Impact on daily clinical practice of the latest evidence on percutaneous closure of patent foramen ovale after cryptogenic stroke: a single-center experience.

Introduction And Objectives: At the end of 2017, three clinical trials demonstrated that, in selected patients, percutaneous closure of patent foramen ovale (PFO) after cryptogenic stroke (CS) reduces the risk of recurrence. Our aim was to determine the impact of these findings on routine clinical practice in a tertiary hospital.

Methods: Patients with CS and percutaneous closure of PFO during 2001-2020 were included.

Association Between Germline Mutations in BRF1, a Subunit of the RNA Polymerase III Transcription Complex, and Hereditary Colorectal Cancer.

Background & Aims: Although there is a genetic predisposition to colorectal cancer (CRC), few of the genes that affect risk have been identified. We performed whole-exome sequence analysis of individuals in a high-risk family without mutations in genes previously associated with CRC risk to identify variants associated with inherited CRC.

Methods: We collected blood samples from 3 relatives with CRC in Spain (65, 62, and 40 years old at diagnosis) and performed whole-exome sequence analyses.

New therapeutic perspectives in non-alcoholic steatohepatitis.

Management of non-alcoholic steatohepatitis is focused on restitution of metabolic derangement, weight loss and drugs able to improve steatosis, ballooning and fibrosis. Life-style interventions based on Mediterranean diet and increasing physical activity are the first line therapy. In patients with unsuccessful life-style intervention several drugs are under development: agonist PPAR, agonist GLP-1R and agonist FXR together with drugs focussing on inflammation, ballooning, apoptosis and fibrosis.

POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance.

Purpose: Germ-line mutations in the exonuclease domains of POLE and POLD1 have been recently associated with polyposis and colorectal cancer (CRC) predisposition. Here, we aimed to gain a better understanding of the phenotypic characteristics of this syndrome to establish specific criteria for POLE and POLD1 mutation screening and to help define the clinical management of mutation carriers.

Methods: The exonuclease domains of POLE and POLD1 were studied in 529 kindred, 441 with familial nonpolyposis CRC and 88 with polyposis, by using pooled DNA amplification and massively parallel sequencing.

Exome Sequencing Reveals AMER1 as a Frequently Mutated Gene in Colorectal Cancer.

Purpose: Somatic mutations occur at early stages of adenoma and accumulate throughout colorectal cancer progression. The aim of this study was to characterize the mutational landscape of stage II tumors and to search for novel recurrent mutations likely implicated in colorectal cancer tumorigenesis.

Experimental Design: The exomic DNA of 42 stage II, microsatellite-stable colon tumors and their paired mucosae were sequenced.

Germline Mutations in FAN1 Cause Hereditary Colorectal Cancer by Impairing DNA Repair.

Identification of genes associated with hereditary cancers facilitates management of patients with family histories of cancer. We performed exome sequencing of DNA from 3 individuals from a family with colorectal cancer who met the Amsterdam criteria for risk of hereditary nonpolyposis colorectal cancer. These individuals had mismatch repair-proficient tumors and each carried nonsense variant in the FANCD2/FANCI-associated nuclease 1 gene (FAN1), which encodes a nuclease involved in DNA inter-strand cross-link repair.

Comprehensive molecular characterisation of hereditary non-polyposis colorectal tumours with mismatch repair proficiency.

Background: Hereditary non-polyposis colorectal cancer (CRC) without mismatch repair (MMR) defects occurs in almost half of high-risk CRC families, but its genetic cause(s) is(are) still unknown. We aimed to identify unique molecular features that differentiate hereditary from sporadic MMR-proficient colorectal tumours.

Methods: Genomic alterations in 16 tumours from 14 Amsterdam I-II families were studied using the genome-wide copy number OncoScan™ FFPE microarray.

New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis.

Germline mutations in DNA polymerase ɛ (POLE) and δ (POLD1) have been recently identified in families with multiple colorectal adenomas and colorectal cancer (CRC). All reported cases carried POLE c.1270C>G (p.

Longer telomeres are associated with cancer risk in MMR-proficient hereditary non-polyposis colorectal cancer.

Aberrant telomere length measured in blood has been associated with increased risk of several cancer types. In the field of hereditary non-polyposis colorectal cancer (CRC), and more particularly in Lynch syndrome, caused by germline mutations in the mismatch repair (MMR) genes, we recently found that cancer-affected MMR gene mutation carriers had shorter telomeres and more pronounced shortening of telomere length with age than controls and unaffected MMR gene mutation carriers. Here we evaluate blood telomere length in MMR-proficient hereditary non-polyposis CRC, i.

Telomere length and genetic anticipation in Lynch syndrome.

Telomere length variation has been associated with increased risk of several types of tumors, and telomere shortening, with genetic anticipation in a number of genetic diseases including hereditary cancer syndromes. No conclusive studies have been performed for Lynch syndrome, a hereditary colorectal cancer syndrome caused by germline mutations in the DNA mismatch repair genes. Here we evaluate telomere length in Lynch syndrome, both as a cancer risk factor and as a mechanism associated with anticipation in the age of cancer onset observed in successive generations of Lynch syndrome families.

Genetic variant in the telomerase gene modifies cancer risk in Lynch syndrome.

Lynch syndrome (LS) is an inherited cancer-predisposing disorder caused by germline mutations in the mismatch repair (MMR) genes. The high variability in individual cancer risk observed among LS patients suggests the existence of modifying factors. Identifying genetic modifiers of risk could help implement personalized surveillance programs based on predicted cancer risks.

Thalidomide in refractory bleeding due to gastrointestinal angiodysplasias.

