Cytotoxic and Anti-Inflammatory Triterpenoids in the Vines and Leaves of Momordica charantia.

The vines and leaves of Momordica charantia L. are used as herbal medicines to treat inflammation-related disorders. However, their safety profile remains uncharacterized, and the constituents in their extracts that exert anti-inflammatory and adverse effects remain unclear. This study isolated the characteristic cucurbitane-type triterpenoid species in the vines and leaves of M. charantia L. and analyzed their cytotoxicity, anti-inflammatory effects, and underlying mechanisms. Four structurally related triterpenoids-momordicines I, II, IV, and (23E) 3ß,7ß,25-trihydroxycucurbita-5,23-dien-19-al (TCD)-were isolated from the triterpenoid-rich fractions of extracts from the vines and leaves of M. charantia. Momordicine I was cytotoxic on normal cells, momordicine II exerted milder cytotoxicity, and momordicine IV and TCD had no obvious adverse effects on cell growth. TCD had anti-inflammatory activity both in vivo and in vitro. In lipopolysaccharide-stimulated RAW 264.7 cells, TCD inhibited the inhibitor kappa B kinase/nuclear factor-κB pathway and enhanced the expression of nuclear factor erythroid 2-related factor 2, heme oxygenase-1, and glutamate-cysteine ligase modifier subunit through the extracellular signal-regulated kinase1/2 and p38. Thus, the vines and leaves of M. charantia should be used with caution. An extraction protocol that can enrich TCD but remove momordicine I would likely enhance the safety of the extract.

Newly Diagnosed Leptospirosis and Subsequent Hemorrhagic Stroke: A Nationwide Population-Based Cohort Study.

BACKGROUND AND PURPOSE: Preceding infection as an important risk factor for ischemic stroke has been reported but neglected for hemorrhagic stroke, especially in young and middle-aged patients. This study investigates whether newly diagnosed leptospirosis is associated with an increased risk of stroke. METHODS: We identified 3699 in-patients who were aged ≥18 years and newly diagnosed with leptospirosis. We also randomly selected a comparison cohort 14 796 in-patients from the general population by using a propensity score matching method (at a 1:4 ratio). We analyzed the risks of stroke by using Cox proportional hazard regression models. RESULTS: The adjusted hazard ratio (HR; 95% CI) of stroke for the leptospirosis group was 1.14 (0.93-1.38; P=0.200) as opposed to the comparison group after adjusting sex, age, and comorbidities. However, adjusted HR (95% CI) of ischemic stroke and hemorrhagic stroke was 1.01 (0.80-1.29) and 1.58 (1.12-2.23), respectively. The strength of association between leptospirosis and hemorrhagic stroke remained statistically significant after variation of leptospirosis and stroke definitions. The post hoc subgroup analysis indicated that a patient with leptospirosis had a significantly greater risk of hemorrhagic stroke in male (adjusted HR, 1.62 [95% CI, 1.08-2.44]) and individuals between age 18 and 39 (adjusted HR, 3.67 [95% CI, 1.33-10.14]). The risk of hemorrhagic stroke among people with leptospirosis was highest in the first 2 years after diagnosis (adjusted HR, 1.97 [95% CI, 1.15-3.38]). CONCLUSIONS: A 2.49-fold risk of stroke was found among the leptospirosis cohort of aged younger than 39 years. Age acted as an effect modifier between the leptospirosis and risk of new-onset stroke.

Flat foot and spinal degeneration: Evidence from nationwide population-based cohort study.

BACKGROUND/PURPOSE: Flat foot can alter the lower limb alignment and cause knee and back pain. To explore the association between flat foot and spinal degeneration. METHODS: By using a claims dataset containing 1 million random samples, individuals with flat foot were identified between January 1, 2000, and December 31, 2013. The study assembled a flat foot group and a matched non-flat foot group. Definition of flat foot was according to International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. The diagnosis date was defined as the index date for follow-up initiation. The follow-up period was defined as the duration from the index date (or nested index date for controls) to the occurrence of spinal degenerative joint disease (DJD), or December 31, 2013. The primary outcome was record of spinal DJD retrieved from the same database. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), with the control group as a reference. RESULTS: We identified 13,965 patients (most aged <30 years, 88%); 2793 patients were assigned to the flat foot group and 11,172 individuals to the non-flat foot group matched by age, sex, and index year. The mean follow-up duration was approximately 74 months. In total, 329 (11.78%) patients in the study group and 931 (8.33%) patients in the comparison group developed spinal DJD. The adjusted HR (95% CI) of spinal DJD for study group was 1.423(1.250-1.619) compared with the control. Sensitivity analyses with propensity score match and different scenario about spinal DJD enrollment showed similar results. Subgroup analysis showed that in patients aged >45 years with history of flat foot, the adjusted hazard ratios were 1.434, 3.065, 3.110, and 2.061 in association with spondylosis, intervertebral disc disorder, cervical stenosis, thoracic-lumbar-sacral stenosis, respectively. CONCLUSION: Flat foot was found to be an independent risk factor for subsequent spinal DJD.

