ß-Thalassemia trait association with autoimmune diseases: ß-globin locus proximity to the immunity genes or role of hemorphins?

Thalassemia major continues to be a significant health problem for Mediterranean, Afro-Arabic countries, India and South Easth Asia. It was generally assumed that the ß-thalassemia heterozygotes do not bear significant medical risks except a mild microcytic anemia. Nonetheless, increasing number of reports associate ß-thalassemia trait with autoimmune conditions, nephritis, diabetes, arthritis, fibromyalgia and asthma. Available sparse data indicate reduced incidence of systemic lupus erythematosus (SLE) in ß-thalassemia heterozygotes; yet, if two conditions coexist, the SLE manifestations occur much severer. These associations make sense when considering that the hemoglobin ß-chain locus at 11p15.5 resides in close proximity to eight genes with profound roles in immune regulation: STIM1, CD151, TC21/RRAS2, SIGIRR/TOLL/IL1R8, pp52/LSP1 (lymphocyte specific protein), TRIM21, toll interacting protein (TOLLIP) and SLEN3. ß-Thalassemia trait accompaniment to autoimmune disease may be the result of haplotypal associations between the close proximity genes. An alternative explanation to thalassemia heterozygosity: autoimmune disease association may be the changed concentrations of hemorphins. Hemorphins are endogenous opioid peptides derived via proteolytical cleavage of hemoglobin. They are shown to bind diverse opioid receptors and act anti-inflammatory. Their reduced expression in thalassemia heterozygosity may explain a proinflammatory stage and autoimmunity vulnerability.

Employing volcanic tuff minerals in interior architecture design to reduce microbial contaminants and airborne fungal carcinogens of indoor environments.

Indoor volatile organic compounds (VOCs) have posed significant risks to human health since people have both shifted to a life spent, for the most part, indoors. Further, changes in materials used in the construction of buildings, furnishings, and tools either leak or encourage the production of VOCs. Whether these enclosed areas are residences, hospitals or workplaces (specifically composting facilities or closed farm buildings for raising livestock), VOCs can rise to levels that threaten people's health. VOCs can either originate from phenolic and benzene-like compounds in building materials and office furniture or from molds (fungi) growing inside improperly ventilated or sealed buildings. Regardless of the source, exposure to VOCs could lead to significant health concerns from sick-building syndrome, 'leukemia houses,' in-hospital fungemia cases or occupation-associated cancer epidemics due to aflatoxicosis. Innovative 21st-century building materials could offer solutions to these challenges. We propose that volcanic materials, clays and minerals (volcanic tuff, modified clay montmorillonite and mineral clinoptilolite), in their original or chemically modified form, could act like synthetic lungs in building walls, breathing and filtering VOCs, and thus limiting human exposure to disease.

Two possible cases of Trichosporon infections in bone-marrow-transplanted children: the first case of T. japonicum isolated from clinical specimens.

Trichosporon spp. are emerging as opportunistic agents that cause systemic diseases in immunocompromised hosts. Trichosporonosis carries a poor prognosis in neutropenic patients. Trichosporon japonicum was isolated from the air and named by Sugita et al. Here we present the first case of T. japonicum isolated from a clinical specimen. Two cases of acute myeloid leukemia who had Trichosporon isolates are discussed because of their rarity and growing importance. T. asahii was isolated from the throat, feces and urine of the first patient. T. japonicum was isolated from the sputum of the second patient. Both cases produced high MICs to itraconazole, and low MICs to fluconazole and voriconazole. In virulance factor investigations there was (++) biofilm formation in T. japonicum but not in T. asahii. Conventional mycological studies were not adequate for the identification of the isolate at the species level. In our second case as in the first one, the isolate was identified as T. asahii with 99.9% accuracy by API 20C AUX. Although two T. asahii isolates from the same patient yielded identical typing profiles by arbitrary primed-PCR, the isolates of the two different patients showed different arbitrary primed-PCR typing profiles. However, the genetic identification of the other patient's strain gave the result of T. japonicum.

Medroxyprogesterone acetate induces c6 glioma chemosensitization via antidepressant-like lysosomal phospholipidosis/myelinosis in vitro.

The authors have previously shown that medroxyprogesterone acetate (MPA) inhibits growth and increases drug sensitivity in C6 glioma with myeloid bodies. Myeloid bodies can occur in cells either due to robust toxicity with mitochondrial membrane disruption or due to milder events such as seen in lysosomal-phospholipidosis. Exact patterns of myelinosis accompanying to MPA chemo-sensitization is important, because uncoupling of nuclear versus mitochondrial toxicity of anti-neoplastics by MPA would lead to safer employment of glioma chemotherapy with reduced neurotoxicity. By monitoring and comparing cell kinetics with fine structural features of cell death, the authors estimated subcellular effects accompanying growth-inhibitory drug actions in C6 glioma. The analysis revealed that MPA induced mainly lysosomal phospholipidosis, while inhibiting clonogenicity alone and augmenting procarbazine efficacy. It induced apoptosis in combination with cisplatin. It reduced mitochondrial-damage-based early cytotoxicity of methotrexate, yet it did not hinder its anti-clonogenic efficacy. Progesterone analogues - similar to antidepressants - inhibit cholesterol esterification, and this efficacy relates with their P-glycoprotein inhibition. Reducing esterification and plasma-membrane localization of cholesterol may lead MPA induction of lysosomal phospholipidosis, growth indolency, and drug sensitization in glioma.

