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Abstract: (–)-Epigallocatechin-3-gallate (EGCG), the major active polyphenol extracted from green tea, has been shown to induce apoptosis and inhibit cell proliferation, cell invasion, angiogenesis and metastasis. Herein, we evaluated the in vivo efects of EGCG in acute myeloid leukaemia (AML) using an acute promyelocytic leukaemia (APL) experimental model (PML/RARa). Haematological analysis revealed that EGCG treatment reversed leucocytosis, anaemia and thrombocytopenia, and prolonged survival of PML/RARa mice. Notably, EGCG reduced leukaemia immature cells and promyelocytes in the bone marrow while increasing mature myeloid cells, possibly due to apoptosis increase and cell diferentiation. The reduction of promyelocytes and neutrophils/monocytes increase detected in the peripheral blood, in addition to the increased percentage of bone marrow cells with aggregated promyelocytic leukaemia (PML) bodies staining and decreased expression of PML-RAR oncoprotein corroborates our results. In addition, EGCG increased expression of neutrophil diferentiation
markers such as CD11b, CD14, CD15 and CD66 in NB4 cells; and the combination of all-trans retinoic acid (ATRA) plus EGCG yield higher increase the expression of CD15 marker. These fndings could be explained by a decrease of peptidyl-prolyl isomerase NIMA-interacting 1 (PIN1) expression and reactive oxygen species (ROS) increase. EGCG also decreased expression of substrate oncoproteins for PIN1 (including cyclin D1, NF-?B p65, c-MYC, and AKT) and 67 kDa laminin receptor (67LR) in the bone marrow cells. Moreover, EGCG showed inhibition of ROS production in NB4 cells in the presence of N-acetyl-L-cysteine (NAC), as well as a partial blockage of neutrophil diferentiation and apoptosis, indicating that EGCG-activities involve/or are in response of oxidative stress. Furthermore, apoptosis of spleen cells was supported by increasing expression of BAD and BAX, parallel to BCL-2 and c-MYC decrease. The reduction of spleen weights of PML/RARa mice, as well as apoptosis induced by EGCG
in NB4 cells in a dose-dependent manner confrms this assumption. Our results support further evaluation of EGCG in clinical trials for AML, since EGCG could represent a promising option for AML patient ineligible for current mainstay treatments

Hematopoietic stem cells (HSC) are responsible for the production of blood and immune cells during life. HSC fate decisions are dependent on signals from specialized microenvironments in the bone marrow, termed niches. The HSC niche is a tridimensional environment that comprises cellular, chemical, and physical elements. Introductorily, we will revise the current knowledge of some relevant elements of the niche. Despite the importance of the niche in HSC function, most experimental approaches to study human HSCs use bidimensional models. Probably, this contributes to the failure in translating many in vitro findings into a clinical setting. Recreating the complexity of the bone marrow microenvironment in vitro would provide a powerful tool to achieve in vitro production of HSCs for transplantation, develop more effective therapies for hematologic malignancies and provide deeper insight into the HSC niche. We previously demonstrated that an optimized decellularization method can preserve with striking detail the ECM architecture of the bone marrow niche and support HSC culture. We will discuss the potential of this decellularized scaffold as HSC niche model. Besides decellularized scaffolds, several other methods have been reported to mimic some characteristics of the HSC niche. In this review, we will examine these models and their applications, advantages, and limitations

