Effect of estrogen suppression on lung function in pulmonary Lymphangioleiomyomatosis

Background: Lymphangioleiomyomatosis (LAM), a rare progressive disease, is characterized by the proliferation of abnormal smooth muscle cells (LAM cells) in the lung, which leads to cystic parenchymal destruction and progressive respiratory failure. Estrogen receptors are present in LAM cells. LAM affects almost exclusively women of childbearing age. These findings, along with reports of disease progression during pregnancy or treatment with exogenous estrogens, have led to the assumption that hormonal factors play an important role in the pathogenesis of LAM. So, various therapies aim at preventing estrogen receptors (ER) by lowering circulating estrogen levels, by trying to block ER activity, or by attempting to lower ER expression in LAM. Prior experience have yielded conflicting results. Objective: The goal of this study was to evaluate, retrospectively, the effect of estrogen suppression in 21 patients with LAM. Design: We evaluated hormonal assays, pulmonary function tests and gas-exchange at baseline and after 12, 24 and 36 months after initiating hormonal manipulation. Results: The mean yearly rates of decline in FEV1 and DLCO are lower than those observed in prior studies and just DLCO decline was statistically significant. We also found an improvement of mean value of FVC and PaO2. Conclusions: Estrogen suppression appears to prevent decline in lung function in LAM.

Biomarkers in chronic obstructive pulmonary diseases. Clinical and functional correlations.

Asthma and chronic obstructive pulmonary disease (COPD) are two distinct lung diseases with distinctive clinical and inflammatory features. A proportion of asthmatic patients experience a fixed airflow obstruction that persists despite optimal pharmacologic treatment for reasons that are still largely unknown. We found that patients with asthma and COPD sharing a similar fixed airflow obstruction have an increased lung function decline and frequency of exacerbations. Nevertheless, the decline in lung function is associated with specific features of the underlying inflammation. Airway inflammation increases during asthma exacerbation and disease severity. Less is known about the correlations between symptoms and airway inflammation in COPD patients. We found that there is no correlation between symptoms and lung function in COPD patients. Nevertheless symptoms changes are associated with specific inflammatory changes: cough is associated with an increase of sputum neutrophils in COPD, dyspnoea is associated with an increase of eosinophils. The mechanisms of this correlation remain unknown. Neutrophils inflammation is associated with bacterial colonization in stable COPD. Is not known whether inhaled corticosteroids might facilitate bacterial colonization in COPD patients. We found that the use of inhaled corticosteroids in COPD patients is associated with an increase of airway bacterial load and with an increase of airway pathogen detection. Bacterial and viral infections are the main causes of COPD and asthma exacerbations. Impaired innate immune responses to rhinovirus infections have been described in adult patients with atopic asthma. Whether this impaired immune condition is present early in life and whether is modulated by a concomitant atopic condition is currently unknown. We found that deficient innate immune responses to rhinovirus infection are already present early in life in atopic patients without asthma and in asthmatic subjects. These findings generalize the scenario of increased susceptibility to viral infections to other Th2 oriented conditions.

Development of strategies for vascular damage repair in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive and rare disease with so far unclear pathogenesis, limited treatment options and poor prognosis. Unbalance of proliferation and migration in pulmonary arterial smooth muscle cells (PASMCs) is an important hallmark of PAH. In this research Sodium butyrate (BU) has been evaluated in vitro and in vivo models of PAH. This histone deacetylase inhibitor (HDACi) counteracted platelet-derived growth factor (PDGF)-induced ki67 expression in PASMCs, and arrested cell cycle mainly at G0/G1 phases. Furthermore, BU reduced the transcription of PDGFRbeta, and that of Ednra and Ednrb, two major receptors in PAH progression. Wound healing and pulmonary artery ring assays indicated that BU inhibited PDGF-induced PASMC migration. BU strongly inhibited PDGF-induced Akt phosphorylation, an effect reversed by the phosphatase inhibitor calyculinA. In vivo, BU showed efficacy in monocrotaline-induced PAH in rats. Indeed, the HDACi reduced both thickness of distal pulmonary arteries and right ventricular hypertrophy. Besides these studies, Serial Analysis of Gene Expression (SAGE) has be used to obtain complete transcriptional profiles of peripheral blood mononuclear cells (PBMCs) isolated from PAH and Healthy subjects. SAGE allows quantitative analysis of thousands transcripts, relying on the principle that a short oligonucleotide (tag) can uniquely identify mRNA transcripts. Tag frequency reflects transcript abundance. We enrolled patients naïve for a specific PAH therapy (4 IPAH non-responder, 3 IPAH responder, 6 HeritablePAH), and 8 healthy subjects. Comparative analysis revealed that significant differential expression was only restricted to a hundred of down- or up-regulated genes. Interestingly, these genes can be clustered into functional networks, sharing a number of crucial features in cellular homeostasis and signaling. SAGE can provide affordable analysis of genes amenable for molecular dissection of PAH using PBMCs as a sentinel, surrogate tissue. Altogether, these findings may disclose novel perspectives in the use of HDACi in PAH and potential biomarkers.

