Rhizoma Coptidis Inhibits LPS-Induced MCP-1/CCL2 Production in Murine Macrophages via an AP-1 and NFκB-Dependent Pathway

Introduction. The Chinese extract Rhizoma coptidis is well known for its anti-inflammatory, antioxidative, antiviral, and antimicrobial activity. The exact mechanisms of action are not fully understood. Methods. We examined the effect of the extract and its main compound, berberine, on LPS-induced inflammatory activity in a murine macrophage cell line. RAW 264.7 cells were stimulated with LPS and incubated with either Rhizoma coptidis extract or berberine. Activation of AP-1 and NFκB was analyzed in nuclear extracts, secretion of MCP-1/CCL2 was measured in supernatants. Results. Incubation with Rhizoma coptidis and berberine strongly inhibited LPS-induced monocyte chemoattractant protein (MCP)-1 production in RAW cells. Activation of the transcription factors AP-1 and NFκB was inhibited by Rhizoma coptidis in a dose- and time-dependent fashion. Conclusions. Rhizoma coptidis extract inhibits LPS-induced MCP-1/CCL2 production in vitro via an AP-1 and NFκB-dependent pathway. Anti-inflammatory action of the extract is mediated mainly by its alkaloid compound berberine

Focused Assessment with Sonography for Urinary Schistosomiasis (FASUS)-pilot evaluation of a simple point-of-care ultrasound protocol and short training program for detecting urinary tract morbidity in highly endemic settings.

BACKGROUND: Urogenital schistosomiasis (UGS) causes inflammation and fibrosis of the urinary tract. In resource-limited settings, affordable tools for morbidity assessment in clinical care are needed. Point-of-care ultrasound has not yet been validated for UGS-related pathology. METHODS: We developed a protocol for Focused Assessment with Sonography for Urinary Schistosomiasis (FASUS), assessing pathology of the bladder wall, ureters and kidneys. Following standardized training, two clinicians performed FASUS on children and adults with hematuria in Lambaréné, Gabon. Recorded ultrasound clips were remotely reviewed by two ultrasound experts as a diagnostic reference. RESULTS: In 2015 and 2016, scans were performed in 118 patients. The image quality was sufficient in 90% of bladder views and more than 97% of kidney views. UGS-compatible pathology was detected in 51/118 (43%) by the operator and in 46/107 (43%) by the experts among baseline scans of sufficient quality. Inter-rater agreement between operators and experts was very good (κ > 0.8) for hydronephrosis and good (κ > 0.6) for bladder wall thickening. CONCLUSIONS: FASUS is a promising clinical, point-of-care tool for detecting UGS-related urinary tract morbidity in symptomatic patients. Based on larger validation studies, appropriate diagnostic and therapeutic algorithms for the use of FASUS should be established

S100A1: A Multifaceted Therapeutic Target in Cardiovascular Disease

Cardiovascular disease is the leading cause of death worldwide, showing a dramatically growing prevalence. It is still associated with a poor clinical prognosis, indicating insufficient long-term treatment success of currently available therapeutic strategies. Investigations of the pathomechanisms underlying cardiovascular disorders uncovered the Ca2+ binding protein S100A1 as a critical regulator of both cardiac performance and vascular biology. In cardiomyocytes, S100A1 was found to interact with both the sarcoplasmic reticulum ATPase (SERCA2a) and the ryanodine receptor 2 (RyR2), resulting in substantially improved Ca2+ handling and contractile performance. Additionally, S100A1 has been described to target the cardiac sarcomere and mitochondria, leading to reduced pre-contractile passive tension as well as enhanced oxidative energy generation. In endothelial cells, molecular analyses revealed a stimulatory effect of S100A1 on endothelial NO production by increasing endothelial nitric oxide synthase activity. Emphasizing the pathophysiological relevance of S100A1, myocardial infarction in S100A1 knockout mice resulted in accelerated transition towards heart failure and excessive mortality in comparison with wild-type controls. Mice lacking S100A1 furthermore displayed significantly elevated blood pressure values with abrogated responsiveness to bradykinin. On the other hand, numerous studies in small and large animal heart failure models showed that S100A1 overexpression results in reversed maladaptive myocardial remodeling, long-term rescue of contractile performance, and superior survival in response to myocardial infarction, indicating the potential of S100A1-based therapeutic interventions. In summary, elaborate basic and translational research established S100A1 as a multifaceted therapeutic target in cardiovascular disease, providing a promising novel therapeutic strategy to future cardiologists

Focused Assessment with Sonography for Urinary Schistosomiasis (FASUS)—pilot evaluation of a simple point-of-care ultrasound protocol and short training program for detecting urinary tract morbidity in highly endemic settings

