Immunological mechanisms of fecal microbiota transplantation in recurrent Clostridioides difficile infection

Fecal microbiota transplantation (FMT) is a successful method for treating recurrent Clostridioides difficile (C. difficile) infection (rCDI) with around 90% efficacy. Due to the relative simplicity of this approach, it is being widely used and currently, thousands of patients have been treated with FMT worldwide. Nonetheless, the mechanisms underlying its effects are just beginning to be understood. Data indicate that FMT effectiveness is due to a combination of microbiological direct mechanisms against C. difficile, but also through indirect mechanisms including the production of microbiota-derived metabolites as secondary bile acids and short chain fatty acids. Moreover, the modulation of the strong inflammatory response triggered by C. difficile after FMT seems to rely on a pivotal role of regulatory T cells, which would be responsible for the reduction of several cells and soluble inflammatory mediators, ensuing normalization of the intestinal mucosal immune system. In this minireview, we analyze recent advances in these immunological aspects associated with the efficacy of FMT.     

Patent foramen ovale in a large population of ischemic stroke patients: diagnosis, age distribution, gender, and race

BACKGROUND: Patent foramen ovale (PFO) is a well-recognized risk factor for ischemic strokes. The true prevalence of PFO among stroke patients is still under debate. Transesophageal echocardiography (TEE) is the "gold standard" in diagnosing PFO but the physiology requires right-to-left atrial shunting. In this report, we evaluate the prevalence of PFO in a diverse group of ischemic stroke patients studied by TEE. METHODS: TEE of 1,663 ischemic stroke patients were reviewed for cardiac source of embolism, including PFO and atrial septal aneurysm (ASA). Agitated saline bubble injection was performed to look for right to left atrial shunting. Success of maneuvers to elevate right atrial pressure (RAP) was noted by looking at the atrial septal bulge. RESULTS: Among 1,435 ischemic stroke patients analyzed, the presence or absence of PFO could not be determined in 32.1% because bulging of the septum could not be demonstrated in patients with negative contrast study despite aggressive maneuvers to elevate RAP. Of the remaining 974 patients, 294 patients (30.2%) had a PFO. The mean age was 61.5 years in both groups, with a bimodal distribution of PFO and the highest prevalence occurring in < or =30-year-old group. Prevalence of PFO was similar in men (32.4%) and women (28.15%, P = 0.15); and in Caucasian (32.1%) and African American (27.7%; P = 0.15). ASA was present in 2.02% and hypermobile septum in 2.49% of the 1,435 patients. PFO was seen in 79.3% of the patients with ASA. CONCLUSION: Successful elevation of RAP cannot be achieved in a significant number of patients undergoing TEE and determination of PFO may be difficult. In our series, the true prevalence of PFO among ischemic stroke patients was 30.2% taking into account only those patients who showed no shunting despite bulging of the atrium septum into the left atrium (PFO absent group) during the contrast study. There was no gender or racial difference in the prevalence of PFO, but there was a bimodal distribution in prevalence with age.     

Atypical antioxidant activity of non-phenolic amino-coumarins

Coumarin compounds have been described as anti-inflammatories, and chemotherapeutic agents as well as antioxidants. However, the origin of the antioxidant activity of non phenolic coumarins remains obscure. In the present report, we demonstrate that non-phenolic 7-dialkyl-aminocoumarins may also have significant antioxidant properties against free radicals derived from 2,2′-azobis(2-amidinopropane) dihydrochloride under aerobic conditions. This atypical behaviour is due to the presence of traces of very reactive hydroxycinnamic acid-type compounds. Changing functional groups at the C-3 and C-4 positions shifts the reactivity of the compounds from peroxyl to alkoxyl free radicals. Kinetic and theoretical studies based on Density Functional Theory support the formation of reactive hydroxycinnamic acid and directly link the antioxidant behaviour of the compounds to hydrogen atom transfer.

Relevant antioxidant properties of non-phenolic 7-dialkyl-aminocoumarins against free radicals derived from 2,2′-azobis(2-amidinopropane) dihydrochloride under aerobic conditions have been experimentally and theoretically demonstrated.     

Prostate-specific membrane antigen (PSMA)-mediated laminin proteolysis generates a pro-angiogenic peptide

Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase expressed in a number of tissues. PSMA participates in various biological functions depending on the substrate available in the particular tissue; in the brain, PSMA cleaves the abundant neuropeptide N-acetyl-aspartyl-glutamate to regulate release of key neurotransmitters, while intestinal PSMA cleaves polyglutamated peptides to supply dietary folate. PSMA expression is also progressively upregulated in prostate cancer where it correlates with tumor progression as well as in tumor vasculature, where it regulates angiogenesis. The previous research determined that PSMA cleavage of small peptides generated via matrix metalloprotease-mediated proteolysis of the extracellular matrix protein laminin potently activated endothelial cells, integrin signaling and angiogenesis, although the specific peptide substrates were not identified. Herein, using enzymatic analyses and LC/MS, we unequivocally demonstrate that several laminin-derived peptides containing carboxy-terminal glutamate moieties (LQE, IEE, LNE) are bona fide substrates for PSMA. Subsequently, the peptide products were tested for their effects on angiogenesis in various models. We report that LQ, the dipeptide product of PSMA cleavage of LQE, efficiently activates endothelial cells in vitro and enhances angiogenesis in vivo. Importantly, LQE is not cleaved by an inactive PSMA enzyme containing an active site mutation (E424S). Endothelial cell activation by LQ was dependent on integrin beta-1-induced activation of focal adhesion kinase. These results characterize a novel PSMA substrate, provide a functional rationale for the upregulation of PSMA in cancer cells and tumor vasculature and suggest that inhibition of PSMA could lead to the development of new angiogenic therapies.     

Electrocardiographic prediction of the site of lesion in the anterior descending artery in acute myocardial infarction

INTRODUCTION AND OBJECTIVES: The goal of this study was to analyze the value of electrocardiography in predicting the site of the lesion in the left anterior descending coronary artery, in relation to the first septal and the first diagonal branches, in patients with acute anterior myocardial infarction. METHOD: Ninety consecutive patients who were admitted to the coronary unit with acute anterior myocardial infarction from July 1998 to May 2000 were studied retrospectively. The electrocardiographic changes were analyzed and correlated with the site of the lesion in the anterior descending artery, as determined by coronary angiography. RESULTS: The most useful parameters in predicting the site of the lesion in the left anterior descending coronary artery in acute anterior myocardial infarction are: 1) For lesions proximal to the first septal branch, ST-segment elevation in aVR (p < 0.001) and the absence of Q wave in V4-V6 (p = 0.01). 2) For lesions proximal to the first diagonal branch, abnormal Q wave in aVL (p = 0.01) and ST depression in III (p = 0.05). 3) For lesions proximal to both the first septal and first diagonal branches, ST elevation in aVR (p < 0.001), abnormal Q wave in aVL (p = 0.02), and absence of Q wave in V4-V6 (p = 0.01). 4) For lesions distal to both the first septal and first diagonal branches, abnormal Q wave in V4-V6 (p = 0.001) and absence of ST depression in III (p < 0.001). CONCLUSIONS: In acute anterior myocardial infarction, electrocardiography is useful for predicting the site of the lesion in the left anterior descending coronary artery in relation to the first septal and the first diagonal branches.