The Assessment of Blood Loss During Total Knee Arthroplasty When Comparing Intravenous vs Intracapsular Administration of Tranexamic Acid.

BACKGROUND: Administration of tranexamic acid topically and intravenously has demonstrated effectiveness in decreasing blood loss and transfusion rates. METHODS: We randomized 131 patients undergoing primary total knee arthroplasty to receive either intracapsular (69) or intravenous tranexamic acid (62). Postoperative blood loss was calculated using the formula derived by Nadler et al. The number of units transfused was recorded, as well as length of hospital stay. RESULTS: We found no statistically significant difference on calculated blood loss (postoperative day [POD] 1: 624 ± 326 vs 644 ± 292; P = .71, POD 2: 806 ± 368 vs 835 ± 319; P = .64, and POD 3: 1076 ± 419 vs 978 ± 343; P = .55). There was no difference in number of blood transfusions, length of stay, or complications. CONCLUSION: Intracapsular tranexamic acid is not inferior to intravenous tranexamic acid in decreasing blood loss and blood transfusion rate in primary total knee arthroplasty.

Pegylated interferon-α induced hypoferremia is associated with the immediate response to treatment in hepatitis C.

UNLABELLED: Pegylated interferon-α (PEG-IFN-α) forms an integral part of the current treatment for hepatitis C virus (HCV) infection. PEG-IFN-α suppresses HCV production by augmenting the innate antiviral immune response. Recent studies have reported the induction of hepcidin, the iron regulatory hormone, by IFN-α in vitro. As hepcidin plays an important role in innate immunity, we hypothesized that this finding may be of clinical relevance to HCV and investigated the changes in iron homeostasis during the first 24 hours of treatment. Blood samples were obtained from HCV patients immediately prior to and 6, 12, and 24 hours following the first dose of PEG-IFN-α/ribavirin (RBV). Samples were analyzed for hepcidin, cytokine, iron levels, and HCV viral load, and hepcidin messenger RNA (mRNA) expression was quantified in peripheral blood mononuclear cells. Hepcidin induction by IFN-α was further analyzed in cell culture. In HCV patients a single dose of PEG-IFN-α/RBV resulted in a significant increase in serum hepcidin, peaking at 12 hours, coinciding with a 50% reduction in serum iron and transferrin saturation over the 24-hour period. Patients with a ≥ 2 log decline in HCV viral load over the first 24 hours had significantly lower SI and TS levels at 12 and 24 hours. Moreover, 24-hour SI levels were an independent predictor of the immediate HCV viral decline, an indicator of ultimate treatment outcome. In cell culture, a direct induction of hepcidin by IFN-α was seen, controlled by the STAT3 transcription factor. CONCLUSION: Hepcidin induction occurs following the initiation of PEG-IFN-α treatment for HCV, and is mediated by way of STAT3 signaling. The subsequent hypoferremia was greatest in those with the most significant decline in viral load, identifying systemic iron withdrawal as a marker of immediate interferon-α efficacy in HCV patients.

Stop feeding cancer: pro-inflammatory role of visceral adiposity in liver cancer.

Liver cancer is the fifth most common cancer in the world with an estimated over half a million new cases diagnosed every year. Due to the difficulty in early diagnosis and lack of treatment options, the prevalence of liver cancer continues to climb with a 5-year survival rate of between 6% and 11%. Coinciding with the rise of liver cancer, the prevalence of obesity has rapidly increased over the past two decades. Evidence from epidemiological studies demonstrates a higher risk of hepatocellular carcinoma (HCC) in obese individuals. Obesity is recognised as a low-grade inflammatory disease, this is of particular relevance as inflammation has been proposed as the seventh hallmark of cancer development with abdominal visceral adiposity considered as an important source of pro-inflammatory stimuli. Emerging evidence points towards the direct role of visceral adipose tissue rather than generalised body fat in carcinogenesis. Cytokines such as IL-6 and TNF-α secreted from visceral adipose tissue have been demonstrated to induce a chronic inflammatory condition predisposing the liver to a protumourigenic milieu. This review focuses on excess visceral adiposity rather than simple obesity; particularly adipokines and their implications for chronic inflammation, lipid accumulation, insulin resistance, Endoplasmic Reticulum (ER) stress and angiogenesis. Evidence of molecular signalling pathways that may give rise to the onset and progression of HCC in this context are depicted. Delineation of the pro-inflammatory role of visceral adiposity in liver cancer and its targeting will provide better rational and therapeutic approaches for HCC prevention and elimination. The concept of a central role for metabolism in cancer is the culmination of an effort that began with one of the 20th century's leading biochemists and Nobel laureate of 1931, Otto Warburg.

