.79±0.26)% vs (5.73±0.45)%, P<0.01]infiltrated into the colon lamina propria was significantly decreased compared with DSS group. The protein expression levels of TNF-α, IL-6 and CXCL-1 in EcN-Elafin group and EcN-WT group were significantly lower than those in DSS group. Conclusion: Elafin-expressing EcN can protect against DSS-induced acute colitis in mice and may have provided an effective and cost-efficient method for the treatment of IBD.

[Protective effects of sucralfate on gastric mucosal injury induced by Helicobacter pylori and its effects on gastrointestinal flora in mice].

Objective: To investigate the effects of sucralfate suspension gel (SC) on Helicobacter pylori (H.pylori) colonization, H.pylori-induced gastric mucosal injury and gastrointestinal microecology in mice. Methods: C57BL/6J mice were randomly divided into 3 groups, including normal control (NC) group, H.pylori model (HP) group, and SC prevention (HP+SC) group. H.pylori infection mouse model was established by gavage with H.pylori Sydney strain (SS1). And HP+SC group was also administered with SC for 14 days. After mice were sacrificed, the gastric mucosa was taken for HE staining, immunohistochemical (IHC) staining [H.pylori, zonula occludens-1 (ZO-1), Occludin, interleukin (IL)-8, IL-10 and tumor necrosis factor-α (TNF-α)], qPCR (IL-8, IL-10, TNF-α) . And cell ultrastructure was observed by electron microscopy. Microbiota communities in the gastric mucosa or fecal were investigated using 16S ribosomal RNA (rRNA) gene sequencing. The detection of H.pylori in IHC staining or Giemsa staining was defined as H.pylori infection. Results: The H.pylori positive rate of HP group was 91.67%, and that of HP+SC group was 50.00%. The EDS of HP group were significantly higher than those of the NC group [(3.42±0.19) vs (1.17±0.17), P<0.05], while EDS of HP+SC group (2.42±0.29) were significantly lower than that of HP group (P<0.05). The mRNA levels and immunostaining scores of IL-8, IL-10 and TNF-α in HP group was higher than NC group (all P<0.05). Compared with HP group, mRNA levels and IHC scores of IL-8 significantly decreased (all P<0.05) in HP+SC group, while those of IL-10 and TNF-α was similar between two groups (all P>0.05). The IHC scores of ZO-1 and Occludin in HP group was significantly lower than NC group (all P<0.05), and that of ZO-1 and Occludin in the HP+SC group increased compared with HP group [(2.00±0.26) vs (1.17±0.48), P>0.05; (3.50±0.43) vs (2.33±0.21), P<0.05]. Compared with NC group, the diversity of gastric microbiota in HP group was significantly lower, and diversity of gut microbiota decreased insignificantly. There was no significant difference between HP+SC group and HP group in gastric or gut microbiota. Conclusion: SC reduces H.pylori colonization, protects H.pylori-induced gastric mucosal injury, decreases H.pylori-induced IL-8 expression, enhances Occludin. However, its effects on H.pylori-induced gastrointestinal microbiota disorders are limited.

Gout and risk of knee replacement for severe knee osteoarthritis in the Singapore Chinese Health Study.

OBJECTIVE: While cross-sectional and retrospective case-control studies suggest that gout is associated with knee osteoarthritis (KOA), no prospective study has evaluated the risk of total knee replacement (TKR) for KOA in association with gout. We prospectively evaluated the association between gout and the risk of TKR due to severe KOA. DESIGN: We used data from the Singapore Chinese Health Study (SCHS), a prospective cohort with 63,257 Chinese adults aged 45-74 years at recruitment (1993-1998). Self-report of physician-diagnosed gout was enquired at follow-up I interview (1999-2004) from 52,322 subjects. TKR cases for KOA after follow-up I were identified via linkage with nationwide hospital discharge database through 31 December 2011. Multivariable Cox proportional hazards regression model was applied with adjustment for potential risk factors of KOA. RESULTS: Among 51,858 subjects (22,180 men and 29,678 women) included in this analysis, after average 9.7 follow-up years, there were 1,435 cases of TKR. Gout was associated with 39% higher risk of TKR in women [hazard ratio (HR) 1.39; 95% confidence interval (CI) 1.08-1.79] but not in men (HR 0.78; 95% CI 0.49-1.23). The positive gout-TKR association in women remained after excluding participants with self-reported history of arthritis (HR 1.57; 95% CI 1.04-2.37). This association was stronger in women who were lean (body mass index [BMI] < 23 kg/m2) (HR 2.17; 95% CI 1.30-3.64) compared to their heavier counterparts (Pinteraction = 0.016). CONCLUSION: Gout is associated with risk of severe KOA, especially in lean women, suggesting the crystal arthritis may play a role in the pathogenesis or progression of OA.

