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Clinical Journal of the American... Jul 2008Calciphylaxis, or calcific uremic arteriolopathy, is a well-described entity in end-stage kidney disease and renal transplant patients; however, little systematic... (Review)
Review
BACKGROUND AND OBJECTIVES
Calciphylaxis, or calcific uremic arteriolopathy, is a well-described entity in end-stage kidney disease and renal transplant patients; however, little systematic information is available on calciphylaxis from nonuremic causes. This systematic review was designed to characterize etiologies, clinical features, laboratory abnormalities, and prognosis of nonuremic calciphylaxis.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
A systematic review of literature for case reports and case series of nonuremic calciphylaxis was performed. Cases included met the operational definition of nonuremic calciphylaxis-histopathologic diagnosis of calciphylaxis in the absence of end-stage kidney disease, renal transplantation, or acute kidney injury requiring renal replacement therapy.
RESULTS
We found 36 cases (75% women, 63% Caucasian, aged 15 to 82 yr) of nonuremic calciphylaxis. Primary hyperparathyroidism, malignancy, alcoholic liver disease, and connective tissue disease were the most common reported causes. Preceding corticosteroid use was reported for 61% patients. Protein C and S deficiencies were seen in 11% of patients. Skin lesions were morphologically similar to calcific uremic arteriolopathy. Mortality rate was 52%, with sepsis being the leading cause of death.
CONCLUSION
Calciphylaxis should be considered while evaluating skin lesions in patients with predisposing conditions even in the absence of end-stage kidney disease and renal transplantation. Nonuremic calciphylaxis is reported most often in white women. Mineral abnormalities that are invoked as potential causes in calcific uremic arteriolopathy are often absent, suggesting that heterogeneous mechanisms may contribute to its pathogenesis. Nonuremic calciphylaxis is associated with high mortality, and there is no known effective treatment.
Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Biomarkers; Calciphylaxis; Connective Tissue Diseases; Female; Humans; Hyperparathyroidism, Primary; Liver Diseases, Alcoholic; Male; Middle Aged; Neoplasms; Prognosis; Protein C Deficiency; Protein S Deficiency; Risk Factors; Sepsis; Skin; Skin Diseases
PubMed: 18417747
DOI: 10.2215/CJN.00530108 -
Journal of Thrombosis and Haemostasis :... Dec 2020Retinal vascular occlusion is a leading cause of sight loss. Both retinal artery occlusion (RAO) and retinal vein occlusion (RVO) have been associated with... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Retinal vascular occlusion is a leading cause of sight loss. Both retinal artery occlusion (RAO) and retinal vein occlusion (RVO) have been associated with hypercoagulable states; however, the burden of thrombophilia in these patients is unclear.
OBJECTIVES
This study aims at estimating the prevalence of inherited and acquired thrombophilias in adults with RAO or RVO through a systematic review and meta-analysis of the literature.
PATIENTS/METHODS
PubMed and EMBASE were systematically searched from inception to 29 February 2020. All studies reporting prevalences of factor V Leiden (FVL) and prothrombin (F-II) G20210A mutations, methylenetetrahydrofolate reductase (MTHFR) C677T and plasminogen activator inhibitor (PAI) 4G polymorphisms, antithrombin III (AT-III), protein C (PC) and protein S (PS) activity deficiencies, hyperhomocysteinemia, and antiphospholipid (APL) antibodies in adults with RAO or RVO were included. Pooled prevalences and 95% confidence intervals (CI) were calculated.
RESULTS
Ninety-five studies were included; FVL and F-II mutations were found in 6% (95% CI: 5-8) and 3% (95% CI: 2-4) of individuals with RVO, respectively, whereas AT-III, PC, and PS activity deficiencies were found in <2%. The MTHFR C677T and PAI 4G homozygous polymorphism were observed in 13% (95% CI: 10-17) and 23% (95% CI: 16-31) of RVO, respectively; 8% presented APL antibodies. Similar findings were observed in individuals with RAO.
CONCLUSIONS
Compared with healthy subjects, patients with retinal vascular occlusion showed similar prevalences of inherited and acquired thrombophilias. These findings do not support routine thrombophilia screening in individuals with RAO or RVO.
