Arben Santo

The histone deacetylase inhibitor trichostatin A upregulates regulatory T cells and modulates autoimmunity in NZB/W F1 mice

We sought to determine if the histone deacetylase inhibitor (HDI), trichostatin A (TSA), would alter systemic lupus erythematosus (SLE) in NZB/W mice. Fourteen to sixteen-week-old female NZB/W F1 mice were given TSA (1.0mg/kg body weight (BW)) intraperitonealy (i.p.) daily, TSA (1.0mg/kg BW) i.p.+anti-CD25 (250mg/mouse) i.p. every third day, only anti-CD25 (250mg/mouse) i.p., DMSO or isotype IgG. Disease progression was assessed as they aged. Mice were sacrificed at 26 or 38 weeks of age, tissues collected and evaluated. At 36 weeks, TSA-treated animals had decreased anti-double stranded DNA (dsDNA) autoantibodies and decreased protein excretion compared to controls. Spleen size and the percentage of CD4+CD69+ cells were decreased, with an increase in CD4+CD25+ T cells in the TSA-treated mice. Real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis of T cells showed a decrease in IL-6 production but an increase in TGF-beta1 and Foxp3 in the TSA-treated animals. Kidney analysis showed a decrease in IgG and C3 deposition, decrease in pathologic glomerular disease and renal MCP-1, MMP-9, and IL-6 mRNA expression. Anti-CD25-treated mice euthanized at 26 weeks of age showed decreased Foxp3+CD4+CD25+ T cells compared to TSA-treated mice. These data suggest TSA administration modulates lupus-like disease, in part, by increasing T regulatory cells.

The antioxidant enzyme peroxiredoxin and its protective role in neurological disorders

Peroxiredoxin (Prx) represents a family of sulfhydryl-dependent peroxidases that reduce hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively. There are six known mammalian isozymes (Prx1–6), classified as typical 2-Cys, atypical 2-Cys, or 1-Cys Prxs. In addition to their well-established peroxide-scavenging activity, Prxs also participate in the regulation of various cell signaling pathways. Experimental studies provide substantial evidence for a protective role of Prxs in various neurological disorders involving oxidative and inflammatory stress. There is also evidence suggesting a potential benefit of Prxs in certain neurological diseases in human subjects. This review first describes the biochemical properties and molecular regulation of Prxs, then summarizes the major findings on the neuroprotective functions of Prxs and finally discusses the feasibility of using natural compounds, including those from herbal remedies to augment Prx expression to counteract oxidative neurological disorders.

Interferon regulatory factor‐1 gene deletion decreases glomerulonephritis in MRL/lpr mice

To investigate the role of interferon regulatory factor‐1 (IRF‐1) in the development of lupus nephritis, IRF‐1–/– genotype mice were bred onto the MRL/lpJfaslpr (MRL/lpr) background. We examined kidney mesangial cell function and disease progression. Endpoints evaluated included inflammatory mediators, autoantibody production, immune complex deposition, renal pathology, Tu2004cell subset analysis, and duration of survival. Mesangial cells cultured from IRF‐1–/– mice produced significantly lower levels of nitric oxide and IL‐12 but not TNF‐α when stimulated with LPSu2004+u2004IFN‐γ. IRF‐1–/– mice showed less aggravated dermatitis compared to the wild‐type mice. Anti‐double‐stranded DNA production and proteinuria were significantly decreased in IRF‐1–/– mice compared to IRF‐1+/+ mice. IgG and C3 deposition as well as glomerulonephritis were decreased in IRF‐1–/– mice at 26u2004wk of age compared to the IRF‐1+/+ mice. Splenic CD4–CD8–CD44+ Tu2004cells were decreased while CD4+CD25+ Tu2004cells were increased in the IRF‐1–/– mice when compared to IRF‐1+/+ mice. Survival rates (ED50) were 22u2004wk for IRF‐1+/+ mice and 45u2004wk for IRF‐1–/– mice. These findings suggest an important role of IRF‐1 in mediating renal disease in MRL/lpr mice.

