Pathobiological Mechanisms Research Articles

CD44 Deficiency Is Associated with Increased Susceptibility to Stress-Induced Anxiety-like Behavior in Mice.

CD44 is a cell surface adhesion molecule and its principal ligand is hyaluronic acid (HA), a key component of the brain's extracellular matrix. CD44 levels are decreased in the cerebrospinal fluid (CSF) of depressed individuals, and the CD44 gene has been identified in genome wide association study as a possible risk gene in suicidal behavior. In order to define the pathobiological mechanisms by which CD44 may affect behavior, we investigated the role of CD44 using male CD44 knockout (CD44KO) and wild-type mice that underwent chronic mild stress (CMS). Behavior was characterized using the sucrose preference and forced swim tests, open field, novel object recognition, social preference, and the elevated plus maze tests. Gene expression in hippocampus was evaluated using quantitative real-time PCR. Brain monoamines and their metabolites were assessed by high-performance liquid chromatography and serum HA and IL-1β levels were measured using ELISA and electrochemiluminescence assays. CD44KO mice were more susceptible to stress-induced anxiety-like behavior and displayed increased anhedonia and despair than the wild-type controls. The behavioral phenotype of stressed CD44KO mice was associated with reduced cortical serotonergic and striatal dopaminergic turnover. The hippocampal expression of the receptor for HA-mediated motility (RHAMM) was reduced in the non- stressed CD44KO mice compared with WT mice, in a value similar to that observed in WT mice following exposure to stress. Taken together, our experiments suggest that CD44 plays a key role in stress response in mice.

T-cell immunology in sarcoidosis: Disruption of a delicate balance between helper and regulatory T-cells.

Although the aetiology of sarcoidosis is not yet completely understood, immunological changes within the T-cell compartment are characteristic for an exaggerated antigen-driven immune response. In this review, we describe the most recent findings on T-cell subset responses and regulation in sarcoidosis. We discuss how future immunological research can advance the field to unravel pathobiological mechanisms of this intriguingly complex disease. Research into the field of T-cell plasticity has recently challenged the long-held T helper type 1 (Th1) paradigm in sarcoidosis and striking parallels with autoimmune disorders and common variable immunodeficiency were recognized. For instance, it was demonstrated that Th17.1-cells rather than Th1-cells are responsible for the exaggerated IFN-γ production in pulmonary sarcoidosis. Furthermore, impaired regulatory T-cell function and alterations within the expression of co-inhibitory receptors that control T-cell responses, such as PD-1, CTLA-4 and BTNL2, raise new questions regarding T-cell regulation in pulmonary sarcoidosis. It becomes increasingly clear that Th17(.1)-cells and regulatory T-cells are key players in sarcoidosis T-cell immunology. New findings on plasticity and co-inhibitory receptor expression by these subsets help build a more comprehensive model for T-cell regulation in sarcoidosis and will finally shed light on the potential of new treatment modalities.

Pregnancy and multiple sclerosis: from molecular mechanisms to clinical application

Translational research generally refers to a "bench to bedside" approach where basic science discoveries in models move to clinical trials in humans. However, a "bedside to bench to bedside" approach may be more promising with respect to clinical relevance, since it starts with a clinical observation that can serve as a research paradigm to elucidate mechanisms and translate them back into novel therapeutic approaches. The effect of pregnancy on human autoimmune disorders in general, and multiple sclerosis (MS) in particular, serves as an intriguing example of how this can be used to understand disease pathobiology and discover new therapeutic targets. Disease activity in MS undergoes pronounced shifts in the time before, during, and after pregnancy. The most well-known and established example is a reduction in relapse rates in the last trimester by 70-80%. However, disease activity reappears in the first few months after delivery, temporarily overshooting pre-pregnancy levels. This phenomenon has since its first description served as a model for investigating novel treatment options in animal models and has cumulated in successful phase 2a and 2b trials in female MS patients. However, recently, a number of other clinical observations have been made that might be similarly suitable to offer additional insights into pathobiological mechanisms of MS activity, progression, and possibly even incidence. Here, we outline the various changes in the clinical course of MS that have been described in relation to pregnancy, both short term and long term, and discuss how these may inform the development of novel treatments for autoimmune diseases.