Exaggerated Pulmonary Hypertension During Mild Exercise in Chronic Mountain Sickness

Chronic mountain sickness (CMS) is an important public health problem and is characterized by exaggerated hypoxemia, erythrocytosis, and pulmonary hypertension. While pulmonary hypertension is a leading cause of morbidity and mortality in patients with CMS, it is relatively mild and its underlying mechanisms are not known. We speculated that during mild exercise associated with daily activities, pulmonary hypertension in CMS is much more pronounced.

Radiopaque stomach contents in postmortem CT in suicidal oral medication intoxication: report of three cases

In clinical medicine, plane radiography is used for detecting the remains of medications in the stomach in oral medication intoxication cases. Since postmortem computed tomography (CT), performed prior to autopsy, is currently intensively entering the forensic routine, the technique was applied to three fatal cases of oral medication intoxication. Here we report CT and autopsy findings for these cases. In all three cases, hyperdense areas within the stomach content were documented. The measurement of Hounsfield Units (HU) beyond 74HU showed mean values of 338, 88 and 98HU. Postmortem CT also showed brain edema and pulmonary aspiration in one case. At autopsy, tablet remains in the stomach were detected microscopically in all three cases. The ex vivo CT scans of the ingested medicaments showed similar HU values. Despite the fact that further case studies are necessary beyond this one, and in spite of its limitations, postmortem CT was found to be a useful screening and documentation method for stomach contents in oral medication intoxication.

Improved detection of pulmonary nodules on energy-subtracted chest radiographs with a commercial computer-aided diagnosis software: comparison with human observers

To retrospectively analyze the performance of a commercial computer-aided diagnosis (CAD) software in the detection of pulmonary nodules in original and energy-subtracted (ES) chest radiographs.

Diagnosis of fatal pulmonary fat embolism with minimally invasive virtual autopsy and post-mortem biopsy

We report a case of a 78-year-old female with a proximal femur fracture caused by an accidental fall who died suddenly 1h after orthopaedic prosthesis insertion. Post-mortem computed tomography (CT) scan and histological examination of samples obtained with post-mortem percutaneous needle biopsies of both lungs were performed. Analysis of the medical history and the clinical scenario immediately before death, imaging data, and biopsy histology established the cause of death without proceeding to traditional autopsy. It was determined to be acute right ventricular failure caused by massive pulmonary fat embolism. Although further research in post-mortem imaging and post-mortem tissue sampling by needle biopsies is necessary, we conclude that the use of CT techniques and percutaneous biopsy, as additional tools, can offer a viable alternative to traditional autopsy in selected cases and may increase the number of minimally invasive forensic examinations performed in the future.

Safety and Efficacy of Ranibizumab in Diabetic Macular Edema (RESOLVE Study): A 12-month, randomized, controlled, double-masked, multicenter phase II study

The expression of vascular endothelial growth factor (VEGF) is elevated in diabetic macular edema (DME). Ranibizumab binds to and inhibits multiple VEGF variants. We investigated the safety and efficacy of ranibizumab in DME involving the foveal center.

