Home About us Contact
|
Home About us Contact | ||
|
|
||
Current Therapies (current + therapy)
Selected AbstractsNaphthoquinones and bioactive compounds from tobacco as modulators of neuronal nitric oxide synthase activityPHYTOTHERAPY RESEARCH, Issue 12 2009Priya Venkatakrishnan Abstract Studies were conducted with extracts of several varieties of tobacco in search of neuronal nitric oxide synthase (nNOS) inhibitors which may be of value in the treatment of stroke. Current therapies do not directly exploit modulation of nNOS activity due to poor selectivity of the currently available nNOS inhibitors. The properties of a potentially novel nNOS inhibitor(s) derived from tobacco extracts, and the concentration-dependent, modulatory effects of the tobacco-derived naphthoquinone compound, 2,3,6-trimethyl-1,4-naphthoquinone (TMN), on nNOS activity were investigated, using 2-methyl-1,4-naphthoquinone (menadione) as a control. Up to 31 µM, both TMN and menadione stimulated nNOS-catalysed l -citrulline production. However, at higher concentrations of TMN (62.5,500 µM), the stimulation was lost in a concentration-dependent manner. With TMN, the loss of stimulation did not decrease beyond the control activity. With menadione (62.5,500 µM), the loss of stimulation surpassed that of the control (78 ± 0.01% of control activity), indicating a true inhibition of nNOS activity. This study suggests that potential nNOS inhibitors are present in tobacco, most of which remain to be identified. Copyright © 2009 John Wiley & Sons, Ltd. [source] Costs of caring for a child with cancer: a questionnaire surveyCHILD: CARE, HEALTH AND DEVELOPMENT, Issue 4 2007C. Eiser Abstract Background Current therapies for childhood cancer have resulted in improved survival rates. However, this has been achieved at considerable price to families, with financial costs including additional expenditure and loss of earnings having been described. The impact of these extra costs for UK families and the extent to which help from charities and government benefits is able to alleviate this is unknown. Methods Questionnaires concerning income, expenditure, employment and financial support were completed by 145 parents, recruited from three United Kingdom Children's Cancer Study Group treatment centres. Results Parents' responses highlighted increased expenditure related mainly to travel to treatment centres. The majority of families (55%) had spent between Ł50,100 in the past week over and above pre-illness expenditure, with a further 18% spending more than Ł100. Many parents (mainly mothers) had either given up or reduced outside employment in order to care for their child and this was associated with further financial problems for 42.7% of families. Despite help from charities and government benefits for the majority of families, extra costs were associated with money worries for 68.3% of families. Conclusions Although families are offered timely information about their entitlement to benefits, financial problems are incurred by families of a child with cancer partly because legislation prevents benefits being claimed for the first 3 months of a child's illness , the time when expenses are still at their highest. Furthermore, because benefits are backdated only to the point at which the claim was made, families do not recoup all their costs. Waiving of the 84-day wait period for children undergoing chemotherapy and radiotherapy, and the introduction of weekly bridging payments while a Disability Living Allowance claim is being assessed, would ameliorate this problem and so improve the treatment experience for families. [source] Opposite effect of fluticasone and salmeterol on fibronectin and tenascin-C expression in primary human lung fibroblastsCLINICAL & EXPERIMENTAL ALLERGY, Issue 5 2009M. Degen Summary Background Airway remodelling is a key feature of asthma and chronic obstructive pulmonary disease (COPD). The remodelling process involves the deposition of extracellular matrix (ECM) proteins within the airways. Current therapies for asthma and COPD consist of inhaled corticosteroids and long-acting ,2 -agonists (LABA). However, their effect on airway remodelling is not well understood so far. Objective In this study we investigated the effect of fluticasone and salmeterol, either alone or in combination, on fibronectin and tenascin-C protein, isoform, and mRNA levels in primary human lung fibroblasts. Methods In our model, fibroblasts cultured in serum-free medium represented a non-inflammatory condition and stimulation with 5% fetal calf serum and/or TGF-,1 mimicked a pro-fibrotic environment with activation of tissue repair. Using these two different conditions, the effects of fluticasone and salmeterol on fibronectin and tenascin-C protein and mRNA levels were analysed by immunoblotting and semi-quantitative RT-PCR. Results In both conditions, fluticasone increased fibronectin transcript and protein levels, whereas it decreased those of tenascin-C. Salmeterol neither affected fibronectin and tenascin-C synthesis significantly nor did it influence the effect of fluticasone when applied in combination. Furthermore, we found that treatment with fluticasone had an opposite effect on extra domain A and B containing fibronectin isoforms generated by alternative splicing compared with total fibronectin transcript levels, whereas tenascin-C isoforms were not differently modulated by fluticasone. Conclusions Our results indicate that standard therapies for inflammatory lung disorders influence ECM protein composition and relative expression levels. In contrast to corticosteroids, LABA did not significantly alter the expression of tenascin-C and fibronectin in cultures of primary human lung fibroblasts. [source] Recent advances in the management and prophylaxis of