Topics: Adult; Factor V; Humans; Methylenetetrahydrofolate Reductase (NADPH2); Prothrombin; Retinal Vein Occlusion; Risk Factors; Thrombophilia
PubMed: 32805772
DOI: 10.1111/jth.15068 -
Thrombosis Research Mar 2018Despite high rates of venous thromboembolism (VTE) among patients with hematologic malignancies, few tools exist to assist providers in identifying those patients at... (Review)
Review
INTRODUCTION
Despite high rates of venous thromboembolism (VTE) among patients with hematologic malignancies, few tools exist to assist providers in identifying those patients at highest risk for this potentially fatal complication. Laboratory biomarkers, such as d-dimer, have demonstrated utility in some clinical settings to distinguish patients at increased risk.
MATERIALS AND METHODS
We performed a systematic review of the literature utilizing search terms including "biomarker", "venous thromboembolism", "hematologic malignancy", "lymphoma", "myeloma" and "leukemia" in the Medline database. A total of 25 studies investigating laboratory biomarkers of increased thrombotic risk in the setting of hematologic malignancy were identified and included in this review.
RESULTS AND CONCLUSIONS
The most studied biomarkers, d-dimer and fibrinogen, demonstrated some degree of efficacy in identifying high-risk patients at levels >4.0 mg/L or <1.0 g/L respectively. Additional markers which demonstrated promise included thrombin generation, mean platelet volume, soluble VEGF, soluble P-selectin and extracellular vesicles. Other biomarkers reviewed, which did not consistently demonstrate significant associations with VTE included prothrombin fragments F1 + 2, factor VIII, protein C, protein S, von Willebrand antigen and activity, antithrombin, thrombin antithrombin complex, antiphospholopid antibody, plasminogen activator inhibitor, tissue factor pathway inhibitor and several variants associated with known hypercoagulable states (factor V Leiden, prothrombin gene variant, methylenetetrahydrofolate reductase variant). Data to support any of the biomarkers discussed here in routine clinical decision-making are currently lacking, but additional investigation in clinical studies, ideally in combination with clinical factors known to be associated with increased thrombotic risk, is warranted.
Topics: Biomarkers; Female; Hematologic Neoplasms; Humans; Male; Risk Factors; Venous Thromboembolism
PubMed: 29407626
DOI: 10.1016/j.thromres.2018.01.037 -
International Journal of Clinical and... 2015Outcome prediction following traumatic brain injury (TBI) is a widely investigated field of research. Several outcome prediction models have been developed for prognosis... (Review)
Review
Outcome prediction following traumatic brain injury (TBI) is a widely investigated field of research. Several outcome prediction models have been developed for prognosis after TBI. There are two main prognostic models: International Mission for Prognosis and Clinical Trials in Traumatic Brain Injury (IMPACT) prognosis calculator and the Corticosteroid Randomization after Significant Head Injury (CRASH) prognosis calculator. The prognosis model has three or four levels: (1) model A included age, motor GCS, and pupil reactivity; (2) model B included predictors from model A with CT characteristics; and (3) model C included predictors from model B with laboratory parameters. In consideration of the fact that interventions after admission, such as ICP management also have prognostic value for outcome predictions and may improve the models' performance, Yuan F et al developed another prediction model (model D) which includes ICP. With the development of molecular biology, a handful of brain injury biomarkers were reported that may improve the predictive power of prognostic models, including neuron-specific enolase (NSE), glial fibrillary acid protein (GFAP), S-100β protein, tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), myelin basic protein (MBP), cleaved tau protein (C-tau), spectrin breakdown products (SBDPs), and ubiquitin C-terminal hydrolase-L1 (UCH-L1), and sex hormones. A total of 40 manuscripts reporting 11 biomarkers were identified in the literature. Many substances have been implicated as potential biomarkers for TBI; however, no single biomarker has shown the necessary sensitivity and specificity for predicting outcome. The limited number of publications in this field underscores the need for further investigation. Through fluid biomarker analysis, the advent of multi-analyte profiling technology has enabled substantial advances in the diagnosis and treatment of a variety of conditions. Application of this technology to create a bio-signature for TBI using multiple biomarkers in combination will hopefully facilitate much-needed advances. We believe that further investigations about brain injury biomarkers may improve the predictive power of the contemporary outcome calculators and prognostic models, and eventually improve the care of patients with TBI.
PubMed: 26884899
DOI: No ID Found -
Frontiers in Cardiovascular Medicine 2022The discovery that cardiac sarcomere proteins are substrates for S-glutathionylation and that this post-translational modification correlates strongly with diastolic...