Influences of innate immunity, autophagy, and fibroblast activation in the pathogenesis of lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by accumulation of extracellular matrix (ECM) and impaired gas exchange. The pathobiological mechanisms that account for disease progression are poorly understood but likely involve alterations in innate inflammatory cells, epithelial cells, and fibroblasts. Thus we seek to review the most recent literature highlighting the complex roles of neutrophils and macrophages as both promoters of fibrosis and defenders against infection. With respect to epithelial cells and fibroblasts, we review the data suggesting that defective autophagy promotes the fibrogenic potential of both cell types and discuss new evidence related to matrix metalloproteinases, growth factors, and cellular metabolism in the form of lactic acid generation that may have consequences for promoting fibrogenesis. We discuss potential cross talk between innate and structural cell types and also highlight literature that may help explain the limitations of current IPF therapies.

Sildenafil citrate therapy for secondary pulmonary arterial hypertension due to chronic obstructive lung disease

Pulmonary arterial hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance, leading to right ventricular failure and premature death. Pathobiologic mechanisms of the disease include pulmonary endothelial dysfunction, which leads to impaired production of vasodilators, such as nitric oxide and prostacyclin, and overexpression of vasoconstrictors, such as endothelin-1.Sildenafil inhibits phosphodiesterase type 5, an enzyme that metabolizes cyclic guanosine monophosphate, thereby enhancing the cyclic guanosine monophosphate-mediated relaxation and growth inhibition of vascular smooth-muscle cells, including those in the lung. MethodsIn this prospective study 139 patients with symptomatic pulmonary arterial hypertension (2ry to COPD) received placebo or sildenafil (20mg) orally three times daily for 12weeks. The end point was the change from baseline to week 12 in the distance walked in six minutes. The change in mean pulmonary-artery pressure and the incidence of clinical worsening were also assessed, but the study was not powered to assess mortality. ResultsThe distance walked in six minutes increased from baseline in sildenafil group; the mean placebo-corrected treatment effects were 51m (+13.0 percent), for 20mg of sildenafil, (P<0.001). Sildenafil dose reduced the mean pulmonary-artery pressure (P=0.04), and was associated with side effects such as flushing, dyspepsia, and diarrhea. The incidence of clinical worsening did not differ significantly between the patients treated with sildenafil and those treated with placebo. ConclusionSildenafil improves exercise capacity, and hemodynamic in patients with symptomatic pulmonary arterial hypertension.

Therapy and research progress of pediatric epiphyseal injury

The epiphysis is an unique structure in pediatric skeletons, which mainly reflect in its unique blood supply, anatomical structure, pathological basis and so on.Epiphyseal injury is common in children with skeletal injury.Fracture, tumor, infection can cause epiphysis injury, and inappropriate treatment is often easy to cause growth obstacle and skeletal deformity.Its treatment is relatively difficult.At present, there had not yet formed a consistent therapeutic strategy.Aiming at the pathobiologic basis, causes, mechanism and clinical manifestation of pediatric epiphyseal injury, now, its diagnosis, therapeutic strategy, the principle of treatment and the latest research progress were summarized, which would provide useful guidance for clinical treatment of pediatric epiphysis injury. Key words: Epiphysis injury; Clinical diagnosis; Therapeutic strategy; Child

Phosphorylation inactivation of endothelial nitric oxide synthesis in pulmonary arterial hypertension.

The impairment of vasodilator nitric oxide (NO) production is well accepted as a typical marker of endothelial dysfunction in vascular diseases, including in the pathophysiology of pulmonary arterial hypertension (PAH), but the molecular mechanisms accounting for loss of NO production are unknown. We hypothesized that low NO production by pulmonary arterial endothelial cells in PAH is due to inactivation of NO synthase (eNOS) by aberrant phosphorylation of the protein. To test the hypothesis, we evaluated eNOS levels, dimerization, and phosphorylation in the vascular endothelial cells and lungs of patients with PAH compared with controls. In mechanistic studies, eNOS activity in endothelial cells in PAH lungs was found to be inhibited due to phosphorylation at T495. Evidence pointed to greater phosphorylation/activation of protein kinase C (PKC) α and its greater association with eNOS as the source of greater phosphorylation at T495. The presence of greater amounts of pT495-eNOS in plexiform lesions in lungs of patients with PAH confirmed the pathobiological mechanism in vivo. Transfection of the activating mutation of eNOS (T495A/S1177D) restored NO production in PAH cells. Pharmacological blockade of PKC activity by β-blocker also restored NO formation by PAH cells, identifying one mechanism by which β-blockers may benefit PAH and cardiovascular diseases through recovery of endothelial functions.

