bluuebunny/crossref_metadata_2025_split huggingface dataset:
Paroxysmal Nocturnal Hemoglobinuria (PNH): Long Term Follow up of 48 Patients in a Single Institution.
Authors: Ruiz Jefferson , Medeiros Larissa A. , Funke Vaneuza A.M. , Bonfim Carmem M.S. , Bitencourt Marco A. , Setubal Daniela C. , Pettengil Claudia , Nunes Elenaide C. , Oliveira Michel M. , Neto Jose Zanis , Medeiros Carlos R. , Malvezzi Mariester , Pasquini Ricardo 
Published: October 2019

Abstract
Background: PNH is a clonal acquired disease characterized by poor expression of CD55 and CD59, adding higher lytic activity to the complement pathway, ending up in hemolysis, pancytopenia and thrombosis. The clinical variability and the lack of effective therapeutics make the treatment of PNH a real challenge.
Material and methods: A retrospective analysis of 48 patients diagnosed with PNH between feb/1997 and march/2006 admitted to our center was performed. Before 1999, diagnosis was made by HAM and SACAROSIS tests. From this point immunophenotyping analysis was used to establish diagnosis. Bone marrow aspirate and biopsy, cytogenetic and biochemistry analysis were performed for exclusion of comorbities. Patients were divided in two groups: 1) de novo PNH associated with marrow failure (MF) and 2) PNH as an evolution of severe aplastic anemia (SAA) or mielodysplastic syndrome (MDS). Response was defined as reduction at hemolytic episodes as well as improvement of CBC and transfusion requirements.
Results: Median age was 24 years (range 9–75); male patients constituted 58% of the sample (male/female: 1,4:1). De novo PNH with associated marrow failure occurred in 22 patients (group 1) and evolutive PNH in 15, being 13 from previous SAA and 2 from previous hypoplastic MDS (group 2). Thirty seven patients were followed at our clinic during this time: 25 (67,5%) received immunesupression with cyclosporine and steroids. Overall response (partial or complete) after one year of therapy was 84% (31/37). The remaining 11 patients (32,5%) received steroids alone, androgens or only observation, four of them remained with stable disease. HLA match hematopoietic stem cell transplantation (HSCT) was performed in 18/48 (38%), being 11 from group 1 and 7 from group 2. Main indications were: pancytopenia (77%), thrombosis (17%) and AML (6%).
Only nine patients died (19%): five after HSCT and 4 of those followed at our clinic (massive thrombosis and hemolysis). Overall survival after HSCT was 72% with median follow-up of 890 days. Overall survival among outpatient clinic patients was 86% with a median follow-up of 2340 days. Most frequent outpatient events were: hemolysis (48%), pancytopenia (13%), thrombosis (13 %), renal failure (9%) and infection (8%).Fourteen patients (37%) remained without symptoms.
Conclusions:Immunosuppressive therapy with cyclosporine and corticosteroids is an excellent strategy in patients with PNH and associated marrow failure, leading to durable clinical responses.The present data supports previous published indications for HSCT: ASS and thrombosis.Overall survival of PNH patients who received HSCT achieved 72%.
HbA Is More Effective Than HbF for Improving the Clinical Course in Sickle Cell Disease.
Authors: Bezerra Marcos A.C. , Fattori Andre , Santos Magnum N. , Albuquerque Dulcineia M. , Sonati Maria F. , Saad Sara T.O. , Araujo Aderson S. , Costa Fernando F. 
Published: October 2019

Abstract
It is well known that high levels of HbF exert a protective effect on the clinical outcome of sickle cell disease. For this reason hydroxyurea, a drug that increases levels of HbF, is standard treatment for sickle cell disease patients with severe clinical courses. We present, herein, two groups of patients with sickle cell disease (HbS / β thalassemia) with differing genotypes who present similar quantities of HbS, but who clearly have differences in the amounts of HbF and HbA. The table below presents the genotypes, and the hematological and clinical data of the two groups of patients. Data presented in the table demonstrate that the clinical course of the patients with a high percentage of HbA is very mild, whilst the clinical course of the patients with high levels of HbF is severe. It is important to note that the amount of HbA + HbF is not statistically different in the two groups (22.8±8.3 e 28.1±1.8). There were no other factors, such as haplotypes or α genotypes that could have interfered with the clinical presentation of the patients. Taken together, the data presented suggest that a protection against hemoglobin S polymerization in patients may be more effective in the presence of HbA compared to similar amounts of HbF. In this case, it would be possible to speculate that a therapy aiming to induce the production of HbA, even in small amounts, may be more effective in the treatment of sickle cell disease than the increase in the production of HbF.
Comparison between S/ beta thal IVSI-5 and S / beta thal IVSI-6 patients: Genotypes (S / beta thal) Hb (g/dL) HbS (%) HbA (%) HbF (%) S (n) T (%) HAI / HAC (%) S: Splenectomy (no of patients); T: Transfusion (more than 3 transfusion events); HAI: Hospital Admission for Infection events; HAC: Hospital Admission for pain Crisis (frequency: more than 3 vaso-occlusives episodes). All values (with the exception of HbS) were statistically different between the 2 groups (p<0.001, Wilcoxon rank sum test). S / IVSI-5(G-> C) n = 18 7.4±1.0 72.9±8.2 5.2±1.3 17.6±9.1 6 72 89(16) S / IVSI-6(T -> C) n = 20 11.6±0.9 67.4±1.7 26.3±1.4 1.8±1.2 0 0 5 (1)
Hematological and Clinical Findings Predictive of Mortality in Italian Patients with Sickle-Cell Disease: A Case-Control Study.
Authors: Maggio Aurelio , Di Salvo Veronica , Rigano Paolo , Giangreco Antonino , Renda Maria Concetta , Renda Disma 
Published: October 2019