Abstract: Purpose F-18-fluorodeoxiglucose (F-18-FDG)-PET/CT has been widely used to evaluate multiple myeloma.Tc-99m-sestamibi (MIBI) scintigraphy has also been proposed for assessing multiple myeloma, but its use with state-of-the-art single-photon emission computed tomography/computed tomography (SPECT/CT) technology has not been fully evaluated.This study aimed to compare these two imaging modalities in multiple myeloma staging. Materials and methods Sixty-two patients with recently diagnosed multiple myeloma were submitted to whole-body(18)F-FDG-PET/CT and whole-body MIBI scans plus SPECT/CT of the chest and abdomen/pelvis. Number of focal lesions, contiguous soft tissue involvement (CSTI), extramedullary lesions (EMLs) and diffuse bone marrow (BM) involvement were recorded. Results PET/CT was positive in 59 patients (95%) and MIBI SPECT/CT in 58 (93%) (P = 0.69). MIBI detected more diffuse bone marrow involvement than PET/CT (respectively 78 vs. 58% of the patients), while PET/CT demonstrated more focal lesions than MIBI SPECT/CT (81 vs. 54% of the patients) (P = 0.002). PET/CT detected EMLs in four subjects and MIBI in one subject. CSTI was found in 28 (45%) and 23 (37%) patients on PET/CT and MIBI images, respectively (P = 0.36). Three patients with lytic lesions and no FDG uptake were MIBI positive, and two subjects with lytic lesions without MIBI uptake were FDG positive. Conclusion MIBI SPECT/CT performs similarly to(18)F-FDG-PET/CT in identifying sites of active disease in multiple myeloma staging. MIBI is more efficient than FDG for detecting the diffuse involvement of bone marrow but less efficient for detecting focal lesions. Some patients presented a 'mismatch' pattern of FDG/MIBI uptake

Resumo: A associação de mutações em genes relacionados às anemias hemolíticas hereditárias (AH) pode afetar o fenótipo da doença. Compreender sua base genética é crucial para evitar erros diagnósticos e para o manejo clínico adequado. As ß-talassemias (BT) são caracterizadas por uma redução da produção de ß-globina causada principalmente por mutações de ponto no gene HBB ou em regiões próximas. O desequilíbrio entre a produção das globinas a e ß resulta em eritropoiese ineficaz e hemólise. A esferocitose hereditária (EH) é caracterizada por anormalidades nas proteínas da membrana eritrocitária, com esferócitos osmoticamente frágeis, graus variados de hemólise e anemia. A EH relacionada à deficiência de espectrina é clinicamente heterogênea, variando de hemólise bem compensada a anemia grave. Aqui descrevemos dois casos de pacientes com anemia hemolítica microcítica e hipocrômica grave com HbA2 elevada, clinicamente compatível com BT intermediaria ou maior. No entanto, o sequenciamento do gene HBB revelou apenas traço BT, não justificando a apresentação clínica. A pesquisa de deleções ou outras mutações para BT foi negativa. Prosseguimos então com investigação genética adicional através de exoma. Investigar mutações adicionais relacionadas às AH que possam contribuir para um fenótipo de anemia grave em pacientes com traço BT. Dados clínico-laboratoriais foram coletados pela avaliação de prontuários. O sequenciamento do gene HBB foi inicialmente realizado por Sanger. O exoma foi realizado utilizando a plataforma Illumina HiSeq2500. O CEP da instituição aprovou a pesquisa e as pacientes assinaram TCLE. A paciente 1 apresentava quadro de eventual necessidade transfusional, sobrecarga hepática moderada de ferro e esplenomegalia. O esfregaço de sangue periférico mostrava hemácias microcíticas e hipocrômicas, esferócitos e eritroblastos circulantes. Seu pai era assintomático, com anemia hiperproliferativa microcítica hipocrômica leve, e sua mãe apresentava hemoglobina e reticulócitos normais. A paciente 2 apresentava dependência transfusional, hematopoiese paravertebral extramedular, sobrecarga hepática moderada de ferro, hipertensão pulmonar leve e úlceras em pernas. O esfregaço de sangue periférico mostrava hemácias microcíticas e hipocrômicas, moderada quantidade de esferócitos e eritroblastos circulantes; os dados dos seus familiares não estavam disponíveis. O exoma foi realizado e, além das mutações da ß-globina previamente conhecidas, foram encontradas mutações no gene da espectrina na paciente 1 (SPTB p.Leu 880Gln) e na paciente 2 (SPTB p.Asp536Asn). O pai da paciente 1 foi diagnosticado com uma mutação heterozigótica no gene HBB, enquanto sua mãe foi diagnosticada com a mutação heterozigótica SPTB p.Leu 880Gln, clinicamente silenciosa. Ambas mutações da espectrina já foram descritas na literatura: SPTB p.Leu 880Gln foi relatada em associação com uma mutação no gene SPTA1, resultando em anemia moderada, enquanto a mutação SPTB p.Asp536Asn foi descrita em um indivíduo não anêmico. Nossos resultados indicam que a associação de mutações heterozigóticas de BT e espectrina pode resultar em um fenótipo de anemia moderada a grave. Os dados mostram que, em casos de anemia grave associada com traço BT, as mutações responsáveis pela EH devem ser investigadas

