C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor

The acute inflammatory response is frequently accompanied by serious thrombotic events. We show that C-reactive protein (CRP), an acute- phase reactant that markedly increases its serum concentration in response to inflammatory stimuli, induced monocytes to express tissue factor (TF), a potent procoagulant. Purified human CRP in concentrations commonly achieved in vivo during inflammation (10 to 100 micrograms/mL) induced a 75-fold increase in TF procoagulant activity (PCA) of human peripheral blood mononuclear cells (PBM), with a parallel increase in TF antigen levels. CRP-induced PCA was completely blocked by a monoclonal antibody against human TF but not by irrelevant murine IgG. Dot blot analysis showed a significant increase of TF mRNA after 4 hours of incubation with CRP, followed by a peak of PCA within 6 and 8 hours. Actinomycin D and cycloheximide blocked CRP-stimulated PCA, suggesting that de novo TF protein synthesis was required. Endotoxin (LPS) contamination of CRP was excluded as the mediator of TF synthesis because: (1) CRP was Limulus assay negative; (2) induction of TF PCA by CRP was not blocked by Polymyxin B, in contrast to LPS- induced PCA; (3) antihuman CRP IgG inhibited CRP-induced PCA, but not LPS-induced PCA; (4) CRP was able to stimulate TF production in LPS- pretreated PBM refractory to additional LPS stimulation; and, (5) unlike LPS, CRP was incapable of inducing TF in human umbilical vein endothelial cells. We suggest that CRP-mediated TF production in monocytes may contribute to the development of disseminated intravascular coagulation and thrombosis in inflammatory states.     

Long-term cardiopulmonary sequelae in patients with sleep apnea and chronic lung disease

Both obstructive sleep apnea and chronic lung disease can be associated with intermittent or chronic hypoxemia leading to pulmonary hypertension and cor pulmonale. When these problems coexist, it is possible that the cardiopulmonary effects are additive. We hypothesized that hemodynamic disturbances in patients with apnea and lung disease would be more severe than in those with apnea alone, and that hemodynamic improvement should follow apnea cure, but perhaps at a slower rate than in those with apnea alone. To test these hypotheses, we prospectively followed 24 patients with sleep apnea syndrome. They were divided into 3 nonrandomized groups. Nineteen patients had both apnea and lung disease. Nine of these agreed to curative tracheostomy (Group 1). The other 10 subjects (Group 2) refused tracheostomy but accepted noncurative therapies, including nocturnal oxygen (n = 9), uvulopalatopharyngoplasty (n = 2), and protriptyline (n = 4). Five subjects with apnea but without clinically obvious lung disease received tracheostomies (Group 3). Subjects were followed at yearly intervals (mean follow-up, 27.2 months) with radionuclide motion studies and, in 15 of 24 who consented, right heart catheterization. The 3 groups did not vary with respect to age, percent ideal weight, or severity of apnea symptoms. The severity of right-sided hemodynamic dysfunction in the group with apnea but no obvious lung disease was less than that in the 2 groups with lung disease. A substantial decrease in pulmonary artery pressure (p = 0.056) and significant improvement in right ventricular ejection fraction occurred in the tracheostomized group with both apnea and lung disease. Pulmonary vascular resistance decreased in both groups receiving tracheostomy.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Influence of Surgical Factors on Persisting Symptoms 3 Years after Esophageal Cancer Surgery: A Population-Based Study in Sweden

Background

Little is known about the long-term effects of surgical approach and type of anastomosis in the surgical treatment of esophageal cancer on patient-reported outcomes.

Methods

A Swedish nationwide, population-based cohort study included patients undergoing esophagectomy for esophageal cancer in 2001–2005. The predefined exposures included surgical approach (transhiatal or transthoracic) and anastomotic technique (hand-sewn or mechanical). The outcomes were esophageal-specific symptoms 3 years after the surgery. Symptoms were measured using the cancer-specific quality of life questionnaire, the QLQ-C30, supplemented by an esophageal cancer-specific module (QLQ-OES18), both developed by the European Organisation for Research and Treatment of Cancer. Logistic regression models were used to estimate relative risk, expressed as odds ratios (OR) with 95 % confidence intervals (CI), of experiencing symptoms as assessed by the questionnaires.

Results

Among the 178 included patients, there was an 84 % participation rate. No statistically significant differences were found regarding surgical approach. However, point estimates indicate that patients operated on with a transhiatal approach had a lower risk for symptoms of nausea and vomiting (OR = 0.5, 95 % CI 0.1–1.9), diarrhea (OR = 0.5, 95 % CI 0.2–1.8), and trouble swallowing (OR = 0.4, 95 % CI 0–3), and a slightly higher risk for loss of appetite (OR = 2, 95 % CI 0.7–5.6) compared with patients operated on with a transthoracic approach. Anastomotic technique did not seem to influence the risk for any of the selected symptoms.