Medroxyprogesterone and tamoxifen augment anti-proliferative efficacy and reduce mitochondria-toxicity of epirubicin in FM3A tumor cells in vitro.

We have shown that low doses of medroxyprogesterone acetate (MPA- 2.6 microM) and tamoxifen (TAM- 270 nM) could augment the effectiveness of epirubicin in breast tumor cells. In this study, we monitored early cell kinetics (24-96 h plating and S-phase) and mitochondrial morphology during chemo-endocrine treatments to delineate the epirubicin sensitizing mechanism. S-phase fractions with radioactive thymidine uptake, plating efficacy, and transmission electron microscopic analysis were taken for 24-h periods until the 7th day after drug treatments. Despite strongly enhancing the clonogenic killing, both MPA and TAM did not affect epirubicin induced early cytotoxicity. Instead, they augmented the S-phase inhibition, which was even more pronounced for TAM. Epirubicin induced prominent swelling and crista damage of mitochondria and fragmentation of nuclei. Mitochondria were a normal size during a combination of epirubicin with either MPA- or tamoxifen treatment, despite the persistence of chromatin fragmentation and strong synergism on the clonogenic killing of breast tumor cells. Low dosage endocrine agent-induced anthracycline sensitization may be independent of mitochondrial toxicity. Further studies would be worthwhile, since the uncoupling of mitochondrial toxicity from the anti-neoplastic effect may also mean obviated cardiac toxicity in clinic.

Medroxyprogesterone - valproic acid - aspirin. MVA regime to reduce transfusion associated mortality in late-term hemoglobinopathies. Hypothesis and rationale.

Medroxyprogesterone acetate (MPA) - a safe depot contraceptive - is shown previously to reduce painful crises of sickle cell anemia, which is parallel with the recent findings showing progesterone induction of fetal hemoglobin genes. This would be a way to reduce transfusions for late term thalassemia major and sickle cell-disease cases with no chances left for a stem cell transplantation. In these patients, transfusional hemosiderosis causes irreversible damage to many organs despite the available iron-chelating agents. Pharmacological strategies either target the conformal structure of the defective adult hemoglobin or aim to activate fetal hemoglobin concentrations. The only concern on MPA may be its thromboembolic risks, which may be uncoupled with agents acting both anti-coagulant and inductive on the blood oxygen-carrying affinity. Such agents could be valproic acid and aspirin. Valproic acid is being safely used to treat epilepsy and its histone acetylating function may lead its induction of fetal hemoglobin. Aspirin was shown to increase oxygen affinity of hemoglobin via acetylating lysine residues and its general acetylating activity on proteins such as histones makes it also an interesting candidate to activate fetal hemoglobin. We propose that combining MPA with clinically available doses of valproic acid and aspirin would be beneficial in terms of both reduced coagulation risks and increased oxygen affinity to decrease the transfusions and to improve the prognosis in late-phase hemoglobin disorders.

Noscapine and diltiazem augment taxol and radiation-induced S-phase arrest and clonogenic death of C6 glioma in vitro.

BACKGROUND: Radiation therapy after surgical resection is the approved treatment of gliomas, and survival benefits are reported with taxane-based chemotherapy. We investigated whether these regimes could be augmented with blood-brain barrier permeable drugs, N and D. Noscapine is an opioid antitussive, which acts anti cancer via blocking microtubule dynamics. Diltiazem is a calcium channel-blocking cardiac antiarrythmic, which also blocks tumor growth and P-glycoprotein. METHODS: Effects of N (11.1 micromol/L), D (11.1 micromol/L), and T (11.7 micromol/L) were monitored in C6 glioma cells via S phase, colony formation, and fine structure analysis. RESULTS: Taxol depleted S phase from 35.2% to 12.2%. Both N and D synergistically augmented T-mediated S-phase depletion, and they also effectively reduced colonies, which were more potent by N by 49%. Taxol reduced colonies by 98%, and there were almost no surviving colonies in copresence of T with either N or D. Colony reduction by radiotherapy was increased strongly by T and significantly by N. Taxol and radiation profoundly increased number of mitochondria. Both D and N suppressed this increase via myelinosis and autophagy. CONCLUSION: Noscapine and D should be further tested in animal models because of their potential and already-present clinical applicability.

Fecal fungal flora of pediatric healthy volunteers and immunosuppressed patients.

