The role of measuring exhaled breath biomarkers in sarcoidosis: A systematic review

Introduction: Sarcoidosis is a chronic granulomatous disease of unknown aetiology with a variable clinical course and prognosis. There is a growing need to identify non-invasive biomarkers to differentiate between clinical phenotypes, identify those at risk of disease progression and monitor response to treatment. Objectives: We undertook a systematic review and meta-analysis, to evaluate the utility of breath-based biomarkers in discriminating sarcoidosis from healthy controls, alongside correlation with existing non-breath based biomarkers used in clinical practice, radiological stage, markers of disease activity and response to treatment. Methods: Electronic searches were undertaken during November 2017 using PubMed, Ebsco, Embase and Web of Science to capture relevant studies evaluating breath-based biomarkers in adult patients with sarcoidosis. Results: 353 papers were screened; 21 met the inclusion criteria and assessed 25 different biomarkers alongside VOCs in exhaled breath gas or condensate. Considerable heterogeneity existed amongst the studies in terms of participant characteristics, sampling and analytical methods. Elevated biomarkers in sarcoidosis included 8-isoprostane, carbon monoxide, neopterin, TGF-β1, TNFα, CysLT and several metallic elements including chromium, silicon and nickel. Three studies exploring VOCs were able to distinguish sarcoidosis from controls. Meta-analysis of four studies assessing alveolar nitric oxide showed no significant difference between sarcoidosis and healthy controls (2.22ppb; 95% CI -0.83, 5.27) however, a high degree of heterogeneity was observed with an I2 of 93.4% (p<0.001). Inconsistent or statistically insignificant results were observed for correlations between several biomarkers and radiological stage, markers of disease activity or treatment. Conclusions: The evidence for using breath biomarkers to diagnose and monitor sarcoidosis remains inconclusive with many studies limited by small sample sizes and lack of standardisation. VOCs have shown promising potential but further research is required to evaluate their prognostic role

Pain and autonomic dysfunction in patients with sarcoidosis and small fibre neuropathy

Small fibre neuropathy (SFN) has been demonstrated in sarcoidosis. However, a systematic analysis of neuropathic pain and autonomic symptoms, key features of SFN, has not been performed. Clinimetric evaluation of pain and autonomic symptoms using the neuropathic pain scale (NPS) and the modified Composite Autonomic Symptoms Scale (mCOMPASS) was used in sarcoidosis patients for this study. A total of 91 sarcoidosis patients (n = 23 without SFN symptoms, n = 43 with SFN symptoms but normal intraepidermal nerve fibre density (IENFD), n = 25 with SFN symptoms and reduced IENFD) were examined. NPS and mCOMPASS were assessed twice (reliability studies). Severity of pain was compared between the subgroups. Correlation between NPS and a visual analogue pain scale (VAS) was assessed (validity studies). Healthy controls (n = 105) completed the mCOMPASS for comparison with patients’ scores. Patients with sarcoidosis, SFN complaints, and reduced IENFD demonstrated more severe pain scores on the NPS. The mCOMPASS differentiated between subjects with and without SFN symptoms. A significant correlation was obtained between the NPS and VAS, indicating good construct validity. Good reliability values were obtained for all scales. The use of the NPS to evaluate SFN symptoms is suggested, as it shows differences between patients with SFN symptoms with normal or reduced IENFD values. The mCOMPASS might be used to select patients for further testing

The effects of ginger supplementation on markers of inflammatory and oxidative stress: a systematic review and meta-analysis of clinical trials

The present systematic review and meta-analysis was conducted to investigate the effects of ginger supplementation on markers of inflammatory and oxidative stress. PubMed, Embase, Scopus and Web of Science were systematically searched to identify relevant clinical trials evaluating the effects of ginger on serum CRP (C-reactive protein), TNF-α (tumor necrosis factor‐alpha), IL-6 (interleukin-6), PGE2 (Prostaglandin E2), TAC (Total antioxidant capacity) and MDA (Malondialdehyde) from inception up to September 2019. Mean difference (MD) and its 95 % confidence interval (CI) was determined using a random effects model. Potential publication bias was assessed using visual inspection of funnel plot and Egger's weighted regression tests. After excluding irrelevant records, 20 full-text articles that included 25 separate studies were included to the meta-analysis. Pooled results of the present study indicated a statistically significant effect of ginger on serum CRP, TNF-α, IL-6, TAC and MDA levels following ginger supplementation. Also, the effects of ginger on serum PGE2 was marginally significant. Moreover, the significant heterogeneity disappeared in subgroup analysis performed by age, duration, dosage, and quality. This current analysis indicates that ginger supplementation has significant effects on serum inflammatory markers