A new calorimetric technique is described which allows the measurement of metabolic heat rates in biological materials which are triggered by changes in the oxygen tension. It uses the high permeability for oxygen of a thin-walled Teflon flow channel of a chip calorimeter in order to adjust variable but defined oxygen concentrations in the samples. Using this technique, for the first time, the heat production rate of sickle cell erythrocytes (SS-RBCs) in sickled and non-sickled state could be compared. To measure heat rate changes in real time when sickled SS-RBCs return to the non-sickled state, the heat dissipation was measured during the re-oxygenation of the cell samples which had been treated before under anoxic conditions. We found higher heat production rate of the blood cells in non-sickled state, which is in agreement with the reported increased glucose uptake

The development of inhibitory antibodies against factor VIII (FVIII) (inhibitor) is the major complication in haemophilia A patients. The FVIII‐binding antibodies development comprises a polyclonal immunoglobulin (Ig) G response. Recent studies showed strong correlation between the presence of neutralizing anti‐FVIII antibodies (inhibitors) and IgG4 subclass. The aim of this study was to evaluate anti‐FVIII IgG subclasses in haemophilia A patients with inhibitor both in a cross‐sectional and in a longitudinal analysis. Inhibitors were determined by Nijmegen–Bethesda assay. Anti‐FVIII IgG subclasses were performed by ELISA, and samples from 20 healthy individuals were used to validate the test. We studied 25 haemophilia A patients with inhibitor, previously treated exclusively with plasma‐derived FVIII concentrates or bypassing agents. The IgG subclasses distributions were evaluated in two groups of patients classified according to inhibitor response. IgG1 and IgG4 antibodies were most prominent in haemophilia A patients with inhibitors when compared with IgG2 and IgG3. This study reports for the first time the behaviour of FVIII‐binding IgG1 and IgG4 subclasses in a longitudinal analysis, in a clinical setting, of high‐response inhibitor haemophilia A patients, showing the correlation of IgG4 and the inhibitor titres. In spite of being considered a non‐pathologic antibody subclass with anti‐inflammatory properties in other situations, IgG4 is correlated with the presence of high‐titre inhibitor in the haemophilia setting. The comprehension of the IgG4 role in immune response may be crucial to establish the process for designing specific tolerance to FVIII

