Cardiac complications of infectious endocarditis

Factors predisposing to cardiac complications and influencing hospital survival, were analysed in a retrospective study of 101 cases of infective endocarditis. Heart failure occurred in 52 p. 100 of our patients. A significantly greater incidence of heart failure was observed in endocarditis with no preexisting heart disease (p less than 0.01), aortic and mitral valve involvement (p less than 0.01), staphylococcus aureus infections (p less than 0.05), arrhythmias (p less than 0.001), and conduction disturbances (p less than 0.01). Significantly more patients with congestive cardiac failure died in hospital (51 p. 100) than those without congestive cardiac failure (17 p. 100) (p less than 0.001). Severe heart failure before treatment (p less than 0.05), streptococcus D endocarditis (p = 0.05), supraventricular arrhythmias (p less than 0.05), and intracardiac conduction disturbances (p less than 0.05), significantly increased the hospital mortality in patients with congestive heart failure. Electrocardiographic findings revealed arrhythmias in 34 p. 100 of cases, more commonly with mitral valve involvement (71 p. 100) and 52 p. 100 died in hospital. The development of intracardiac conduction disturbance during the course of 18 cases of endocarditis (aortic valve in 11 cases) was associated with a hospital mortality rate of 60 p. 100. The incidence of pericarditis and pulmonary embolism was 4 and 7 p. 100 respectively, and all patients died in hospital. Acute inferior myocardial infarction compatible with coronary embolism was suspected in one patient. Early cardiac valve replacement improved the hospital survival in patients with cardiac complications of infective endocarditis.     

Morphometry and localization of the temporal transverse Heschl’s gyrus in magnetic resonance imaging: a guide for cortical stimulation of chronic tinnitus

Purpose

Subjective tinnitus is considered a phantom auditory phenomenon. Recent studies show that electrical or magnetic stimulation of the cortex can alleviate some tinnitus. The usual target of the stimulation is the primary auditory cortex (PAC) on Heschl’s gyrus (HG). The objective of this study was to specify the anatomy of HG by magnetic resonance imaging (MRI).

Methods

Cerebral MRI of 60 patients with chronic tinnitus, carried out before neuronavigated repetitive transcranial magnetic stimulation targeting the auditory cortex, were included. 3D-T1 MRI was reformatted in Talairach–Tournoux’s stereotactic space, then the following steps were performed: morphometry of HG, localization of the probabilistic center of the PAC (pcPAC) chosen at the junction between the medial third and the lateral two-thirds of HG, relative to external and cortical landmarks, and identification of its coordinates relative to the bicommissural line (AC-PC).

Results

In relation to external landmarks, the pcPAC was identified around 5 cm above the root of the helix of the ear in the direction of a point on the vertex located 4 cm behind the coronal suture, for both sides. In Talairach–Tournoux’s stereotactic space with the anterior commissure as the origin, the pcPAC coordinates were x = 43, y = ?20, z = 6.8 on the right side, and x = ?42.5, y = ?21.5, and z = 6.5 on the left. Probabilistic maps of the presence of HG pointed to a relative contraction of data in space, despite inter- and intraindividual differences.

Conclusion

The choice of our stimulation target was established in the middle of the theoretical position of the PAC. MRI allows a reliable identification of the target structure.     

Roscovitine is a proteostasis regulator that corrects the trafficking defect of F508del-CFTR by a CDK-independent mechanism

Background and Purpose

The most common mutation in cystic fibrosis (CF), F508del, causes defects in trafficking, channel gating and endocytosis of the CF transmembrane conductance regulator (CFTR) protein. Because CF is an orphan disease, therapeutic strategies aimed at improving mutant CFTR functions are needed to target the root cause of CF.

Experimental Approach

Human CF airway epithelial cells were treated with roscovitine 100 μM for 2 h before CFTR maturation, expression and activity were examined. The mechanism of action of roscovitine was explored by recording the effect of depleting endoplasmic reticulum (ER) Ca²⁺ on the F508del-CFTR/calnexin interaction and by measuring proteasome activity.