Bile Acid Sequestrants for Lipid and Glucose Control

Bile acids are generated in the liver and are traditionally recognized for their regulatory role in multiple metabolic processes including bile acid homeostasis, nutrient absorption, and cholesterol homeostasis. Recently, bile acids emerged as signaling molecules that, as ligands for the bile acid receptors farnesoid X receptor (FXR) and TGR5, activate and integrate multiple complex signaling pathways involved in lipid and glucose metabolism. Bile acid sequestrants are pharmacologic molecules that bind to bile acids in the intestine resulting in the interruption of bile acid homeostasis and, consequently, reduction in low-density lipoprotein cholesterol levels in hypercholesterolemia. Bile acid sequestrants also reduce glucose levels and improve glycemic control in persons with type 2 diabetes mellitus (T2DM). This article examines the mechanisms by which bile acid–mediated activation of FXR and TGR5 signaling pathways regulate lipid and glucose metabolism and the potential implications for bile acid sequestrant–mediated regulation of lipid and glucose levels in T2DM

Role of the polymorphonuclear leukocyte: Interaction with nosocomial pathogens

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47898/1/10096_2005_Article_BF01964115.pd

A Review of the Rationale for Additional Therapeutic Interventions to Attain Lower LDL-C When Statin Therapy Is Not Enough

Statins alone are not always adequate therapy to achieve low-density lipoprotein (LDL) goals in many patients. Many options are available either alone or in combination with statins that makes it possible to reach recommended goals in a safe and tolerable fashion for most patients. Ezetimibe and bile acid sequestrants reduce cholesterol transport to the liver and can be used in combination. Niacin is very effective at lowering LDL, beyond its ability to raise high-density lipoprotein and shift LDL particle size to a less atherogenic type. When statins cannot be tolerated at all, red yeast rice can be used if proper formulations of the product are obtained. Nutrients can also be added to the diet, including plant stanols and sterols, soy protein, almonds, and fiber, either individually or all together as a portfolio diet. A clear understanding of how each of these strategies works is essential for effective results

Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease

<p>Abstract</p> <p>Background</p> <p>Statins are a class of medications that reduce cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Whether statins can benefit patients with dementia remains unclear because of conflicting results. We hypothesized that some of the confusion in the literature might arise from differences in efficacy of different statins. We used a large database to compare the action of several different statins to investigate whether some statins might be differentially associated with a reduction in the incidence of dementia and Parkinson's disease.</p> <p>Methods</p> <p>We analyzed data from the decision support system of the US Veterans Affairs database, which contains diagnostic, medication and demographic information on 4.5 million subjects. The association of lovastatin, simvastatin and atorvastatin with dementia was examined with Cox proportional hazard models for subjects taking statins compared with subjects taking cardiovascular medications other than statins, after adjusting for covariates associated with dementia or Parkinson's disease.</p> <p>Results</p> <p>We observed that simvastatin is associated with a significant reduction in the incidence of dementia in subjects ≥65 years, using any of three models. The first model incorporated adjustment for age, the second model included adjusted for three known risk factors for dementia, hypertension, cardiovascular disease or diabetes, and the third model incorporated adjustment for the Charlson index, which is an index that provides a broad assessment of chronic disease. Data were obtained for over 700000 subjects taking simvastatin and over 50000 subjects taking atorvastatin who were aged >64 years. Using model 3, the hazard ratio for incident dementia for simvastatin and atorvastatin are 0.46 (CI 0.44–0.48, <it>p </it>< 0.0001) and 0.91 (CI 0.80–1.02, <it>p </it>= 0.11), respectively. Lovastatin was not associated with a reduction in the incidence of dementia. Simvastatin also exhibited a reduced hazard ratio for newly acquired Parkinson's disease (HR 0.51, CI 0.4–0.55, <it>p </it>< 0.0001).</p> <p>Conclusion</p> <p>Simvastatin is associated with a strong reduction in the incidence of dementia and Parkinson's disease, whereas atorvastatin is associated with a modest reduction in incident dementia and Parkinson's disease, which shows only a trend towards significance.</p

Environmental and genetic risk factors and gene-environment interactions in the pathogenesis of chronic obstructive lung disease.