The discovery that cardiac sarcomere proteins are substrates for S-glutathionylation and that this post-translational modification correlates strongly with diastolic dysfunction led to new concepts regarding how levels of oxidative stress affect the heartbeat. Major sarcomere proteins for which there is evidence of S-glutathionylation include cardiac myosin binding protein C (cMyBP-C), actin, cardiac troponin I (cTnI) and titin. Our hypothesis is that these S-glutathionylated proteins are significant factors in acquired and familial disorders of the heart; and, when released into the serum, provide novel biomarkers. We consider the molecular mechanisms for these effects in the context of recent revelations of how these proteins control cardiac dynamics in close collaboration with Ca fluxes. These revelations were made using powerful approaches and technologies that were focused on thin filaments, thick filaments, and titin filaments. Here we integrate their regulatory processes in the sarcomere as modulated mainly by neuro-humoral control of phosphorylation inasmuch evidence indicates that S-glutathionylation and protein phosphorylation, promoting increased dynamics and modifying the Frank-Starling relation, may be mutually exclusive. Earlier studies demonstrated that in addition to cTnI as a well-established biomarker for cardiac disorders, serum levels of cMyBP-C are also a biomarker for cardiac disorders. We describe recent studies approaching the question of whether serum levels of S-glutathionylated-cMyBP-C could be employed as an important clinical tool in patient stratification, early diagnosis in at risk patients before HFpEF, determination of progression, effectiveness of therapeutic approaches, and as a guide in developing future therapies.
PubMed: 36762302
DOI: 10.3389/fcvm.2022.1060716 -
European Respiratory Review : An... Sep 2018Fibrotic interstitial pneumonias are a group of rare diseases characterised by distortion of lung interstitium. Patients with mutations in surfactant-processing genes,...
Fibrotic interstitial pneumonias are a group of rare diseases characterised by distortion of lung interstitium. Patients with mutations in surfactant-processing genes, such as surfactant protein C (), surfactant protein A1 and A2 ( and ), ATP binding cassette A3 () and Hermansky-Pudlak syndrome (, and ), develop progressive pulmonary fibrosis, often culminating in fatal respiratory insufficiency. Although many mutations have been described, little is known about the optimal treatment strategy for fibrotic interstitial pneumonia patients with surfactant-processing mutations.We performed a systematic literature review of studies that described a drug effect in patients, cell or mouse models with a surfactant-processing mutation. In total, 73 articles were selected, consisting of 55 interstitial lung disease case reports/series, two clinical trials and 16 cell or mouse studies. Clinical effect parameters included lung function, radiological characteristics and clinical symptoms, while experimental outcome parameters included chemokine/cytokine expression, surfactant trafficking, necrosis and apoptosis. SP600125, a c-jun N-terminal kinase (JNK) inhibitor, hydroxychloroquine and 4-phenylbutyric acid were most frequently studied in disease models and lead to variable outcomes, suggesting that outcome is mutation dependent.This systematic review summarises effect parameters for future studies on surfactant-processing disorders in disease models and provides directions for future trials in affected patients.
Topics: Animals; Disease Models, Animal; Genetic Predisposition to Disease; Humans; Idiopathic Interstitial Pneumonias; Lung; Mice; Mutation; Phenotype; Pulmonary Surfactant-Associated Proteins; Respiratory System Agents; Treatment Outcome
PubMed: 29997245
DOI: 10.1183/16000617.0135-2017 -
Critical Care (London, England) Dec 2012Data from interventional trials of systemic anticoagulation for sepsis inconsistently suggest beneficial effects in case of acute lung injury (ALI). Severe systemic... (Review)
Review
BACKGROUND
Data from interventional trials of systemic anticoagulation for sepsis inconsistently suggest beneficial effects in case of acute lung injury (ALI). Severe systemic bleeding due to anticoagulation may have offset the possible positive effects. Nebulization of anticoagulants may allow for improved local biological availability and as such may improve efficacy in the lungs and lower the risk of systemic bleeding complications.
METHOD
We performed a systematic review of preclinical studies and clinical trials investigating the efficacy and safety of nebulized anticoagulants in the setting of lung injury in animals and ALI in humans.
