Specialized pro-resolving mediators as modulators of immune responses.

Specialized pro-resolving mediators (SPMs) are endogenous small molecules produced mainly from dietary omega-3 polyunsaturated fatty acids by both structural cells and cells of the active and innate immune systems. Specialized pro-resolving mediators have been shown to both limit acute inflammation and promote resolution and return to homeostasis following infection or injury. There is growing evidence that chronic immune disorders are characterized by deficiencies in resolution and SPMs have significant potential as novel therapeutics to prevent and treat chronic inflammation and immune system disorders. This review focuses on important breakthroughs in understanding how SPMs are produced by, and act on, cells of the adaptive immune system, specifically macrophages, B cells and T cells. We also highlight recent evidence demonstrating the potential of SPMs as novel therapeutic agents in topics including immunization, autoimmune disease and transplantation.

COPD is associated with increased cardiovascular disease risk independent of phenotype.

BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide that frequently presents with concomitant cardiovascular diseases. Despite the pathological distinction between individual COPD phenotypes such as emphysema and chronic bronchitis, there is a lack of knowledge about the impact of COPD phenotype on cardiovascular disease risk. Thus, this study aimed to utilize a nationally representative sample to investigate cardiovascular disease prevalence in patients with COPD with emphysema and chronic bronchitis phenotypes. METHODS: Data from 31,560 adults including 2504 individuals with COPD, collected as part of the National Health and Nutrition Examination Survey (1999-2018), were examined. RESULTS: A significantly increased cardiovascular disease risk, including coronary heart disease, heart failure, myocardial infarction and stroke, was identified in patients with COPD among all disease phenotypes. Particularly, compared to those without COPD, individuals with chronic bronchitis presented with 1.76 (95% CI: 1.41-2.20) times greater odds, individuals with emphysema with 2.31 (95% CI: 1.80-2.96) times greater odds, while those with a concurrent phenotype (combined chronic bronchitis and emphysema) exhibited 2.98 (95% CI: 2.11-4.21) times greater odds of reporting cardiovascular diseases. CONCLUSION: Our data confirms that patients with COPD present an elevated risk of developing cardiovascular disease among all phenotypes, with the most marked increase being in those with concurrent chronic bronchitis and emphysema phenotypes. These findings emphasize the need for awareness and appropriate cardiovascular screening in COPD.

Mechanical Feed-Forward Loops Contribute to Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis is a progressive scarring disease characterized by extracellular matrix accumulation and altered mechanical properties of lung tissue. Recent studies support the hypothesis that these compositional and mechanical changes create a progressive feed-forward loop in which enhanced matrix deposition and tissue stiffening contribute to fibroblast and myofibroblast differentiation and activation, which further perpetuates matrix production and stiffening. The biomechanical properties of tissues are sensed and responded to by mechanotransduction pathways that facilitate sensing of changes in mechanical cues by tissue resident cells and convert the mechanical signals into downstream biochemical signals. Although our understanding of mechanotransduction pathways associated with pulmonary fibrosis remains incomplete, recent progress has allowed us to begin to elucidate the specific mechanisms supporting fibrotic feed-forward loops. The mechanosensors discussed here include integrins, Piezo channels, transient receptor potential channels, and nonselective ion channels. Also discussed are downstream transcription factors, including myocardin-related transcription factor and Yes-associated protein/transcriptional coactivator with PDZ-binding motif. This review describes mechanosensors and mechanotransduction pathways associated with fibrosis progression and highlights promising therapeutic insights.

TRPV4 Protects the Lung from Bacterial Pneumonia via MAPK Molecular Pathway Switching.