Lung and gastrointestinal complications are leading causes of death in SCORE, a multi-ethnic Singapore systemic sclerosis cohort.

OBJECTIVES: To assess contemporary outcomes and predictors of mortality in the well-characterized multi-ethnic systemic sclerosis cohort Singapore (SCORE). METHOD: From 2008, patients diagnosed with systemic sclerosis (SSc) fulfilling the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) or Very Early Diagnosis of Systemic Sclerosis (VEDOSS) criteria were recruited from three major tertiary rheumatology centres in Singapore. Mortality was verified with the Singapore National Registry of Deaths and in-hospital cause of death was determined by two independent reviewers, up to 10 December 2013. A Cox proportional hazard (PH) regression analysis was used to examine the association between demographic and clinical indices and mortality, controlling for age and race. RESULTS: Of the 349 patients (86.8% female; 77.7% Chinese), 97.4% fulfilled the ACR/EULAR 2013 criteria. The mean age at diagnosis was 46.2 years. The prevalence of limited (lcSSc), diffuse (dcSSc) cutaneous SSc, and SSc-overlap syndromes was 34.4, 37.1, and 26.8%, respectively. Thirty-five patients died after a mean follow-up of 2.1 years (743.6 person-years). Fifty-seven per cent of deaths were attributed to SSc, with pulmonary arterial hypertension (PAH), interstitial lung disease (ILD), and gastrointestinal (GI) complications as the leading causes of death. Multivariate analysis (n = 275) showed that smoking [hazard ratio (HR) 4.0, 95% confidence interval (CI) 1.5-10.6], SSc-overlap (HR 6.0, 95% CI 1.8-19.1), baseline renal involvement (HR 2.5, 95% CI 1.1-6.0), pulmonary artery systolic pressure (PASP) ≥ 40 mmHg on echocardiography (HR 5.1, 95% CI 2.2-11.7), treatment for peripheral vasculopathy (HR 2.6, 95% CI 1.1-6.5), and parenteral nutrition (HR 8.8, 95% CI 2.2-34.3) were independent predictors of mortality. CONCLUSIONS: PAH, ILD, and GI complications were leading causes of death in this cohort. We identified a high-risk group of patients who would benefit from closer monitoring and early intervention.

[Expression of elafin in peripheral blood in inflammatory bowel disease patients and its clinical significance].

OBJECTIVE: To quantify the expression of elafin mRNA in peripheral blood in patients with inflammatory bowel disease (IBD) and to explore its value in assessment of the activity and severity of IBD. METHODS: From July 1 2015 to August 15 2015, 23 patients with IBD admitted to Peking University First Hospital were selected, including 15 cases with ulcerative colitis (UC) and 8 cases with Crohn's disease (CD). Among those, 5 cases were in remission (UC 3, CD 2), 6 cases were mild active (UC 3, CD 3), 3 cases were moderate active (UC 1, CD 2), and 9 cases were severe active (UC 8, CD 1). A total of 21 healthy individuals were selected as the control group. Peripheral blood samples of IBD patients and healthy controls were collected. The expression of elafin mRNA in peripheral blood leukocytes was detected by fluorescence quantitative real-time PCR. Mann-Whitney test was performed for comparison between the two groups. The correlation between the expression of elafin mRNA in peripheral blood and IBD activity score was analyzed by Pearson correlation analysis after transformation of variables. RESULTS: The median expression of elafin mRNA in peripheral blood leukocytes in IBD group and control group was 0.005 8 (0.000 2, 0.043 5) and 0.015 3 (0.002 1, 0.175 8), respectively, with no significant difference (P>0.05). However, in the active IBD patients it was lower than that in the controls (0.004 6 (0.000 2, 0.034 8) vs 0.015 3 (0.002 1, 0.175 8), P<0.05) and also lower than that in the remission patients(0.004 6 (0.000 2, 0.034 8) vs 0.023 1 (0.012 6, 0.043 5), P<0.05); in the active UC patients it was lower than that in the controls(0.003 7 (0.000 2, 0.027 0) vs 0.015 3 (0.002 1, 0.175 8), P<0.05). The expression of elafin mRNA in peripheral blood was negatively correlated with modified Mayo score in UC patients (r=-0.513, P<0.05) and with the Crohn's Disease Activity Index (CDAI) of Best score in CD patients (r=-0.889, P<0.05). CONCLUSION: The expression of elafin mRNA in peripheral blood in active IBD patients is decreased, which may be correlated with the activity of IBD, and negatively correlated with corresponding disease activity score, suggesting that it may play a protective role in IBD and may be helpful in predicting disease activity.