Background Urogenital schistosomiasis (UGS) causes inflammation and fibrosis of the urinary tract. In resource-limited settings, affordable tools for morbidity assessment in clinical care are needed. Point-of-care ultrasound has not yet been validated for UGS-related pathology. Methods We developed a protocol for Focused Assessment with Sonography for Urinary Schistosomiasis (FASUS), assessing pathology of the bladder wall, ureters and kidneys. Following standardized training, two clinicians performed FASUS on children and adults with hematuria in Lambaréné, Gabon. Recorded ultrasound clips were remotely reviewed by two ultrasound experts as a diagnostic reference. Results In 2015 and 2016, scans were performed in 118 patients. The image quality was sufficient in 90% of bladder views and more than 97% of kidney views. UGS-compatible pathology was detected in 51/118 (43%) by the operator and in 46/107 (43%) by the experts among baseline scans of sufficient quality. Inter-rater agreement between operators and experts was very good (κ > 0.8) for hydronephrosis and good (κ > 0.6) for bladder wall thickening. Conclusions FASUS is a promising clinical, point-of-care tool for detecting UGS-related urinary tract morbidity in symptomatic patients. Based on larger validation studies, appropriate diagnostic and therapeutic algorithms for the use of FASUS should be established

Physician and Patient Predictors of Evidence-Based Prescribing in Heart Failure: A Multilevel Study

BACKGROUND: The management of patients with heart failure (HF) needs to account for changeable and complex individual clinical characteristics. The use of renin angiotensin system inhibitors (RAAS-I) to target doses is recommended by guidelines. But physicians seemingly do not sufficiently follow this recommendation, while little is known about the physician and patient predictors of adherence. METHODS: To examine the coherence of primary care (PC) physicians' knowledge and self-perceived competencies regarding RAAS-I with their respective prescribing behavior being related to patient-associated barriers. Cross-sectional follow-up study after a randomized medical educational intervention trial with a seven month observation period. PC physicians (n = 37) and patients with systolic HF (n = 168) from practices in Baden-Wuerttemberg. Measurements were knowledge (blueprint-based multiple choice test), self-perceived competencies (questionnaire on global confidence in the therapy and on frequency of use of RAAS-I), and patient variables (age, gender, NYHA functional status, blood pressure, potassium level, renal function). Prescribing was collected from the trials' documentation. The target variable consisted of ≥50% of recommended RAAS-I dosage being investigated by two-level logistic regression models. RESULTS: Patients (69% male, mean age 68.8 years) showed symptomatic and objectified left ventricular (NYHA II vs. III/IV: 51% vs. 49% and mean LVEF 33.3%) and renal (GFR<50%: 22%) impairment. Mean percentage of RAAS-I target dose was 47%, 59% of patients receiving ≥50%. Determinants of improved prescribing of RAAS-I were patient age (OR 0.95, CI 0.92-0.99, p = 0.01), physician's global self-confidence at follow-up (OR 1.09, CI 1.02-1.05, p = 0.01) and NYHA class (II vs. III/IV) (OR 0.63, CI 0.38-1.05, p = 0.08). CONCLUSIONS: A change in physician's confidence as a predictor of RAAS-I dose increase is a new finding that might reflect an intervention effect of improved physicians' intention and that might foster novel strategies to improve safe evidence-based prescribing. These should include targeting knowledge, attitudes and skills

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events

Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial

Aims The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM). Methods and results ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64-0.99; DM: HR: 1.16, 95% CI: 0.91-1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50-0.94; DM: HR: 1.64, 95% CI: 1.15-2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71-1.93; DM: HR: 2.39, 95% CI: 1.30-4.42; P = 0.07 for interaction). Conclusion This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without D

Methicillin-resistant Staphylococcus aureus as a cause of invasive infections in Central Africa: a case report and review of the literature

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) colonization and infection are increasingly being reported worldwide and are associated with severe illness. The vast majority of MRSA infections are skin and soft tissue infections, while invasive disease remains rare. In Western countries, the epidemiology of MRSA is well documented, but from Central Africa, reports on MRSA are very limited. Case presentation and review of the literature. The clinical features, epidemiology, and characteristics of MRSA in Central Africa, as well as the treatment options, are discussed. We present a case of severe invasive CA-MRSA infection with pneumonia, pericarditis, and bacteremia in a previously healthy young woman in Gabon. Several virulence factors, like Panton-Valentine leukocidin and type I arginine catabolic mobile element, may play a role in the ability of CA-MRSA to cause severe invasive infections. Based on studies from Gabon and Cameroon (no reports were available from other countries), we find that the prevalence of MRSA is relatively low in this region. Treatment depends primarily on local prevalence and resistance profile of MRSA combined with clinical characteristics. Severe invasive infection with CA-MRSA is a rare disease presentation in Central Africa, where this pathogen is still relatively uncommon. However, cases of MRSA may be complicated by the human immunodeficiency virus (HIV) and tuberculosis epidemics, and also the limited availability of effective antibiotic