Background. As an alternative to phenotyping, large-scale DNA-based assays, which are feasible for high-throughput donor red blood cell typing, were developed for determination of blood group polymorphisms. However, high-throughput genotyping platforms based on these technologies are still expensive and the inclusion of single nucleotide polymorphisms and analysis of the alleles depend on the manufacturer's determination. To overcome this limitation and in order to develop an assay to enable the screening of rare donors, we developed a SNaPshot assay for analysis of nine single nucleotide polymorphisms related to antigens that are difficult to assess using conventional serology. Materials and methods. The single polymerase chain reaction multiplex SNaPshot reaction was optimized to identify nine single nucleotide polymorphisms determining 16 alleles: KEL*3/KEL*4, KEL*6/KEL*7, DI*1/DI*2, DI*3/DI*4, YT*1/YT*2, CO*1/CO*2, DO*1/DO*2, DO*4, DO*5. We designed a single multiplex PCR with primers encompassing the blood group single nucleotide polymorphisms and performed an internal reaction with probe primers able to discriminate the alleles after fragment analysis. The SNaPshot assay was validated with 140 known alleles previously determined by PCR restriction fragment length polymorphism. Results. We were able to simultaneous detect nine single nucleotide polymorphisms defining 16 blood group alleles on an assay based on a multiplex PCR combined with a single base extension using genomic DNA. Discussion. This study demonstrates a robust genotyping strategy for conducting rare donor screening which can be applied in blood centers and could be an important tool for identifying antigen-negative donors and, therefore, for providing rare blood

Abstract: Hematopoietic cell kinase (HCK) belongs to the Src kinase family (SFK) involved in the oncogenic process and hematological malignancy. Some SFK inhibitors are currently under investigation in clinical trials for leukemia after demonstrating efficacy in patients with solid tumors. We have previously reported that HCK is overexpressed in leukemic cells and its inhibition by lentivirus resulted in reduction of cell growth and increased cell death (Roversi et al. BBA Mol Basis Dis. 2017, 1863(2):450-61). In light of the genomic and molecular diversity of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), the development of chemical compounds specific for new molecular targets is currently an important subject. To investigate the in vitro and in vivo effects of a new chemical compound targeting HCK inhibition (iHCK), alone or in combination with the most used drugs for treatment of MDS and AML (Azacytidine - Aza - or Cytarabine - Ara-C). After iHCK development, we tested its activity alone or in combination with Aza or Ara-C in CD34+ cells isolated from AML patients (n=5) as well as in a panel of myeloid leukemia cell lines (KG1, HL-60, HEL and K562). Additionally, we tested the iHCK in normal and malignant cells cultured in a 3D bioscaffold obtained by decellularization of bovine bone marrow (Bianco et al. Biomat Sci 2019, 7(4):1516-28), in order to mimic the bone marrow niche. After informed written consent and approval of the Ethical Committee of University of Campinas (CAAE 1000.0.146.00-11), in accordance to the Helsinki Declaration, CD34+ cells were isolated from bone marrows of healthy donors (HD), MDS and AML patients and were treated with iHCK or vehicle (DMSO) in liquid culture, for three days. Meanwhile, HS-5 mesenchymal cells were cultured into the 3D bioscaffold. iHCK or vehicle treated CD34+ cells were introduced into the 3D bioscaffold containing HS-5 and evaluated after 7 and 14 days, by light microscopy (hematoxilin and eosin regular staining) and immunohistochemistry (expression of CD34 and CD90 antigens). NOD.CB17-Prkdcscid/J mice received 2 Gy irradiation followed by transplantation with caudal intravenous injection of leukemia cells obtained from hCG-PML-RARa transgenic mice. After acute promyelocytic leukemia (APL) establishment, animals were treated or not with intraperitoneally iHCK and peripheral blood was collected for hematological analysis and protein was extracted from spleen and bone marrows for Western Blot analysis. ANOVA and Student's T-Test were used. In leukemia cell lines and primary cells, the combinatory treatment of iHCK and Cytarabine (1µM) or 5-Azacitidine (1µM) demonstrated synergistic effects, compared to either drug alone, on the reduction of growth and induction of cell death (P<0.001; Figure 1). Further, Western blot revealed increased BAX expression and decreased BCL-XL expression. Moreover, iHCK treatment was able to reduce the activation of oncogenic pathways, MAPK/ERK and PI3K/AKT, leading to severe reduction of ERK, AKT and p70S6 phosphorylation. Treatment with iHCK reduced CD34+ MDS and AML cells proliferation cultured into the 3D bioscaffold but had no effect upon normal CD34+cells. In vivo analysis showed that APL mice treated with iHCK (5µM) for 48h had reduced leukocyte number compared to APL mice treated with vehicle (13.2±1.1 vs 49.4±18.8; P<0.001). No alterations in hemoglobin levels and platelet were found. Likewise, the in vivo iHCK (2.5µM, 5.0µM or 10.0µM) treatment decreased the phosphorylation of ERK, AKT and P70S6K proteins of leukemic cells (Figure 2).The iHCK pharmacological inhibitor has an antiproliferative activity in leukemic cells without altering cell death and survival rate of normal cells, demonstrating on-target malignant cell killing activity as a single agent or in combination with Azacytidine (Aza) or Cytarabine (Ara-C)