Cruciferous Dithiolethione-Mediated Coordinated Induction of Total Cellular and Mitochondrial Antioxidants and Phase 2 Enzymes in Human Primary Cardiomyocytes : Cytoprotection Against Oxidative/Electrophilic Stress and Doxorubicin Toxicity

3H-1,2-dithiole-3-thione (D3T), a cruciferous organosulfur compound, induces cytoprotective enzymes in animal cardiovascular cells. However, it remains unknown if D3T also upregulates antioxidants and phase 2 enzymes in human cardiomyocytes, and protects against cell injury induced by oxidative/electrophilic species as well as doxorubicin. In this study, we found that D3T (10–50 μM) potently induced a series of antioxidants and phase 2 enzymes in primary cultured human cardiomyocytes, including superoxide dismutase (SOD), glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx) glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1 (NQO1), aldose reductase (AR), and heme oxygenase (HO). D3T treatment also caused elevation of SOD, GSH, GR, GPx and GST in the isolated mitochondria. We also observed a time-dependent induction by D3T of mRNA expression for Cu,ZnSOD, MnSOD, γ-glutamylcysteine ligase, GR, GSTA1, GSTM1, NQO1, AR, and HO-1. Pretreatment with D3T conferred concentration-dependent protection against cell injury induced by xanthine oxidase (XO)/xanthine, H2O2, 3-morpholinosydnonimine, 4-hydroxy-2-nonenal, and doxorubicin. Pretreatment with D3T also reduced the formation of intracellular reactive oxygen species by XO/xanthine, H2O2, and doxorubicin. In conclusion, this study demonstrated that D3T potently upregulated many antioxidants and phase 2 enzymes in human cardiomyocytes, which was accompanied by increased resistance to oxidative/electrophilic stress and doxorubicin toxicity.

Furuncular myiasis of the foot caused by the tumbu fly, Cordylobia anthropophaga: Report in a Medical Student Returning from a Medical Mission trip to Tanzania.

Cutaneous myiasis in humans is a temporary parasitic infestation of the skin by fly larvae or maggots of a variety of Dipteran families. In the United States, autochthonous cases of myiasis are infrequently seen. Most cases of cutaneous myiasis are acquired when traveling to tropical areas of Africa, Central America or South America. This case report involves a 26-year-old male medical student who visited Tanzania on a medical mission trip. Three weeks following his return to the United States he developed a furuncular lesion on the side of the fifth digit on his right foot, which contained the larva of the tumbu fly, Cordylobia anthropophaga.

Soil-acquired cutaneous nocardiosis on the forearm of a healthy male contracted in a swamp in rural eastern Virginia

A 45-year-old man complained of pain and swelling on his right wrist after receiving a scratch while playing paintball in a swampy area of eastern Virginia. Two weeks later, he noticed a pimple-like lesion developing, which quickly grew in size and then ulcerated. Because of the severity of his condition, the patient was taken to the emergency room where surgical drainage of the abscess was carried out and the pus was sent for culture and sensitivity testing. Enlarged and tender lymph nodes were palpable going up the arm and surrounding the right axillary area. Three days following culture of pus from his lesion, colonies of Nocardia brasiliensis were isolated. He was successfully treated with an extended regimen of trimethoprim-sulfamethoxazole. Because of its low incidence, nocardiosis is usually not considered in the initial diagnosis. The rapidity with which his infection developed from a pimple-like lesion into an extensive ulcerated area, the involvement of his lymphatic system, the extended time needed to successfully treat his infection, and the potential for infection to rapidly disseminate, reinforces the necessity for laboratory identification and immediate treatment of severe pyogenic cutaneous lesions.

Lyme disease: case report of persistent Lyme disease from Pulaski County, Virginia.

