Tuberculosis immunopathology: the neglected role of extracellular matrix destruction

The extracellular matrix in the lung must be destroyed for Mycobacterium tuberculosis—the agent that causes tuberculosis (TB)—to spread. The current paradigm proposes that this destruction occurs as a result of the action of proinflammatory cytokines, chemokines, immune cells, and lipids that mediate TB-associated necrosis in the lung. However, this view neglects the fact that lung matrix can only be degraded by proteases. We propose an original conceptual framework of TB immunopathology that may lead directly to treatments that involve inhibition of matrix metalloproteinase activity to hinder matrix destruction and reduce the morbidity and mortality associated with T

FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death.

Arrhythmias, a common cause of sudden cardiac death, can occur in structurally normal hearts, although the mechanism is not known. In cardiac muscle, the ryanodine receptor (RyR2) on the sarcoplasmic reticulum releases the calcium required for muscle contraction. The FK506 binding protein (FKBP12.6) stabilizes RyR2, preventing aberrant activation of the channel during the resting phase of the cardiac cycle. We show that during exercise, RyR2 phosphorylation by cAMP-dependent protein kinase A (PKA) partially dissociates FKBP12.6 from the channel, increasing intracellular Ca(2+) release and cardiac contractility. FKBP12.6(-/-) mice consistently exhibited exercise-induced cardiac ventricular arrhythmias that cause sudden cardiac death. Mutations in RyR2 linked to exercise-induced arrhythmias (in patients with catecholaminergic polymorphic ventricular tachycardia [CPVT]) reduced the affinity of FKBP12.6 for RyR2 and increased single-channel activity under conditions that simulate exercise. These data suggest that "leaky" RyR2 channels can trigger fatal cardiac arrhythmias, providing a possible explanation for CPVT

Ectopic endometrium in human foetuses is a common event and sustains the theory of müllerianosis in the pathogenesis of endometriosis, a disease that predisposes to cancer

<p>Abstract</p> <p>Background</p> <p>Endometriosis is a gynecological disease defined by the histological presence of endometrial glands and stroma outside the uterine cavity. Women with endometriosis have an increased risk of different types of malignancies, especially ovarian cancer and non-Hodgkin's lymphoma. Though there are several theories, researchers remain unsure as to the definitive cause of endometriosis. Our objective was to test the validity of the theory of müllerianosis for endometriosis, that is the misplacing of primitive endometrial tissue along the migratory pathway of foetal organogenesis</p> <p>Methods</p> <p>We have collected at autopsy 36 human female foetuses at different gestational age. We have performed a morphological and immunohistochemical study (expression of oestrogen receptor and CA125) on the pelvic organs of the 36 foetuses included en-block and totally analyzed.</p> <p>Results</p> <p>In 4 out of 36 foetuses we found presence of misplaced endometrium in five different ectopic sites: in the recto-vaginal septum, in the proximity of the Douglas pouch, in the mesenchimal tissue close to the posterior wall of the uterus, in the rectal tube at the level of muscularis propria, and in the wall of the uterus. All these sites are common location of endometriosis in women.</p> <p>Conclusion</p> <p>We propose that a cause of endometriosis is the dislocation of primitive endometrial tissue outside the uterine cavity during organogenesis.</p

Superluminal group velocity through near-maximal neutrino oscillations

Recently it was suggested that the observation of superluminal neutrinos by the OPERA collaboration may be due to group velocity effects resulting from close-to-maximal oscillation between neutrino mass eigenstates, in analogy to known effects in optics. We show that superluminal propagation does occur through this effect for a series of very narrow energy ranges, but this phenomenum cannot explain the OPERA measurement.Comment: Reworking includes corrections due to finite width of the wave packet, further references, and comments on other corrections, causality, the new OPERA results, and why the size of neutrino wave packet provides important constraint

Effects of long-term low-dose oxygen supplementation on the epithelial function, collagen metabolism and interstitial fibrogenesis in the guinea pig lung

<p>Abstract</p> <p>Background</p> <p>The patient population receiving long-term oxygen therapy has increased with the rising morbidity of COPD. Although high-dose oxygen induces pulmonary edema and interstitial fibrosis, potential lung injury caused by long-term exposure to low-dose oxygen has not been fully analyzed. This study was designed to clarify the effects of long-term low-dose oxygen inhalation on pulmonary epithelial function, edema formation, collagen metabolism, and alveolar fibrosis.</p> <p>Methods</p> <p>Guinea pigs (n = 159) were exposed to either 21% or 40% oxygen for a maximum of 16 weeks, and to 90% oxygen for a maximum of 120 hours. Clearance of inhaled technetium-labeled diethylene triamine pentaacetate (Tc-DTPA) and bronchoalveolar lavage fluid-to-serum ratio (BAL/Serum) of albumin (ALB) were used as markers of epithelial permeability. Lung wet-to-dry weight ratio (W/D) was measured to evaluate pulmonary edema, and types I and III collagenolytic activities and hydroxyproline content in the lung were analyzed as indices of collagen metabolism. Pulmonary fibrotic state was evaluated by histological quantification of fibrous tissue area stained with aniline blue.</p> <p>Results</p> <p>The clearance of Tc-DTPA was higher with 2 week exposure to 40% oxygen, while BAL/Serum Alb and W/D did not differ between the 40% and 21% groups. In the 40% oxygen group, type I collagenolytic activities at 2 and 4 weeks and type III collagenolytic activity at 2 weeks were increased. Hydroxyproline and fibrous tissue area were also increased at 2 weeks. No discernible injury was histologically observed in the 40% group, while progressive alveolar damage was observed in the 90% group.</p> <p>Conclusion</p> <p>These results indicate that epithelial function is damaged, collagen metabolism is affected, and both breakdown of collagen fibrils and fibrogenesis are transiently induced even with low-dose 40% oxygen exposure. However, these changes are successfully compensated even with continuous exposure to low-dose oxygen. We conclude that long-term low-dose oxygen exposure does not significantly induce permanent lung injury in guinea pigs.</p