Dombrock blood group system has 10 antigens being two antithetical and eight antigens of high prevalence attached to the outer surface of the red blood cell (RBC) membrane through a glycosylphosphatidylinositol (GPI)‐linked glycoprotein of 314 amino acids.1 The Donull [Gy(a–)] phenotype has been reported to be associated with both DO*01 and DO*02 alleles as a result of exon deletion, nonsense mutation, nucleotide deletion, and missense mutation. To date, seven DO null alleles have been reported.2 Here we describe a new DO*01 silent allele in a Brazilian patient, caused by a c.728_729insG nonsense mutation, leading to a Gy(a–) phenotype

Abstract: The therapeutic landscape for people living with hemophilia A (PwHA) has changed dramatically in recent years, but many clinical challenges remain, including the development of inhibitory antibodies directed against factor VIII (FVIII) that occur in about 30% of people with severe hemophilia A. Emicizumab, a FVIII mimetic bispecific monoclonal antibody, provides safe and effective bleeding prophylaxis for many PwHA, but clinicians still explore therapeutic strategies that result in immunologic tolerance to FVIII to enable effective treatment with FVIII for problematic bleeding events. This immune tolerance induction (ITI) to FVIII is typically accomplished through repeated long-term exposure to FVIII using a variety of protocols. Meanwhile, gene therapy has recently emerged as a novel ITI option that provides an intrinsic, consistent source of FVIII. As gene therapy and other therapies now expand therapeutic options for PwHA, we review the persistent unmet medical needs with respect to FVIII inhibitors and effective ITI in PwHA, the immunology of FVIII tolerization, the latest research on tolerization strategies, and the role of liver-directed gene therapy to mediate FVIII ITI

To review the literature for outcome measures for oral viral infections in cancer patients. A secondary aim was to update the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) clinical practice guidelines for the management of oral viral infections in cancer patients.
Databases were searched for articles published in the English language, 1981-2013. Studies that met the eligibility criteria were reviewed systematically. The data about the outcome measures were classified according to the aim of the study: prevention, treatment, or non-interventional. The results of interventional studies were compared to the 2010 MASCC/ISOO publication.
Multiple clinical and laboratory tests were used to measure oral viral infections, with great variability between studies. Most of the studies were about Herpes Simplex Virus (HSV). The outcome measure that was most commonly used was the presence of HSV infection diagnosed based on a combination of suggestive clinical presentation with a positive laboratory result. HSV culture was the most commonly reported laboratory outcome measure. Acyclovir and valacyclovir were consistently reported to be efficacious in the management of oral herpetic infections. No new data on the quality of life and economic aspects was found.
Considering the variability in outcome measures reported to assess oral herpetic infections the researcher should select carefully the appropriate measures based on the objective of the study. Acyclovir and valacyclovir are effective in the management of oral herpetic infections in patients receiving treatment for cancer. Studies on newer anti-viral drugs may be useful to address the issue of anti-viral resistance