Defective bone morphogenic protein signaling underlies hepcidin deficiency in HFE hereditary hemochromatosis.

UNLABELLED: Hereditary hemochromatosis (HH) is a common inherited iron overload disorder. The vast majority of patients carry the missense Cys282Tyr mutation of the HFE gene. Hepcidin, the central regulator of iron homeostasis, is deficient in HH, leading to unchecked iron absorption and subsequent iron overload. The bone morphogenic protein (BMP)/small mothers against decapentaplegic (Smad) signaling cascade is central to the regulation of hepcidin. Recent data from HH mice models indicate that this pathway may be defective in the absence of the HFE protein. Hepatic BMP/Smad signaling has not been characterized in a human HFE-HH cohort to date. Hepatic expression of BMP/Smad-related genes was examined in 20 HFE-HH males with significant iron overload, and compared to seven male HFE wild-type controls using quantitative real-time reverse transcription polymerase chain reaction. Hepatic expression of BMP6 was appropriately elevated in HFE-HH compared to controls (P = 0.02), likely related to iron overload. Despite this, no increased expression of the BMP target genes hepcidin and Id1 was observed, and diminished phosphorylation of Smad1/Smad5/Smad8 protein relative to iron burden was found upon immunohistochemical analysis, suggesting that impaired BMP signaling occurs in HFE-HH. Furthermore, Smad6 and Smad7, inhibitors of BMP signaling, were up-regulated in HFE-HH compared to controls (P = 0.001 and P = 0.018, respectively). CONCLUSION: New data arising from this study suggest that impaired BMP signaling underlies the hepcidin deficiency of HFE-HH. Moreover, the inhibitory Smads, Smad6, and Smad7 are identified as potential disruptors of this signal and, hence, contributors to the pathogenesis of this disease.

Transforming growth factor beta-1 and interleukin-17 gene transcription in peripheral blood mononuclear cells and the human response to infection.

INTRODUCTION: The occurrence of severe sepsis may be associated with deficient pro-inflammatory cytokine production. Transforming growth factor beta-1 (TGFbeta-1) predominantly inhibits inflammation and may simultaneously promote IL-17 production. Interleukin-17 (IL-17) is a recently described pro-inflammatory cytokine, which may be important in auto-immunity and infection. We investigated the hypothesis that the onset of sepsis is related to differential TGFbeta-1 and IL-17 gene expression. METHODS: A prospective observational study in a mixed intensive care unit (ICU) and hospital wards in a university hospital. Patients (59) with severe sepsis; 15 patients with gram-negative bacteraemia but without critical illness and 10 healthy controls were assayed for TGFbeta-1, IL-17a, IL-17f, IL-6 and IL-1beta mRNA in peripheral blood mononuclear cells (PBMC) by quantitative real-time PCR and serum protein levels by ELISA. RESULTS: TGFbeta-1 mRNA levels are reduced in patients with bacteraemia and sepsis compared with controls (p=0.02). IL-6 mRNA levels were reduced in bacteraemic patients compared with septic patients and controls (p=0.008). IL-1beta mRNA levels were similar in all groups, IL-17a and IL-17f mRNA levels are not detectable in peripheral blood mononuclear cells. IL-6 protein levels were greater in patients with sepsis than bacteraemic and control patients (p<0.0001). Activated TGFbeta-1 and IL-17 protein levels were similar in all groups. IL-1beta protein was not detectable in the majority of patients. CONCLUSIONS: Down regulation of TGFbeta-1 gene transcription was related to the occurrence of infection but not the onset of sepsis. Interleukin-17 production in PBMC may not be significant in the human host response to infection.

Oxidative stress induced lung cancer and COPD: opportunities for epigenetic therapy.

Reactive oxygen species (ROS) form as a natural by-product of the normal metabolism of oxygen and play important roles within the cell. Under normal circumstances the cell is able to maintain an adequate homeostasis between the formation of ROS and its removal through particular enzymatic pathways or via antioxidants. If however, this balance is disturbed a situation called oxidative stress occurs. Critically, oxidative stress plays important roles in the pathogenesis of many diseases, including cancer. Epigenetics is a process where gene expression is regulated by heritable mechanisms that do not cause any direct changes to the DNA sequence itself, and disruption of epigenetic mechanisms has important implications in disease. Evidence is emerging that histone deacetylases (HDACs) play decisive roles in regulating important cellular oxidative stress pathways including those involved with sensing oxidative stress and those involved with regulating the cellular response to oxidative stress. In particular aberrant regulation of these pathways by HDACs may play critical roles in cancer progression. In this review we discuss the current evidence linking epigenetics and oxidative stress and cancer, using chronic obstructive pulmonary disease and non-small cell lung cancer to illustrate the importance of epigenetics on these pathways within these disease settings.

