Efficacy of erzhu jiedu recipe on hepatitis B cirrhosis with hyperalphafetoproteinemia: A randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Hepatitis B cirrhosis with hyperalphafetoproteinemia is the intermediate stage of liver cirrhosis progressing to hepatocellular carcinoma (HCC), there is no effective way to treat precancerous lesions of liver in modern medicine. In recent decades, clinical and experimental evidence shows that Chinese medicine (CM) has a certain beneficial effect on Hepatitis B Cirrhosis. Therefore, this trial aims to evaluate the efficacy and safety of a CM erzhu jiedu recipe (EZJDR) for the treatment of Hepatitis B Cirrhosis with Hyperalphafetoproteinemia. METHODS: We designed a randomized, double blind, placebo-controlled clinical trial. A total of 72 patients of Hepatitis B Cirrhosis with hyperalphafetoproteinemia were randomized in 2 parallel groups. Patients in the control group received placebo granules similar to the EZJDR. In the EZJDR group, patients received EZJDR twice a day, after meals, for 48 weeks. The primary efficacy measures were changes in serum alpha-fetoprotein (AFP) and alpha-fetoprotein alloplasm (AFP-L3); The secondary indicators of efficacy are changes in liver function indicators, HBV-DNA level; Liver stiffness measurement (LSM); Hepatic portal vein diameter; T lymphocyte subgroup indexes during treatment. All data will be recorded in case report forms and analyzed by Statistical Analysis System software. Adverse events will also be evaluated. RESULTS: The results showed that EZJDR can significantly inhibit the levels of AFP and AFP-L3 in patients with hepatitis B cirrhosis and hyperalphafetoproteinemia and have good security. ETHICS AND DISSEMINATION: The study protocol was approved by the Medical Ethics Committee of Shuguang Hospital, affiliated with University of Traditional Chinese Medicine, Shanghai (NO.2018-579-08-01). TRIAL REGISTRATION: This trial was registered on Chinese Clinical Trial Center (NO.ChiCTR1800017165).

Traditional Chinese medicine on treating splenomegaly due to portal hypertension in cirrhosis: A protocol for systematic review and meta-analysis.

BACKGROUND: Liver cirrhosis is a common clinical chronic progressive disease. Due to the obstruction of blood flow after cirrhosis, it leads to long-term congestion of splenic sinus, hyperplasia of fibrous tissue and proliferation of splenic myeloid cells, resulting in hepatocirrhosis and splenomegaly. At present, western medicine still uses splenectomy and interventional therapy are the main treatment, but the adverse reactions are more and the curative effect is not good. Many clinical trials have proved that Traditional Chinese medicine has a great therapeutic effect on Hepatocirrhosis with splenomegaly, which can effectively delay the development of the disease and improve the survival rate of patients. This systematic review aims to evaluate the efficacy and safety of Traditional Chinese medicine in the treatment of hepatocirrhosis with splenomegaly. METHODS: The databases of Pubmed, CENTRAL (The Cochrane Central Register of Controlled Trials), China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform (WANFANG Data), Weipu Information Chinese Periodical Service Platform (VIP), and China Biomedical Literature Service System (SinoMed) will be searched online to collect randomized controlled trials related to the treatment of hepatocirrhosis with splenomegaly with Traditional Chinese medicine The time is limited from the construction of the library to November 2020. We will use the criteria provided by Cochrane 5.1.0 for quality assessment and risk assessment of the included studies, and use the Revman 5.3 and Stata 13.0 software so as to systematically review the effectiveness of Traditional Chinese medicine for hepatocirrhosis with splenomegaly. ETHICS AND DISSEMINATION: This systematic review will evaluate the efficacy and safety of Traditional Chinese medicine for hepatocirrhosis with splenomegaly. Because all data used in this systematic review and meta-analysis have been published, this review does not require ethical approval. In addition, all data will be analyzed anonymously during the review process. RESULTS: In this study, we will evaluate the efficacy of Traditional Chinese medicine in the treatment of cirrhosis with splenomegaly. CONCLUSION: The conclusion of this study will be evidence to ensure the efficacy of Traditional Chinese medicine© in the treatment of cirrhosis with splenomegaly and provide guidance for its treatment. TRIAL REGISTRATION NUMBER: INPLASY2020110121.