Sickle cell disease (SCD) is a complex disease that is characterized by the polymerization of deoxyhemoglobin S, altered red blood cell membrane biology, endothelial activation, hemolysis, a procoagulant state, acute and chronic inflammation, and vaso-occlusion. Among the physiological changes that occur during pregnancy, oxygen is consumed by fetal growth, and pregnant women with SCD are more frequently exposed to low oxygen levels. This might lead to red blood cells sickling, and, consequently, to vaso-occlusion. The mechanisms by which SCD affects placental physiology are largely unknown, and chronic inflammation might be involved in this process. This study aimed to evaluate the gene expression profile of inflammatory response mediators in the placentas of pregnant women with sickle cell cell anemia (HbSS) and hemoglobinopathy SC (HbSC). Our results show differences in a number of these genes. For the HbSS group, when compared to the control group, the following genes showed differential expression: IL1RAP (2.76-fold), BCL6 (4.49-fold), CXCL10 (-2.12-fold), CXCR1 (-3.66-fold), and C3 (-2.0-fold). On the other hand, the HbSC group presented differential expressions of the following genes, when compared to the control group: IL1RAP (4.33-fold), CXCL1 (3.05-fold), BCL6 (4.13-fold), CXCL10 (-3.32-fold), C3 (-2.0-fold), and TLR3 (2.38-fold). Taken together, these data strongly suggest a differential expression of several inflammatory genes in both SCD (HbSS and HbSC), indicating that the placenta might become an environment with hypoxia, and increased inflammation, which could lead to improper placental development

Resumo: O plasma rico em plaquetas (PRP), ou lisado plaquetário, é um produto autólogo obtido através de técnicas de separação por centrifugação do sangue do próprio indivíduo, utilizando-se a camada mais rica em plaquetas. As plaquetas secretam diversos fatores de crescimento que, quando liberados em áreas de lesão tecidual, estimulam a proliferação celular e o processo de cicatrização da região. É crescente o número de pacientes com diabetes em todo o mundo e a cura das feridas de pé diabético por alterações neurológicas e/ou vasculares é ainda um desafio. A maior adversidade é o tempo de cicatrização que se associa com desfechos desfavoráveis de amputação. O objetivo deste estudo é avaliar, através da mensuração dos tamanhos das úlceras e da escala de dor, a aplicabilidade do PRP em úlceras de pé diabético de paciente tipo 2, determinando as possíveis contribuições no processo cicatricial

Acquired ADAMTS13 inhibitor causing thrombotic thrombocytopenic purpura (TTP) may be precipitated by some infections, inflammatory diseases or neoplasia. We reported a case of refractory TTP precipitated by a newly diagnosed localized Castleman's disease (CD). TTP was initially treated with plasma exchange and immunosuppressive therapy with corticosteroids; however the treatment failed to promote sustained response. During hospitalization, an abdominal tumor was diagnosed and resected; the histological analysis revealed a CD of hyaline-vascular variant rich stroma. After tumor removal, the patient achieved a long-lasting clinical remission and normalized ADAMTS13 activity. This clinical case describes a novel association of acquired ADAMTS13 inhibitor and CD. The antibody to ADAMTS13 developed along with the systemic manifestation of CD and promptly disappeared after the resection of the tumor. There are reports of neoplasia-associated thrombotic microangiopathy however direct evidence of CD-dependent ADAMTS13 inhibitor had not yet been reported