NF-kappaB regulation: the nuclear response.

Nuclear factor kappaB (NF-kappaB) is an inducible transcription factor that tightly regulates the expression of a large cohort of genes. As a key component of the cellular machinery NF-kappaB is involved in a wide range of biological processes including innate and adaptive immunity, inflammation, cellular stress responses, cell adhesion, apoptosis and proliferation. Appropriate regulation of NF-kappaB is critical for the proper function and survival of the cell. Aberrant NF-kappaB activity has now been implicated in the pathogenesis of several diseases ranging from inflammatory bowel disease to autoimmune conditions such as rheumatoid arthritis. Systems governing NF-kappaB activity are complex and there is an increased understanding of the importance of nuclear events in regulating NF-kappaB's activities as a transcription factor. A number of novel nuclear regulators of NF-kappaB such as IkappaB-zeta and PDZ and LIM domain 2 (PDLIM2) have now been identified, adding another layer to the mechanics of NF-kappaB regulation. Further insight into the functions of these molecules raises the prospect for better understanding and rational design of therapeutics for several important diseases.

Unmasking the pathological and therapeutic potential of histone deacetylases for liver cancer.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, currently ranking as one of the highest neoplastic-related mortalities in the world. Due to the difficulty in early diagnosis and lack of effective treatment options, the 5-year survival rate of HCC remains extremely low. Histone deacetylation is one of the most important epigenetic mechanisms, regulating cellular events such as differentiation, proliferation and cell cycle. Histone deacetylases (HDACs), the chief mediators of this epigenetic mechanism, are often aberrantly expressed in various tumours including HCC. Areas covered: This review focuses on the most up-to-date findings of HDACs and their associated molecular mechanisms in HCC onset and progression. In addition, a potential network between HDACs and non-coding RNAs including microRNAs and long noncoding RNAs underlying hepatocarcinogenesis is considered. Expert opinion: Unmasking the role of HDACs and their association with HCC pathogenesis could have implications for future personalized therapeutic and diagnostic targeting.

Improved Early Postoperative Range of Motion in Total Knee Arthroplasty Using Tranexamic Acid: A Retrospective Analysis.

The use of tranexamic acid (TXA) in total knee arthroplasty (TKA) has become common practice. Recent literature has demonstrated a reduction in postoperative knee swelling and drain output while using TXA. Our purpose is to analyze the range of motion (ROM) following TKA in patients who received TXA compared with a control group. We hypothesize that patients treated with TXA will have improved early postoperative ROM when compared with controls. A retrospective chart review was performed for patients who underwent TKA from 2010 to 2012 performed by a single orthopaedic surgeon. Patients were stratified into three cohorts by route of TXA administration including intravenous (IV), topical, and a control group. Dependent variables analyzed included extension, flexion, and total arc ROM on each postoperative day (POD), average ROM across all three postoperative days, as well as pre-to-postoperative differences in ROM. Demographic data were recorded for each patient. A total of 174 patients were included for analysis, 75 controls and 99 receiving TXA. A significant difference was found between the treatment groups and the control for all variables (for each, p ≤ 0.002). There were no significant differences in ROM between the IV and topical TXA treatment groups (for each, p ≥ 0.558). A multivariate analysis demonstrated no significant difference between the groups in complication rate or demographic variables. The use of TXA may improve early postoperative ROM following TKA.

Antiviral activity of bone morphogenetic proteins and activins.

