Years and Volumes

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Articles from this Volume

Sonia Clavero, David F Bishop, Urs Giger, Mark E Haskins, and Robert J Desnick

Congenital Erythropoietic Porphyria (CEP) is an enzyme deficiency which occurs in red blood cells at birth. As a result, exposure to sunlight may lead to skin blistering, vesicle formation and scarring, while secondary infections in these lesions may lead to disfigurement of the face and hands. Medical management is focused on protecting affected individuals from sunlight or ultraviolet light exposure.  In this work, Clavero et al. identified the first feline model of CEP based on clinical phenotype and confirmed by biochemical and molecular genetic studies. Results indicate a synergistic interaction of two mutations in the URO-synthase polypeptide caused this feline model of human CEP. Future identification of cats with a CEP-like phenotype may permit the establishment of a colony and the opportunity to evaluate stem cell and gene transfer therapies prior to human trials.

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Posted by MolMed Editor on Sep 5, 2010 12:00 AM CDT
Maria A Brito, Ana R Vaz, Sandra L Silva, Ana S Falcão, Adelaide Fernandes, Rui FM Silva, and Dora Brites

Hyperbilirubinemia, or increased levels of bilirubin in the blood, may lead to neurotoxicity and neuronal death.  Although the mechanisms of nerve cell damage by unconjugated bilirubin (UCB) appear to involve a disruption of redox status and excitotoxicity, the contribution of nitric oxide (NO) and N-methyl-D-aspartate (NMDA) glutamate receptors is unclear.  Brito et al. therefore investigated the role of NO and NMDA glutamate receptors in UCB neurotoxicity. Results reinforce the involvement of oxidative stress and data highlight important steps in neuronal oxidative damage by UCB. Inhibitors and receptor antagonists may represent therapeutic tools to reduce risk associated with oxidative stress and neurotoxicity in unconjugated hyperbilirubinemia.

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Posted by MolMed Editor on Sep 4, 2010 12:00 AM CDT
Teresina Laragione And Pércio S Gulko

Rheumatoid arthritis (RA) is a common chronic autoimmune disease affecting about one percent of the population and is commonly associated with disability and deformities. RA joint pathology is characterized by inflammation of the synovium, which produces several proinflammatory cytokines and proteases. Like a malignant tumor, synovial inflammation invades and destroys cartilage and bone. Fibroblast-like synoviocytes (FLS) have a central role in cartilage and bone invasion and destruction. Laragione and Gulko used rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), to assess the role of the mTOR pathway in invasive FLS. Rapamycin significantly reduced RA and FLS invasion suppressing the mTOR signaling pathway. This suggests rapamycin may play a role in RA therapy by reducing damage and erosive changes mediated by FLS.

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Posted by MolMed Editor on Sep 3, 2010 12:00 AM CDT
Abid A Kazi and Charles H Lang

Muscle serves as the largest protein reservoir in the body and may be used as anenergy source when necessary. Muscle wasting is associated with catabolic insults such as sepsis, alcohol abuse and aging. Proline Rich Akt Substrate 40kDa (PRAS40) is a binding protein which has complex effects on cell metabolism. Despite reports implicating PRAS40 as a regulator of protein translation initiation in a variety of cells, there is a paucity of information related to its role in skeletal muscle. To address this, Kazi and Lang examined changes in myocyte protein synthesis, cell proliferation and cell cycle in response to PRAS40 knockdown. Results indicate PRAS40 plays an important role in cell size regulation and affects cell proliferation and differentiation.  Understanding the role of PRAS40 may prove important in designing new strategies to manage muscle wasting associated with catabolic insults.

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Posted by MolMed Editor on Sep 3, 2010 12:00 AM CDT
Hanna Schierbeck, Heidi Wähämaa, Ulf Andersson, And Helena Erlandsson Harris

High mobility group box-1 (HMGB1) is a ubiquitous nonhistone nuclear protein as well as an extracellular molecule regulating innate and adaptive immunity. Extracellular HMGB1 plays an important pathogenic role in infectious and sterile inflammation.  Several HMGB1 specific antagonists have provided beneficial results in multiple preclinical models of inflammatory disease.  However, since no HMGB1 blocking therapies have been approved for clinical use, Scheirbeck et al. studied effects on HMGB1 release by well-established antirheumatic compounds.  Results demonstrate that treatment with dexamethasone, chloroquine or gold sodium thiomalate have the ability to inhibit HMGB1 release and that further study in this area is warranted.  