Abstract
Background: the number of cases with Sickle-Cell Disease (SCD) registered in Italy at 2000 was 928. Six-hundred-twenty-two (67%) of these were with Sickle-Cell/βthalassemia. Moreover, while the main causes of death in Afro-American patients with SCD is well known, we do not have many informations in Italian subjects. For this reason, we carried ahead a case-control study in this group of patients.
Aim of the study: the evaluation of the main hematological and clinical parameters predictive of mortality.
Materials and Methods: clinical and hematological findings of 14 SCD died patients were compared with a SCD alive control population homogeneous for age, sex, phenotype and number of painful crises per year. Two alive control subjects were studied for each died patient.
Results: the main causes of death were: Acute Chest Syndromes (ACS) (n°6), Cardiovascular Diseases (n°3),Hepatic Failure (n°1),Hodgkin Lymphoma (n°1), Stroke (n°1), Lung Cancer (n°1), Surgery Complication (n°1). The main correlated hematological findings with mortality were Hb (gr/dl) levels (p=<.05), WBC count (103 / ml) (p= <.05), ferritin levels (ng/ml) (p=<.01). The main correlated clinical features were: the number of crises >3/year (Odd Ratio= 1.64; p= <.01), previous stroke (Odd Ratio= 1.53; p= <.01), HU treatment (Odd Ratio=<.01; p=<.01), leg ulcers (Odd Ratio=1.46;p=<.01).
Conclusions: these data suggest that the main causes of death in Italian patients with SCD are similar to those reported for Afro-American subjects (M.H. Steinberg, JAMA, April 2, Vol. 289, N°13, 1645–1651). Particularly, the lack of HU treatment, anemia, high ferritin levels, number of crises per year and previous stroke are the most important predictive factors of mortality.
HbQ-Iran [α75 (EF4) Asp→His]/−α3.7/β° IVSII.1 G→A in an Iranian Child: First Reported Case.
Authors: Muniz Adriana , Nagel Ronald L. , Rahimi Zhoreh , Raygani Asad V. , Akramipour Reza , Bahremand Fariborz 
Published: October 2019

Abstract
HbQ-Iran [α75 (EF4) Asp→His] is an α-chain variant first described in 1970, which substitution is not involved in the interchain contacts of hemoglobin. It has a slow-moving migration pattern on cellulose acetate at alkaline pH, that resembles the Hb S, but with normal solubility. The quantity of this variant in the heterozygous state has been reported to be 17–19%. Heterozygotes individuals with HbQ-Iran are hematologically asymptomatic and the combination with α+-thalassemia and β0- thalassemia has not been reported up to now.
We here described the hematological characteristics of a 5 years old child referred to the clinic of Kermanshah University. Physical examination revealed no enlargement of the spleen, and the initial blood count indicated a mild microcytic anemia with low levels of Hb (10g/dL), a hematocrit of 30.5% and low MCV and MCH (59.3fL and 19.6pg) respectively. DNA analysis revealed the presence of HbQ-Iran, −α3.7 kb deletion of the alpha globin genes and also the presence of the mutation (IVSII.1.G→A) β0-thalassemia in the child. The study of the family revealed the presence of a minor β-thalassemia in the father and the HbQ-Iran in the mother. Both parents were heterozygous for the −α3.7 deletion (−α3.7/α α) in the α-globin genes. The coinheritance of HbQ-Iran with −α3.7 deletion and β-thalassemia resulted in an elevation of the levels of HbQ-Iran to 22.4%. However, the remainder hematological values of the young patient indicated a significant reduction in MCV (59.3 fL) and MCH (19.6 pg), an elevation of HbF (6.3%) and of HbA2 (3.7%) according to a picture of a minor β-thalassemia. This result demonstrated that HbQ-Iran is a benign structural variant, that in combination with β0-thalassemia and in the presence of a α+-thalassemia, produce a minor β-thalassemia picture with moderate anemia and elevation of HbF. The application of DNA technologies allowed the identification for the first time of the presence in one individual of three already known mutations, emphasizing the unique genetic heterogeneity of this population.
Beneficial Effect of Hydroxyurea on Avascular Necrosis of Femoral Head in Adult Sickle Cell Disease (Homozygous) - One Year Prospective Study in Orissa, India.
Authors: Jena Rabindra , Swain Trupti R. 
Published: October 2019