Understanding the control of viral infections is of broad importance. Chronic hepatitis C virus (HCV) infection causes decreased expression of the iron hormone hepcidin, which is regulated by hepatic bone morphogenetic protein (BMP)/SMAD signalling. We found that HCV infection and the BMP/SMAD pathway are mutually antagonistic. HCV blunted induction of hepcidin expression by BMP6, probably via tumour necrosis factor (TNF)-mediated downregulation of the BMP co-receptor haemojuvelin. In HCV-infected patients, disruption of the BMP6/hepcidin axis and genetic variation associated with the BMP/SMAD pathway predicted the outcome of infection, suggesting that BMP/SMAD activity influences antiviral immunity. Correspondingly, BMP6 regulated a gene repertoire reminiscent of type I interferon (IFN) signalling, including upregulating interferon regulatory factors (IRFs) and downregulating an inhibitor of IFN signalling, USP18. Moreover, in BMP-stimulated cells, SMAD1 occupied loci across the genome, similar to those bound by IRF1 in IFN-stimulated cells. Functionally, BMP6 enhanced the transcriptional and antiviral response to IFN, but BMP6 and related activin proteins also potently blocked HCV replication independently of IFN. Furthermore, BMP6 and activin A suppressed growth of HBV in cell culture, and activin A inhibited Zika virus replication alone and in combination with IFN. The data establish an unappreciated important role for BMPs and activins in cellular antiviral immunity, which acts independently of, and modulates, IFN.

Endoplasmic reticulum stress--a double edged sword for Z alpha-1 antitrypsin deficiency hepatoxicity.

Several diverse disorders, including the liver disorder Z alpha-1 antitrypsin deficiency as well as cystic fibrosis, Alzheimer's, and Parkinson's disease arise from the same general disease mechanism and are now categorized under the term "conformational diseases", characterized by abnormal folding and subsequent aggregation of an underlying protein. In recent years, several important research advances in the cell biology of aggregation-prone mutant proteins and pathobiological mechanisms of liver disease in general have proven paramount to our understanding of Z alpha-1 antitrypsin deficiency. This liver disease underlines the principle mechanisms of conformational disorders contained within the four pillars of endoplasmic reticulum stress: (1) protein degradation, (2) endoplasmic overload response, (3) unfolded protein response and (4) cellular death pathway. This four-stage model of Z alpha-1 antitrypsin hepatoxicity is elegant in its simplicity and helps explain the clinical manifestations of this condition. Endoplasmic reticulum stress responses have evolved to be protective, however when they are ineffective, toxic damage occurs demonstrating how these responses can be described as a double edged sword. In this context, one of the most perplexing problems in modern biology is to understand how the cell "chooses" between adaptation and demise in response to stress. When one pathway becomes predominant, a delicate balance is perturbed and either an adaptive or a lethal response ensues. Understanding how the endoplasmic reticulum stress signals potentially play a role in directing a clinical outcome may lead to better prospects of more rational approaches to investigation and therapy for this liver disease.

Hereditary hemochromatosis should be considered a conformational disorder.

Hereditary hemochromatosis (HH) is a genetic disease associated with iron overload, in which individuals homozygous for the mutant C282Y HFE associated allele are at risk of developing liver disease, diabetes and arthritis. Conformational diseases are a class of disorders associated with the expression of misfolded protein and examples include conditions such as Alzheimer's, Parkinson's, Z alpha 1-antitrypsin deficiency and Huntington's diseases. HFE C282Y is a mutant protein that does not fold correctly forming aggregates and is retained in the Endoplasmic Reticulum (ER). Consequently, we propose that HH associated with the C282Y HFE mutation should be considered a conformational disorder.

The therapeutic properties of resminostat for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer with increases in new cases being reported annually. Histopathologists have identified hepatic steatosis as a characteristic of a broad range of chronic liver diseases that are associated with the onset and development of HCC. In this context, epigenetic modifications may serve as precancerous factors predisposing normal cells to the initiation of carcinogenesis. This study demonstrated that hepatic tumorigenesis and differentiated adipocytes may modulate both global histone deacetylase (HDAC) expression and specific class I HDAC genes in the tumour microenvironment. The novel class I HDAC inhibitor Resminostat was shown to reduce the proliferation of HCC cells along with its specificity in targeting class I HDACs and oncogenes. The combined effect of Resminostat with several pharmaceutical agents such as Sorafenib, Cisplatin and Doxorubicin was also demonstrated. The inhibition of heat shock protein 90 (HSP90) has been demonstrated as a potential therapeutic option for HCC. In line with this, the specific HSP90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) was selected and it was found that the combination of Resminostat and 17-AAG may provide a "smart" clinical strategy for HCC patients by targeting cellular communication within the tumour microenvironment. This study provides an insight into the use of Resminostat as an epigenetic based therapeutic for HCC along with other pharmaceutical options, in particular by targeting the cell-to-cell communication that occurs between hepatoma and adipocytes.