Successful treatment of refractory edema with traditional herbal medicine: A case report.

RATIONALE: Refractory edema is characterized by persistent swelling which does not react to diuretic use and sodium restriction. Traditional herbal medicine, Gwack Rhyung Tang and Chunggan extract effectively treated refractory lower limb edema caused by cirrhosis and improved liver function. PATIENT CONCERNS: A 64-year-old male patient with a history of hypertension, diabetes mellitus, hepatic encephalopathy, and cellulitis presented lower limb edema which did not react to diuretics for more than 7 months. DIAGNOSES: Refractory edema caused by cirrhosis. INTERVENTIONS: The patient was treated for 25 days using Gwack Rhyung Tang and Chunggan extract. OUTCOMES: Loss of body weight, decrease in circumferences of both lower limb and improvement of liver function biochemistry results are checked. There was no recurrence or aggravation of the condition up to 3 weeks of follow-up periods. LESSONS: Traditional herbal medicine can be an effective alternative for refractory edema due to cirrhosis with improving liver function.

Voltage during atrial fibrillation is superior to voltage during sinus rhythm in localizing areas of delayed enhancement on magnetic resonance imaging: An assessment of the posterior left atrium in patients with persistent atrial fibrillation.

BACKGROUND: Bipolar electrogram voltage during sinus rhythm (VSR) has been used as a surrogate for atrial fibrosis in guiding catheter ablation of persistent atrial fibrillation (AF), but the fixed rate and wavefront characteristics present during sinus rhythm may not accurately reflect underlying functional vulnerabilities responsible for AF maintenance. OBJECTIVE: The purpose of this study was determine whether, given adequate temporal sampling, the spatial distribution of mean AF voltage (VmAF) better correlates with delayed-enhancement magnetic resonance imaging (MRI-DE)-detected atrial fibrosis than VSR. METHODS: AF was mapped (8 seconds) during index ablation for persistent AF (20 patients) using a 20-pole catheter (660 ± 28 points/map). After cardioversion, VSR was mapped (557 ± 326 points/map). Electroanatomic and MRI-DE maps were co-registered in 14 patients. RESULTS: The time course of VmAF was assessed from 1-40 AF cycles (∼8 seconds) at 1113 locations. VmAF stabilized with sampling >4 seconds (mean voltage error 0.05 mV). Paired point analysis of VmAF from segments acquired 30 seconds apart (3667 sites; 15 patients) showed strong correlation (r = 0.95; P <.001). Delayed enhancement (DE) was assessed across the posterior left atrial (LA) wall, occupying 33% ± 13%. VmAF distributions were (median [IQR]) 0.21 [0.14-0.35] mV in DE vs 0.52 [0.34-0.77] mV in non-DE regions. VSR distributions were 1.34 [0.65-2.48] mV in DE vs 2.37 [1.27-3.97] mV in non-DE. VmAF threshold of 0.35 mV yielded sensitivity of 75% and specificity of 79% in detecting MRI-DE compared with 63% and 67%, respectively, for VSR (1.8-mV threshold). CONCLUSION: The correlation between low-voltage and posterior LA MRI-DE is significantly improved when acquired during AF vs sinus rhythm. With adequate sampling, mean AF voltage is a reproducible marker reflecting the functional response to the underlying persistent AF substrate.