Mechanical cell-matrix interactions can drive the innate immune responses to infection; however, the molecular underpinnings of these responses remain elusive. This study was undertaken to understand the molecular mechanism by which the mechanosensitive cation channel, transient receptor potential vanilloid 4 (TRPV4), alters the in vivo response to lung infection. For the first time, to our knowledge, we show that TRPV4 protects the lung from injury upon intratracheal Pseudomonas aeruginosa in mice. TRPV4 functions to enhance macrophage bacterial clearance and downregulate proinflammatory cytokine secretion. TRPV4 mediates these effects through a novel mechanism of molecular switching of LPS signaling from predominant activation of the MAPK, JNK, to that of p38. This is accomplished through the activation of the master regulator of inflammation, dual-specificity phosphatase 1. Further, TRPV4's modulation of the LPS signal is mechanosensitive in that both upstream activation of p38 and its downstream biological consequences depend on pathophysiological range extracellular matrix stiffness. We further show the importance of TRPV4 on LPS-induced activation of macrophages from healthy human controls. These data are the first, to our knowledge, to demonstrate new roles for macrophage TRPV4 in regulating innate immunity in a mechanosensitive manner through the modulation of dual-specificity phosphatase 1 expression to mediate MAPK activation switching.

Choice of antifibrotic medication and disease severity predict weight loss in idiopathic pulmonary fibrosis.

PURPOSE: Although safety and tolerability of approved antifibrotics has been reported extensively, little is known about their effects on weight. We analyzed predictors of weight change after one year of uninterrupted antifibrotic therapy in patients followed at our institution's interstitial lung disease clinic. METHODS/RESULTS: We identified 80 patients on antifibrotic therapy (44 pirfenidone/36 nintedanib) with at least one year of follow-up and no therapy interruptions. Thirty-five patients (44%) lost more than 5% of their baseline body weight, and 11 (19%) lost more than 10%. A higher proportion of patients on nintedanib experienced a clinically significant weight loss (>5%) versus pirfenidone (61% vs 30%, p = 0.005). Univariate and multivariate analyses identified nintedanib therapy and a higher composite physiologic index (CPI) as predictors of weight loss. CONCLUSIONS: Weight loss is common among IPF patients on antifibrotic therapy. Nintedanib therapy and more advanced disease were identified as predictors of weight loss in this population.

Two foreign bodies embedded in the intraventricular septum: A case report.

A 23-year old male was presented at the outpatient clinic of our department reporting that he had been subjected to insertion of foreign bodies in his chest. Physical examination was unremarkable. Imaging studies revealed the presence of two bodies in the subcutaneous tissue of the anterior chest wall and two needle-shaped intramyocardial bodies that were impacted in the intraventricular septum. Due to late appearance, the position, and because of the absence of symptoms, it was decided that the patient should be managed conservatively. Today, five years after the incident, the patient remains asymptomatic and he is followed-up regularly.

Should diaphragmatic involvement preclude resection of large hepatic tumors?

BACKGROUND: Treatment of peripherally located liver tumors with diaphragmatic invasion is technically demanding but does not preclude resection for cure. The aim of the present study was to compare patients undergoing combined liver and diaphragmatic resection with those submitted to hepatectomy alone so as to evaluate the safety, effectiveness, and value of this complex surgical procedure. METHODS: From January 2000 to September 2011, 36 consecutive patients underwent en bloc liver-diaphragm resection (group A). These were individually matched for age, gender, tumor size, pathology, and co-morbitidies with 36 patients who underwent hepatectomy alone during the same time (group B). Operative time, warm ischemia time, blood loss, required transfusions, postoperative complications, and long-term survival were evaluated. RESULTS: Mean operative time was significantly longer in group A than in group B (165 vs 142 min; P = 0.004). The two groups were comparable regarding warm ischemia time, intraoperative blood loss, required transfusions, and postoperative laboratory value fluctuations. Some 33 % of group A patients developed complications postoperatively as opposed to 23 % of group B patients (P = 0.03). The mortality rate was 2.8 % in group A compared to 0 % in group B. Postoperative follow-up demonstrated 60 % 1-year survival for group A patients as opposed to 80 % 1-year survival for group B patients, a difference that is practically eliminated the longer the follow-up period is extended (35 vs 40 % 3-year survival and 33 vs 37 % 5-year survival for group A and group B patients, respectively). CONCLUSIONS: En bloc diaphragmatic and liver resection is a challenging but safe surgical procedure that is fully justified when diaphragmatic infiltration cannot be ruled out and the patient is considered fit enough to undergo surgery.

Viewpoint: a multidisciplinary approach to the assessment of patients with systemic sclerosis-associated interstitial lung disease.