respiratory syncytial virus infectionACTA PAEDIATRICA, Issue 2001A Greenough Respiratory syncytial virus (RSV) infection is an important cause of morbidity, particularly in prematurely born infants who have had chronic lung disease. Current therapy is essentially supportive. Overall, the results of randomized trials do not support the use of bronchodilators, corticosteroids or Ribavirin. Nitric oxide and exogenous surfactant may improve the respiratory status of those infants who require ventilatory support. Nosocomial infection can be reduced by appropriate handwashing. There is no safe and effective vaccine for use in infants. Immunoprophylaxis reduces hospitalization and requirement for intensive care. Palivizumab, a humanized monoclonal antibody, is preferred to RSV immune globulin as the immunoprophylactic agent. Immunoprophylaxis should be reserved for infants at highest risk of severe respiratory syncytial virus infection, if this strategy is to be used most cost-effectively. [source] Current therapy of HIVJOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, Issue 1 2010Anja Verena Potthoff Summary Antiretroviral therapy has improved continuously. Almost every year a new drug has been approved. Nucleoside analogs still build the backbone of antiretroviral therapy. They inhibit reverse transcriptase and thus the transcription of RNA to DNA. They are combined with non-nucleoside reverse transcriptase inhibitors or protease inhibitors. New therapeutic approaches are attachment or entry inhibitors, integrase inhibitors and maturation inhibitors. Multiple prospective multicenter studies have proven the life prolonging effect of antiretroviral therapy. With the optimal therapy life expectancy of HIV patients is only slightly reduced, similar to that of those with chronic diseases such as diabetes mellitus. One result of the higher age of HIV patients is an increase in concomitant diseases and medications. Drug interactions have to be considered and avoided. There has been a long discussion about the best time point to start antiretroviral therapy. In the late 1990s, every infected patient was treated hoping to eliminate the virus, ignoring the CD4+ cell count and viral load. This caused multiple (long-term) side effects and a rising resistance problem. The guidelines now recommend starting therapy at about 350/,l CD4 lymphocytes. Due to its complexity antiretroviral therapy should be initiated and monitored in specialized centers. [source] The chemokine system and CCR5 antagonists: potential in HIV treatment and other novel therapiesJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 2 2009H. Dhami PharmD (Student) Summary Since the recognition of human acquired immune deficiency syndrome, numerous classes of pharmacologic therapeutics have been developed to manage the disease. Current therapy includes co-administration of combinations of drugs classified by their mechanism of action as ,transcriptase inhibitors', ,protease inhibitors', ,integrase inhibitors' and the more recent ,fusion inhibitors'. This review focuses on the chemokine system and the recognition of chemokine receptors as targets for anti-human immunodeficiency virus (HIV) therapy. The FDA-approved chemokine (C,C motif) receptor 5 (CCR5) antagonist maraviroc (Selzentry®) is discussed in detail, along with another compound vicriviroc, currently in clinical trials. The mechanism of action, pharmacokinetics, toxicity and current status of research on CCR5 antagonists is described. Further, potential therapeutic uses of these agents other than anti-HIV therapy are discussed. [source] Review article: diagnosis and treatment of non-alcoholic fatty liver diseaseALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2008M. K. OH Summary Background, Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent condition affecting adults and children, leading to significant morbidity. It is often associated with the metabolic syndrome, although multiple pathogenetic mechanisms have been suggested. In the coming decades, it promises to be the leading cause of liver disease in industrial countries. Aim, To provide a comprehensive, updated review of diagnosis and management of NAFLD and to appraise the evolution of new modalities in these areas. Methods, An Ovid MEDLINE search was performed to identify pertinent original research and review articles. Selected references in these articles were also evaluated. Results, The diagnosis of hepatic steatosis and steatohepatitis or non-alcoholic steatohepatitis (NASH) is not yet possible without liver biopsy. This is impractical given the large numbers affected by the condition. Current therapy has focused on improving insulin resistance and mediators of inflammation, factors probably associated with disease progression. Conclusions, There are no proven non-invasive diagnostic modalities to distinguish NAFLD and NASH, but new biomarker panels are approximating the liver biopsy in accuracy. Therapeutic targets of drug development are in early stages, but a multifaceted approach will probably yield several treatment options in the years to come. [source] Treating nonalcoholic fatty liver diseaseLIVER INTERNATIONAL, Issue 9 2007Nahum Méndez-Sánchez Abstract Nonalcoholic fatty liver disease (NAFLD) is a chronic illness with multiple consequences. The spectrum of disease ranges from simple steatosis, with benign prognosis, to a potentially progressive form, nonalcoholic steatohepatitis, which may lead to liver fibrosis and cirrhosis, leading to an increase in morbidity and mortality. Furthermore, hepatocellular carcinoma incidence in NAFLD is comparable with that observed in hepatitis C-infected patients once cirrhosis is established. Current therapy is limited to lifestyle changes and control of associated metabolic disorders; however, new