Objectives: to assess the efficacy of thalidomide in the treatment of relapsed or refractory bleeding secondary to gastrointestinal angiodysplasia.

Material And Methods: we carried out a prospective study of 12 patients with bleeding due to gastrointestinal angiodysplasia refractory to conventional therapy who were treated with thalidomide. For each patient, we considered: age, sex, underlying disease, previous therapies, dose and duration of thalidomide treatment, evolution of haemoglobin levels and adverse effects of treatment.

Immunological aspects of nonimmediate reactions to beta-lactam antibiotics.

beta-lactam antibiotics are the agents most frequently implied in immune drug adverse reactions. These can be classified as immediate or nonimmediate according to the time interval between the last drug administration and their onset. Mechanisms of immediate IgE-mediated reactions are widely studied and are therefore better understood.

[Generalized secondary peritonitis: predictors of in-hospital mortality and survival and mortality evolutive links].

Background: The knowledge of mortality predictors and evolutive variables linked with in-hospital death can help us to optimize corrective procedures.

Objectives: To identify independent predictors of in-hospital mortality and survival, and independent evolutive links with death in patients with generalized secondary peritonitis (GSP).

Methods: Two hundred and forty-two patients admitted into the hospital due to GSP were followed until in-hospital death or hospital discharge.

[Predictors of intrahospitalary mortality in the upper gastrointestinal variceal bleeding due to chronic liver disease treated endoscopically].

Unlabelled: Upper gastrointestinal variceal bleeding is one of the most serious complications in patients with chronic liver disease. The aim of this trial is to identify in hospital mortality predictors in this illness.

Material And Methods: 106 hospitalizations due to this disease from October 2001 to April 2006 in cohort design.

Antibacterial in vitro activity of fourth generation cephalosporins.

Cefpirome, cefepime and cefaclidine are distinguished by having a positively charged quaternary ammonium at carbon 3 of the dihydrothiazone ring. This confers the distinctive advantages of higher permeability across the outer membrane and low affinity for chromosomal cephalosporinases compared to the third generation cephalosporins which lack this quaternary ammonium moiety. These properties result in a marked advantage against resistant mutants of several species containing either derepressed class C chromosomal beta-lactamases or variant class A beta-lactamase.

Analysis of two gene regions involved in the expression of the imipenem-specific, outer membrane porin protein OprD of Pseudomonas aeruginosa.

A Tn501 mutant of Pseudomonas aeruginosa resistant to imipenem and lacking the imipenem-specific outer membrane porin protein OprD was isolated. The mutation could be complemented to imipenem susceptibility and OprD-sufficiency by a cloned 6-kb EcoRI-PstI fragment of DNA from the region of chromosome of the wild-type strain surrounding the site of Tn501 insertion. However, this fragment did not contain the oprD structural gene as judged by its inability to hybridize with an oligonucleotide corresponding to the N-terminal amino acid sequence of OprD.

Reevaluation, using intact cells, of the exclusion limit and role of porin OprF in Pseudomonas aeruginosa outer membrane permeability.

Earlier studies that used model membrane reconstitution methods have come to different conclusions regarding the exclusion limit of the outer membrane of Pseudomonas aeruginosa and whether OprF is the major channel-forming protein in the outer membrane. In this study, a 6.2-kbp SalI fragment, encoding only two cytoplasmic enzymes, alpha-galactosidase and sucrose hydrolase, and the inner membrane raffinose permease, was cloned behind the m-toluate-inducible tol promoter of vector pNM185 to create plasmid pFB71.

A pleiotropic, posttherapy, enoxacin-resistant mutant of Pseudomonas aeruginosa.

An enoxacin-resistant Pseudomonas aeruginosa mutant (G49) isolated during patient therapy was characterized in detail. The G49 mutant was cross resistant to several classes of antibiotics including quinolones, beta-lactams, chloramphenicol, and tetracycline, but not imipenem or aminoglycosides. Compared with its paired pretherapy isolate G48, this mutant had several alterations in outer membrane proteins including a complete loss of the major porin protein OprF and a substantially altered lipopolysaccharide profile.

Factors involved in the enhanced efficacy against gram-negative bacteria of fourth generation cephalosporins.

The fourth generation cephalosporins, cefpirome and cefepime, demonstrate better activity against strains of Enterobacter cloacae with derepressed beta-lactamase than the third generation compounds cefotaxime and ceftriaxone. Several methodological refinements were used to measure the parameters, predicted by the Zimmermann-Rosselet equation to be important in the efficacy of beta-lactams. Outer membrane permeability was measured by a novel HPLC method.

Reevaluation of the factors involved in the efficacy of new beta-lactams against Enterobacter cloacae.

The roles of outer membrane permeability, beta-lactamase stability, and inhibition of penicillin-binding proteins in the activity of new beta-lactams against Enterobacter cloacae were reappraised by using several methodological improvements. Outer membrane permeability in intact cells was determined by using a high-pressure liquid chromatography (HPLC)-based technique that avoided certain possible artifacts of the traditional methods. Vmax values were calculated from the numbers of enzyme molecules produced per cell and from catalytic constant (Kcat) values, which were obtained with purified beta-lactamase.

Novel method for measurement of outer membrane permeability to new beta-lactams in intact Enterobacter cloacae cells.

The ability of five new beta-lactams to permeate the outer membrane of intact Enterobacter cloacae beta-lactamase-overproducing cells was measured by using a high-pressure liquid chromatography (HPLC)-based technique that avoided certain possible artifacts of the traditional methods. Low concentrations of antibiotics were mixed with bacterial suspensions, and at different times, the cells were removed from the medium by filtration. Residual beta-lactam concentrations in the medium were then assessed by HPLC and UV detection.