Systemic sclerosis (SSc) is a rare and heterogeneous disease affecting the skin and internal organs. SSc-associated ILD (SSc-ILD) is a common and often early manifestation of SSc. This article discusses the rationale for a multidisciplinary approach (MDA) to the early identification and assessment of patients with SSc-ILD. Diagnosis of SSc-ILD is often challenging as patients with early disease can be asymptomatic, and SSc-ILD symptoms, such as exertional dyspnea and cough, are non-specific. High-resolution computed tomography (HRCT) of the lungs is the gold standard for diagnosis of SSc-ILD since pulmonary function tests lack sensitivity and specificity, especially in early disease. On HRCT, most patients with SSc-ILD have a non-specific interstitial pneumonia (NSIP) pattern. In addition, findings of pulmonary hypertension and esophageal dysmotility may be present. The multi-organ involvement of SSc and the diverse spectrum of symptoms support an MDA for the diagnosis and assessment of patients with SSc-ILD, with input from rheumatologists, pulmonologists, gastroenterologists, radiologists, and other specialists. Key Points • Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis (SSc). • Early diagnosis is key to reducing the morbidity and mortality associated with SSc-ILD and other manifestations of SSc. • The multi-organ involvement of SSc supports a multidisciplinary approach to the diagnosis and assessment of patients with SSc-ILD, with input from rheumatologists, pulmonologists, gastroenterologists, radiologists, and other specialists.

Diagnostic Yield, Radiation Exposure, and the Role of Clinical Decision Rules to Limit Computed Tomographic Pulmonary Angiography-Associated Complications.

OBJECTIVES: Computed tomographic pulmonary angiography (CT-PA) is associated with significant cost, contrast, and radiation exposure. Clinical decision rules (CDRs) reduce the need for diagnostic imaging; however, their utility in the medical intensive care unit (MICU) remains unknown. We explored the diagnostic yield and complications associated with CT-PA (radiation exposure and contrast-induced acute kidney injury [AKI]) while investigating the efficacy of CDRs to reduce unnecessary testing. METHODS: All CT-PAs performed in an academic MICU for 4 years were retrospectively reviewed. The Wells and revised Geneva scores (CDRs) and radiation dose per CT-PA were calculated, and the incidence of post-CT-PA AKI was recorded. RESULTS: A total of 439 studies were analyzed; the diagnostic yield was 11% (48 PEs). Positive CT-PAs were associated with a higher Wells score (5.8 versus 3.2, P < 0.001), but similar revised Geneva scores (6.4 versus 6.0, P = 0.32). A Wells score of ≥4 had a positive likelihood ratio of 2.1 with a negative predictive value of 98.2. More than half (88.9%) of patients with a Wells score of ≤4 developed an AKI, with 55.6% of those having recovery of renal function. CONCLUSIONS: There is overutilization of CT-PA in the MICU. The Wells score retains its negative predictive value in critically ill adult patients and may aid to limit radiation exposure and contrast-induced AKI in MICU.

Correlation between mesenteric fat thickness and serum apolipoproteins in patients with peripheral arterial occlusive disease.

BACKGROUND: Visceral fat possesses the most detrimental potential for cardiovascular morbidity through the release of adipokines, as well as metabolic and proinflammatory mediators, which adversely affect metabolic and vascular homeostasis. Among the different types of visceral adipose tissue, mesenteric fat is considered particularly detrimental, due to its close proximity to the portal circulation, affecting directly the liver, which is the main regulator of body metabolic homeostasis. Mesenteric fat can be reliably estimated using abdominal ultrasonography, the only available imaging method able to depict individual mesenteric leaves. Aim of the present study was to investigate the correlation of mesenteric fat thickness (MFT) with serum apolipoprotein levels in patients undergoing digital subtraction angiography in a single center. METHODS: 35 male patients with peripheral arterial disease were examined. After careful examination of the periumbilical area, the mesenteric leaves were identified. The maximal distance between each pair of sequential leaves was measured, and the mean value of the three thickest leaves was determined as the mesenteric fat thickness. Six apolipoprotein fasting serum concentrations were measured using a Luminex proteomics platform (xMAP Multiplex immunoassay): apolipoprotein A-I (apoAI), apolipoprotein A-II (apoAII), apolipoprotein B (apoB), apolipoprotein C-II (apoCII), apolipoprotein C-III (apoCIII) and apolipoprotein E (apoE). RESULTS: MFT correlated with apoAII and apoB serum concentrations. The correlations with apoAII and apoB remained significant following correction for BMI. No correlations were noted between MFT and serum apoAI, apoCII, apoCIII or apoE levels before or after adjustment for BMI. CONCLUSIONS: Our study indicates that MFT is significantly correlated with the concentration of atherogenic low density lipoproteins particles, as well as with apoAII, a determinant of free fatty acids levels. No correlation was observed between mesenteric fat thickness and very low density lipoprotein or chylomicron particles concentration.