Lipidomic and transcriptomic analysis of western diet-induced nonalcoholic steatohepatitis (NASH) in female Ldlr -/- mice.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, particularly in obese and type 2 diabetic individuals. NAFLD ranges in severity from benign steatosis to nonalcoholic steatohepatitis (NASH); and NASH can progress to cirrhosis, primary hepatocellular carcinoma (HCC) and liver failure. As such, NAFLD has emerged as a major public health concern. Herein, we used a lipidomic and transcriptomic approach to identify lipid markers associated with western diet (WD) induced NASH in female mice. METHODS: Female mice (low-density lipoprotein receptor null (Ldlr -/-) were fed a reference or WD diet for 38 and 46 weeks. Transcriptomic and lipidomic approaches, coupled with statistical analyses, were used to identify associations between major NASH markers and transcriptomic & lipidomic markers. RESULTS: The WD induced all major hallmarks of NASH in female Ldlr -/- mice, including steatosis (SFA, MUFA, MUFA-containing di- and triacylglycerols), inflammation (TNFα), oxidative stress (Ncf2), and fibrosis (Col1A). The WD also increased transcripts associated with membrane remodeling (LpCat), apoptosis & autophagy (Casp1, CtsS), hedgehog (Taz) & notch signaling (Hey1), epithelial-mesenchymal transition (S1004A) and cancer (Gpc3). WD feeding, however, suppressed the expression of the hedgehog inhibitory protein (Hhip), and enzymes involved in triglyceride catabolism (Tgh/Ces3, Ces1g), as well as the hepatic abundance of C18-22 PUFA-containing phosphoglycerolipids (GpCho, GpEtn, GpSer, GpIns). WD feeding also increased hepatic cyclooxygenase (Cox1 & 2) expression and pro-inflammatory ω6 PUFA-derived oxylipins (PGE2), as well as lipid markers of oxidative stress (8-iso-PGF2α). The WD suppressed the hepatic abundance of reparative oxylipins (19, 20-DiHDPA) as well as the expression of enzymes involved in fatty epoxide metabolism (Cyp2C, Ephx). CONCLUSION: WD-induced NASH in female Ldlr -/- mice was characterized by a massive increase in hepatic neutral and membrane lipids containing SFA and MUFA and a loss of C18-22 PUFA-containing membrane lipids. Moreover, the WD increased hepatic pro-inflammatory oxylipins and suppressed the hepatic abundance of reparative oxylipins. Such global changes in the type and abundance of hepatic lipids likely contributes to tissue remodeling and NASH severity.

Surgically Induced Necrotizing Scleritis Following Strabismus Surgery Treated Successfully with Topical N-acetylcysteine in a Child with Congenital Fibrosis of Extraocular Muscles and Varadi Papp Syndrome.

INTRODUCTION: Surgically induced necrotizing scleritis (SINS) is a rare but serious disorder that can develop many years after strabismus surgery. It is generally treated with high-dose steroids or immunosuppression. CASE REPORT: We describe a patient with Varadi Papp syndrome and congenital fibrosis of the extraocular muscles, who developed surgically induced necrotizing scleritis a month after strabismus surgery and was successfully managed by oral vitamin C and topical N-acetylcysteine 10%. DISCUSSION: While SINS is conventionally treated with steroids/immunosuppression, a conservative approach may be tried in milder cases. The role of topical N-acetylcysteine in managing this complication needs to be explored.

Evaluation of prepulse inhibition and memory impairments at early stage of cirrhosis may be considered as a diagnostic index for minimal hepatic encephalopathy.

Minimal hepatic encephalopathy (MHE), which represents the early stage of this condition, is not clinically apparent and is prevalent in up to 80% of patients. The poor outcomes of MHE encouraged us to identify more simple methods for early diagnosis of MHE. To this purpose, we evaluated the contemporary manifestations of motor, cognitive and sensorimotor gaiting deficits following bile duct-ligation (BDL). Male Wistar rats were undergone BDL to induce cirrhosis and locomotor, spatial learning and memory and sensorimotor gating were assessed 2, 3, and 4weeks after the operation by rotarod, Morris water-maze and prepulse inhibition (PPI) tests. PPI was examined 6weeks after BDL until appearance of hepatic encephalopathy. Results showed that although PPI was significantly enhanced in the 6-week BDL animals, locomotor activity reduced in 4-week BDL rats compared to the BDL rats after a 2-week period. The total distance travelled and swimming time to reach the platform increased in the 4-week BDL rats and, in contrast, the percentage of time spent and space travelled in correct quadrant decreased. Moreover, memory index decreased in the 3-week BDL group compared to sham-operated group. It was observed an increase in global PPI in 3- and 4-week BDL animals in comparison with either 2-week BDL or sham-operated rats. Consequently, it is indicated that BDL animals manifest spatial learning and memory deficits and PPI disruption in early stage of HE and evaluation of these factors can be considered as indices for simple and early diagnosis of MHE.