Traditional Chinese medication for rheumatoid arthritis: more than what meets the eye.

There is an increasing interest in the role of traditional Chinese medicine (TCM) in rheumatoid arthritis (RA), as evidenced by recent trials comparing their efficacy against established disease-modifying antirheumatic drugs. While the TCM in these trials seem to support a favorable cost-benefit ratio, many products are marketed under the guise of TCM, potentially exposing the user to unpredicted adverse events. We present the case of a patient with RA, who developed side effects from treatment with adulterated TCM. While TCM may be of value in the treatment of rheumatic diseases, their application in routine care continues to warrant careful consideration of safety and reliability.

Eosinophilic Granulomatosis with Polyangiitis preceding allergic bronchopulmonary aspergillosis.

A 61-year-old Chinese man with long-standing, stable Eosinophilic Granulomatosis with Polyangiitis (EGPA) and asthma, presented with acute hypoxemia and declining obstructive pulmonary function. Elevated serum IgE levels, positive Aspergillus fumigatus specific IgE and CT findings of central bronchiectasis with small airway mucoid impaction confirmed new development of Allergic Bronchopulmonary Aspergillosis (ABPA). The maintenance therapy for EGPA, azathioprine, was discontinued. Prednisolone 0.5 mg/kg/day and Itraconazole improved his symptoms and IgE levels. To our knowledge, ABPA occurring in a patient with EGPA has not been reported. Differentiation of EGPA with asthmatic flare vs ABPA vs asthma with aspergillus hypersensitivity is discussed. Heightened Th2 immunity where eosinophils play a central role may link these conditions.

Achieving treat to target in gout: a clinical practice improvement project.

OBJECTIVE: Gout care is suboptimal because of lack of translation of knowledge into real-world practice, despite evidence-based guidelines. We have developed processes to ensure systematic care for gout patients and determined the predictors for achievement of a target serum uric acid (SUA) concentration of < 360 µmol/L in a prospective cohort of Asian gout patients requiring allopurinol therapy. METHODS: A 1-year clinical practice improvement project was undertaken using evidence-based guidelines and quality planning tools. Interventions included comprehensive patient education, enhanced telephone access, reappointments and refills, upward titration of allopurinol with no limitation specified by renal function, and increased frequency of visits until the target SUA concentration was achieved. The primary outcome was the time to achieve an SUA level of <360 µmol/L. RESULTS: We recruited 126 gout patients. The median time to achieving the target SUA concentration was 36.9 weeks [95% confidence interval (CI) 29.3-44.4]. Based on survival analysis, the proportion of patients achieving the target was 8.1% (95% CI 3.2-13.0), 40.6% (95% CI 31.4-50.8), and 72.0% (95% CI 61.2-82.8) at 3, 6, and 12 months, respectively. On average, our patients who achieved the target were seen once every 2 months and achieved the target after a mean of 2.5 (SD = 1.1) visits. Frequency of follow-up visits and older patients not taking aspirin were independent predictors associated with achieving the target outcome, regardless of renal function. CONCLUSIONS: Optimization of control of SUA is achievable, even in the setting of renal impairment, by redesigning and implementing processes involving changes in physician prescribing habits, enhanced nursing interventions, and patient empowerment and education.

[Clinical analysis of 554 patients with colorectal diverticulosis].