Astaxanthin protects steroidogenesis from hydrogen peroxide-induced oxidative stress in mouse Leydig cells.

Androgens, especially testosterone produced in Leydig cells, play an essential role in development of the male reproductive phenotype and fertility. However, testicular oxidative stress may cause a decline in testosterone production. Many antioxidants have been used as reactive oxygen species (ROS) scavengers to eliminate oxidative stress to protect steroidogenesis. Astaxanthin (AST), a natural extract from algae and plants ubiquitous in the marine environment, has been shown to have antioxidant activity in many previous studies. In this study, we treated primary mouse Leydig cells or MA-10 cells with hydrogen peroxide (H2O2) to cause oxidative stress. Testosterone and progesterone production was suppressed and the expression of the mature (30 kDa) form of StAR protein was down-regulated in MA-10 cells by H2O2 and cAMP co-treatment. However, progesterone production and expression of mature StAR protein were restored in MA-10 cells by a one-hour pretreatment with AST. AST also reduced ROS levels in cells so that they were lower than the levels in untreated controls. These results provide additional evidence of the potential health benefits of AST as a potential food additive to ease oxidative stress.

Metformin use is associated with a lower risk of rotator cuff disease in patients with Type 2 diabetes mellitus.

AIMS: Metformin has been mentioned to be protective against inflammation, degeneration, and oxidative stress, conditions that are associated with rotator cuff disease. To access the association between metformin use and risk of rotator cuff disease in patients with type 2 diabetes mellitus (DM). METHODS: This was a retrospective cohort study utilizing Taiwan National Health Insurance Research Database between January 1, 2000, and December 31, 2012 to retrieved participants. Metformin and propensity score matched never metformin users were determined at baseline (between the date of onset of DM and the index date), and followed to December 31, 2013. Propensity scores were adopted to address measurable confounders (including demographic variables, Diabetes Complications Severity Index, relevant comorbidities and co-medication). A multivariable Cox proportional hazards regression model was applied to estimate the adjusted hazard ratios (HRs) for the risk of the first diagnosis of rotator cuff disease on the full cohort and on the propensity score matched cohort. RESULTS: In the propensity score matched cohort, a total of 34,964 individuals (19,416 [55.5%] men), 17,482 individuals were taking metformin, 559 [3.2%] of whom developed rotator cuff disease. Incidence of rotator cuff disease was 4.51 per 10,000 person-months in the metformin users and 5.11 in the controls. Among metformin group, the aHR (95% CI) was 0.879 (0.784-0.984) after full adjustment. The potential beneficial effect on the risk of rotator cuff disease was consistently observed across all subgroups, including sex, age, concomitant other glucose lowering drugs, and level of Diabetes Complications Severity Index (all P for interaction > 0.050). CONCLUSION: Metformin use was associated with a lower risk of rotator cuff disease in patients with type 2 DM.

Human Papillomavirus Infection and the Risk of Erectile Dysfunction: A Nationwide Population-Based Matched Cohort Study.

BACKGROUND: Male patients with genital warts are known for higher rates of sexual dysfunction. This study was conducted to investigate whether human papillomaviruses (HPV) infection is associated with an increased risk of erectile dysfunction (ED). METHODS: Patients aged over 18 with HPV infection (n = 13,296) and propensity score-matched controls (n = 53,184) were recruited from the Longitudinal Health Insurance Database (LHID). The primary endpoint was the diagnosis of ED. Chi-square tests were used to analyze the distribution of demographic characteristics. The Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the development of ED in both groups, after adjusting for sex, age, relevant comorbidities, co-medication, and surgery. RESULTS: ED developed in 181 patients of the study group. The incidence density of ED was 2.53 per 1000 person-years for the HPV group and 1.51 per 1000 person-years for the non-HPV group, with an adjusted HR (95% CI) of 1.63 (1.37-1.94). In stratification analysis, adjusted HR of diabetes-, chronic obstructive pulmonary disease (COPD-), and stroke-subgroup were 2.39, 2.51, and 4.82, with significant p values for interaction, respectively. Sensitivity analysis yields consistent findings. CONCLUSIONS: The patients with HPV infection had a higher risk of subsequent ED in comparison to the non-HPV controls. The mechanism behind such association and its possible role in ED prevention deserves further study in the future.