The protective effect of bee venom on fibrosis causing inflammatory diseases.

Bee venom therapy is a treatment modality that may be thousands of years old and involves the application of live bee stings to the patient's skin or, in more recent years, the injection of bee venom into the skin with a hypodermic needle. Studies have proven the effectiveness of bee venom in treating pathological conditions such as arthritis, pain and cancerous tumors. However, there has not been sufficient review to fully elucidate the cellular mechanisms of the anti-inflammatory effects of bee venom and its components. In this respect, the present study reviews current understanding of the mechanisms of the anti-inflammatory properties of bee venom and its components in the treatment of liver fibrosis, atherosclerosis and skin disease.

Role of prophylactic antibiotics in cirrhotic patients with variceal bleeding.

Bacterial infections are common in cirrhotic patients with acute variceal bleeding, occurring in 20% within 48 h. Outcomes including early rebleeding and failure to control bleeding are strongly associated with bacterial infection. However, mortality from variceal bleeding is largely determined by the severity of liver disease. Besides a higher Child-Pugh score, patients with hepatocellular carcinoma are particularly susceptible to infections. Despite several hypotheses that include increased use of instruments, greater risk of aspiration pneumonia and higher bacterial translocation, it remains debatable whether variceal bleeding results in infection or vice versa but studies suggest that antibiotic prophylaxis prior to endoscopy and up to 8 h is useful in reducing bacteremia and spontaneous bacterial peritonitis. Aerobic gram negative bacilli of enteric origin are most commonly isolated from cultures, but more recently, gram positives and quinolone-resistant organisms are increasingly seen, even though their clinical significance is unclear. Fluoroquinolones (including ciprofloxacin and norfloxacin) used for short term (7 d) have the most robust evidence and are recommended in most expert guidelines. Short term intravenous cephalosporin (especially ceftriaxone), given in a hospital setting with prevalent quinolone-resistant organisms, has been shown in studies to be beneficial, particularly in high risk patients with advanced cirrhosis.

Nutrição funcional no pós-operatório de cirurgia plástica: enfoque na prevenção de seroma e fibrose / Functional nutrition in postoperative plastic surgery: focus on seroma and fibrosis prevention

INTRODUÇÃO: Com base na grande variedade de possíveis sequelas e intercorrências de cirurgias estéticas e no papel da nutrição no processo de recuperação dessas, percebe-se a necessidade de práticas terapêuticas que garantam eficácia do resultado estético final. MÉTODO: O presente estudo caracteriza-se como uma revisão não sistemática que associou possíveis nutrientes, compostos bioativos e fitoterápicos que previnam ou amenizem seroma e fibrose no pós operatório. Para tanto, foram utilizados artigos de revistas científicas do meio eletrônico, legislações nacionais e livros didáticos, publicados entre os anos de 2002 e 2012. RESULTADOS: Demonstrou-se que as principais causas de seroma e fibrose são cicatrização alterada, inflamação, estresse oxidativo e edema. Dessa forma, foi elaborado um guia prático com os nutrientes, compostos bioativos e fitoterápicos que podem ser utilizados a fim de prevenir, controlar ou amenizar as complicações no pós-cirúrgico de procedimentos estéticos. CONCLUSÃO: Salientou-se que para o tratamento das condições abordadas é fundamental que haja um trabalho multiprofissional, enfatizando um acompanhamento médico, nutricional e fisioterápico que abranja as alterações conhecidas na fisiopatologia de seroma e fibrose.