Airway smooth muscle enlargement is associated with protease-activated receptor 2/ligand overexpression in patients with difficult-to-control severe asthma

Asthma is a complex disease with heterogeneous features of airway inflammation and remodeling. The increase in airway smooth muscle (ASM) mass is an essential component of airway remodeling in patients with severe asthma, yet the pathobiological mechanisms and clinical outcomes associated with ASM enlargement remain elusive. We sought to compare ASM area in control subjects and patients with mild-to-moderate or severe asthma and to identify specific clinical and pathobiological characteristics associated with ASM enlargement. Bronchial biopsy specimens from 12 control subjects, 24 patients with mild-to-moderate asthma, and 105 patients with severe asthma were analyzed for ASM area, basement membrane thickness, vessels, eosinophils, neutrophils, T lymphocytes, mast cells, and protease-activated receptor 2 (PAR-2). In parallel, the levels of several ASM mitogenic factors, including the PAR-2 ligands, mast cell tryptase, trypsin, tissue factor, and kallikrein (KLK) 5 and KLK14, were assessed in bronchoalveolar lavage fluid. Data were correlated with asthma severity and control both at inclusion and after 12 to 18months of optimal management and therapy. Analyses across ASM quartiles in patients with severe asthma demonstrated that patients with the highest ASM quartile (median value of ASM area, 26.3%) were younger (42.5vs≥50years old in the other groups, P≤.04) and had lower asthma control after 1year of optimal management (P≤.006). ASM enlargement occurred independently of features of airway inflammation and remodeling, whereas it was associated with PAR-2 overexpression and higher alveolar tryptase (P≤.02) and KLK14 (P≤.03) levels. Increase in ASM mass, possibly involving aberrant expression and activation of PAR-2-mediated pathways, characterizes younger patients with severe asthma with poor asthma control.

Tu1809 Small Intestinal Mucosal Expression of Candidate Pathobiological Mechanisms in IBS-Diarrhea (IBS-D) and Healthy Controls

Tu1809 Small Intestinal Mucosal Expression of Candidate Pathobiological Mechanisms in IBS-Diarrhea (IBS-D) and Healthy Controls