Effects of lung recruitment maneuvers on splanchnic organ perfusion during endotoxin-induced pulmonary arterial hypertension

Lung recruitment maneuvers (RMs), used to reopen atelectatic lung units and to improve oxygenation during mechanical ventilation, may result in hemodynamic impairment. We hypothesize that pulmonary arterial hypertension aggravates the consequences of RMs in the splanchnic circulation. Twelve anesthetized pigs underwent laparotomy and prolonged postoperative ventilation. Systemic, regional, and organ blood flows were monitored. After 6 h (= baseline), a recruitment maneuver was performed with sustained inflation of the lungs. Thereafter, the pigs were randomly assigned to group C (control, n = 6) or group E with endotoxin-induced pulmonary arterial hypertension (n = 6). Endotoxemia resulted in a normotensive and hyperdynamic state and a deterioration of the oxygenation index by 33%. The RM was then repeated in both groups. Pulmonary artery pressure increased during lipopolysaccharide infusion from 17 ± 2 mmHg (mean ± SD) to 31 ± 10 mmHg and remained unchanged in controls (P < 0.05). During endotoxemia, RM decreased aortic pulse pressure from 37 ± 14 mmHg to 27 ± 13 mmHg (mean ± SD, P = 0.024). The blood flows of the renal artery, hepatic artery, celiac trunk, superior mesenteric artery, and portal vein decreased to 71% ± 21%, 69% ± 20%, 76% ± 16%, 79% ± 18%, and 81% ± 12%, respectively, of baseline flows before RM (P < 0.05 all). Organ perfusion of kidney cortex, kidney medulla, liver, and jejunal mucosa in group E decreased to 65% ± 19%, 77% ± 13%, 66% ± 26%, and 71% ± 12%, respectively, of baseline flows (P < 0.05 all). The corresponding recovery to at least 90% of baseline regional blood flow and organ perfusion lasted 1 to 5 min. Importantly, the decreases in regional blood flows and organ perfusion and the time to recovery of these flows did not differ from the controls. In conclusion, lipopolysaccharide-induced pulmonary arterial hypertension does not aggravate the RM-induced significant but short-lasting decreases in systemic, regional, and organ blood flows.

Pulse-pressure variation and hemodynamic response in patients with elevated pulmonary artery pressure: a clinical study

Pulse-pressure variation (PPV) due to increased right ventricular afterload and dysfunction may misleadingly suggest volume responsiveness. We aimed to assess prediction of volume responsiveness with PPV in patients with increased pulmonary artery pressure.

Pulse pressure variation and volume responsiveness during acutely increased pulmonary artery pressure: an experimental study

We found that pulse pressure variation (PPV) did not predict volume responsiveness in patients with increased pulmonary artery pressure. This study tests the hypothesis that PPV does not predict fluid responsiveness during an endotoxin-induced acute increase in pulmonary artery pressure and right ventricular loading.

The adsorption of biomolecules to multi-walled carbon nanotubes is influenced by both pulmonary surfactant lipids and surface chemistry

Background During production and processing of multi-walled carbon nanotubes (MWCNTs), they may be inhaled and may enter the pulmonary circulation. It is essential that interactions with involved body fluids like the pulmonary surfactant, the blood and others are investigated, particularly as these interactions could lead to coating of the tubes and may affect their chemical and physical characteristics. The aim of this study was to characterize the possible coatings of different functionalized MWCNTs in a cell free environment. Results To simulate the first contact in the lung, the tubes were coated with pulmonary surfactant and subsequently bound lipids were characterized. The further coating in the blood circulation was simulated by incubating the tubes in blood plasma. MWCNTs were amino (NH2)- and carboxyl (-COOH)-modified, in order to investigate the influence on the bound lipid and protein patterns. It was shown that surfactant lipids bind unspecifically to different functionalized MWCNTs, in contrast to the blood plasma proteins which showed characteristic binding patterns. Patterns of bound surfactant lipids were altered after a subsequent incubation in blood plasma. In addition, it was found that bound plasma protein patterns were altered when MWCNTs were previously coated with pulmonary surfactant. Conclusions A pulmonary surfactant coating and the functionalization of MWCNTs have both the potential to alter the MWCNTs blood plasma protein coating and to determine their properties and behaviour in biological systems.