Resumo: Uma das complicações mais debilitantes da Anemia Falciforme são as úlceras maleolares, por associarem-se a importantes quadros de dor, infecções secundárias e comprometimento estético. Na medicina ocidental, não há opções terapêuticas completamente satisfatórias para essa complicação, sendo utilizados cicatrizantes locais, antibióticos e curativos, com altas taxas de recorrência e complicações como osteomielite e amputação. Este estudo avaliou o efeito de técnicas da Medicina Tradicional Chinesa (MTC) sobre as úlceras maleolares crônicas de paciente do sexo masculino, HbSS, de 49 anos, em seguimento no Hemocentro UNICAMP. Foram realizadas 8 sessões contemplando acupuntura sistêmica (combinações de Pontos Fonte, Mestre, de Ação Energética e Vasos Maravilhosos), auriculoterapia chinesa e curativo com magnetos. Antes do tratamento e após 4 e 8 sessões, foram coletadas amostras de sangue para realização de hemograma completo, contagem de reticulócitos, dosagem de bilirrubinas, LDH, haptoglobina e Proteína C-Reativa (PCR), além de aplicação de questionários avaliando funcionalidade, impacto da dor e qualidade de vida (SF-6D e Escala de percepção global de mudança), mensuração do diâmetro das lesões e registro fotográfico. O desfecho primário escolhido foi a redução no diâmetro das lesões, e desfechos secundários avaliados foram diminuição da intensidade da dor, do uso de analgésicos, mudança positiva na qualidade de vida e diminuição nos níveis séricos de marcadores de hemólise e inflamação. Paciente apresentava na avaliação inicial 3 úlceras crônicas: maleolo medial esquerdo (aberta há 10 anos, medindo 6×5 cm), maleolo lateral esquerdo (surgiu há 10 anos, 9×6 cm), maleolo lateral direito (aberta há 4 anos, 1×1,5 cm), com agudizações frequentes de dor local e necessidade semanal de analgésicos. Apesar do desfecho primário não ter sido atingido (diminuição do diâmetro das lesões), observou-se grande diminuição do edema nos membros, incrementos positivos nos critérios de limitação, interação social, dor e sensação de vitalidade no SF-6D, assim como mudança positiva na percepção global do paciente ao longo do tratamento (5 pontos de 7) e uso apenas esporádico de analgésicos. Além disso, houve progressiva e importante redução no quadro inflamatório sistêmico, observado através de níveis decrescentes de PCR ao longo das avaliações (77-39-29 mg/L). O uso de técnicas da MTC foi bem aceito pelo paciente, levando a importante melhora na dor e edema local, diminuição no uso de analgésicos, incrementos nos indíces de qualidade de vida e demonstração de diminuição de inflamação sistêmica através de níveis de PCR decrescentes. Na medicina chinesa, inflamação é interpretada como quadro de umidade-calor, com deficiência energética de órgãos do elemento Terra, que são também responsáveis pela produção do sangue no organismo. Os pontos de acupuntura selecionados tiveram função energética de tonificar e mover o sangue, além de auxiliar na resolução da umidade, possivelmente relacionados com a redução de PCR observada após o tratamento. Estes resultados mostram que a acupuntura deve ser considerada como importante tratamento auxiliar das complicações das Doenças Falciformes

graft-versus-host disease (GVHD) is one of the main complications of hematopoietic stem cell transplantation, affecting about 50% to 80% of the patients. Acute GVHD and its clinical manifestations are discussed in this article, as well as the new NIH criteria for the diagnosis and classification of chronic GVHD. Therapy for both chronic and acute GVHD is an important field of discussion, as there is no proven superiority for the majority of therapies used after primary treatment has failed. Hence, this review is meant to be a useful consultation tool for hematologists dealing with this complex transplantation procedure complication