RESULTS
The efficacy of nebulized activated protein C, antithrombin, heparin and danaparoid has been tested in diverse animal models of direct (for example, pneumonia-, intra-pulmonary lipopolysaccharide (LPS)-, and smoke inhalation-induced lung injury) and indirect lung injury (for example, intravenous LPS- and trauma-induced lung injury). Nebulized anticoagulants were found to have the potential to attenuate pulmonary coagulopathy and frequently also inflammation. Notably, nebulized danaparoid and heparin but not activated protein C and antithrombin, were found to have an effect on systemic coagulation. Clinical trials of nebulized anticoagulants are very limited. Nebulized heparin was found to improve survival of patients with smoke inhalation-induced ALI. In a trial of critically ill patients who needed mechanical ventilation for longer than two days, nebulized heparin was associated with a higher number of ventilator-free days. In line with results from preclinical studies, nebulization of heparin was found to have an effect on systemic coagulation, but without causing systemic bleedings.
CONCLUSION
Local anticoagulant therapy through nebulization of anticoagulants attenuates pulmonary coagulopathy and frequently also inflammation in preclinical studies of lung injury. Recent human trials suggest nebulized heparin for ALI to be beneficial and safe, but data are very limited.
Topics: Acute Lung Injury; Administration, Inhalation; Animals; Anticoagulants; Humans; Nebulizers and Vaporizers
PubMed: 22546487
DOI: 10.1186/cc11325 -
Cureus Aug 2022Rheumatoid arthritis (RA) is associated with both local and systemic inflammatory processes via the aberrant regulation of inflammatory pathways and imbalances in... (Review)
Review
A Systematic Review of Nutritional Interventions on Key Cytokine Pathways in Rheumatoid Arthritis and Its Implications for Comorbid Depression: Is a More Comprehensive Approach Required?
Rheumatoid arthritis (RA) is associated with both local and systemic inflammatory processes via the aberrant regulation of inflammatory pathways and imbalances in several mediators of inflammation. Cytokines, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1B, IL-6, IL-17, IL-18, rheumatoid factor, anti-cyclic citrullinated protein, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) have been used in diagnosing and tracking the progression of RA. The primary objective of this review is to identify and summarize which specific dietary patterns and nutritional interventions go beyond symptom management to improve the response to known inflammatory cytokines and possibly decrease markers of inflammation in the RA disease process. Analysis of the 41 identified publications demonstrated that certain dietary patterns, the consumption of specific macronutrients, and supplementation with herbals or other compounds have shown some effect on improving cytokine profiles in patients with RA. This review illustrates the importance of proper patient education on the anti-inflammatory and potential protective impacts substantial dietary change may have on the disease progression and symptoms of RA. Identifying nutritional interventions and dietary patterns that improve the inflammatory cytokine profile, and therefore disease progression and inflammatory comorbidities of RA will help further focus research on treatments that may provide a better overall improvement in quality of life for RA patients by focusing on the root cause inflammatory processes that affect not only joint destruction but also depression-rated disability. This review further notes that while depression is commonly found in patients who suffer from chronic illnesses, it is especially prevalent in the RA population. The pathology of depression is associated with systemic inflammation, which is a known outcome of RA and may explain this strong association. Cytokines IL-6, IL-1, and TNF-α, known mediators involved in the progression of RA, are strongly associated with stress-related disorders including depression and anxiety. The presence of these cytokines is also correlated with the severity and duration of depression. This may signal a potential use of cytokines in diagnosing and following the progression of depression not only in patients with RA but also others. Given the statistics presented on depression and suicide in patients with RA, and the shared inflammatory pathway between the two diseases, depression and suicide screening scales should be included along with analysis of inflammatory markers and disease activity scores (DAS) in any future RA study.
PubMed: 35990558
DOI: 10.7759/cureus.28031 -
The Cochrane Database of Systematic... Mar 2011Disseminated intravascular coagulation (DIC) is an acquired syndrome characterised by systemic intravascular activation of coagulation. There are several obstetric... (Review)
Review
BACKGROUND
Disseminated intravascular coagulation (DIC) is an acquired syndrome characterised by systemic intravascular activation of coagulation. There are several obstetric causes of DIC during pregnancy and postpartum.
OBJECTIVES
To assess the clinical effectiveness and safety of haematological interventions such as heparins (low molecular weight heparin (LMWH) and unfractionated heparin (UFH), danaparoid sodium, synthetic protease inhibitor, antithrombin, human recombinant activated protein C, recombinant human soluble thrombomodulin, recombinant tissue factor pathway inhibitor, recombinant activated factor VIIa and any other types of haematological interventions (except transfusions) for treating DIC during pregnancy and postpartum.