Most hematogenous candidiasis originates from endogeneous host flora. Fungal flora of gastrointestinal system are important source of infection especially in immunosupressed patients. The purpose of this study was to investigate the fecal fungal flora of pediatric patients with hematologic malignancy or disorders and to compare the results with healthy volunteers. For this purpose, fungal etiological agents were investigated retrospectively in stool samples of 80 patients followed in Bone marrow transplantation and Hematology-Oncology units. The diagnosis of patients were as follows: 26 acute myelogeneous leukemia, 19 acute lymphocytic leukemia, 5 lymphoma, 3 chronic myelogeneous leukemia, 2 solid tumor, 4 neuroblastoma and 21 hematologic disorders. In patients, totally 102 fungal growth was detected and 42 (41.2%) C. albicans and 51 (50%) non-albicans Candida species and 9 (8.8%) yeast other than Candida and mould was isolated. The results were compared prospectively with growth in stool samples of 61 healthy children. C. albicans was detected in 16 (43.2%) and non-albicans Candida species in 15 (40.5%) and yeasts other than Candida and mould in 6 (16.2%) of 37 fungal growth in controls. Non-albicans Candida species growth was found significantly higher and C. glabrata was more prevelant in patients than in controls (p < 0.001).

Allogeneic versus autologous versus peripheral stem cell transplantation in CR1 pediatric AML patients: a single center experience.

BACKGROUND: Treatment of childhood acute myelocytic leukemia (AML) in first remission, is still evolving. Allogeneic bone marrow transplantation (BMT) in patients with a donor has been well established, but the role of autologous transplantation remains of interest, particularly in the light of some encouraging results in adults. PROCEDURE: Out of 81 pediatric patients with AML in first CR, 67 were biologically randomized for allogeneic (n = 31), autologous (n = 20), or peripheral stem cell transplant (n = 16) after completing consolidation treatment, with the remaining (n = 11) dropping out or receiving chemotherapy. Disease free survival (DFS) of these different groups were analyzed. RESULTS: Allogeneic transplantation is not superior to autologous and autologous peripheral blood stem cell transplantation (PBSCT) (DFS in 5 years is 61%, 50%, and 75%). The 5 years DFS in the autologous PBSCT group is significantly better than in the autologous BMT group (75% vs. 50%, P < 0.05). CONCLUSION: In pediatric AML patients without a donor, autologous BMT or autologous PBSCT appears to be an effective treatment option with low transplant related mortality especially in less privileged countries where the chemotherapy only results are still low.

Prognostic significance of the TEL-AML1 fusion gene in pediatric acute lymphoblastic leukemia in Turkey.

PURPOSE: The t(12;21) translocation is the most common reciprocal chromosomal rearrangement in pediatric acute lymphoblastic leukemia (ALL). This translocation fuses two genes, TEL and AML1, and results in the production of the TEL-AML1 fusion protein. The authors investigated the incidence and prognostic significance of the TEL-AML1 fusion gene in patients with ALL in Turkey. METHODS: The authors analyzed 219 children with ALL using the reverse transcription-polymerase chain reaction. RESULTS: The TEL-AML1 fusion transcript was detected in 20.1% (44/219) of newly diagnosed children with ALL. -positive patients had precursor B-cell ALL and were 3 to 10 years old at diagnosis. -positive patients had a significantly lower rate of relapse compared with -negative patients. -positive patients have a higher overall survival rate than -negative patients. CONCLUSIONS: These data support that the presence of at diagnosis is an independent favorable prognostic indicator in patients with ALL in Turkey.

[The use of real-time polymerase chain reaction and enzyme immunoassay for the diagnosis of acute parvovirus B19 infections in immunosuppressed patients]. / Immünsüpresif hastalarda akut parvovirus B19 enfeksiyonunun tanisinda enzim immún yóntemi ile gerçek zamanli polimeraz zincir reaksiyonunun kullanimi.

Human parvovirus B19 (PV-B19) infection may lead to very serious clinical situations such as transient aplastic crisis in patients with hemolytic anemia, thrombocytopenia, neutropenia and transient arthritis accompanied with erythema infectiosum, especially in immunosuppressed patients. Early diagnosis of PV-B19 infection is of critical importance especially in immunosuppressed patients since the necessary precautions can be undertaken accordingly. In this study, PV-B19 IgM and IgG antibodies and viral DNA have been searched by enzyme immunoassay (ELISA) and real-time polymerase chain reaction (PCR), respectively, in 50 PV-B19 suspected immunosuppressed patients. Viral IgM, IgG and DNA positivities were detected in 7 (14%), 20 (40%) and 7 (14%) of the patients, respectively. During the first week three patients were found DNA and IgM positive but IgG negative, while four patients were found positive for the viral DNA, IgM and IgGs. The DNA copy numbers were high in all of the patients during the first week, with a gradual decrease during a seven-week follow-up period. IgM antibodies have disappeared in the sixth week in three of the patients and at the end of the seventh week in four of the patients. Although the IgG antibodies were negative in three patients in the first week, they became positive in the second week and the titers gradually increased during the following weeks. According to the results of this study, it can be concluded that, in high risk groups such as immunosuppressed patients, in addition to ELISA, real-time PCR method would be helpful for the early diagnosis of PV-B19 infections.