Non‐invasive Imaging in Interventional Cardiology

Non-invasive cardiac imaging covers a broad spectrum of investigations including echocardiography, radionuclide imaging, computed tomography (CT), and cardiac magnetic resonance (CMR). Major developments have been made over the last couple of decades and non-invasive imaging is currently not only important for our understanding of pathobiological mechanisms that underlie cardiovascular diseases, but also an integral part of the everyday practice of clinical cardiology for diagnosis, risk stratification, management decisions, as well as treatment monitoring and assessment of its effect. Of particular importance are the applications of various non-invasive techniques in the setting of interventional cardiology, an area in which a remarkable progress has been made with the expanding use of coronary and non-coronary stents, cardiac resynchronization therapy, and transcatheter heart-valve devices. The three review articles on echocardiography, cardiac CT, and CMR, which are included in this issue, focus specifically on the important advances and new directions in which the field is heading. The field can only advance and strengthen its role in the decision-making process, when comprehensive evidence-based information is used. We are privileged that the contributors to this issue are international opinion leaders who have made every effort to provide state of the art information on their respective topics. In the first article, Jones et al present the continuous evolution of cardiac CT not only as a valuable research tool, but also as an everyday adjunct to cardiac intervention. After a brief discussion on its diagnostic and prognostic value in the setting of CAD evaluation, they describe three novel functional indices for CAD assessment: non-invasive FFR, transluminal attenuation gradient, and CT perfusion imaging. All three appear promising to broaden the use of cardiac CT for assessing the functional consequences of CAD in addition to anatomy. The authors subsequently discuss the role of cardiac CT in the assessment of patients with previous revascularization, and more pertinent to the theme of this issue, its continuously increasing use for planning and guiding certain interventional procedures, including transcatheter aortic valve implantation, left atrial appendage closures, recanalization of chronic total occlusions, and treatment of bifurcations. In the second paper, Mike Henein provides a comprehensive report on the role of echocardiography, which remains the cornerstone of cardiac imaging. He discusses the key points on patients’ selection for various interventions, monitoring during their performance, as well as the post-intervention outcome assessment of common procedures, including aortic valve implantation, mitral valve repair, mitral valvuloplasty, closure of interatrial shunts, left atrial appendage closure, and ventricular procedures such as alcohol septal reduction for hypertrophic cardiomyopathy and myocardial biopsy, as well as pericardial procedures. Following this, Mavrogeni and Kolovou discuss the strengths and limitations of CMR. They highlight its versatility and ability to provide high quality images depicting the underlying pathology in a spectrum of different clinical scenarios, with an emphasis on its usefulness in the investigation of children and adults with congenital heart disease (CHD). CMR-guided catheterization not only facilitates assessment of pulmonary vascular resistance but in addition, it provides guidance for performance of EP studies. Its role in the management of CHD patients is expanding and potentially CMR-guided interventions will increase in the future. As this is a rapidly growing and highly specialized area, we are planning to include a focused article in the next issue of CCE. Moreover, to provide the readership with comprehensive and balanced information on the strengths and limitations of all non-invasive imaging techniques, there will be two further articles in the same issue: one on SPECT and SPECT/CT and a second on PET and PET/CT, respectively. Covering the full spectrum of non-invasive imaging, the aim is to increase awareness that the various techniques should be used judiciously by clinicians applying an evidence-based approach. Only then, it can be appreciated that they are not competitive but rather complementary to each other, offering unique information applicable to a particular clinical condition/scenario and individual patient. Dr. Anagnostopoulos has nothing to disclose.

Pathobiological mechanisms of peritoneal adhesions: The mesenchymal transition of rat peritoneal mesothelial cells induced by TGF-β1 and IL-6 requires activation of Erk1/2 and Smad2 linker region phosphorylation

Peritoneal adhesions, primarily caused by surgical procedures, are the leading cause of pelvic pain, bowel obstruction, and infertility. TGF-β1 and IL-6 have been found to be elevated in the peritoneal fluid of patients during/after abdominal surgery. However, it remains to be determined whether these cytokines interact and facilitate adhesion formation by promoting mesothelial to mesenchymal transition (MMT). In the present study, isolated rat peritoneal mesothelial cells were treated with TGF-β1 and/or IL-6 which elicited MMT as determined by morphologic and biochemical techniques. During this transition, cellular morphology changed from that of cobblestone polygonal cells to elongated/spindle-shaped fibroblast-like cells. There was decreased expression of genes characteristic of mesothelial cells, such as E-cadherin, and increased expression of genes characteristic of the myofibroblast phenotype, including α-smooth muscle actin and the EDA form of fibronectin, both of which appear to mediate the transfer of force to the extracellular matrix. Partial characterization of relevant signaling pathways identified Erk1/2 activation, which was enhanced by combined TGF-β1/IL-6 administration, as a crucial necessary factor in the transition. Erk1/2 activation as well as the phosphorylation of the linker region of Smad2 and MMT could be blocked by the MEK inhibitor, U0126, suggesting that such activation may be a potential pharmaceutical target to prevent MMT. In addition, the phenotypic transition could be prevented by hydrocortisone.

