The clinical significance of fungi in atopic dermatitis

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases and is caused by multiple factors including genetic factors, skin barrier defects, host immune responses, allergen sensitivity, environmental effects, and infections. Commonly, bacterial and viral infections are present in the eczematous lesions of AD patients and clearly aggravate the symptoms. However, studies of fungal infections in AD are limited in spite of the fact that there are reports showing that Malassezia, Candida, and some dermatophytes can affect the symptoms of AD. Moreover, certain fungal infections are sometimes overlooked and need to be considered particularly in AD patients with treatment failure as clinical features of those fungal infections could mimic eczematous lesions in AD. Here, we review the epidemiology, pathogenesis, clinical manifestations, and overlooked features of fungal infections associated with the symptoms of AD including the diagnosis and effectiveness of fungal treatments in AD patients.     

Sodium Thiosulfate as a Treatment for Calciphylaxis

The use of sodium thiosulfate has emerged as a promising treatment for calciphylaxis, albeit inconclusively in terms of efficacy and variable outcomes. Research in this field has been limited by a paucity of samples due to the rarity of the disease. We herein discuss eight calciphylaxis patients'' responses to STS, the potential predictive factors affecting outcomes and compare our results with previously published literature. We are able to show that lesion severity, concomitant drugs, and dialysis duration may be predictive factors of outcomes. Further, improvement of the wound site may be a clinically relevant prognostic determinant.     

Antibody elutions in Thai patients with a positive direct antiglobulin test

Background

The direct antiglobulin test is performed to determine whether an anaemic patient with evidence of haemolysis has autoimmune or alloimmune haemolytic anaemia.

Materials and methods

We determined the antibody specificity of eluted IgG antibodies from patients’ blood samples with a positive direct antiglobulin test. Overall, 134 Thai patients were included in this study. EDTA blood samples were obtained from recently transfused patients, patients with unexplained anaemia and patients who had serum antibodies detected during routine pre-transfusion tests from different hospital blood banks. These complicated samples were sent to the National Blood Centre of the Thai Red Cross Society for investigation and to find compatible blood components. Each blood sample underwent a direct antiglobulin test with the gel technique using polyspecific antihuman globulin and mononospecific anti-IgG and anti-C3d. Acid eluates were prepared from the samples for which the direct antiglobulin test was positive and the specificities of the eluted antibodies were determined by the gel technique.

Results

Of the samples tested, 101 showed a positive direct antiglobulin test result (75.4%) using polyspecific antihuman globulin sera whereas only 95 samples (70.9%) were positive with anti-IgG or anti-IgG and anti-C3d. Moreover, 54 of 95 eluates (56.8%) were positive for antibody screening and tested with the reagent panel cells. Twenty-one eluates had specific alloantibodies, which were concordant with the findings in the patients’ sera and all patients had a history of blood transfusion. Additionally, 33 eluates contained pan-agglutinins. Interestingly, alloantibodies could be determined using titration studies in 5 of 26 eluates with pan-agglutinins.

Conclusion

Although the direct antiglobulin test is not routinely performed in pre-transfusion screening, this test and elution studies would be useful in patients with a history of previous transfusions, and in those for whom compatible blood cannot be found.     

Biosimilar recombinant human erythropoietin induces the production of neutralizing antibodies

Recombinant human erythropoietin (r-HuEpo) has been used for the treatment of renal anemia. With the loss of its patent protection, there has been an upsurge of more affordable biosimilar agents, increasing patient access to treatment for these conditions. The complexity of the manufacturing process for these recombinant proteins, however, can result in altered properties that may significantly affect patient safety. As it is not known whether various r-HuEpo products can be safely interchanged, we studied 30 patients with chronic kidney disease treated by subcutaneous injection with biosimilar r-HuEpo and who developed a sudden loss of efficacy. Sera from 23 of these patients were positive for r-HuEpo-neutralizing antibodies, and their bone marrow biopsies indicated pure red-cell aplasia, indicating the loss of erythroblasts. Sera and bone marrow biopsies from the remaining seven patients were negative for anti-r-HuEpo antibodies and red-cell aplasia, respectively. The cause for r-HuEpo hyporesponsiveness was occult gastrointestinal bleeding. Thus, subcutaneous injection of biosimilar r-HuEpo can cause adverse immunological effects. A large, long-term, pharmacovigilance study is necessary to monitor and ensure patient safety for these agents.     