treatments are on the way from basic research to bedside. A review of the current literature on treatment of nonalcoholic fatty liver disease is presented in this article. [source] Tagatose, a new antidiabetic and obesity control drugDIABETES OBESITY & METABOLISM, Issue 2 2008Y. Lu A potentially important new drug for treating type 2 diabetes, tagatose, is now in phase 3 clinical trial. The history, development, additional health benefits, mechanisms of action and the potential for the drug are presented in context with a review of the rapidly growing epidemic of type 2 diabetes and treatments for it. An epimer of fructose, the natural hexose tagatose was originally developed by Spherix Incorporated (formerly Biospherics Inc.) as a low-calorie sugar substitute. Only 20% of orally ingested tagatose is fully metabolized, principally in the liver, following a metabolic pathway identical to that of fructose. Following a decade of studies, tagatose became generally recognized as safe for use in foods and beverages under US FDA regulation. The simple sugar is commercially produced by isomerization of galactose, which is prepared from lactose. Early human studies suggested tagatose as a potential antidiabetic drug through its beneficial effects on postprandial hyperglycaemia and hyperinsulinaemia. A subsequent 14-month trial confirmed its potential for treating type 2 diabetes, and tagatose showed promise for inducing weight loss and raising high-density lipoprotein cholesterol, both important to the control of diabetes and constituting benefits independent of the disease. Furthermore, tagatose was shown to be an antioxidant and a prebiotic, both properties cited in the maintenance and promotion of health. No current therapies for type 2 diabetes provide these multiple health benefits. The predominant side effects of tagatose are gastrointestinal disturbances associated with excessive consumption, generally accommodated within 1- to 2-week period. The health and use potentials for tagatose (branded Naturlose® for this use) are given with respect to current type 2 diabetes drugs and markets. Under an FDA-affirmed protocol, Spherix is currently conducting a phase 3 trial to evaluate a placebo-subtracted treatment effect based on a decrease in HbA1c levels. Side effects, contraindications and possibly beneficial new findings will be carefully monitored. It is hoped that early results of the trial may become available by mid-2008. If a subsequent NDA is successful, tagatose may fill a major health need. [source] Incretins and other peptides in the treatment of diabetesDIABETIC MEDICINE, Issue 3 2007J. F. Todd Abstract Glucagon-like peptide-1 (7-36) amide (GLP-1) is a gut hormone, released postprandially, which stimulates insulin secretion and insulin gene expression as well as pancreatic B-cell growth. Together with glucose-dependent insulinotropic polypeptide (GIP), it is responsible for the incretin effect which is the augmentation of insulin secretion following oral administration of glucose. Patients with Type 2 diabetes have greatly impaired or absent incretin-mediated insulin secretion which is mainly as a result of decreased secretion of GLP-1. However, the insulinotropic action of GLP-1 is preserved in patients with Type 2 diabetes, and this has encouraged attempts to treat Type 2 diabetic patients with GLP-1. GLP-1 also possesses a number of potential advantages over existing agents for the treatment of Type 2 diabetes. In addition to stimulating insulin secretion and promoting pancreatic B-cell mass, GLP-1 suppresses glucagon secretion, delays gastric emptying and inhibits food intake. Continuous intravenous and subcutaneous administration significantly improves glycaemic control and causes reductions in both HbA1c and body weight. However, GLP-1 is metabolized extremely rapidly in the circulation by the enzyme dipeptidyl peptidase IV (DPP-IV). This is the probable explanation for the short-lived effect of single doses of native GLP-1, making it an unlikely glucose-lowering agent. The DPP-IV resistant analogue, exenatide, has Food and Drug Administration (FDA) approval for the treatment of Type 2 diabetes and selective DPP-IV inhibitors are under development. Both approaches have demonstrated remarkable efficacy in animal models and human clinical studies. Both are well tolerated and appear to have advantages over current therapies for Type 2 diabetes, particularly in terms of the effects on pancreatic B-cell restoration and potential weight loss. [source] Cancer of the esophagus and gastric cardia: recent advances,DISEASES OF THE ESOPHAGUS, Issue 1 2004G. N. J. Tytgat SUMMARY., Esophageal cancer and cancer of the gastric cardia, in particular adenocarcinomas, have shown a rapid and largely unexplained increase in incidence in many developed countries around the world. These diseases have a poor prognosis and current therapies have a modest impact on survival. This review presents recent advances in the epidemiology, etiology, diagnosis, staging, prevention and treatment of resectable and advanced disease. Although significant progress has been made in these areas of research and patient management over the past years, prognosis for most patients diagnosed with esophageal cancer or cancer of the gastric cardia remains poor. New diagnostic procedures, improved surgical procedures, combined treatment modalities and new treatment modalities are being evaluated and may be expected to contribute to improved patient outcomes and better palliation of symptoms in the future. [source] Glycolipid receptor depletion as an approach to specific antimicrobial therapyFEMS MICROBIOLOGY LETTERS, Issue 1 2006Majlis Svensson Abstract Mucosal pathogens recognize glycoconjugate receptors at the site of infection, and attachment is an