Does digoxin sensitize left ventricular mechanoreceptors?

Summary Afferent nerve fibre activity from left ventricular mechanoreceptors was recorded in 10 anaesthetized cats before and after two intravenous injections of 15 g/kg digoxin at 1 hour interval. These receptors are activated by coronary artery occlusion and induce a depressor cardiovascular reflex resulting in bradycardia and hypotension.Neither the spontaneous activity of the receptor's afferent nerve fibres nor their maximum activity during temporary coronary artery occlusion was affected by digoxin. The results show that digoxin in therapeutic doses has no sensitizing effect on left ventricular mechanoreceptors with vagal afferent fibres. The sensitization of cardiopulmonary baroreflexes by digitalis glycosides shown in previous investigations is thus more likely to be mediated by a central nervous effect of the drug.     

Difficulties in the mutation analysis of plasminogen gene: a study in two patients with ligneous conjunctivitis.

The absence or very low levels of plasminogen cause a rare disabling disease called ligneous conjunctivitis, characterized by the growth of fibrin-rich pseudomembranes in the conjunctiva and on other mucosal surfaces. Several mutations have been detected in the plasminogen gene of patients affected with ligneous conjunctivitis. The human plasminogen gene, located on chromosome 6, has a marked homology with the genes belonging to the plasminogen-apo(a) family, and with a number of pseudogenes and plasminogen-like genes located on chromosome 2. This work describes a series of nucleotide variations related to genes other than the plasminogen one, found during the genetic characterization of plasminogen defect in two unrelated patients with ligneous conjunctivitis. The results of automated sequences of each exon and intron-exon boundaries were compared with those of the human plasminogen gene from the NCBI gene bank. In particular, a co-amplified gene on chromosome 2 mimicking a 14 bp deletion in exon 5 of the plasminogen gene was identified by sequencing two different bands obtained from a long run of the PCR exon 5 product in NuSieve agarose gel, and by PstI restriction enzyme analysis of the same amplicons. Moreover, 21 single nucleotide exchanges due to plasminogen-like genes co-amplification were observed, namely one in exon 1, two in exon 4, three in exons 3, 5 and 16, four in exon 13, and five in exon 17. In conclusion, these data confirm the difficulty of plasminogen genetic analysis and may help researchers to better identify the true plasminogen gene mutations causing molecular defects.     

Erdosteine: antitussive and anti-inflammatory effects

Erdosteine is a multifactorial drug currently used in COPD for its rheologic activity on bronchial secretions and its positive effects on bacterial adhesiveness. Erdosteine produces an active metabolite (Met 1) which was shown to produce antioxidant effects during the respiratory burst of human PMNs, due to the presence of an SH group. The substantial antitussive effects of erdosteine were first documented in clinical trials even though mucolytic agents are regarded as not consistently effective in ameliorating cough in patients with bronchitis, although they may be of benefit to this population in other ways. Actually, a mucolytic drug could exert antitussive effects if it also affects mucus consistency and enhances ciliary function. In the last decade, data from several studies on animal models pointed to the possible antitussive and anti-inflammatory properties of erdosteine and an indirect anti-inflammatory mechanism of action was suggested. Recently, data from some controlled versus placebo studies documented the antioxidant properties of erdosteine in humans and in current smokers with COPD. The mechanism of action was described as related to erdosteine's ability to inhibit some inflammatory mediators and some pro-inflammatory cytokines that are specifically involved in oxidative stress. As oxidative stress is also presumed to impair beta-adrenoceptor function and contribute to airway obstruction, specific controlled studies recently investigated the effect of antioxidant intervention on short-term airway response to salbutamol in nonreversible COPD, according to a double-blind design versus placebo and NAC. Only erdosteine consistently restored a significant short-term reversibility in COPD subjects, previously unresponsive to beta(2) adrenergics. This peculiar activity of erdosteine (to our knowledge never previously assessed) proved related to the ROS scavenging activity (which actually proved equal to that of N), and its significant inhibiting effect on lipoperoxidation (8-isoprostane) proved discriminant between treatments, with antioxidant and anti-inflammatory effects the main determinants of the erdosteine multifactorial properties. In addition, antitussive effects may be regarded as related to its anti-inflammatory properties via the improvement of mucociliary clearance and the reduction of chemokines from epithelial cells. Finally, a sort of "sensitization" of 2-adrenoceptors can also be speculated due to the same mechanisms of action; if confirmed by further controlled studies, this particular property would suggest a novel therapeutic role of erdosteine in COPD.     