INTRODUCTION: Based on the wide range of possible consequences and complications of plastic surgery and the role of nutrition in the recovery process of these, we see the need for therapeutic practices to ensure effectiveness of the final aesthetic result. METHOD: This study is characterized as a non-systematic review of the possible associated nutrients, bioactive compounds and herbal medicines to prevent seroma and fibrosis. Thus, we used scientific journal articles from electronic media, national laws and textbooks published between 2002 and 2012. RESULTS: We demonstrated that the main causes of seroma and fibrosis are changed healing, inflammation, oxidative stress and edema. Thus, we designed a practical guide with nutrients, bioactive compounds and herbal medicines that can be used to prevent, control or mitigate the complications after plastic surgery. CONCLUSION: It was emphasized that for the treatment of covered conditions is essential that there is a multidisciplinary approach, emphasizing a medical, nutritional and therapeutic monitoring covering the known changes in the pathophysiology of seroma and fibrosis.

Antiadhesive role of human amniotic fluid on peritoneal adhesion formation in a rat model. Experimental study.

OBJECTIVE: To determine the role of human amniotic fluid (HAF) in preventing or reducing postoperative adhesions. STUDY DESIGN: Uterine horn adhesion model was carried out in 24 female Wistar rats. The animals were randomized into 4 groups: (1) control, (2) Ringer's lactate, (3) whole HAF, and (4) HAF depleted from cells and proteins. Adhesion grade and histologic findings of adhesion-carrying tissues were evaluated and groups were compared according to these parameters. RESULTS: Rats treated with whole HAF had less adhesion grade when compared to the control group, but the difference was not statistically significant. On the other hand, centrifuged amniotic fluid treatment significantly reduced peritoneal adhesion grade, fibrosis and inflammation (p < 0.05). CONCLUSION: Whole HAF seems to have no beneficial effect on peritoneal adhesion formation, but HAF depleted of protein and cells does have a positive effect on reducing adhesion formation.

Motor vehicle accidents: how should cirrhotic patients be managed?

Motor vehicle accidents (MVAs) are serious social issues worldwide and driver illness is an important cause of MVAs. Minimal hepatic encephalopathy (MHE) is a complex cognitive dysfunction with attention deficit, which frequently occurs in cirrhotic patients independent of severity of liver disease. Although MHE is known as a risk factor for MVAs, the impact of diagnosis and treatment of MHE on MVA-related societal costs is largely unknown. Recently, Bajaj et al demonstrated valuable findings that the diagnosis of MHE by rapid screening using the inhibitory control test (ICT), and subsequent treatment with lactulose could substantially reduce the societal costs by preventing MVAs. Besides the ICT and lactulose, there are various diagnostic tools and therapeutic strategies for MHE. In this commentary, we discussed a current issue of diagnostic tools for MHE, including neuropsychological tests. We also discussed the advantages of the other therapeutic strategies for MHE, such as intake of a regular breakfast and coffee, and supplementation with zinc and branched chain amino acids, on the MVA-related societal costs.

A new candidate as a hemostatic agent for difficult situations during variceal bleeding: Ankaferd blood stopper.

Variceal bleeding is the most challenging emergent situation among the causes of upper gastrointestinal bleeding. Despite substantial improvement, a need remains for therapeutic armamentarium of such cases, which is easy, effective and without side-effect. Ankaferd blood stopper (ABS) is a standardized herbal extract acting as a hemostatic agent on the bleeding or injured areas. In this observational study, a total of four patients with variceal bleeding were treated with endoscopic ABS application. The lesions were bleeding gastric varices (n:3) and bleeding duodenal varix (n:1). ABS was selected as a bridge to definitive therapies due to unavailability or inappropriateness of bleeding lesions to conventional measures. ABS was instilled or flushed onto the bleeding areas by sclerotherotherapy needle or heater probe catheter. Periprocedural control of the bleeding was achieved in all instances. Thereafter, on an elective basis, two patients with gastric varices underwent cyanoacrylate injection, while third underwent Transjugular intrahepatic portosystemic shunt and embolization. The patient with duodenal varix refused further therapy, after a few hours after admission and was discharged. He again presented the same day with rebleeding, but died before any attempt could be made to control his bleeding. ABS seems to be effective in cases of variceal bleeding as a bridge to therapy. Its major advantages are the ease of use and lack of side-effects.