essential first step in disease pathogenesis. Inhibition of attachment may prevent disease, and several approaches have been explored. This review discusses the prevention of bacterial attachment and disease by agents that modify the glycosylation of cell surface glycoconjugates. Glycosylation inhibitors were tested in the urinary tract infection model, where P-fimbriated Escherichia coli rely on glycosphingolipid receptors for attachment and tissue attack. N -butyldeoxynojirimycin blocked the expression of glucosylceramide-derived glycosphingolipids and attachment was reduced. Bacterial persistence in the kidneys was impaired and the inflammatory response was abrogated. N -butyldeoxynojirimycin was inactive against strains which failed to engage these receptors, including type 1 fimbriated or nonadhesive strains. In vivo attachment has been successfully prevented by soluble receptor analogues, but there is little clinical experience of such inhibitors. Large-scale synthesis of complex carbohydrates, which could be used as attachment inhibitors, remains a technical challenge. Antibodies to bacterial lectins involved in attachment may be efficient inhibitors, and fimbrial vaccines have been developed. Glycosylation inhibitors have been shown to be safe and efficient in patients with lipid storage disease and might therefore be tested in urinary tract infection. This approach differs from current therapies, including antibiotics, in that it targets the pathogens which recognize these receptors. [source] Endpoints of therapy in chronic hepatitis B,HEPATOLOGY, Issue S5 2009Jordan J. Feld Because clearance of hepatitis B virus (HBV) infection is rarely, if ever, achievable, the goals of therapy necessarily focus on prevention of bad clinical outcomes. Ideally, therapies would be shown to prevent tangible clinical endpoints like development of cirrhosis, end-stage liver disease and hepatocellular carcinoma. However, these endpoints typically take years or decades to occur and are therefore impractical targets for clinical trials which last only 1-2 years. As a result, surrogate biomarkers that are believed to correlate with long-term outcome are used to evaluate therapy. Of the clinical, biochemical, serological, virological, and histological endpoints that have been evaluated, none has been shown to be ideal on its own. Symptoms are uncommon and aminotransferase levels fluctuate spontaneously. Loss of hepatitis B e antigen (HBeAg) has been the traditional therapeutic endpoint; however, the indefinite durability off treatment and the emergence of HBeAg-negative disease have made it inadequate as the sole goal of therapy. Loss of hepatitis B surface antigen is associated with improved clinical outcomes, but it is rarely achieved with current therapies. Suppression of viral replication, as measured by serum HBV DNA levels, has become the major goal of therapy, particularly if maintained off therapy. Although useful, the significance of viral levels depends on the stage of disease, degree of liver damage, and the type of therapy. Finally, liver biopsy, often considered the gold standard, is invasive, prone to sampling error, and may take years to change significantly. At present, there is no ideal biomarker for evaluation of therapies for hepatitis B. Future research should be directed at development and validation of surrogate markers that accurately predict or reflect clinically relevant outcomes of chronic hepatitis B. (HEPATOLOGY 2009;49:S96,S102.) [source] Surprises from the crystal structure of the hepatitis C virus NS2-3 protease,HEPATOLOGY, Issue 6 2006Jerome Gouttenoire Ph.D. Hepatitis C virus is a major global health problem affecting an estimated 170 million people worldwide. Chronic infection is common and can lead to cirrhosis and liver cancer. There is no vaccine available and current therapies have met with limited success. The viral RNA genome encodes a polyprotein that includes 2 proteases essential for virus replication. The NS2-3 protease mediates a single cleavage at the NS2/NS3 junction, whereas the NS3-4A protease cleaves at 4 downstream sites in the polyprotein. NS3-4A is characterized as a serine protease with a chymotrypsin-like fold, but the enzymatic mechanism of the NS2-3 protease remains unresolved. Here, we report the crystal structure of the catalytic domain of the NS2-3 protease at 2.3 Ĺ resolution. The structure reveals a dimeric cysteine protease with 2 composite active sites. For each active site, the catalytic histidine and glutamate residues are contributed by one monomer, and the nucleophilic cysteine by the other. The carboxy-terminal residues remain coordinated in the 2 active sites, predicting an inactive postcleavage form. Proteolysis through formation of a composite active site occurs in the context of the viral polyprotein expressed in mammalian cells. These features offer unexpected insights into polyprotein processing by hepatitis C virus and new opportunities for antiviral drug design. [source] Lack of association of antineutrophil cytoplasmic antibodies with joint failure as indicated by joint surgery in rheumatoid arthritisINTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 1 2005Andrew BROADFOOT Abstract Aim:, The objective of this study was to investigate a possible association in rheumatoid arthritis (RA) of perinuclear antineutrophil cytoplasmic antibodies (pANCA) and joint failure requiring joint surgery as a well-defined functional end point. Methods:, 188 patients with RA according to the American College of Rheumatology criteria, with a mean duration of disease of 18 years, were enrolled in a cross-sectional study. Patients were assessed for history of joint surgery, previous/current therapies, function according to the modified Health Assessment Questionnaire (mHAQ), rheumatoid factor (RF) and clinical and laboratory parameters of disease activity. ANCA were detected using indirect immunofluorescence. Results:, Overall, 36.7% of patients were pANCA positive (including atypical pANCA) and 35.1% of patients had a history of joint surgery. There was no association between the presence of pANCA and joint surgery. No association was demonstrated between ANCA status and other prognostic markers such as RF, previous or current therapies and disease activity or function. Conclusion:, No association between pANCA and joint surgery was demonstrated in this cohort of RA patients. [source] Helicobacter pylori as a class I carcinogen: Physiopathology and management strategiesJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2007Paraskevi Vogiatzi Abstract The gram-negative bacterium Helicobacter pylori is known as a persistent colonizer of the human stomach, and probably less known is that it is also involved in extraintestinal diseases. Public awareness of its contribution in the development of gastric cancer is less than 15 years old. The efficacy of the current therapies based on antibiotics against H. pylori has been limited by difficulties such as antibiotic resistance and recurrence. As a consequence, the development of promising vaccines was prompted as the best preventive measure. Unfortunately, so far vaccines failed the transition from animal models to human trials. This keynote presentation is to provide a bird's eye view of H. pylori -related gastric diseases, including gastric cancer, with a synthesis of the molecular mechanisms involved, and an exhaustive presentation and discussion of the current therapeutic guidelines and future strategies for prevention or therapy. J. Cell. Biochem. 102: 264,273, 2007. © 2007 Wiley-Liss, Inc. [source] Balneo-Phototherapy: A New Holistic Approach To Treating PsoriasisJOURNAL OF THE AMERICAN ACADEMY OF NURSE PRACTITIONERS, Issue 6 2003Colleen Mikula ANP-C Purpose To present and describe a new holistic therapy for the treatment of psoriasis and demonstrate its outcomes through a case study presentation. Data Sources Selected scientific literature and patient case study. Conclusion Balneo-phototherapy, though new to the United States, has effective, safe outcomes as a new holistic treatment for psoriasis. Implications for Practice Nurse practitioners (NPs) and patients have an additional choice in psoriasis treatment that provides efficacious outcomes with fewer side effects compared to current therapies. [source] Non-ablative 1,550,nm fractional laser therapy versus triple topical therapy for the treatment of melasma: A randomized controlled split-face study,,LASERS IN SURGERY AND MEDICINE, Issue 7 2010Bas S. Wind MD Abstract Background Melasma is a uichronic, often relapsing skin disorder, with poor long-term results from all current therapies. Objective To assess efficacy and safety of non-ablative 1,550,nm fractional laser therapy (FLT) as compared to the gold standard, triple topical therapy (TTT). Study design Twenty-nine patients with melasma were included in a randomized controlled observer-blinded study with split-face design. Each side of the face was randomly allocated to either 4,5 non-ablative FLT sessions (15,mJ/microbeam, 14,20% coverage) or TTT (hydroquinone 5%, tretinoin 0.05%, triamcinolone acetonide 0.1% cream). TTT was applied once daily for 15 weeks until the last FLT session. After this last treatment, patients were asked to apply TTT twice weekly on both sides of the face during follow-up. Improvement of melasma was assessed by patient's global assessment (PGA), patient's satisfaction, physician's global assessment (PhGA), melanin index, and lightness (L -value) at 3 weeks, and at 3 and 6 months after the last treatment. Results Mean PGA and satisfaction were significantly lower at the FLT side (P<0.001). PhGA, melanin index, and L -value showed a significant worsening of hyperpigmentation at the FLT side. At the TTT side, no significant change was observed. At 6 months follow-up, most patients preferred TTT. Side effects of FLT were erythema, burning sensation, edema, and pain. Nine patients (31%) developed PIH after two or more laser sessions. Side effects of TTT were erythema, burning sensation, and scaling. Conclusions Given the high rate of postinflammatory hyperpigmentation, non-ablative 1,550,nm fractional laser at 15,mJ/microbeam is not recommendable in the treatment of melasma. TTT remains the gold standard treatment. Lasers Surg. Med. 42:607,612, 2010. © 2010 Wiley-Liss, Inc. [source] Decreasing incidence of hepatocellular carcinoma among children following universal hepatitis B immunizationLIVER INTERNATIONAL, Issue 5 2003Mei-Hwei Chang Abstract: Hepatocellular carcinoma (HCC) is one of the 10 most common malignant tumors worldwide. Chronic infection with hepatitis B or C virus is closely related to hepatocarcinogenesis. The outcome of current therapies for HCC is not satisfactory. Prevention is the best way to control HCC. Among the various strategies of HCC prevention, immunization against hepatitis B virus infection is the most effective. Universal hepatitis B immunization has proved to be effective in reducing the incidence of HCC to 1/4,1/3 of that in children born before the hepatitis B vaccination era in Taiwan. The problems we face in achieving global control of hepatitis-related HCC include: (1) no effective vaccine for the prevention of hepatitis C and its related HCC; (2) no immunization program for hepatitis B in areas with inadequate resources; (3) poor compliance to the immunization program as a result of ignorance, anxiety, or poverty; and (4) vaccine failure. Integration of the hepatitis B vaccination program into the expanded program of immunization for all infants throughout the world will be most