Key Results

Of the cyclin-dependent kinase (CDK) inhibitors investigated, roscovitine was found to restore the cell surface expression and defective channel function of F508del-CFTR in human CF airway epithelial cells. Neither olomoucine nor (S)-CR8, two very efficient CDK inhibitors, corrected F508del-CFTR trafficking demonstrating that the correcting effect of roscovitine was independent of CDK inhibition. Competition studies with inhibitors of the ER quality control (ERQC) indicated that roscovitine acts on the calnexin pathway and on the degradation machinery. Roscovitine was shown (i) to partially inhibit the interaction between F508del-CFTR and calnexin by depleting ER Ca²⁺ and (ii) to directly inhibit the proteasome activity in a Ca²⁺-independent manner.

Conclusions and Implications

Roscovitine is able to correct the defective function of F508del-CFTR by preventing the ability of the ERQC to interact with and degrade F508del-CFTR via two synergistic but CDK-independent mechanisms. Roscovitine has potential as a pharmacological therapy for CF.Table of Links

Synthesis, SAR, crystal structure, and biological evaluation of benzoquinoliziniums as activators of wild-type and mutant cystic fibrosis transmembrane conductance regulator channels

Chloride channels play important roles in homeostasis and regulate cell volume, transepithelial transport, and electrical excitability. Despite recent progress made in the genetic and molecular aspect of chloride channels, their pharmacology is still poorly understood. The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated epithelial chloride channel for which mutations cause cystic fibrosis. Here we have synthesized benzo[c]quinolizinium and benzo[f]indolo[2,3-a]quinolizinium salts (MPB) and performed a SAR to identify the structural basis for activation of the CFTR chloride channel. Synthesized compounds were evaluated on wild-type CFTR and on CFTR having the glycine-to-aspartic acid missense mutation at codon 551 (G551D-CFTR), using a robot and cell-based assay. The presence of an hydroxyl group at position 6 of the benzo[c]quinolizinium skeleton associated with a chlorine atom at position 10 or 7 and an alkyl chain at position 5 determined the highest activity. The most potent product is 5-butyl-7-chloro-6-hydroxybenzo[c]quinolizinium chloride (8u, MPB-104). 8u is 100 times more potent than the parent compound 8a (MPB-07).     

Selective activation of blood pressure monitoring alarms: effect of noise pollution in the intensive care unit]

OBJECTIVE: To evaluate a selective activation of sounding alarms on non-invasive blood pressure (BP) monitoring according to the patient haemodynamic status. STUDY DESIGN: Prospective study. METHODS: Activation of alarms on BP was regulated with a protocol. Sounding alarms were either inactivated when patient's haemodynamic status was stable (group 1), or activated when it was unstable (group 2). The frequency of BP measurement was one every 15 min. For all mean BP value recorded, the following criteria were analyzed: 1) normality of the value compared to ranges 65-115 mmHg in group 1 or compared to alarm thresholds in group 2; 2) consequences on the care and therapeutic; 3) delay when an abnormal value was detected and managed after more than 15 min. RESULTS: 1,674 hours of monitoring from 42 patients, allowed the analysis of 6,695 measurements of mean BP, 3,092 in group 1 and 3,603 in group 2. In group 1, 2,822 measurements were considered as normal and 3,094 measures in group 2. Eight measurements had consequences on therapeutic in group 1, with only one with delay in care giving. 287 measurements had consequences on therapeutic in group 2, 8 with delay in care giving. Six per cent of abnormal measurements in group 2 were managed with delay. This protocol reduced by 52% the production of sounding alarms on BP, without noxious effects for the patients. CONCLUSION: Selective activation of sounding alarms on BP, according to the patient haemodynamic status, reduced noise pollution and could be one solution to improve monitoring efficiency in intensive care unit.     

Pancreatic hemi-agenesis in MEN1: A clinical report

We first describe a patient with multiple endocrine neoplasia type 1 (MEN1) and dorsal pancreatic hemi-agenesis. Previously, pancreas divisum has been reported in MEN1.Recent data in mice have elucidated the molecular mechanisms of pancreatic endoderm specification. Disinhibition of hedgehog signaling appears to be important in how Gata4 and Gata6 variants cause pancreatic agenesis. Disinhibition of hedgehog signaling has also been observed in Men1 knockout pancreatic islets.Although we cannot exclude a spurious association between dorsal pancreatic hemi-agenesis and MEN1 in our patient, we argue that developmental abnormalities of the pancreas may have to be considered as possibly related to the MEN1 phenotype.