SEARCH STRATEGY
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (27 July 2010), LILACS (1982 to 22 July 2010), ongoing trials registries via the World Health Organization International Clinical Trials Platform Search Portal (22 July 2010), and other relevant websites (22 July 2010).
SELECTION CRITERIA
Randomised controlled trials (RCTs) on any haematological interventions for treating DIC during pregnancy and postpartum.
DATA COLLECTION AND ANALYSIS
There were no included studies.
MAIN RESULTS
We could not find any RCTs on haematological interventions (heparins (LMWH and UFH), danaparoid sodium, synthetic protease inhibitor, antithrombin, human recombinant activated protein C, recombinant human soluble thrombomodulin, recombinant tissue factor pathway inhibitor, recombinant activated factor VIIa and any other types of haematological interventions) for treating DIC during pregnancy and postpartum.
AUTHORS' CONCLUSIONS
This review found no RCTs on the safety and efficacy of haematological interventions for treating DIC during pregnancy and postpartum. Such interventions need to be tested in RCTs assessing outcomes such as maternal death, perinatal death and safety.
Topics: Disseminated Intravascular Coagulation; Female; Humans; Postpartum Period; Pregnancy; Pregnancy Complications, Hematologic
PubMed: 21412921
DOI: 10.1002/14651858.CD008577.pub2 -
The Cochrane Database of Systematic... Apr 2012Sepsis is a common problem in preterm and term infants. The incidence of neonatal sepsis has declined, but mortality remains high. Recombinant human activated protein C... (Review)
Review
BACKGROUND
Sepsis is a common problem in preterm and term infants. The incidence of neonatal sepsis has declined, but mortality remains high. Recombinant human activated protein C (rhAPC) possess a broad spectrum of activity modulating coagulation and inflammation. In septic adults it may reduce mortality, but no significant benefit has been reported in children with severe sepsis.
OBJECTIVES
To determine whether treatment with rhAPC reduces mortality and/or morbidity in neonatal sepsis.
SEARCH METHODS
For this update searches were carried out in May 2011 of the Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE, CINAHL, and abstracts of annual meetings of the Pediatric Academic Societies. Doctoral dissertations, theses and the Science Citation Index for articles on activated protein C were searched. No language restriction was applied.
SELECTION CRITERIA
Randomized or quasi-randomized trials, assessing the efficacy of rhAPC compared to placebo or no intervention as an adjunct to antibiotic therapy of suspected or confirmed severe sepsis in term and preterm infants less than 28 days old. Eligible trials should report at least one of the following outcomes: mortality during initial hospital stay, neurodevelopmental assessment at two years of age or later, length of hospital stay, duration of ventilation, chronic lung disease, periventricular leukomalacia, intraventricular haemorrhage, necrotizing enterocolitis, bleeding, and any other adverse events.
DATA COLLECTION AND ANALYSIS
Review authors were to independently evaluate the articles for inclusion criteria and quality, and abstract information for the outcomes of interest. Differences were to be resolved by consensus. The statistical methods were to include relative risk, risk difference, number needed to treat to benefit or number needed to treat to harm for dichotomous and weighed mean difference for continuous outcomes reported with 95% confidence intervals. A fixed effect model was to be used for meta-analysis. Heterogeneity tests, including the I(2) statistic, were to be performed to assess the appropriateness of pooling the data.
MAIN RESULTS
No eligible trials were identified. In October 2011 rhAPC (Xigris®) was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults. Xigris® (DrotAA)( rhAPC) should no longer be used in any age category and the product should be returned to the distributor.
AUTHORS' CONCLUSIONS
Despite the scientific rationale for its use, there is insufficient data to use rhAPC for the management of severe sepsis in newborn infants. Due to the results among adults with lack of efficacy, an increase in bleeding and resulting withdrawal of rhAPC from the market, neonates should not be treated with rhAPC and further trials should not be conducted.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Chemotherapy, Adjuvant; Humans; Infant, Newborn; Protein C; Recombinant Proteins; Safety-Based Drug Withdrawals; Sepsis
PubMed: 22513930
DOI: 10.1002/14651858.CD005385.pub3