Female Human Papillomavirus Infection Associated with Increased Risk of Ectopic Pregnancy: Early Evidence from Taiwan Population-Based Cohort Study.

BACKGROUND: This is an investigation of the human papillomavirus (HPV) infection and its correlation with the risk of ectopic pregnancy (EP). METHODS: The cohort study includes 11,239 patients with newly diagnosed HPV infections between 2000 and 2012, and by using computer-generated random numbers, patients who do not have HPV infections are selected randomly as the comparison cohort. The HPV infection cohort is matched to comparison individuals at a 1:10 ratio by age and index year. All individuals included in the study were followed up to the point they developed EP, pulled-out from the insurance program, lost to follow-up, or until the end of 2013. A Cox proportional-hazards regression analysis was used to analyze the risk of EP with the hazard ratios (HRs) and 95% confidence intervals (CIs) between the HPV and control cohort. RESULTS: The adjusted hazard ratio (aHR) of EP for HPV patients relative to controls is 1.70 (95% CI = 1.04, 2.78), indicating a positive correlation between EP and HPV in the 13-year follow-up period, after adjusting for age and relevant comorbidities. The sensitivity analyses yield similar results. CONCLUSIONS: A history of HPV infection is a potential risk factor associated with the development of subsequent EP in Taiwanese individuals, especially those diagnosed with an HPV infection within 3 years.

Syphilis and ischemic stroke: Old question revisited by a nationwide cohort study.

BACKGROUND AND PURPOSE: In the era of easily available antibiotic use, this study provides epidemiological evidence for a re-examination of the relationship between syphilis and ischemic stroke (IS). METHODS: Patients aged 18 years and older with newly diagnosed syphilis were included (n = 1585) from 2000 to 2012, and participants without syphilis in the control group (n = 6340) were matched by propensity score (age, sex, index year, insured amount, urbanization, seasons, and comorbidities). The Cox proportional hazard model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of IS. Five different Cox regression models, sensitivity analyses, and negative control were conducted to test our findings. RESULTS: In all, 1585 patients (1055 (66.56%) men; mean (SD) age, 49.59 (20.32) years) had syphilis, and 3.8% had new-onset IS. The syphilis group had a higher risk of IS than the controls (adjusted HR, 1.35; 95% CI, 1.01-1.80; p value < 0.05) after full adjustment. Serial sensitivity analyses yielded consistent results. CONCLUSION: Syphilis patients have higher risk of IS, and our data raise the question of implementation of prophylactic treatment for IS.

Absence of Association between Previous Mycoplasma pneumoniae Infection and Subsequent Myasthenia Gravis: A Nationwide Population-Based Matched Cohort Study.

Mycoplasma pneumoniae (M. pneumoniae) is not only one of the most common pathogenic bacteria for respiratory infection but also a trigger for many autoimmune diseases. Its infection process shared many similarities with the pathogenesis of myasthenia gravis (MG) at cellular and cytokine levels. Recent case reports demonstrated patients present with MG after M. pneumoniae infection. However, no epidemiological studies ever looked into the association between the two. Our study aimed to investigate the relationship between M. pneumoniae infection and subsequent development of MG. In this population-based retrospective cohort study, the risk of MG was analyzed in patients who were newly diagnosed with M. pneumoniae infection between 2000 and 2013. A total of 2428 M. pneumoniae patients were included and matched with the non-M. pneumoniae control cohort at a 1:4 ratio by age, sex, and index date. Cox proportional hazards regression analysis was applied to analyze the risk of MG development after adjusting for sex, age, and comorbidities, with hazard ratios and 95% confidence intervals. The incidence rates of MG in the non-M. pneumoniae and M. pneumoniae cohorts were 0.96 and 1.97 per 10,000 person-years, respectively. Another case-control study of patients with MG (n = 515) was conducted to analyze the impact of M. pneumoniae on MG occurrence as a sensitivity analysis. The analysis yielded consistent absence of a link between M. pneumoniae and MG. Although previous studies have reported that M. pneumoniae infection and MG may share associated immunologic pathways, we found no statistical significance between M. pneumoniae infection and subsequent development of MG in this study.

Non-Typhoidal Salmonella and the Risk of Kawasaki Disease: A Nationwide Population-Based Cohort Study.