In‐Depth Analysis of Hyaline Fibromatosis Syndrome Frameshift Mutations at the Same Site Reveal the Necessity of Personalized Therapy

Hyaline fibromatosis syndrome is an autosomal recessive disease caused by mutations in ANTXR2, a gene involved in extracellular matrix homeostasis. Sixty percent of patients carry frameshift mutations at a mutational hotspot in exon 13. We show in patient cells that these mutations lead to low ANTXR2 mRNA and undetectable protein levels. Ectopic expression of the proteins encoded by the mutated genes reveals that a two base insertion leads to the synthesis of a protein that is rapidly targeted to the ER‐associated degradation pathway due to the modified structure of the cytosolic tail, which instead of being hydrophilic and highly disordered as in wild type ANTXR2, is folded and exposes hydrophobic patches. In contrast, one base insertion leads to a truncated protein that properly localizes to the plasma membrane and retains partial function. We next show that targeting the nonsense mediated mRNA decay pathway in patient cells leads to a rescue of ANTXR2 protein in patients carrying one base insertion but not in those carrying two base insertions. This study highlights the importance of in‐depth analysis of the molecular consequences of specific patient mutations, which even when they occur at the same site can have drastically different consequences.     

Effects of cachaça,a typical Brazilian alcoholic beverage,on submandibular glands of rats: a histomorphometric and biochemical study

Objective

This study aimed to evaluate the effects of chronic consumption of cachaça, a Brazilian beverage containing alcohol, on submandibular glands (SM) of rats by using histomorphometric and biochemical parameters.

Materials and methods

Twenty-four male rats (40 days of age) were assigned into the following four groups (n = 6): two control groups for 75 days (C75) and 105 days (C105), and two experimental groups of cachaça ingestion with ascending concentrations for consecutive 75 days (CA75) and 105 days (CA105). On the right SM glands, the striated, granular and acini ducts were processed for histomorphometric analysis. The left SM glands were weighed and stored at − 80 °C, to evaluate through biochemical tests carried out by spectrophotometric methods, the functional activity of total acid phosphatase (TAP), tartrate-resistant acid phosphatase (TRAP), and alkaline phosphatase (ALP) and to determine the mucin levels.

Results

The absolute and relative weights of the SM glands in both experimental groups were reduced in relation to the controls (p < 0.05). The histomorphometric analysis showed a significant reduction of the acini area (p < 0.05) and non-relevant reduction of striated ducts (p > 0.05). The granular ducts did not show a significant increase of the area (p > 0.05). The TAP and TRAP activities were significantly decreased in the experimental groups (p < 0.05), while the ALP functional activity decreased moderately (p > 0.05). Mucin levels also had a significant reduction when compared with the control groups (p < 0.05).

Conclusions

Chronic consumption of cachaça can cause morphological changes associated with glandular atrophy, loss of biochemical functionality of phosphatases, and the reduction of mucin synthesis.

Clinical relevance

The consumption of cachaça can compromise the functions of the submandibular glands by altering their morphology and enzymatic activity.

     

A clinical approach for cardiovascular monitoring of HIV-infected patients. Results from an observational cohort study.

BACKGROUND: HIV infection is one of the leading causes of acquired heart disease. Because of its high diffusion, systematic echocardiographic monitoring has been proposed to exclude cardiovascular involvement in these patients. The aim of this study was to evaluate an alternative clinical approach by which echocardiographic screening is limited to patients with a clinical suspicion of heart disease. METHODS: We studied 2030 consecutive HIV-infected patients admitted to a tertiary referral hospital (group A). History, physical examination, ECG, and chest X-ray were used to screen HIV-infected patients for cardiovascular involvement. Selected patients were extensively studied, first of all by echocardiography. Cardiovascular and non-cardiovascular deaths were recorded: RESULTS: Cardiovascular involvement was clinically suspected in 201 patients (9.9%; group B). Among them a higher extracardiac mortality was found in presence of pericardial disease (odds ratio [OR] 4.27, 95% confidence interval [CI] 2.01-9.09), while a higher cardiovascular mortality was recorded for patients with cardiomyopathy or myocarditis (OR 2.72, 95% CI 1.09-6.81), and right ventricular dysfunction and/or pulmonary hypertension (OR 4.67, 95% CI 1.44-15.2). Compared with group A, patients in group B had a significantly increased cardiac death rate (0.114 vs 0.018, p < 0.001). A positive echocardiogram slightly increased this rate (from 0.114 to 0.164, p = NS), whereas a negative echocardiogram significantly decreased the cardiac death rate (0.015 vs 0.164, p = 0.004). CONCLUSIONS: Clinical selection of HIV-infected patients with suspected cardiovascular involvement may help identify patients with higher frequency of cardiovascular involvement. Among these patients, echocardiography may be a useful screening tool in those at high risk for cardiovascular death.