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Posted by MolMed Editor on Sep 2, 2010 12:00 AM CDT
Yanning Li, Jinsheng Qi, Kun Liu, Bin Li, Hui Wang, and Jinhai Jia

Chronic vascular complications of diabetes, including microvascular (nephropathy) and macrovascular (atherosclerosis) diseases, are major causes of morbidity and premature mortality.  Evidence shows that inflammation and oxidative stress play important roles in this pathophysiology. While peroxynitrite is a key mediator of diabetic complications, the effect of peroxynitrite on nitration of two key enzymes with roles in inflammation and oxidative stress, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), remains unknown.  Li et al. examined this issue and concluded that in vivo binding of COX-2 and iNOS exists in diabetic angiopathy, and peroxynitrite-induced nitration of COX-2 and iNOS can promote binding, which contributes to diabetic angiopathy. Therefore, scavenging peroxynitrite in order to attenuate binding of COX-2 and iNOS may represent a more effective intervention for this disease.

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Posted by MolMed Editor on Sep 1, 2010 12:00 AM CDT
Ming Long, Lei Yang, Genya Huang, Liping Liu, Yugang Dong, Zhimin Du, Anli Tang, Chenghen Hu, Ruimin Gu, Xiuren Gao, and Lilong Tang

ST segment elevation is used to diagnose acute myocardial infarction (AMI) and is the major clinical criterion for committing patients with chest pain to emergent coronary revascularizations. Despite its frequent usage, the mechanism responsible for ST segment elevation remains unclear. Since ST segment elevation is the major criteria for thrombolytic therapy, Long et al. examined the role of thrombin and its receptor activation in ST segment elevation during acute myocardial infarction. The results demonstrate that thrombin and activation of its receptor significantly enhance ST segment elevation during AMI. This observation suggests that more robust and accurate methods than reduced ST segment times may be required to assess efficacy of anti-thrombin therapies.

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Posted by MolMed Editor on Aug 5, 2010 12:00 AM CDT
Jonathan P Desnick, Jungmin Kim, Xingxuan He, Melissa P Wasserstein, Calogera M Simonaro, and Edward H Schuchman

Types A and B Niemann-Pick disease (NPD) are autosomal recessive sphingolipidoses caused by mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. Type A disease results in infantile neurodegeneration and hepatosplenomegaly with demise in the first few years of life, while Type B includes hepatosplenomegaly, pulmonary disease and survival into adolescence or adulthood. While mutations have been reported in types A and B phenotypes, expression studies are the most accurate way to predict which mutations have residual enzyme activity and may be neuroprotective. Here, Desnick et al. present clinical and molecular findings for six unrelated type A and B patients. The results provide additional information for predicting clinical phenotypes in newly diagnosed infants and children with Niemann-Pick disease.

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Posted by MolMed Editor on Aug 4, 2010 12:00 AM CDT
Juan-Zhang, Hong-Jun Bian, Xiao-Xing Li, Xiao-Bo Liu, Jun-Ping Sun, Na-Li, Yun-Zhang, and Xiao-Ping Ji

Rho-kinase plays a key role in the pathogenesis resulting from heart ischemia reperfusion (I/R) injury. Ischemic preconditioning (IPC), brief periods of repetitive cardiac ischemia reperfusion, protects against subsequent lethal periods of ischemia, decreases Rho-kinase activation, and reduces infarct size. While these results are beneficial, little is known about the mechanism of action. Here, Zhang et al. show that ERK-MAPK signaling is required in ischemic preconditioning in order to oppose the Rho-kinase signaling which leads to apoptosis in vivo. These data may lead to new treatment possibilities for patients suffering from coronary heart disease.

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Posted by MolMed Editor on Aug 3, 2010 12:00 AM CDT
Yu-Mee Wee, Monica Young Choi, Choong-Hoon Kang, Yang-Hee Kim, Jin-Hee Kim, Sang-Kyou Lee, Seung-Young Yu, Song-Cheol Kim, and Duck-Jong Han

Patients with type 1 diabetes face the prospect of complications such as nephropathy, neuropathy, retinopathy and cardiovascular disease. A successful pancreas transplant provides almost normal glucose homeostasis, but patients require lifelong immunosuppressive medication. Wee et al. investigated the effect of the T-cell apoptosis compound tautomycetin (TMC) on rat islet transplantation both alone and in combination with cyclosporine A (CsA). They demonstrate that TMC inhibits T-cell proliferation without affecting islet or splenocyte viability. The authors also found that islet allograft survival could be prolonged through a combination of TMC and subtherapeutic doses of CsA. Furthermore, the same experimental doses of either immunosuppressive agent alone did not result in any beneficial effect on islet allografts. This novel combination of known agents may lead to greater long-term success of pancreas transplants in those suffering with diabetes.

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Posted by MolMed Editor on Aug 2, 2010 12:00 AM CDT
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