Central hepatectomy under sequential hemihepatic control.

PURPOSE: Central hepatectomy is a complex, parenchymal-sparing procedure which has been associated with increased blood loss, prolonged operating time, and increased duration of remnant hypoxia. In this report, we compare two different techniques of vascular control, namely sequential hemihepatic vascular control (SHHVC) and selective hepatic vascular exclusion (SHVE) in central hepatectomies. METHODS: From January 2000 to September 2011, 36 consecutive patients underwent a central hepatectomy. SVHE was applied in 16 consecutive patients, and SHHVC was applied in 20 patients. Both groups were comparable regarding their demographics. RESULTS: Total operative time and morbidity rates were similar in both groups. Warm ischemia time was significantly longer in SVHE patients (46 min vs 28 min, p = 0.03). Total blood loss and number of transfusions per patient were also higher in the SVHE group (650 vs. 400 mL, p = 0.04 and 2.2 vs. 1.2 units, p = 0.04, respectively). AST values were significantly higher in SVHE on days 1 and 3 compared to SHHVC patients (650 vs. 400, p = 0.04 and 550 vs. 250, p = 0.001, respectively). CONCLUSION: Sequential hemihepatic vascular control is a safe technique for central hepatectomies. Decreased intraoperative blood loss and transfusions and attenuated liver injury are the main advantages of this approach.

Giant sternal metastasis secondary to follicular carcinoma of the thyroid gland: report of a case.

A 70-year-old woman was admitted to our department for investigation and treatment of a progressively enlarging multinodular goiter and a fast growing mass infiltrating the sternum. The patient was euthyroid, but computed tomography (CT) and ultrasonography showed a mass in the anterior mediastinum infiltrating the sternum, with a dominant nodule in the right lobe of the thyroid. Fine needle aspiration biopsy results from both the cervical and the mediastinal masses were suggestive of follicular thyroid carcinoma. The patient underwent total thyroidectomy, thymectomy, and total removal of the mass, along with parts of the sternum, sternocleidomastoid muscle, and attached ribs. The thoracic wall was reconstructed with gortex dual mesh covered by muscle flaps from both pectoralis major muscles. Pathological analysis of both masses confirmed the fine needle aspiration findings and the patient received three cycles of radioactive iodine treatment. She had an uneventful postoperative course, but died of a stroke 8 years later.

Stretching the Function of Innate Immune Cells.

The importance of innate immune cells to sense and respond to their physical environment is becoming increasingly recognized. Innate immune cells (e.g. macrophages and neutrophils) are able to receive mechanical signals through several mechanisms. In this review, we discuss the role of mechanosensitive ion channels, such as Piezo1 and transient receptor potential vanilloid 4 (TRPV4), and cell adhesion molecules, such as integrins, selectins, and cadherins in biology and human disease. Furthermore, we explain that these mechanical stimuli activate intracellular signaling pathways, such as MAPK (p38, JNK), YAP/TAZ, EDN1, NF-kB, and HIF-1α, to induce protein conformation changes and modulate gene expression to drive cellular function. Understanding the mechanisms by which immune cells interpret mechanosensitive information presents potential targets to treat human disease. Important areas of future study in this area include autoimmune, allergic, infectious, and malignant conditions.

Systemic sclerosis-associated interstitial lung disease.