Drenagem linfática em paciente com dermatofibrose e flebite de membro inferior: relato de caso / Lymph drainage in patients with dermatofibrosis and phlebitis of the lower limb: case report

O presente estudo objetivou avaliar a drenagem linfática como forma coadjuvante de tratamento, em uma paciente idosa com dermatofibrose, flebite de membro inferior e queixa de dores na perna, localizada em região pós-flebítica. Foi realizado tratamento clínico inicial por três meses com drogas venotônicas (diosmin), anti-inflamatórios, analgésicos e repouso, porém com pouca melhora clínica. Foi, então, associada ao tratamento clínico, a drenagem linfática manual e mecânica. Os resultados obtidos incluíram a redução dos sintomas dolorosos e da hiperpigmentação do local acometido. Este trabalho sugere que a drenagem linfática obteve melhora do quadro clínico de paciente portadora de dermatofibrose, sugerindo novas pesquisas para caracterização mais específica dessa abordagem.

This study aimed at evaluating lymphatic drainage as a complementary form of treatment in an elderly patient with dermatofibrosis and phlebitis of the lower limb. The patient complained of pain in the post-phlebitic region. Initially three months of clinical treatment was performed using vasotonic(diosmine), anti-inflammatory and analgesic drugs and the patient was told to rest. However this treatment was not very effective. Manual and mechanical lymph drainage was associated to the clinical treatment. The results gave a significant improvement in the symptoms and the hyperpigmentation of the affected area. This study suggests that lymph drainage obtained improves the clinical of patient with dermatofibrosis, suggesting new research for more specific characterization of this approach.

Láser y otras fuentes de luz en el tratamiento de manchas en vino de Oporto / Laser treatment of Port wine stain

El tratamiento con láser de lesiones vasculares cutáneas está avanzando rápidamente en los últimos años. La mancha en vino de Oporto (Port wine stain [PWS]) es una de las primeras lesiones tratadas con láser con éxito. El láser de colorante pulsado (PDL) se ha desarrollado basándose en el concepto de la fototermólisis selectiva y ha supuesto una revolución en el tratamiento de PWS. Sin embargo, la respuesta obtenida es variable, alcanzándose un aclaramiento sustancial del color de la lesión tras varias sesiones. Diversos estudios demuestran que la modificación de parámetros del PDL como el aumento en la amplitud de pulso, mayor longitud de onda, o fluencias más altas asociadas a un sistema de enfriamiento, consiguen un aumento en la selectividad y mejoran la respuesta. Por otra parte, lesiones profundas, gruesas o sobreelevadas responden pobremente a los tratamientos convencionales. El objetivo de nuestro estudio es la revisión de los distintos tipos de láser así como otras fuentes de luz que se están desarrollando para el tratamiento de éstas y otras lesiones vasculares

Laser treatment of vascular skin lesions is rapidly improving. Port wine stain (PWS) is one of the first lesions successfully treated with laser. The pulsed dye laser (PDL) has been developed on the concept of selective photothermolysis and has revolutionized PWS treatment. Eventhough the response is variable, substantial blanching can be obtained after several sessions. Greater selectivity and better response have been achieved by modifying PDL parameters such as longer pulse width, longer wavelength, or higher energy fluencies with cooling skin devices. It is known that thick, deep or raised lesions present poor response to conventional treatments. The aim of this study is to review the different lasers and other light sources which are developing for the treatment of PWS and other vascular lesions

Attenuation of renal fibrosis by curcumin in rat obstructive nephropathy.