Interactions of human- and rat-organic anion transporters with pravastatin and cimetidine

We have elucidated the interactions of human and rat organic anion transporters (hOATs and rOATs) with pravastatin and cimetidine. Pravastatin inhibited hOAT1/rOAT1, hOAT2/rOAT2, hOAT3/rOAT3, and hOAT4. The mode of inhibition was noncompetitive for hOAT1 and hOAT2, whereas it was competitive for hOAT3 and hOAT4. Cimetidine also inhibited hOAT1/rOAT1, hOAT3/rOAT3, and hOAT4. The mode of inhibition was a combination of competitive and noncompetitive manners for hOAT1, whereas it was competitive for hOAT3. The effects of OAT inhibitors on OAT1, OAT2, and OAT3 exhibited some but not so remarkable interspecies differences between humans and rats. In conclusion, we have characterized pravastatin and cimetidine as OAT inhibitors.     

Successful peripheral blood stem cell mobilization using pegfilgrastim in allogeneic stem cell transplantation

Pegfilgrastim is produced by binding a 20,000-dalton polyethylene glycol molecule to granulocyte colony-stimulating factor (G-CSF), increasing the mass of the compound, and resulting in a longer-lasting form of G-CSF. This makes it more convenient to use pegfilgrastim as a single-day injection. This study was a prospective phase II single-center trial. Fifteen normal related donors received pegfilgrastim 12 mg subcutaneously to mobilize peripheral blood stem cells (PBSC) for allogeneic stem cell transplantation. Leukapheresis was planned to start 3 days after injection. All harvests were successful. Median number of leukapheresis was 2 days (range 1–3 days). There were 7/15 donors who only required single leukapheresis. The maximum concentration of white blood cells (WBC) and circulating CD34 cells occurred 3 days after pegfilgrastim injection (WBC: median 62,200/μl; CD34: median 69.76/μl). The median yield of CD34 cells was 6.78 × 10⁶/kg recipient weight. The median CD3 cells was 1.89 × 10⁸/kg recipient weight. The main adverse events were bone pain and headache. Median neutrophil and platelet engraftments in the recipients occurred on day 12 and day 13, respectively, after transplantation. PBSC mobilization with single-day injection of pegfilgrastim in normal donor is feasible. Further comparisons of this protocol to standard G-CSF for allogeneic stem cell mobilization should be conducted in future.     

Attenuation of eNOS expression in cadmium-induced hypertensive rats

Cadmium (Cd) has been reported to induce hypertension in both humans and animals; however, its mechanism has not been clearly elucidated. Vascular tone is one of the factors contributing to hypertension. This study was conducted to investigate the effects of Cd exposure on vascular muscarinic receptor responses to acetylcholine (ACh) in isolated aortas. Male Sprague-Dawley rats were exposed to Cd via drinking water (5, 10 and 50 ppm) for 3 months. Cd 10 and 50 ppm exposure caused significant decreases in the sensitivity of vascular muscarinic receptors to ACh. However, Cd exposure did not alter the vascular relaxation induced by sodium nitroprusside (SNP) which is a nitric oxide donor. Consistent with the reduction of ACh-induced relaxation, treatment with Cd decreased endothelial nitric oxide synthase (eNOS) protein level in blood vessels. These results suggested that Cd suppressed ACh-induced vascular relaxation by interfering with muscarinic receptor function, and its downstream signaling pathway may be one of the contributing factors for the development of hypertension.     

Interaction of human and rat organic anion transporter 2 with various cephalosporin antibiotics

Cephalosporin antibiotics are thought to be excreted into the urine via organic anion transporters (OATs) and OAT can mediate nephrotoxicity by cephalosporins, particularly by cephaloridine. The purpose of this study was to elucidate the interaction of human-OAT2 and rat-OAT2 with cephalosporin antibiotics using proximal tubule cells stably expressing human-OAT2 and rat-OAT2. Human-OAT2 is localized to the basolateral side of the proximal tubule, whereas rat-OAT2 is localized to the apical side of the proximal tubule. Cephalosporins tested were cephalothin, cefoperazone, cefazolin, ceftriaxone, cephaloridine, cefotaxime, cefadroxil and cefamandole. These cephalosporins dose-dependently inhibited organic anion uptake mediated by human-OAT2 and rat-OAT2. There was no species difference observed for the effects of OAT2 with cephalosporins between human and rat transporters. Kinetic analysis revealed that the inhibitory effects for human-OAT2 were competitive. Cephaloridine significantly decreased the viability of cells stably expressing human-OAT2, human-OAT1, human-OAT3 and human-OAT4. The decreased viability of cells stably expressing human-OAT1, human-OAT3 and human-OAT4 but not human-OAT2 was reversed by probenecid. In conclusion, human-OAT2 interacts with cephalosporins, and thus, human-OAT2 may mediate the uptake of cephalosporins on the basolateral side of the proximal tubule. The interaction of human-OAT2 with cephalosporins was the weakest among the basolateral human-OATs tested. In addition, it is suggested that human-OATs mediate cephaloridine-induced nephrotoxicity.