Systemic sclerosis is an autoimmune connective tissue disease, which is characterised by immune dysregulation and progressive fibrosis that typically affects the skin, with variable internal organ involvement. It is a rare condition that affects mostly young and middle-aged women, resulting in disproportionate morbidity and mortality. Currently, interstitial lung disease is the most common cause of death among patients with systemic sclerosis, with a prevalence of up to 30% and a 10-year mortality of up to 40%. Interstitial lung disease is more common among African Americans and in people with the diffuse cutaneous form of systemic sclerosis or anti-topoisomerase 1 antibodies. Systemic sclerosis-associated interstitial lung disease most commonly presents with dyspnoea, cough, and a non-specific interstitial pneumonia pattern on CT scan, with a minority of cases fulfilling the criteria for usual interstitial pneumonia. The standard therapy has traditionally been combinations of immunosuppressants, particularly mycophenolate mofetil or cyclophosphamide. These immunosuppressants can be supplemented by targeted biological and antifibrotic therapies, whereas autologous haematopoietic stem-cell transplantation and lung transplantation are reserved for refractory cases.

Pulmonary Manifestations of Systemic Sclerosis and Mixed Connective Tissue Disease.

Systemic sclerosis (SSc) is a rare disease characterized by widespread collagen deposition resulting in fibrosis. Although skin involvement is the most common manifestation and also the one that determines the classification of disease, mortality in SSc is usually a result of respiratory compromise in the form of interstitial lung disease (ILD) or pulmonary hypertension (PH). Clinically significant ILD is seen in up to 40% of patients and PH in up to 20%. Treatment with either cyclophosphamide or mycophenolate has been shown to delay disease progression, whereas rituximab and lung transplantation are reserved for refractory cases.

Sonographic assessment of regional adiposity.

OBJECTIVE: Various noninvasive imaging techniques, including CT, MRI, and sonography, have been used for accurate estimation of regional fat deposits. Among these techniques, sonography has attracted considerable attention because it combines safety, cost-effectiveness, and accuracy. The aim of this review is to present an overview of the studies in which sonographic techniques have been used to estimate visceral adiposity, the indexes derived, and the correlation between the indexes and metabolic and cardiovascular markers. CONCLUSION: It is highly plausible that sonography will be used in clinical practice for the routine assessment of regional adiposity.

Immunohistochemical determination of the extracellular matrix modulation in a rat model of choline-deprived myocardium: the effects of carnitine.

Choline has been identified as an essential nutrient with crucial role in many vital biological functions. Recent studies have demonstrated that heart dysfunction can develop in the setting of choline deprivation even in the absence of underlying heart disease. Matrix metalloproteinases (MMPs) are responsible for extracellular matrix degradation, and the dysregulation of MMP-2 and MMP-9 has been involved in the pathogenesis of various cardiovascular disorders. The aim of the study was to investigate the role of MMPs and their inhibitors (TIMPs), in the pathogenesis of choline deficiency-induced cardiomyopathy, and the way they are affected by carnitine supplementation. Male Wistar Albino adult rats were divided into four groups and received standard or choline-deficient diet with or without L-carnitine in drinking water (0.15% w/v) for 1 month. Heart tissue immunohistochemistry for MMP-2, MMP-9, TIMP-1, and TIMP-2 was performed. Choline deficiency was associated with suppressed immunohistochemical expression of MMP-2 and an increased expression of TIMP-2 compared to control, while it had no impact on TIMP-1. MMP-9 expression was decreased without, however, reaching statistical significance. Carnitine did not affect MMP-2, MMP-9, TIMP-1 or TIMP-2 expression. The pattern of TIMP and MMP modulation observed in a choline deficiency setting appears to promote fibrosis. Carnitine, although shown to suppress fibrosis, does not seem to affect MMP-2, MMP-9, TIMP-1 or TIMP-2 expression. Further studies will be required to identify the mechanism underlying the beneficial effects of carnitine.

Incidental findings on computed tomography angiography in patients evaluated for pulmonary embolism.