Expression of hereditary hemochromatosis C282Y HFE protein in HEK293 cells activates specific endoplasmic reticulum stress responses.

BACKGROUND: Hereditary Hemochromatosis (HH) is a genetic disease associated with iron overload, in which individuals homozygous for the mutant C282Y HFE associated allele are at risk for the development of a range of disorders particularly liver disease. Conformational diseases are a class of disorders associated with the expression of misfolded protein. HFE C282Y is a mutant protein that does not fold correctly and consequently is retained in the Endoplasmic Reticulum (ER). In this context, we sought to identify ER stress signals associated with mutant C282Y HFE protein expression, which may have a role in the molecular pathogenesis of HH. RESULTS: Vector constructs of Wild type HFE and Mutant C282Y HFE were made and transfected into HEK293 cell lines. We have shown that expression of C282Y HFE protein triggers both an unfolded protein response (UPR), as revealed by the increased GRP78, ATF6 and CHOP expression, and an ER overload response (EOR), as indicated by NF-kappaB activation. Furthermore, C282Y HFE protein induced apoptotic responses associated with activation of ER stress. Inhibition studies demonstrated that tauroursodeoxycholic acid, an endogenous bile acid, downregulates these events. Finally, we found that the co-existence of both C282Y HFE and Z alpha 1-antitrypsin protein (the protein associated with the liver disease of Z alpha 1-antitrypsin deficiency) expression on ER stress responses acted as potential disease modifiers with respect to each other. CONCLUSION: Our novel observations suggest that both the ER overload response (EOR) and the unfolded protein response (UPR) are activated by mutant C282Y HFE protein.

Z alpha1-antitrypsin polymerizes in the lung and acts as a neutrophil chemoattractant.

BACKGROUND: Alpha1-antitrypsin (A1AT) is an abundant protein that is synthesized in the liver and is secreted into the plasma. From the plasma, A1AT diffuses into various body compartments, including the lung where it provides much of the antiprotease protection. The current understanding of the pathogenesis of emphysema in A1AT-deficient individuals focuses on the polymerization of mutant protein within the liver, which results in a deficiency of circulating A1AT and a protease-antiprotease imbalance in the lungs. METHODS AND RESULTS: In this study, we evaluated BAL fluid samples from five healthy volunteers, five individuals with ZA1AT deficiency, and an individual with the PiZZ phenotype who had received a liver transplant. We show that the lung itself is a source of A1AT. In addition, the Z protein formed in the lung polymerizes, and these polymers are detectable in lung epithelial lining fluid by enzyme-linked immunosorbent assay and Western blot analysis. Finally, we show that polymeric ZA1AT is a potent neutrophil chemoattractant that is similar to polymerized MA1AT. CONCLUSIONS: Our findings suggest that the polymerization of locally produced ZA1AT is a contributory factor to the lung inflammation experienced by those with A1AT deficiency and that standard antiprotease therapies may not address this problem.

Long noncoding RNAs in liver cancer: what we know in 2014.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer with an estimated over half a million new cases diagnosed annually. Due to the difficulty in early diagnosis and lack of effective treatment options, HCC is currently ranked as the second highest neoplastic-related mortality in the world, with an extremely low 5-year survival rate of between 6 and 11%. Long noncoding RNAs (lncRNAs), are genes lacking protein coding ability, have recently emerged as pivotal participants in biological processes, often dysregulated in a range of cancers, including HCC. AREAS COVERED: In this review, we highlight the recent findings of lncRNAs in HCC pathogenesis, with particular attention on epigenetic events. In silico analysis was utilized to emphasize intrinsic linkages within the ncRNA families associated with hepatocarcinogenesis. EXPERT OPINION: While our understanding of lncRNAs in the onset and progression of HCC is still in its infancy, there is no doubt that understanding the activities of ncRNAs will certainly secure strong biomarkers and improve treatment options for HCC patients.

Greater trochanteric hip pain.

In the patient with lateral hip pain, there is a broad differential diagnosis, making appropriate evaluation and management challenging. Greater trochanteric pain syndrome is a term used to denote chronic lateral hip pain and encompasses several painful soft tissue diagnoses including coxa saltans, trochanteric bursitis, and gluteus minimus and medius tendon tears. An overview of these common causes is presented through a series of cases that encompass the anatomic associations, classic presentations, diagnostic tests, and management strategies unique to each disorder. By reviewing this information, we hope to provide clinicians with the tools to evaluate greater trochanteric pain syndrome efficiently and effectively.