Emerging differential roles of the pRb tumor suppressor in trichodysplasia spinulosa-associated polyomavirus and Merkel cell polyomavirus pathogeneses

BackgroundMerkel cell carcinoma (MCC) and trichodysplasia spinulosa (TS) are two proliferative cutaneous diseases caused by the Merkel cell polyomavirus (MCPyV) and trichodysplasia spinulosa-associated polyomavirus (TSPyV) respectively. Recently, studies have elucidated a key role of the small tumor (sT) antigen in the proliferative pathogenic mechanisms of MCPyV and likely TSPyV. While both sT antigens have demonstrated a capacity in regulating cellular pathways, it remains unknown whether MCPyV and TSPyV sT antigens contribute similarly or differentially to cell proliferation. ObjectivesThe present study aims to explore the proliferative potential of MCPyV and TSPyV sT antigens by investigating their regulatory effects on the retinoblastoma protein (pRb) tumor suppressor. Study designInducible cell lines expressing MCPyV sT or TSPyV sT were created using a lentiviral packaging system. Cellular proteins were extracted and subjected to SDS-PAGE followed by Western blot detection and densitometric analysis. ResultsExpression of TSPyV sT markedly enhanced the phosphorylation of pRb in Western blot experiments. In contrast, expression of MCPyV sT did not alter pRb phosphorylation under the same experimental conditions. Densitometric analysis revealed that TSPyV sT antigen expression nearly doubled the ratio of phosphorylated to total pRb (P<0.001, Student’s T-test), while MCPyV sT antigen expression did not cause significant change in pRb phosphorylation status. ConclusionGiven that hyperphosphorylation of pRb is associated with dysregulation of the cell cycle, S-phase induction, and increased cell proliferation, our findings support an important role of TSPyV-mediated pRb deactivation in the development of TS. The observation that the pRb tumor suppressor is inactivated by TSPyV sT but not MCPyV sT provides further insights into the distinct pathobiological mechanisms of MCC and TS.

Asthma phenotypes and IgE responses.

The discovery of IgE represented a major breakthrough in allergy and asthma research, whereas the clinical interest given to IgE in asthma has been blurred until the arrival of anti-IgE biotherapy. Novel facets of the complex link between IgE and asthma have been highlighted by the effect of this treatment and by basic research. In parallel, asthma phenotyping recently evolved to the concept of endotypes, relying on identified/suspected pathobiological mechanisms to phenotype patients, but has not yet clearly positioned IgE among biomarkers of asthma.In this review, we first summarise recent knowledge about the regulation of IgE production and its main receptor, FcεRI. In addition to allergens acting as classical IgE inducers, viral infections as well as air pollution may trigger the IgE pathway, notably resetting the threshold of IgE sensitivity by regulating FcεRI expression. We then analyse the place of IgE in different asthma endo/phenotypes and discuss the potential interest of IgE among biomarkers in asthma.

Intracoronary imaging of coronary atherosclerosis: validation for diagnosis, prognosis and treatment.

While coronary atherosclerosis is a leading cause of mortality, evaluation of coronary lesions was previously limited to either indirect angiographic assessment of the lumen silhouette or post mortem investigations. Intracoronary (IC) imaging modalities have been developed that allow for visualization and characterization of coronary atheroma in living patients. Used alone or in combination, these modalities have enhanced our understanding of pathobiological mechanisms of atherosclerosis, identified factors responsible for disease progression, and documented the ability of various medications to reverse the processes of plaque growth and destabilization. These methodologies have established a link between in vivo plaque characteristics and subsequent coronary events, thereby improving individual risk stratification, paving the way for risk-tailored systemic therapies and raising the option for pre-emptive interventions. Moreover, IC imaging is increasingly used during coronary interventions to support therapeutic decision-making in angiographically inconclusive disease, guide and optimize procedural results in selected lesion and patient subsets, and unravel mechanisms underlying stent failure. This review aims to summarize current evidence regarding the role of IC imaging for diagnosis and risk stratification of coronary atherosclerosis, and to describe its clinical role for guiding percutaneous coronary interventions. Future perspectives for in-depth plaque characterization using novel techniques and multimodality imaging approaches are also discussed.

Protracted bacterial bronchitis: The last decade and the road ahead.