RATIONALE: To investigate how often computed tomography (CT) pulmonary angiography contributes to establishing a diagnosis in patients presenting to the emergency department and how it performs compared to chest radiograph. OBJECTIVES: The objective of this study was to measure the ability to identify a diagnosis and to investigate the prevalence and significance of incidental findings in patients evaluated with computed tomography pulmonary angiography in the emergency department. METHODS: All adult patients evaluated with CT angiography over a 2-year period (January 1, 2011 to December 31, 2012) were included in the analysis. A total of 641 records were identified. Chest radiographs and CT angiography reports were reviewed to determine whether they could provide a diagnosis in patients without pulmonary embolism (PE). Studies negative for PE were stratified into three categories according to significance: type I prompted immediate action, type II required follow up, and type III had findings of limited significance. MEASUREMENTS AND MAIN RESULTS: CT angiography identified a diagnosis in 22.46% of the patient population and in 14.31% of patients without PE. In patients who had CT angiography with chest radiograph, diagnoses were provided in 14.01 and 9.86% of patients, respectively. When analysis was isolated to patients with low probability for PE, CT angiography provided a diagnosis in 20% and chest radiography in 10.23% of patients. The majority of missed cases represented infiltrates too small to be detected by radiography and were believed to represent lung infections by the interpreting radiologist. Among studies negative for PE, 15% were type I, 17.07% were type II, 48.1% were type III, and the rest were normal. CONCLUSIONS: CT angiography is superior to chest radiography at providing a diagnosis in patients investigated for PE, even when no PE is present. However, in patients at low risk for PE, the clinical benefit of the additional diagnoses is questionable.

CT pulmonary angiography utilization in the emergency department: diagnostic yield and adherence to current guidelines.

The aim is to investigate the patterns of computed tomography pulmonary angiography (CTPA) use and adherence to current guidelines. Medical records of patients investigated with CTPA for pulmonary embolism (PE) in a single academic hospital from January 2011 until December 2012 were reviewed. Wells scores were calculated retrospectively by researchers blinded to the results of the CTPA. "Avoidable imaging" was defined as imaging performed against current recommendations of the European Society of Cardiology or the PIOPED investigation group. A total of 646 patients underwent testing; 61 cases of PE were diagnosed (9.4%). Potentially avoidable imaging was performed in 49.5% and 71.5% of patients, depending on the criteria used; 11.5% of imaging studies were performed in low-risk patients with negative D-dimer assays. There is evidence of CTPA overuse and D-dimer underuse. Adherence to guidelines and appropriate use of D-dimer assay might reduce avoidable imaging and ionizing radiation exposure.

Heart dysfunction induced by choline-deficiency in adult rats: the protective role of L-carnitine.

Choline is a B vitamin co-factor and its deficiency seems to impair heart function. Carnitine, a chemical analog of choline, has been used as adjunct in the management of cardiac diseases. The study investigates the effects of choline deficiency on myocardial performance in adult rats and the possible modifications after carnitine administration. Wistar Albino rats (n=24), about 3 months old, were randomized into four groups fed with: (a) standard diet (control-CA), (b) choline deficient diet (CDD), (c) standard diet and carnitine in drinking water 0.15% w/v (CARN) and (d) choline deficient diet and carnitine (CDD+CARN). After four weeks of treatment, we assessed cardiac function under isometric conditions using the Langendorff preparations [Left Ventricular Developed Pressure (LVDP-mmHg), positive and negative first derivative of LVDP were evaluated], measured serum homocysteine and brain natriuretic peptide (BNP) levels and performed histopathology analyses. In the CDD group a compromised myocardium contractility compared to control (P=0.01), as assessed by LVDP, was noted along with a significantly impaired diastolic left ventricular function, as assessed by (-) dp/dt (P=0.02) that were prevented by carnitine. Systolic force, assessed by (+) dp/dt, showed no statistical difference between groups. A significant increase in serum BNP concentration was found in the CDD group (P<0.004) which was attenuated by carnitine (P<0.05), whereas homocysteine presented contradictory results (higher in the CDD+CARN group). Heart histopathology revealed a lymphocytic infiltration of myocardium and valves in the CDD group that was reduced by carnitine. In conclusion, choline deficiency in adult rats impairs heart performance; carnitine acts against these changes.