Hemolysis and consequent release of cell-free hemoglobin (CFHb) impair vascular nitric oxide (NO) bioavailability and cause oxidative and inflammatory processes. Hydroxyurea (HU), a common therapy for sickle cell disease (SCD), induces fetal Hb production and can act as an NO donor. We evaluated the acute inflammatory effects of intravenous water-induced hemolysis in C57BL/6 mice and determined the abilities of an NO donor, diethylamine NONOate (DEANO), and a single dose of HU to modulate this inflammation. Intravenous water induced acute hemolysis in C57BL/6 mice, attaining plasma Hb levels comparable to those observed in chimeric SCD mice. This hemolysis resulted in significant and rapid systemic inflammation and vascular leukocyte recruitment within 15 minutes, accompanied by NO metabolite generation. Administration of another potent NO scavenger (2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide) to C57BL/6 mice induced similar alterations in leukocyte recruitment, whereas hemin-induced inflammation occurred over a longer timeframe. Importantly, the acute inflammatory effects of water-induced hemolysis were abolished by the simultaneous administration of DEANO or HU, without altering CFHb, in an NO pathway mediated manner. In vitro, HU partially reversed the Hb-mediated induction of endothelial proinflammatory cytokine secretion and adhesion molecule expression. In summary, pathophysiological levels of hemolysis trigger an immediate inflammatory response, possibly mediated by vascular NO consumption. HU presents beneficial anti-inflammatory effects by inhibiting rapid-onset hemolytic inflammation via an NO-dependent mechanism, independently of fetal Hb elevation. Data provide novel insights into mechanisms of hemolytic inflammation and further support perspectives for the use of HU as an acute treatment for SCD and other hemolytic disorders

Abstract: Thrombotic antiphospholipid syndrome (t-PAPS) is characterized by arterial, venous, or microvascular occlusions, which are explained, in part, by the presence of antiphospholipid (aPL) antibodies. Although there is much evidence indicating that isolated aPL antibodies increase the activity of platelets obtained from healthy volunteers, platelet function in t-PAPS has not been as widely studied. To evaluate platelet reactivity in t-PAPS patients. Platelet aggregation, protein expression, and cyclic nucleotide levels were carried out in platelet rich plasma (PRP) or washed platelets (WPs) obtained from t-PAPS or healthy volunteers. ADP-induced aggregation was significantly higher in PRP obtained from t-PAPS than obtained from the control. The protein expression of P2Y12 receptor and Gs alpha was significantly higher and lower, respectively in WPs from t-PAPS patients. In PRP incubated with iloprost or sodium nitroprusside, the residual platelet reactivity induced by ADP was still higher in PRP from t-PAPS than from the control. Lower intracellular levels of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) were observed in unstimulated PRP from t-PAPS patients. The protein expression of soluble guanylate cyclase subunits and phosphodiesterases types 3 and 5 did not differ. The antiplatelet activity of ticagrelor was similar between the groups and cilostazol significantly potentiated this response. Isolated aPL antibodies obtained from t-PAPS patients potentiated ADP-induced aggregation in healthy platelets but did not affect the inhibitory responses induced by iloprost or sodium nitroprusside. The overexpression of P2Y12 receptor, accompanied by lower levels of cAMP and cGMP levels produced greater amplitude of ADP aggregation in platelets from t-PAPS patients

Abstract: Avaliar a adesão ao tratamento de pessoas com doença falciforme acompanhadas em um hemocentro da região norte de Minas Gerais. Estudo observacional, descritivo, conduzido a partir da avaliação de prontuários e aplicação de questionários a 70 portadores de doença falciforme, com posterior análise estatística descritiva. O estudo foi aprovado pelo Comitê de Ética em Pesquisa. O questionário foi organizado em três seções. A primeira seção contém questões sociodemográficas, a segunda contém perguntas relacionadas à farmacoterapia e à submissão dos pacientes a atendimentos especializados e exames, e a terceira questiona acerca da adesão ao tratamento, a partir de adaptação de Morisky-Green e Brief Medication Questionnaire. Dentre a amostra, 78,6% dos pacientes residiam entre 101 e 400 km de distância do hemocentro e 74,3% relataram necessitar de condução da prefeitura para acesso ao serviço de saúde. Foi frequente a prescrição de ácido fólico (92,9%) e todos os participantes com até 5 anos estavam em uso de penicilina. Entrevistados relataram uso de hidroxiureia (35,7%) e quelante de ferro (11,4%). 27,1% revelaram possuir alguma dificuldade no tratamento, sendo 78,4% relacionadas à obtenção dos medicamentos. A análise da adesão ao tratamento detectou escore alto ou médio em 97,1% dos entrevistados