Objective: Most patients with asymptomatic colorectal diverticulosis are easily overlooked. However, some of diverticulosis become diverticulitis, bleeding and even perforation, which cause extensive harm to patients. The purpose of this study is to analyze the incidence, clinical features, diagnosis and treatment of colorectal diverticulosis in order to improve the clinical understanding of diverticulosis and its related complications. Methods: A descriptive cohort study was carried out. Clinical data of 554 patients with colorectal diverticulosis confirmed by CT, colonoscopy, digestive tract radiography or operation in Peking University First Hospital from January 2009 to June 2019 were retrospectively analyzed. Patients with malignant tumors, autoimmune diseases, long term use of immunosuppressive drugs, chronic liver diseases and renal diseases, and mental disorders were excluded. The analysis parameters included gender, onset age, clinical symptoms, location of diverticulitis, treatment and prognosis. According to the criteria established by the World Society of Emergency Surgery (WSES), acute diverticulitis was divided into 5 stages based on the extension of the infectious process. Stage 0 was simple diverticulitis and stage 1-4 was complicated diverticulitis. Results: Among the 554 patients with colorectal diverticulosis, 358 (64.6%) were males, the median onset age was 63 years; 191 patients (34.5%) had various digestive symptoms, of whom 113 (20.4%) had chronic constipation and abdominal distension, 78 (14.1%) had chronic diarrhea and abdominal pain; the other 363 patients had no obvious abdominal symptoms. Four hundred and six patients were found by colonoscopy and 465 patients were found by CT. Twenty-five patients were diagnosed by lower gastrointestinal tract radiography and 3 were confirmed during operation. There were 339 patients with multiple diverticula (61.2%) and 215 patients with single diverticulum (38.8%). 76.5% (424/554) of diverticula were located in colon, 37.0% (205/554) in ascending colon, 21.3% (118/554) in multiple sites, and 2.2% (12/554) in rectum. The median diameter of diverticulum was 7 mm, and 78 cases (14.1%) was ≥30 mm. Forty-nine patients (8.8%) developed acute diverticulitis, including 13 patients with simple diverticulitis and 36 patients with complicated diverticulitis. Among 36 patients with complicated diverticulitis, 29 (80.6%) were males, 27 (75.0%) had recurrent abdominal pain and fever before onset; diverticula of 25 cases were located in sigmoid colon; 11 cases in ascending colon. Nine cases developed sigmoid colon perforation and 8 cases developed vesicocolonic fistula, and these 17 patients underwent surgical treatment. The other 19 cases with complicated diverticulitis developed gastrointestinal bleeding, of whom 18 cases were male, 11 cases were located in ascending colon; 13 cases were healed after conservative treatment, 4 cases received endoscopic hemostatic intervention, and 2 cases underwent surgery. Conclusions: Colorectal diverticulosis is more common in male patients, and CT and colonoscopy are main diagnostic methods. The symptoms of complicated colonic diverticulitis are related to the location of diverticulum. In addition to symptomatic treatment, surgical procedures are the most important treatments.

Use of rituximab in the treatment of refractory systemic lupus erythematosus: Singapore experience.

We performed a retrospective study of 10 patients with refractory systemic lupus erythematosus treated with rituximab to determine the efficacy, safety and impact on hospitalization days. Patients received rituximab according to a standardized protocol, all achieved B-cell depletion with clinical improvement in nine patients. At 12 months, BILAG scores improved significantly from a median of 13.5 (range 3-20) at baseline to 1 (range 0-27) (p < 0.05). There was significant reduction in urinary total protein excretion with stabilization of renal function in patients with nephritis. Two out of three patients with thrombocytopenia had normalization of platelet counts. The median duration of B-cell depletion was 6 months (range 6-18). Two patients required retreatment and responded well. There were no adverse outcomes following rituximab therapy. Patients with lupus nephritis spent a median of 17.1 days per year (range 1.9-49) in hospital on conventional treatment which was reduced to 0 days (range 0-14.8, p = 0.027) post-rituximab treatment. The cost of hospitalization was 5989 Singapore dollars per patient-year while on conventional treatment and 5792 Singapore dollars per patient-year post-rituximab. This study adds to the growing literature of rituximab efficacy with potential cost saving in lupus nephritis.

Atherogenic serum lipid profile is an independent predictor for gouty flares in patients with gouty arthropathy.