SummaryCough is the single most common reason for primary care physician visits and, when chronic, a frequent indication for specialist referrals. In children, a chronic cough (>4 weeks) is associated with increased morbidity and reduced quality of life. One common cause of childhood chronic cough is protracted bacterial bronchitis (PBB), especially in children aged <6 years. PBB is characterized by a chronic wet or productive cough without signs of an alternative cause and responds to 2 weeks of appropriate antibiotics, such as amoxicillin‐clavulanate. Most children with PBB are unable to expectorate sputum. If bronchoscopy and bronchoalveolar lavage are performed, evidence of bronchitis and purulent endobronchial secretions are seen. Bronchoalveolar lavage specimens typically reveal marked neutrophil infiltration and culture large numbers of respiratory bacterial pathogens, especially Haemophilus influenzae. Although regarded as having a good prognosis, recurrences are common and if these are frequent or do not respond to antibiotic treatments of up to 4‐weeks duration, the child should be investigated for other causes of chronic wet cough, such as bronchiectasis. The contribution of airway malacia and pathobiologic mechanisms of PBB remain uncertain and, other than reduced alveolar phagocytosis, evidence of systemic, or local immune deficiency is lacking. Instead, pulmonary defenses show activated innate immunity and increased gene expression of the interleukin‐1β signalling pathway. Whether these changes in local inflammatory responses are cause or effect remains to be determined. It is likely that PBB and bronchiectasis are at the opposite ends of the same disease spectrum, so children with chronic wet cough require close monitoring. Pediatr Pulmonol. 2016;51:225–242. © 2015 Wiley Periodicals, Inc.

Abstract 12714: Aldosterone Activates Raptor to Promote Pulmonary Artery Smooth Muscle Cell Proliferation and Pulmonary Arterial Hypertension

In pulmonary arterial hypertension (PAH), elevated levels of aldosterone (ALDO) induce a vasculopathy that is characterized by dysregulated pulmonary artery smooth muscle cell (PSMC) growth. Upregulation of the mammalian target of rapamycin complex 1 subunit Raptor induces PSMC growth; however, the factors regulating Raptor in PAH are not known. We hypothesized that Raptor activation by ALDO induces PSMC proliferation, hypertrophic vascular remodeling, and PAH. To test this hypothesis, PSMCs were exposed to vehicle (V) control or ALDO (10 -7 mol/l) for 1 h. Compared to V-treated cells, ALDO increased expression of P-Raptor(Ser792) and the Raptor target P-p70S6K(Thr389) by 68% (P&lt;0.01) and 50% (P&lt;0.01), respectively, without affecting total Raptor/p70S6K levels. Raptor upregulation in ALDO-treated cells also increased PSMC proliferation by 19% (P&lt;0.01), assessed by BrdU incorporation. To explore the relevance of ALDO-Raptor signaling in vivo , we studied the monocrotaline (MCT) model of PAH, which is characterized by hyperALDO. In a prevention protocol, MCT-PAH rats were treated with spironolactone (SP)(25 mg/kg/d) in the drinking water to inhibit ALDO and/or intravenous Staramine-mPEG labeled with Raptor-siRNA (2 mg/kg dose x4)(si-Raptor). Anti-Raptor and anti-α-SM actin immunohistochemistry showed that compared to controls (N=4), Raptor expression and vessel thickness was increased in MCT-PAH rats (N=5) by 87% (P&lt;0.01) and 5.8-fold (P&lt;0.01), respectively, and pulmonary artery systolic pressure (PASP) was increased significantly (25 ± 4 vs. 77 ± 12 mmHg, P&lt;0.01) as assessed by catheterization. Compared to MCT-PAH, MCT-si-Raptor (N=5) decreased Raptor levels by 31% (P&lt;0.05), arteriole thickness by 41% (P&lt;0.05), and PASP (77 ± 12 vs. 46 ± 5 mmHg, P&lt;0.05) without affecting central blood pressure significantly. A further benefit was observed in MCT-si-Raptor+SP rats (N=5) for arterial thickness (-57%, P&lt;0.01) and PASP (46 ± 5 vs. 39 ± 5 mmHg, P&lt;0.05) compared to MCT-si-Raptor. Taken together, Raptor activation by ALDO induces PSMC proliferation in vitro to promote PAH in vivo . Identifying ALDO-Raptor signaling as a pathobiological mechanism underlying pulmonary vascular remodeling may have novel therapeutic implications for PAH patients.

Vulnerable plaque imaging: updates on new pathobiological mechanisms.