Current understanding of the pathogenesis of chronic obstructive pulmonary disease (COPD), a source of substantial morbidity and mortality in the United States, suggests that chronic inflammation leads to the airways obstruction and parenchymal destruction that characterize this condition. Environmental factors, especially tobacco smoke exposure, are known to accelerate longitudinal decline of lung function, and there is substantial evidence that upregulation of inflammatory pathways plays a vital role in this process. Genetic regulation of both inflammatory responses and anti-inflammatory protective mechanisms likely underlies the heritability of COPD observed in family studies. In alpha-1 protease inhibitor deficiency, the only genetic disorder known to cause COPD, lack of inhibition of elastase activity, results in the parenchymal destruction of emphysema. Other genetic polymorphisms have been hypothesized to alter the risk of COPD but have not been established as causes of this condition. It is likely that multiple genetic factors interacting with each other and with a number of environmental agents will be found to result in the development of COPD

Genome-Wide Association Study Implicates Chromosome 9q21.31 as a Susceptibility Locus for Asthma in Mexican Children

Many candidate genes have been studied for asthma, but replication has varied. Novel candidate genes have been identified for various complex diseases using genome-wide association studies (GWASs). We conducted a GWAS in 492 Mexican children with asthma, predominantly atopic by skin prick test, and their parents using the Illumina HumanHap 550 K BeadChip to identify novel genetic variation for childhood asthma. The 520,767 autosomal single nucleotide polymorphisms (SNPs) passing quality control were tested for association with childhood asthma using log-linear regression with a log-additive risk model. Eleven of the most significantly associated GWAS SNPs were tested for replication in an independent study of 177 Mexican case–parent trios with childhood-onset asthma and atopy using log-linear analysis. The chromosome 9q21.31 SNP rs2378383 (p = 7.10×10−6 in the GWAS), located upstream of transducin-like enhancer of split 4 (TLE4), gave a p-value of 0.03 and the same direction and magnitude of association in the replication study (combined p = 6.79×10−7). Ancestry analysis on chromosome 9q supported an inverse association between the rs2378383 minor allele (G) and childhood asthma. This work identifies chromosome 9q21.31 as a novel susceptibility locus for childhood asthma in Mexicans. Further, analysis of genome-wide expression data in 51 human tissues from the Novartis Research Foundation showed that median GWAS significance levels for SNPs in genes expressed in the lung differed most significantly from genes not expressed in the lung when compared to 50 other tissues, supporting the biological plausibility of our overall GWAS findings and the multigenic etiology of childhood asthma

Idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a non-neoplastic pulmonary disease that is characterized by the formation of scar tissue within the lungs in the absence of any known provocation. IPF is a rare disease which affects approximately 5 million persons worldwide. The prevalence is estimated to be slightly greater in men (20.2/100,000) than in women (13.2/100,000). The mean age at presentation is 66 years. IPF initially manifests with symptoms of exercise-induced breathless and dry coughing. Auscultation of the lungs reveals early inspiratory crackles, predominantly located in the lower posterior lung zones upon physical exam. Clubbing is found in approximately 50% of IPF patients. Cor pulmonale develops in association with end-stage disease. In that case, classic signs of right heart failure may be present. Etiology remains incompletely understood. Some environmental factors may be associated with IPF (cigarette smoking, exposure to silica and livestock). IPF is recognized on high-resolution computed tomography by peripheral, subpleural lower lobe reticular opacities in association with subpleural honeycomb changes. IPF is associated with a pathological lesion known as usual interstitial pneumonia (UIP). The UIP pattern consists of normal lung alternating with patches of dense fibrosis, taking the form of collagen sheets. The diagnosis of IPF requires correlation of the clinical setting with radiographic images and a lung biopsy. In the absence of lung biopsy, the diagnosis of IPF can be made by defined clinical criteria that were published in guidelines endorsed by several professional societies. Differential diagnosis includes other idiopathic interstitial pneumonia, connective tissue diseases (systemic sclerosis, polymyositis, rheumatoid arthritis), forme fruste of autoimmune disorders, chronic hypersensitivity pneumonitis and other environmental (sometimes occupational) exposures. IPF is typically progressive and leads to significant disability. The median survival is 2 to 5 years from the time of diagnosis. Medical therapy is ineffective in the treatment of IPF. New molecular therapeutic targets have been identified and several clinical trials are investigating the efficacy of novel medication. Meanwhile, pulmonary transplantation remains a viable option for patients with IPF. It is expected that, during the next decade, considerable progress will be made toward the understanding and treatment of this devastating illness