urgent and important for HCC control. The reduction of the incidence of HCC will be seen in adults 30,40 years of age after the launch of the universal hepatitis B vaccination program. This concept of cancer vaccine can be applied to other infectious agents and their related cancers. [source] Competitive AMPA receptor antagonistsMEDICINAL RESEARCH REVIEWS, Issue 2 2007Daniela Catarzi Abstract Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) where it is involved in the physiological regulation of different processes. It has been well established that excessive endogenous Glu is associated with many acute and chronic neurodegenerative disorders such as cerebral ischaemia, epilepsy, amiotrophic lateral sclerosis, Parkinson's, and Alzheimer's disease. These data have consequently added great impetus to the research in this field. In fact, many Glu receptor antagonists acting at the N -methyl- D -aspartic acid (NMDA), 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA), and/or kainic acid (KA) receptors have been developed as research tools and potential therapeutic agents. Ligands showing competitive antagonistic action at the AMPA type of Glu receptors were first reported in 1988, and the systemically active 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline (NBQX) was first shown to have useful therapeutic effects in animal models of neurological disease in 1990. Since then, the quinoxaline template has represented the backbone of various competitive AMPA receptor antagonists belonging to different classes which had been developed in order to increase potency, selectivity and water solubility, but also to prolong the "in vivo" action. Compounds that present better pharmacokinetic properties and less serious adverse effects with respect to the others previously developed are undergoing clinical evaluation. In the near future, the most important clinical application for the AMPA receptor antagonists will probably be as neuroprotectant in neurodegenerative diseases, such as epilepsy, for the treatment of patients not responding to current therapies. The present review reports the history of competitive AMPA receptor antagonists from 1988 up to today, providing a systematic coverage of both the open and patent literature. © 2006 Wiley Periodicals, Inc. [source] Desmoplastic small round cell tumor in childhood: The St. Jude Children's Research Hospital experiencePEDIATRIC BLOOD & CANCER, Issue 3 2007Raya Saab MD Abstract Background Desmoplastic small round cell tumor (DSRCT) is a rare, primarily intra-abdominal tumor that has a poor outcome with current therapies. Procedure We retrospectively reviewed patient characteristics, presenting symptoms, tumor pathology, treatment, and outcome of 11 pediatric patients with DSRCT at our institution. Results The cohort included 1 female and 10 male patients. Median age at diagnosis was 14 years (range 5,21 years). In eight (73%) patients, the primary tumor was abdominal or pelvic, and in one patient each, it was submental, mediastinal, and paratesticular. Nine (82%) patients had metastatic disease. All tumors showed polyphenotypic differentiation by immunohistochemistry. The EWS-WT1 transcript was detected in six of seven tumors tested. One tumor showed rhabdomyoblastic differentiation after therapy. All patients received chemotherapy; eight underwent surgical resection, seven received primary site radiation, and four received myeloablative chemotherapy with stem-cell support. Three (27%) patients are alive 23 months, 8 years, and 10 years from diagnosis. Two died of treatment-related toxicity, six died of disease. None of the patients in whom surgery and initial chemotherapy failed to induce complete remission survived. Conclusions DSRCT is an aggressive malignancy that does not respond well to contemporary treatments, and patients who do not enter complete remission after initial chemotherapy and surgery appear to have a particularly dismal outcome. Patients with localized extra-abdominal disease have a better prognosis, most likely due to increased feasibility of resection. Better understanding of molecular and genetic mechanisms of tumorigenesis and treatment-related changes may contribute to development of more effective therapy for DSRCT. Pediatr Blood Cancer 2007;49:274,279. © 2006 Wiley-Liss, Inc. [source] Miglustat (Zavesca®) in type 1 Gaucher disease: 5-year results of a post-authorisation safety surveillance programmePHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 9 2009Carla E. M. Hollak MD Abstract Purpose Miglustat (Zavesca®) is an orally-available substrate reduction therapy (SRT) for treatment of mild-to-moderate type 1 Gaucher disease (GD1) in adult patients unsuitable for enzyme replacement therapy (ERT). Miglustat has not been evaluated in children with GD1, and is not used during pregnancy and breast-feeding. A non-interventional, prospective, web-based safety surveillance programme was initiated at the time of the European launch of miglustat in 2003, and is ongoing. We report the first 5 years of collected data, focusing on neurological manifestations. Methods Data were collected on 122 GD1 patients between March 2003 and April 2008, representing 244 patient-years cumulative miglustat post-authorisation experience. The electronically-captured data collected from participating physicians includes patient demographics, prior and current therapies, baseline disease manifestations and concurrent conditions, disease severity, duration of miglustat exposure, and safety-relevant information. Results Mean (SD) age at baseline was 46.1 (16.5) years. At baseline, bone disease and neurological manifestations were reported in 55.6 and 28.6% of patients, respectively; the latter included peripheral neuropathy (7.2%) and a wide variety of neurological