Early identification of vulnerable, rupture-prone atherosclerotic plaques with the optimal goal of cardiovascular event prevention is a field of vigorous research. Despite the advances in imaging modalities and the in vivo identification of many characteristics of vulnerability, few of these plaques actually rupture and even fewer lead to clinical events, questioning the predictive value of the above techniques in clinical practice. Factors causing the higher local vulnerability of the culprit plaque within a prothrombotic environment of widespread inflammation are generally unknown. Newly recognized local features, including microcalcifications and biomechanical factors, seem to contribute. In this review article, we target on new mechanisms, implicated in vulnerable plaque formation and rupture, analysing their potential clinical value.

Insulin resistance, glucose intolerance and diabetes mellitus in obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is a highly prevalent disorder, which conveys an increased risk of cardiovascular disease and death. Type 2 diabetes mellitus (T2DM), glucose intolerance and insulin resistance (IR) are common in subjects with OSA, but a shared intimate relationship with obesity makes discerning an independent link challenging. Nonetheless, mechanistic studies suggest that OSA could contribute to impaired glucose metabolism via the effects of sleep fragmentation, sympathetic excitation and intermittent hypoxia (IH) on pancreatic B-cell function, insulin sensitivity, and systemic inflammation. In particular, emerging data suggest that IH may have an important detrimental effect on adipose tissue function and inflammation. Similarly, data from population-and clinic-level studies suggest that OSA is independently related with the prevalence and incidence of T2DM and IR, and may also lead to worse glycaemic control in diabetics. However, the ability of continuous positive airway pressure (CPAP) therapy to make a meaningful impact on T2DM or IR remains uncertain. In this review we explore the available evidence linking OSA with IR, glucose intolerance and T2DM, and discuss potential pathobiological mechanisms by which sleep disordered breathing can affect metabolic health.

Pathways to Parkinsonism Redux: convergent pathobiological mechanisms in genetics of Parkinson's disease.

In the past few years, there have been a large number of genes identified that contribute to the lifetime risk of Parkinson's disease (PD). Some genes follow a Mendelian inheritance pattern, but others are risk factors for apparently sporadic PD. Here, we will focus on those genes nominated by genome-wide association studies (GWAS) in sporadic PD, with a particular emphasis on genes that overlap between familial and sporadic disease such as those encoding a-synuclein (SNCA), tau (MAPT), and leucine-rich repeat kinase 2 (LRRK2). We will advance the view that there are likely relationships between these genes that map not only to neuronal processes, but also to neuroinflammation. We will particularly discuss evidence for a role of PD proteins in microglial activation and regulation of the autophagy-lysosome system that is dependent on microtubule transport in neurons. Thus, there are at least two non-mutually exclusive pathways that include both non-cell-autonomous and cell-autonomous mechanisms in the PD brain. Collectively, these data have highlighted the amount of progress made in understanding PD and suggest ways forward to further dissect this disorder.

Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease.

Background and aimsNon-alcoholic steatohepatitis (NASH), the potentially progressive form of nonalcoholic fatty liver disease (NAFLD), is the pandemic liver disease of our time. Although there are several animal models of NASH, consensus regarding the optimal model is lacking. We aimed to compare features of NASH in the two most widely-used mouse models: methionine-choline deficient (MCD) diet and Western diet.MethodsMice were fed standard chow, MCD diet for 8 weeks, or Western diet (45% energy from fat, predominantly saturated fat, with 0.2% cholesterol, plus drinking water supplemented with fructose and glucose) for 16 weeks. Liver pathology and metabolic profile were compared.ResultsThe metabolic profile associated with human NASH was better mimicked by Western diet. Although hepatic steatosis (i.e., triglyceride accumulation) was also more severe, liver non-esterified fatty acid content was lower than in the MCD diet group. NASH was also less severe and less reproducible in the Western diet model, as evidenced by less liver cell death/apoptosis, inflammation, ductular reaction, and fibrosis. Various mechanisms implicated in human NASH pathogenesis/progression were also less robust in the Western diet model, including oxidative stress, ER stress, autophagy deregulation, and hedgehog pathway activation.ConclusionFeeding mice a Western diet models metabolic perturbations that are common in humans with mild NASH, whereas administration of a MCD diet better models the pathobiological mechanisms that cause human NAFLD to progress to advanced NASH.