Ets1 Induces Dysplastic Changes When Expressed in Terminally-Differentiating Squamous Epidermal Cells

BACKGROUND: Ets1 is an oncogene that functions as a transcription factor and regulates the activity of many genes potentially important for tumor initiation and progression. Interestingly, the Ets1 oncogene is over-expressed in many human squamous cell cancers and over-expression is highly correlated with invasion and metastasis. Thus, Ets1 is believed to mainly play a role in later stages of the oncogenic process, but not early events. METHODOLOGY/PRINCIPAL FINDINGS: To better define the role of Ets1 in squamous cell carcinogenesis, we generated a transgenic mouse model in which expression of the Ets1 oncogene could be temporally and spatially regulated. Upon Ets1 induction in differentiating cells of stratified squamous epithelium, these mice exhibited dramatic changes in epithelial organization including increased proliferation and blocked terminal differentiation. The phenotype was completely reversed when Ets1 expression was suppressed. In mice where Ets1 expression was re-induced at a later age, the phenotype was more localized and the lesions that developed were more invasive. Many potential Ets1 targets were upregulated in the skin of these mice with the most dramatic being the metalloprotease MMP13, which we demonstrate to be a direct transcriptional target of Ets1. CONCLUSIONS/SIGNIFICANCE: Collectively, our data reveal that upregulation of Ets1 can be an early event that promotes pre-neoplastic changes in epidermal tissues via its regulation of key genes driving growth and invasion. Thus, the Ets1 oncogene may be important for oncogenic processes in both early and late stages of tumor development

FKBP12.6 Deficiency and Defective Calcium Release Channel (Ryanodine Receptor) Function Linked to Exercise-Induced Sudden Cardiac Death

AbstractArrhythmias, a common cause of sudden cardiac death, can occur in structurally normal hearts, although the mechanism is not known. In cardiac muscle, the ryanodine receptor (RyR2) on the sarcoplasmic reticulum releases the calcium required for muscle contraction. The FK506 binding protein (FKBP12.6) stabilizes RyR2, preventing aberrant activation of the channel during the resting phase of the cardiac cycle. We show that during exercise, RyR2 phosphorylation by cAMP-dependent protein kinase A (PKA) partially dissociates FKBP12.6 from the channel, increasing intracellular Ca2+ release and cardiac contractility. FKBP12.6−/− mice consistently exhibited exercise-induced cardiac ventricular arrhythmias that cause sudden cardiac death. Mutations in RyR2 linked to exercise-induced arrhythmias (in patients with catecholaminergic polymorphic ventricular tachycardia [CPVT]) reduced the affinity of FKBP12.6 for RyR2 and increased single-channel activity under conditions that simulate exercise. These data suggest that “leaky” RyR2 channels can trigger fatal cardiac arrhythmias, providing a possible explanation for CPVT

Models of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a major global health problem and is predicted to become the third most common cause of death by 2020. Apart from the important preventive steps of smoking cessation, there are no other specific treatments for COPD that are as effective in reversing the condition, and therefore there is a need to understand the pathophysiological mechanisms that could lead to new therapeutic strategies. The development of experimental models will help to dissect these mechanisms at the cellular and molecular level. COPD is a disease characterized by progressive airflow obstruction of the peripheral airways, associated with lung inflammation, emphysema and mucus hypersecretion. Different approaches to mimic COPD have been developed but are limited in comparison to models of allergic asthma. COPD models usually do not mimic the major features of human COPD and are commonly based on the induction of COPD-like lesions in the lungs and airways using noxious inhalants such as tobacco smoke, nitrogen dioxide, or sulfur dioxide. Depending on the duration and intensity of exposure, these noxious stimuli induce signs of chronic inflammation and airway remodelling. Emphysema can be achieved by combining such exposure with instillation of tissue-degrading enzymes. Other approaches are based on genetically-targeted mice which develop COPD-like lesions with emphysema, and such mice provide deep insights into pathophysiological mechanisms. Future approaches should aim to mimic irreversible airflow obstruction, associated with cough and sputum production, with the possibility of inducing exacerbations