Conclusions

Surgical approach and type of anastomosis do not seem to influence the risk of general and esophageal-specific cancer symptoms 3 years after surgery for esophageal cancer.     

Paediatric use of second-line anti-tuberculosis agents: a review

Childhood multidrug-resistant tuberculosis (MDR-TB) is an emerging global epidemic. With the imminent roll-out of rapid molecular diagnostic tests, more children are likely to be identified and require treatment. As MDR-TB is resistant to the most effective first-line drugs, clinicians will have to rely on second-line medications which are less effective and often associated with more pronounced adverse effects than first-line therapy. Despite the fact that most of these agents were discovered many years ago, robust information is lacking regarding their pharmacokinetic and pharmacodynamic properties, adverse effects and drug interactions, especially in children. Children differ from adults in the way that drugs are administered, the manner in which they are metabolised and in the adverse effects experienced. The interaction of these drugs with human immunodeficiency virus infection and antiretroviral therapy is also poorly documented. This article reviews the available second-line drugs currently used in the treatment of MDR-TB in children and discusses medication properties and adverse effects while potential interactions with antiretroviral therapy are explored.     

Hepatoprotective and cytoprotective properties of Hyptis suaveolens against oxidative stress–induced damage by CCl4 and H2O2

ObjectiveTo investigate capacity of Hyptis suaveolens (H. suaveolens) methanol extract as an antioxidant to protect against carbon tetrachloride (CCl₄)-induced oxidative stress, hepatotoxicity in Albino Wistar rats and cytoprotective effect of hydrogen peroxide (H₂O₂) induced cell death in HepG₂ cell line.MethodsTwo different doses of methanol extract of H. suaveolens were evaluated for the hepatoprotective activity against carbon tetrachloride (CCl₄) induced hepatotoxicity in rats. Animals in Group I: served as control, group II: H. suaveolens (100 mL/kg b.w), group III: H. suaveolens (50 mL/kg b.w) + CCl₄ (1 mg/kg), group IV: H. suaveolens (100 mL/kg b.w) + CCl₄ (1 mL/kg) and group V: CCl₄ (1 mL/kg). Histopathologic changes of liver were also evaluated. Cytotoxicity was also determined by 3, (4,5-dimethylthiazol-2-yl)2,5-diphenyl-tetrazolium bromide (MTT) assay.ResultsOral sigle dose treatment of CCl₄ produced a marked elevation in the serum levels of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and Lactate dehydrogenase (LDH). Histopathological analysis of the liver of CCl₄-induced rats revealed marked liver cell necrosis with inflammatory collections that were conformed to increase in the levels of SOD, GSH, GST, GR and LPO. Treatment with H₂O₂ significantly induced death of HepG₂ cell. Pretreatment with H. suaveolens methanol extract inhibited or attenuated H₂O₂ induced cytotoxicity.ConclusionsThis study shows that H. suaveolens methanol extract can be proposed to protect the liver against CCl₄-induced oxidative damage in rats and protect the cells against H₂O₂-induced oxidative damage in HepG₂ cells. The hepatoprotective and cytoprotective effects might be correlated with its antioxidant and free radical scavenger effects.     

Glucose‐dependent insulinotropic polypeptide signaling in pancreatic β‐cells and adipocytes

Glucose‐dependent insulinotropic polypeptide (GIP) was the first incretin to be identified. In addition to stimulating insulin secretion, GIP plays regulatory roles in the maintenance, growth and survival of pancreatic islets, as well as impacting on adipocyte function. The current review focuses on the intracellular signaling pathways by which GIP contributes to the regulation of β‐cell secretion and survival, and adipocyte differentiation and lipogenesis. Studies on signaling underlying the insulinotropic actions of the incretin hormones have largely been carried out with glucagon‐like peptide‐1. They have provided evidence for contributions by both protein kinase A (PKA) and exchange protein directly activated by cyclic adenosine monophosphate (EPAC2), and their probable role in GIP signaling is discussed. Recent studies have shown that inhibition of the kinase apoptosis signal‐regulating kinase 1 (ASK1) by GIP plays a key role in reducing mitochondria‐induced apoptosis in β‐cells through protein kinase B (PKB)‐mediated pathways, and that GIP‐induced post‐translational modification of voltage‐ dependent K⁺ (Kv) channels also contributes to its prosurvival role. Through regulation of gene expression, GIP tips the balance between pro‐ and anti‐apoptotic members of the B‐cell lymphoma‐2 (Bcl‐2) protein family towards β‐cell survival. GIP also plays important roles in the differentiation of pre‐adipocytes to adipocytes, and in the regulation of lipoprotein lipase expression and lipogenesis. These events involve interactions between GIP, insulin and resistin signaling pathways. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00196.x, 2012)