symptoms and signs. In addition, 23.2% had other health conditions relevant to neurological status. During the reporting period, new neurological manifestations were reported in 23 (18.9%) patients, principally tremor. Thirty-five (28.7%) patients discontinued treatment, predominantly for gastrointestinal (GI) disturbances (11.5%), two-thirds of which occurred during the first 6 months. Conclusion The safety profile of miglustat in GD1 patients included in the safety surveillance programme is overall consistent with that reported in the registration and other clinical trials, and no new safety finding was identified. Copyright © 2009 John Wiley & Sons, Ltd. [source] Molecular targeted therapies for diffuse large B-cell lymphoma based on apoptosis profiles,THE JOURNAL OF PATHOLOGY, Issue 5 2010Saskia AGM Cillessen Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common type of adult non-Hodgkin lymphoma and is treated with chemotherapy in combination with rituximab. Despite this aggressive therapy, the disease is fatal in 30,40% of patients. Inhibition of the apoptosis signalling pathways is strongly related to response to chemotherapy and eventual clinical outcome. In order to survive, lymphoma cells depend on disruption of the apoptosis pathway by mutations in apoptosis inducing genes or by continuous expression of anti-apoptotic proteins. The development of molecules targeting these apoptosis inhibitors provides a very promising opportunity to specifically target tumour cells without toxicity to non-malignant cells in DLBCL patients. Sensitivity for most of these antagonists can be predicted based on biological markers, suggesting the possibility of pre-defining patients who will most likely benefit from these targeted therapies. Experimental therapies aimed at restoring the upstream apoptosis pathway or targeting apoptosis inhibitors are currently being tested in clinical trials and are expected to be effective particularly in chemotherapy-refractory DLBCL, providing hope for patients who are refractory to current therapies. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Nephrogenic Systemic Fibrosis Among Liver Transplant Recipients: A Single Institution Experience and Topic UpdateAMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2006M. Maloo Nephrogenic systemic fibrosis (NSF) is a recently characterized systemic fibrosing disorder developing in the setting of renal insufficiency. NSF's rapidly progressive nature resulting in disability within weeks of onset makes early diagnosis important. Two reports of NSF after liver transplantation are known of. We present three cases of NSF developing within a few months after liver transplantation and review the current literature. Loss of regulatory control of the circulating fibrocyte, its aberrant recruitment, in a milieu of renal failure and a recent vascular procedure appear important in its development. Known current therapies lack consistent efficacy. Only an improvement in renal function has the greatest likelihood of NSF's resolution. Delayed recognition may pose a significant barrier to functional recovery in the ubiquitously deconditioned liver transplant patient. Early recognition and implementation of aggressive physical therapy appear to have the greatest impact on halting its progression. [source] Mast cells and type I interferon responses in the skin of patients with juvenile dermatomyositis: Are current therapies just scratching the surface?ARTHRITIS & RHEUMATISM, Issue 9 2010Lisa G. Rider First page of article [source] DNA hypomethylation in rheumatoid arthritis synovial fibroblastsARTHRITIS & RHEUMATISM, Issue 12 2009Emmanuel Karouzakis Objective Rheumatoid arthritis synovial fibroblasts (RASFs) are phenotypically activated and aggressive. We undertook this study to investigate whether the intrinsic activation of RASFs is due to global genomic hypomethylation, an epigenetic modification. Methods Global genomic hypomethylation was assessed by immunohistochemistry, flow cytometry, and L1 promoter bisulfite sequencing. The levels of Dnmt1 were determined in synovial tissue and cultured SFs by Western blotting before and after treatment with cytokines and growth factors. Normal SFs were treated for 3 months with a nontoxic dose of the DNA hypomethylation drug 5-azacytidine (5-azaC), and changes in gene expression were revealed using complementary DNA arrays. The phenotypic changes were confirmed by flow cytometry. Results In situ and in vitro, RASF DNA had fewer 5-methylcytosine and methylated CG sites upstream of an L1 open-reading frame than did DNA of osteoarthritis SFs, and proliferating RASFs were deficient in Dnmt1. Using 5-azaC, we reproduced the activated phenotype of RASFs in normal SFs. One hundred eighty-six genes were up-regulated >2-fold by hypomethylation, with enhanced protein expression. These included growth factors and receptors, extracellular matrix proteins, adhesion molecules, and matrix-degrading enzymes. The hypomethylating milieu induced irreversible phenotypic changes in normal SFs, which resembled those of the activated phenotype of RASFs. Conclusion DNA hypomethylation contributes to the chronicity of RA and could be responsible for the limitation of current therapies. [source] Anal intraepithelial neoplasia and anal cancer in dermatological practiceAUSTRALASIAN JOURNAL OF DERMATOLOGY, Issue 3 2007Asoka Herat SUMMARY Anal intraepithelial neoplasia is considered to be a precursor lesion of invasive anal cancer. It is now increasingly recognized in high-risk groups, such as men who have sex with men and HIV-infected patients. Human papillomaviruses are considered to be an important aetiological agent in both anal intraepithelial neoplasia and anal cancer. Dermatologists are likely to encounter these conditions among the