OBJECTIVES: To test whether curcumin has a protective action against interstitial inflammation and the development of renal fibrosis in obstructive nephropathy. We also tested whether inhibition of nuclear factor kappa-B (NF-kappaB) and activator protein-1 (AP-1) by curcumin is involved in these mechanisms. METHODS: Adult male rats underwent unilateral ureteral obstruction. The rats were treated with curcumin (200 mg/kg/day or 800 mg/kg/day), NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC; 200 mg/kg/day), or vehicle by gavage. Sham-operated rats served as controls. Seven days after unilateral ureteral obstruction, the activity of NF-kappaB and AP-1 was examined by electrophoretic mobility shift assay using nuclear protein extracts from the renal cortex. Gene expression of chemokines and pro-fibrotic molecules was determined by real-time reverse transcriptase-polymerase chain reaction. Macrophage infiltration and collagen III accumulation in the cortical interstitium was examined immunohistochemically. RESULTS: Both curcumin and PDTC significantly attenuated interstitial macrophage influx and renal fibrosis. Ureteral occlusion activated both NF-kappaB and AP-1-DNA binding. Curcumin and PDTC significantly inhibited NF-kappaB activity, but not AP-1. Gene expression of chemokines and pro-fibrotic molecules was upregulated in unilateral ureteral obstruction that was attenuated by either curcumin or PDTC. CONCLUSIONS: Curcumin protected against the renal interstitial inflammation and fibrosis elicited by ureteral occlusion. Inhibition of the NF-kappaB-dependent pathway is at least in part involved in the mechanisms, but AP-1 inhibition is unlikely to be involved in the beneficial effects of curcumin.

Dynamic nature of atrial fibrillation substrate during development and reversal of heart failure in dogs.

BACKGROUND: Clinical atrial fibrillation (AF) often results from pathologies that cause atrial structural remodeling. The reversibility of arrhythmogenic structural remodeling on removal of the underlying stimulus has not been studied systematically. METHODS AND RESULTS: Chronically instrumented dogs were subjected to 4 to 6 weeks of ventricular tachypacing (VTP; 220 to 240 bpm) to induce congestive heart failure (CHF), followed by a 5-week recovery period leading to hemodynamic normalization at 5-week recovery (Wk5(rec)). The duration of burst pacing-induced AF under ketamine/diazepam/isoflurane anesthesia increased progressively during VTP and recovered toward baseline during the recovery period, paralleling changes in atrial dimensions. However, even at full recovery, sustained AF could still be induced under relatively vagotonic morphine/chloralose anesthesia. Wk5(rec) dogs showed no recovery of CHF-induced atrial fibrosis (3.1+/-0.3% for controls versus 10.7+/-1.0% for CHF and 12.0+/-0.8% for Wk5(rec) dogs) or local conduction abnormalities (conduction heterogeneity index 1.8+/-0.1 in controls versus 2.3+/-0.1 in CHF and 2.2+/-0.2 in Wk5(rec) dogs). One week of atrial tachypacing failed to affect the right atrial effective refractory period significantly in CHF dogs but caused highly significant effective refractory period reductions and atrial vulnerability increases in Wk5(rec) dogs. CONCLUSIONS: Reversal of CHF is followed by normalized atrial function and decreased duration of AF; however, fibrosis and conduction abnormalities are not reversible, and a substrate that can support prolonged AF remains. Early intervention to prevent fixed structural abnormalities may be important in patients with conditions that predispose to the arrhythmia.

The protective effect of HD-03 in CCl4-induced hepatic encephalopathy in rats.

The liver is a major parenchymal organ involved in many functional activities in the body. Hepatic encephalopathy is a syndrome characterized by increased blood ammonia level and is one of the major complications of cirrhosis. In the present study the protective effect of HD-03, a poly-herbal formulation, was evaluated against CCl4-induced hepatic encephalopathy in rats. Hepatic encephalopathy was induced in Wistar rats by administration of CCl4 at a dose of 1 mL/kg orally in liquid paraffin (1:1) twice a week for 90 days. The liver enzymes (SGPT and SGOT) and blood ammonia levels were significantly (p < 0.001) higher in the CCl4-intoxicated group compared with the untreated control group. Administration of HD-03 at a dose of 750 mg/kg orally as an aqueous suspension significantly prevented the elevation of SGPT, SGOT and blood ammonia levels. Histomorphometric evaluation of liver and brain showed a protective effect of the HD-03 treatment, thus correlating with the changes in biochemical profiles. The protective effect of HD-03 against CCl4-induced encephalopathy may be due to the improved hepatocellular function, which in turn helps in regulating the metabolism of ammonia. However, further studies are required to measure the activity of enzymes involved in the urea cycle and brain aromatic amino acids in order to elucidate the exact mechanism of action of HD-03.