A 50-year-old woman from Pulaski, Virginia, presented to a local clinic with headaches, fever, generalized joint pain, excessive thirst and fluid intake, and a progressing rash on her back. On physical examination, she had a large circular red rash on her back with a bull’s-eye appearance, 16 × 18 cm in diameter. Serologic tests confirmed a diagnosis of Lyme disease. The patient could recall a walk through the woods 3 weeks prior, although she never noticed a tick on her body. Following a prolonged course of antibiotics, this case report presents a patient with ongoing symptoms consistent with post-treatment Lyme disease.

Graphene Quantum Dots Protect against Copper Redox-Mediated Free Radical Generation and Cardiac Cell Injury

In this work, we investigated the effects of graphene quantum dots (GQDs) on copper redox-mediated free radical generation and cell injury. Using electron paramagnetic resonance (EPR) spectrometry in conjunction with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trap, we found that GQDs at a concentration as low as 1 μg/ml significantly inhibited Cu(II)/H2O2-mediated hydroxyl radical formation. GQDs also blocked Cu(II)-catalyzed nucleophilic addition of H2O to DMPO to form a DMPO-OH adduct in the absence of H2O2, suggesting a potential for GQDs to inhibit copper redox activity. Indeed, we observed that the presence of GQDs prevented H2O2-mediated reduction of Cu(II) to Cu(I) though GQDs themselves also caused the reduction of Cu(II) to Cu(I). To further investigate the effects of GQDs on copper redox activity, we employed the Cu(II)/hydroquinone system in which copper redox activity plays an essential role in the oxidation of hydroquinone to semiquinone radicals with consequent oxygen consumption. Using oxygen polarography as well as EPR spectrometry, we demonstrated that the presence of GQDs drastically blocked the oxygen consumption and semiquinone radical formation resulting from the reaction of Cu(II) and hydroquinone. These results suggested that GQDs suppressed free radical formation via inhibiting copper redox activity. Lastly, using cultured human cardiomyocytes, we demonstrated that the presence of GQDs also protected against Cu(II)/H2O2-mediated cardiac cell injury as indicated by morphological changes (e.g., cell shrinkage and degeneration). In conclusion, our work shows, for the first time, the potential for using GQDs to counteract copper redox-mediated biological damage.

An unfortunate case of acquired hemochromatosis: a case report review of the clinical presentation, diagnosis, management, and prognosis

Background While blood transfusions are commonly used for prophylaxis and treatment for acute chest syndromes and strokes in sickle cell patients, accumulation of excess iron resulting in secondary hemochromatosis remains a rare disease. Chelation is the mainstay for preventing and treating iron overload to deter potential end-organ damages; it is rare when therapy fails. Case report A 52-year-old African American woman with chronic anemia secondary to sickle cell anemia and history of multiple blood transfusions presented with elevated serum ferritin (8000 ng/mL) and bilirubin (16.8 mg/dL). She had no previous personal or family history of liver disease. A magnetic resonance cholangiopancreatography (MRCP) and a liver biopsy confirmed the secondary hemochromatosis with marked fibrosis and 4+ iron deposits, but since she was therapeutically on deferasirox, her treatment regimen involved only closer monitoring. Her hemochromatosis led to readmission within a year for rapid progression of cardiac and hepatic failure. Conclusion Since chronically transfused sickle cell patients are at a significantly higher risk of mortality due to the secondary hemochromatosis and end-stage organ damage, knowledge of prophylactic iron chelation is important. Minimizing unnecessary transfusions should be strongly emphasized to reduce the sequelae as iron burden remains a threat. The effectiveness of iron-chelating therapy is best monitored via periodic magnetic resonance imaging, liver transaminases, bilirubin, creatinine, ferritin, and cardiac function tests. Despite the prophylactic treatment and quarterly blood work, in this case the initial presentation did not correlate with the severity of end-stage liver failure. The damage was not discovered until proven by liver biopsy and MRCP, too late to deter the sequelae and the mortality exactly 1 year after diagnosis of the secondary hemochromatosis.