OBJECTIVE: Atherogenic serum lipid profile possesses pro-inflammatory properties and is associated with more active RA. While prevalent in patients with gout, whether atherogenic lipid profile is associated with gouty flares is unknown. This study aims to investigate whether atherogenic serum lipid predicts gouty flares in patients with gout. METHODS: Adult patients (age > or =21 yrs) who suffered from gout were prospectively followed between September 2006 and November 2007 and their demographic, clinical and laboratory data were collected. Episodes of gouty flares over this observation period were recorded and factors predictive of gouty flares were studied by regression models. RESULTS: Of the 100 patients, 80 were men, 65 were ethnic Chinese, 31 were Malay and the rest were Indian and Caucasian. The mean age and duration of gout (+/-S.D.) were 61.9 +/- 14.0 and 6.6 +/- 7.8 yrs, respectively. The mean serum uric acid and creatinine levels were 537.6 +/- 142.8 and 173.6 +/- 119.9 micromol/l, respectively. In univariate analysis, longer duration of gout, higher adjusted mean serum creatinine, lower adjusted mean fasting serum, total cholesterol and high-density lipoprotein cholesterol (HDL-C) levels were associated with gouty flares. After adjustment for potential confounders in multivariate regression models, longer duration of gout and lower adjusted mean fasting serum HDL-C level remained independently predictive of gouty flares. CONCLUSIONS: Low serum high-density lipoprotein cholesterol level was an independent predictor for gouty flares. Whether optimizing serum HDL-C level can benefit patients with gout in terms of reducing gouty flares needs to be addressed by controlled trials.

Mortality and osteoporotic fractures: is the link causal, and is it modifiable?

Osteoporosis is a global problem with an expected increase in fracture prevalence and public health burden as the world's population ages. Although excess mortality is well-described in those with low bone mineral density as well as those with recent hip and vertebral fractures, some uncertainty remains about whether this link is causal. Survival depends greatly on the fracture types, age, gender, and race. Deaths are predominately due to comorbidities, but may also be attributed to the fracture event itself, either directly or indirectly. The goal of osteoporosis care is prevention of fractures and ultimately reduction in morbidity and mortality. Until recently, there have been no data showing that osteoporosis treatment improves mortality, and even now the extent of these data are rather limited. Large observational cohort studies over considerable time are needed to determine whether improving osteoporosis quality of care will improve mortality rates.

Utility of the Morisky Medication Adherence Scale in gout: a prospective study.

BACKGROUND: The outcomes of any chronic illness often depend on patients' adherence with their treatment. A tool is lacking to assess adherence in gout that is standardized, allows real-time feedback, and is easy to understand. OBJECTIVE: We set out to evaluate the utility of the 8-item Morisky Medication Adherence Scale (MMAS-8) in monitoring medication adherence in a multiethnic Asian gout cohort on urate-lowering therapy (ULT). METHODS: This cohort study recruited patients with gout where baseline and 6-monthly clinical data, self-report of adherence, and health status by Gout Impact Scale (GIS) and EuroQoL-5 dimension 3 levels were collected. Those who received at least 9 months of ULT were analyzed. Convergent and construct validities of MMAS-8 were evaluated against medication possession ratio (MPR) and known groups, clinical outcomes, and patient-reported outcomes. Internal consistency and test-retest reliability were assessed using Cronbach's alpha and intraclass correlation coefficient (ICC), respectively. RESULTS: Of 91 patients, 92.3% were male, 72.5% Chinese with mean age 53.5 years. MMAS-8 (mean 6.17) and MPR (mean 96.3%) were poorly correlated (r=0.069, P=0.521). MMAS-8 did not differ between those who did or did not achieve target serum urate (SU) <360 µmol/L (P=0.852); or among those whose SU improved, stagnated, or worsened during follow-up (P=0.777). Adherence was associated with age (ß=0.256, P=0.015) and education level (P=0.011) but not comorbidities, polypharmacy, or flare frequency. Concerns for medication side effects and anxiety or depression were associated with lower MMAS-8 (P<0.005). Internal consistency was acceptable (α=0.725) and test-retest reliability was satisfactory (ICC =0.70, 95% confidence interval [CI] 0.36-0.88). CONCLUSION: MMAS-8 had limited construct validity in assessing medication adherence to ULT in our gout patients. Nevertheless, it identified patients bothered or worried about ULT side effects, and those with underlying anxiety or depression, for whom targeted education and coping support may be useful.