Objective: The aim of this study was to investigate the relationship between non-typhoidal Salmonella (NTS) infection and the risk of Kawasaki disease (KD) by using a nationwide population-based data set in Taiwan. Methods: In this retrospective cohort study, we enrolled 69,116 patients under 18 years of age, with NTS from January 1st, 2000, to December 31st, 2013, using the population-based National Health Insurance Research Database of Taiwan. A comparison group without NTS was matched (at a 1:4 ratio) by propensity score. The two cohorts were followed from the initial diagnosis of NTS until the date of KD development or December 31st, 2013. Cox proportional hazard regression analysis was conducted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for covariates. Also, we conducted sensitivity analyses to examine our findings. Results: After adjusting for covariates, the risk of KD for the children with NTS was significantly higher than that of the comparison group (hazard ratio = 1.31; 95% confidence interval = 1.03-1.66; p < 0.01). Stratified analysis showed that the associated risk of the investigated outcome was significant in children aged ≤2 years (aHR= 1.31, 95% C.I. 1.02-1.69), in female patients (aHR= 1.46, 95% C.I. 1.03-2.08), and in those without allergic diseases. Conclusions: NTS is associated with an increased risk of KD in Taiwanese children.

Association Between Severity of Leptospirosis and Subsequent Major Autoimmune Diseases: A Nationwide Observational Cohort Study.

Introduction: Infections play a role in autoimmune diseases (AD). Leptospirosis has been linked to the trigger of systemic lupus erythematosus. Objective: To investigate subsequent risk of major AD in hospitalized Taiwanese for Leptospirosis. Methods: Retrospective observational cohort study was employed. The enrolled period was from 2000 to 2012. In the main model, we extracted 4026 inpatients with leptospirosis from the Taiwan National Health Insurance Research Database (NHIRD) and 16,104 participants without leptospirosis at a 1:4 ratio propensity-score matched (PSM) by age, gender, index year, and comorbidities. The follow-up period was defined as the time from the initial diagnosis of leptospirosis to major AD occurrence or 2013. This study was re-analyzed by frequency-matching as a sensitivity analysis for cross-validation. Univariable and multivariable Cox proportional hazards regression models were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: The adjusted HR (95% CI) of major ADs for the leptospirosis group was 4.45 (3.25-6.79) (p < 0.001) compared to the controls after full adjustment. The risk of major ADs was 5.52-fold (95% CI, 3.82-7.99) higher in leptospirosis patients hospitalized for seven days and above than the controls, while 2.80-fold (95% CI, 1.68-5.61) in those hospitalized less than seven days. The sensitivity analysis yields consistent findings. Stratified analysis revealed that the association between leptospirosis and major ADs was generalized in both genders, and all age groups. Conclusions: Symptomatic leptospirosis is associated with increased rate of subsequent major ADs, and the risk seems to be higher in severe cases.

The Potential Role of Human Papillomavirus Infection in Bell's Palsy: A Hypothesis-Generating Study Based on a Nationwide Cohort.

Objective: Our purpose was to investigate whether people with a previous human papillomavirus (HPV) infection were associated with an increased risk of Bell's palsy (BP). Methods: By using Taiwan population-based data, patients aged > 18 years with HPV infection (n = 22,260) from 2000 to 2012 were enrolled and compared with control subjects who had never been diagnosed with an HPV infection at a 1:4 ratio matched by sex, age, index date, and co-morbidities (n = 89,040). The index date was the first date of HPV diagnosis. All the patients were tracked until the occurrence of BP. Cox proportional hazards regression was applied to estimate the hazard ratios (HRs) for the development of BP in both groups. Results: The HPV group had 1.25 [95% confidence interval (CI) = 1.03-1.51] times higher risk of BP compared with the non-HPV group after adjusting for sex, age, and co-morbidities. The association of HPV and BP was significant in the sensitivity analyses. In the subgroup analysis, the impact of HPV infection on the risk of BP was more pronounced in the elderly > 50 years [adjusted hazard ratio (aHR) =1.86; 95% CI = 1.37-2.52], hypertension (aHR = 1.65; 95% CI = 1.17-2.31), and chronic obstructive pulmonary disease (aHR = 2.14, 95% CI 1.333.43) subgroups. Conclusions: Patients with HPV infection have a higher risk of subsequent BP compared with non-HPV patients. More rigorous studies are needed to confirm if and how specific HPV genotypes are associated with BP and the possible role of vaccines in disease prevention.

Candida Infection as an Early Sign of Subsequent Sjögren's Syndrome: A Population-Based Matched Cohort Study.