Chronic liver injury, TGF-beta, and cancer.

Cells termed myofibroblasts are prominent in the injury response of all epithelial tissues. They exhibit proliferation, migration, production of collagen and other extracellular matrix (ECM) molecules, and contraction, all for containing the injury and closing the wound. When the injury is limited in time, the final stage of the repair involves a dismantling of the cellular apparatus and restoration of normal tissue structure. With multiple cycles of repair, however, there is net accumulation of ECM, to the detriment of tissue structure and function. Repair-related ECM coalesces into fibrous bundles and, over time, undergoes changes that render it resistant to degradation. The result is a scar. In the skin, a scar may have cosmetic importance only. In the liver, however, extensive scarring is the setting for unregulated growth and neoplasia; also, fibrous bands disrupt normal blood flow, leading to portal hypertension and its complications. With regard to therapy for fibrosis, the first consideration is elimination of the injury factor. However, given that many liver diseases do not have effective therapies at present, strategies targeting fibrogenesis per se are under development. The main source of myofibroblast-like cells and ECM production in the liver is the perisinusoidal stellate cell, which responds to injury with a pleiotypic change termed activation. Activation is orchestrated by cytokines and the ECM itself. Among the cytokines involved in this process, transforming growth factor-beta (TGF-beta) is particularly prominent. The early changes in ECM include de novo production of a specific "fetal" isoform of fibronectin, which arises from sinusoidal endothelial cells. It is stimulated by TGF-beta and acts directly on stellate cells to promote their activation. Based on these and other advances in understanding the fundamentals of the injury response, several strategies now exist for altering fibrogenesis, ranging from agents that block TGF-beta to traditional Chinese herbal extracts. Arrest of fibrogenesis, even with underlying cirrhosis, is likely to extend life or prolong the time to transplant. Whether it reduces the risk of hepatocellular carcinoma remains to be proven. Although TGF-beta antagonists are effective anti-fibrogenic agents, they will require detailed safety testing because of the finding that several forms of epithelial neoplasia are associated with altered regulation of TGF-beta.

Chronic liver injury, TGF-beta, and cancer

Cells termed myofibroblasts are prominent in the injury response of all epithelial tissues. They exhibit proliferation, migration, production of collagen and other extracellular matrix (ECM) molecules, and contraction, all for containing the injury and closing the wound. When the injury is limited in time, the final stage of the repair involves a dismantling of the cellular apparatus and restoration of normal tissue structure. With multiple cycles of repair, however, there is net accumulation of ECM, to the detriment of tissue structure and function. Repair-related ECM coalesces into fibrous bundles and, over time, undergoes changes that render it resistant to degradation. The result is a scar. In the skin, a scar may have cosmetic importance only. In the liver, however, extensive scarring is the setting for unregulated growth and neoplasia; also, fibrous bands disrupt normal blood flow, leading to portal hypertension and its complications. With regard to therapy for fibrosis, the first consideration is elimination of the injury factor. However, given that many liver diseases do not have effective therapies at present, strategies targeting fibrogenesis per se are under development. The main source of myofibroblast-like cells and ECM production in the liver is the perisinusoidal stellate cell, which responds to injury with a pleiotypic change termed activation. Activation is orchestrated by cytokines and the ECM itself. Among the cytokines involved in this process, transforming growth factor-beta (TGF-beta) is particularly prominent. The early changes in ECM include de novo production of a specific "fetal" isoform of fibronectin, which arises from sinusoidal endothelial cells. It is stimulated by TGF-beta and acts directly on stellate cells to promote their activation. Based on these and other advances in understanding the fundamentals of the injury response, several strategies now exist for altering fibrogenesis, ranging from agents that block TGF-beta to traditional Chinese herbal extracts. Arrest of fibrogenesis, even with underlying cirrhosis, is likely to extend life or prolong the time to transplant. Whether it reduces the risk of hepatocellular carcinoma remains to be proven. Although TGF-beta antagonists are effective anti-fibrogenic agents, they will require detailed safety testing because of the finding that several forms of epithelial neoplasia are associated with altered regulation of TGF-beta.