differential diagnoses to be considered in high-risk patients presenting with perianal and anal lesions. Anal cancer rates are also increasing among the HIV-infected and HIV-non-infected population. The successful treatment of anal intraepithelial neoplasia may reduce the risk of subsequent development of anal cancer. However, current therapies for anal intraepithelial neoplasia may be associated with treatment-related morbidity and are not well validated. It is currently not proven that they reduce the likelihood of the development of anal cancer. Nevertheless, screening for anal intraepithelial neoplasia is being advocated for high-risk groups and may become standard dermatological care for these patients. In view of recent developments in the understanding of this condition, this article reviews the current understanding of anal intraepithelial neoplasia and its treatment from a dermatological perspective. [source] Mechanism of tyrosinase inhibition by deoxyArbutin and its second-generation derivativesBRITISH JOURNAL OF DERMATOLOGY, Issue 6 2008S. Chawla Summary Background, Disorders, such as age spots, melasma and hyperpigmentation at sites of actinic damage, emanate from the augmentation of an increased amount of epidermal melanin. Objectives, The ineptness of current therapies in treating these conditions, as well as high cytotoxicity, mutagenicity, poor skin penetration and low stability of skin-depigmenting formulations led us to investigate new compounds that meet the medical requirements for depigmentation agents. We have shown previously that the tyrosinase inhibitor deoxyArbutin (dA) is a more effective and less toxic skin lightener than hydroquinone (HQ). Methods, The efficacy and reversibility of dA and its derivatives on inhibiting tyrosine hydroxylase and DOPAoxidase was assessed using standard assays. Results, dA and its second-generation derivatives inhibit tyrosine hydroxylase and DOPAoxidase activities of tyrosinase dose dependently thereby inhibiting melanin synthesis in intact melanocytes, when used at concentrations that retain 95% cell viability in culture. This depigmenting effect was completely reversible when the compounds were removed. Tyrosinase inhibition was also observed in vitro when tested using human and purified mushroom tyrosinase, establishing that they are direct enzyme inhibitors. Lineweaver,Burk reciprocal plot analysis using mushroom tyrosinase illustrated that dA and its derivatives are more robust competitive inhibitors than HQ, when tyrosine is used as substrate. Conclusions, Thus, dA and its second-generation derivatives, which inhibit melanogenesis at safe concentrations by specifically acting on the tyrosinase enzyme at a post-translational level, are promising agents to ameliorate hyperpigmented lesions or lighten skin. [source] Predictable signs of benign course of polypoidal choroidal vasculopathy: based upon the long-term observation of non-treated eyesACTA OPHTHALMOLOGICA, Issue 4 2010Akiko Okubo Abstract. Purpose:, To find predictable signs of benign polypoidal choroidal vasculopathy (PCV). Methods:, Medical records of 13 eyes from 12 patients who were followed up for 5 years or longer without treatment among 258 consecutive patients with PCV were reviewed retrospectively. The main outcomes measured were best corrected visual acuity (BCVA) and fundus findings during the follow-up period. Results:, The average age at presentation was 68 years, and the average follow-up period after diagnosis was 80 months (range, 62,119 months). The initial mean logarithmic value of the minimal angle of resolution (logMAR) BCVA was 0.28 ± 0.26, and the final mean logMAR BCVA was 0.62 ± 0.72. The difference in the logMAR BCVA values between the two points was not statistically significant (p > 0.05). The trend of change from baseline at 2-year follow-up was consistent with those at 5-year follow-up in nine eyes. Fundus findings at the initial examination were classified into two patterns: (i) reddish-orange nodules and detachment of the retinal pigment epithelium with/without detachment of the neurosensory retina (nine eyes); (ii) reddish-orange nodules alone, or nodules and small subretinal haemorrhage (four eyes). In the eyes with the first pattern, clinical course and visual prognosis were variable. An absence of hard exudates could be a sign to maintain a benign clinical course or stable vision with this pattern. The eyes with the second pattern took a benign clinical course with stable vision. Conclusions:, There is certainly a group of PCV eyes with a benign prognosis. Considering the huge cost and risk of current therapies, the initial ocular findings could be deciding factors that determine the necessity for further treatment. [source] Current and possible future treatment of ocular adnexal lymphomasACTA OPHTHALMOLOGICA, Issue 2008A PETTITT Purpose To review the current and possible future therapies of ocular adnexal lymphomas. Methods Ocular adnexal lymphomas represent approx. 8% of all extranodal lymphomas. The majority of these can be classified as extranodal marginal zone (MALT) lymphomas, and are usually staged as Stage IE disease. Results Recommended therapy in Stage IE tumours is low-dose radiotherapy, while disseminated disease (>Stage IIE) is treated with chemotherapy. Although often responding to initial therapy, the MALT lymphomas tend to recur in distant extranodal sites. Few biomarkers are available to aid prediction of either recurrence or systemic dissemination, which occurs in up to 25% of patients. The ocular morbidity associated with current therapies is not insignificant, and, therefore, more effective treatment is being sought. Conclusion The newer treatment options, including rituximab and doxycyclin, will be discussed [source] | ||||||||||||||||||||||||||||||||||