BACKGROUND: Candida infection is prevalent in patients with Sjögren's syndrome (SjS), which usually takes years to reach diagnosis. Is the link a two-way street? The role of Candida infection before SjS has not been examined clearly. This study was conducted to provide epidemiological evidence regarding the relationship between the first acquisition of Candida infection and subsequent SjS. METHODS: Totally, 23,494 individuals newly diagnosed with Candida infection were enrolled from 2000, to 2012. Controls (N = 93,976) were selected at a 1:4 ratio through propensity score matched (PSM) using the greedy algorithm. Exposure was defined according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. MAIN OUTCOMES AND MEASURES: SjS was recorded in the Registry for Catastrophic Illness Patients Database (RCIPD). Cox proportional hazard model was used to analyze the association and sensitivity analyses for cross-validation. RESULTS: Of 117,470 individuals (106,077 [89%] women), 23,494 individuals (20.0%) had Candida infection and 104 individuals (0.1%) developed SjS. The incidence of SjS was higher in the exposed group compared with the controls (1.92 vs. 0. 98 per 10,000 person-years) with adjusted hazard ratio (aHR) 1.90 (95% CI, 1.25-2.87). The aHRs in subgroups of aged 18-30 years, oral candidiasis and depression were 4.30 (95% CI, 1.60-11.55), 4.70 (4.70-13.93) and 6.34 (2.16-18.66). Sensitivity analyses yield consistent results. CONCLUSIONS: Residents in Taiwan with Candida infection have higher risk of SjS. For early diagnosis of SjS, clinicians are advised to take Candida infection into account in some situation.

Risk of subsequent atrial fibrillation in patients with myasthenia gravis: A population-based cohort study.

ABSTRACT: The purpose of this study was to explore the association between myasthenia gravis (MG) and the risk of atrial fibrillation (AF) in an Asian population. The risk was analyzed in a cohort of 5528 patients with history of MG and 5528 individuals without MG using a hospitalization claim dataset. Both groups were matched by age, sex, index year and baseline comorbidities as an original analysis. A Cox proportional hazard model was used to estimate the hazard ratio and 95% confidence interval of AF after adjusting for demographic and relevant clinical covariates. The adjusted hazard ratio of the MG group compared with that of the non-MG group was 1.03 (95% confidence interval, 0.76-1.38) for AF. A stratified analysis showed that compared with the propensity score matched non-MG group, there was no increased risk of developing AF based on age categories, gender, or comorbidities. Different time follow-up periods results showed no increased risk of AF compared with the non-MG group. Overall, in the Taiwanese cohort, MG is not associated with an increased risk of AF.

The association between Candida infection and ankylosing spondylitis: a population-based matched cohort study.

AIMS: To explore whether newly diagnosed Candida infection increases the risk of developing ankylosing spondylitis (AS). METHODS AND MATERIALS: We investigated 61,550 patients with newly diagnosed Candida infection between 1997 and 2013 from the Taiwan National Health Insurance Research Datasets to conduct a population-based matched-cohort study. Controls were 61,550 subjects without Candida infection and propensity score matched with the Candida exposure cohort. The follow-up period was defined as month from the initial diagnosis of Candida infection (or nested index date for controls) to the date of AS, or 31 December 2013. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the occurrence of AS. RESULTS: The incidence rates of AS in the Candida group and comparison group were respectively 4.58 and 3.88 per 100,000 person-months. The adjusted HR (95% CI) of AS for the Candida group was 1.19 (0.99-1.44) compared to the control group after adjustment for age, gender and all covariates (95% CI = 1.77-2.27). However, an adjusted hazard ratio (aHR) of 1.77-fold (95% CI = 1.26-2.53) significant increase in the risk of developing AS was observed after 6 years of follow-up, when exposure to Candida was at baseline. The effect of Candida infection was significantly time varying (p value for interaction between follow-up period and Candida infection is .018). CONCLUSIONS: A risk of AS was found after Candida infection, and a year of follow-up acts as an effect modifier between the Candida infection and risk of AS. Key messages What is already known on this subject? Links between spondyloarthritis and fungal infections have been found in animal studies before. What does this study add? Our study demonstrated that Candida infection is an independent risk factor for developing ankylosing spondylitis in terms of gender, age and relevant variables and comorbidities. A risk of ankylosing spondylitis was found after Candida infection, and year of follow-up acts as an effect modifier between the Candida infection and risk of AS. Clinicians should be aware of possible Candida infection in managing patients with ankylosing spondylitis. Implications: Clinicians must pay greater attention to patients with newly diagnosed Candida infection. Specifically, they should conduct tests for ankylosing spondylitis. Further research is needed to examine if and how treatment of Candida infection alleviates symptoms of AS.