Abstract
Avascular nacrosis (AVN) of femoral head in Sickle cell Disease, (Homozygous) (SCD) is a progressive and crippling complication seen commonly in India. AVN evolves slowly from cumulative effect of recurrent small episodes of ischemia or infarction within the spongiosa of bone. This complication can occur in the absence of painful crisis for which a satisfactory treatment is yet to be found. Though Hydroxyurea inhibits polymerization of HbS by raising HbF level, its role on AVN of femoral head is not known. Forty six adult SCD with AVN of Femoral head with or without painful crisis received hydroxyurea at a dose of 20 mg/ kg/ day orally while 18 adult SCD with AVN of femoral head, without painful crisis were taken as control. Both the groups received folic acid (1 mg/ day), red cell transfusion and ibuprofen as required. All patients were advised adequate rest and to avoid prolong standing and walking. Clinical, hematological and radiological evaluation were done once in three month for one year.
RESULT: Pain in the hip joints were completely absent both during rest and activity after a median period of 6 months in 11 patients (73.3%,out of 15 cases) in early stage of AVN (minimum necrosis, crescent sign).Radiological abnormalities disappeared completely in these patients after a median period of 9 months. Similar benefits were observed in 7 cases (35%, out of 20 cases) of SCD with segmental collapse of femoral head. Most advanced cases of AVN (complete degeneration and collapse of femoral head) were resistant with least benefits in 3 patients (25.4%, out of 11 cases) with only reduction of pain at rest without any improvement in radiological changes and quality of activity. In control groups though pain was relieved during rest in 4 cases (22.2%) no improvement in radiological picture and pain during activity was observed. Chi square analysis detected a significant rise in Hb F level and benefit in hydroxyurea treated group. Thus hydroxyurea administration in early stages of AVN due to SCD is beneficial.
Hb F Malta I in Association with Hb F Sardinia (AyT) and Hb Valletta in Heterozygotes: Quantification of the Six Globins Suggests Developmental Control of the XMN-I Site and Interplay with the (AT)xTy Sequence in Connection with Globin Gene Switching.
Authors: Felice Alexander , Borg Joseph , Cassar Wilma , Galdies Ruth , Pizzuto Monica , Caruana Maryrose , Scerri Christian 
Published: October 2019

Abstract
Although the precise biochemical mechanisms of globin gene switching remain elusive, considerable insight is gained by in vivo expression profiling through quantification of the hemoglobin / globin phenotype of informative heterozygosities and homozygosities / compound heterozygosities in the context of specific regulatory DNA sequence diversity such as the XMN-I or the [(AT)xTy] sequence polymorphisms.
The quantification of normal and abnormal globins of Hb F Malta-I (or a2b2, 117(G19)His>Arg) heterozygotes which are in tight linkage disequilibrium with Hb Valletta (or a2b2 287(f3)Thr>Pro) i.e. Gyo, GyFMalta-I, AyI, bV and bA together with extensive haplotyping of homozygotes and heterozygotes including the XMN-I dimorphism in the Gy promoter and the (AT)xTy polymorphism (BP1 binding site) 5′ to the b globin genes had suggested that the XMN-I dimorphism was largely inactive in the normal newborn. In contrast the Hb F levels and the proportion of Gy globin in anemic adult beta-thalassemia homozygotes and compound heterozygotes differed significantly, depending on the XMN-I genotype (TT, TC or CC) Here, we document the occurrence of seven newborn who were heterozygous at three globin loci permitting quantification by reverse phase liquid chromatography of the six globin products; Gyo, GyFMalta-I, AyI, AyT, bV and bA in the context of genotypic variation at the XMN-I and (AT)xTy sequences. The data were compared with those of newborn HbF-Malta-I-Hb-Valletta heterozygotes and anemic adult beta thalassemia homozygotes / compound heterozygotes. The globin quantification together with haplotype data were analysed using the general linear model (two-way ANOVA) by SPSS version 12. The data excluded significant effect of the XMN-I dimorphism alone on relative y/b globin gene expression in the newborn. On the other hand, the (AT)xTy polymorphism with BP1 binding sites of 21 [(AT)7T7], 23 [(AT)9T5], or 25 [(AT)11T3], nucleotides in trans over-ride XMN-I. In contrast, it is the XMN-I dimorphism that over-rides the (AT)xTy diversity in the anemic adult beta thalassemia homozygotes or compound heterozygotes. The GyFMalta-I/Gyo ratio of the newborn heterozygotes with Hb F Malta-I and the AyT/AyI ratio of the newborn heterozygotes with HbF-Malta-I and HbF-Sardinia suggested that the developmental regulation of the XMN-I site may be subject to cis/trans interplay with the (AT)xTy sequences.
Mechanism of Immune System Activation by (1,4)-α-D-glucan Isolated from Tinospora cordifolia in Macrophages.
Authors: Nair P.K. Raveendran , Melnick Steven J. , Khatib Ziad A. , Ramachandran Reshma , Escalon Enrique A. , Ramachandran Cheppail 
Published: October 2019

Abstract
We have characterized and reported the immunostimulating properties of a novel polysaccharide - (1,4)-α-D-glucan (RR1)- isolated from the medicinal plant Tinospora cordifolia [23]. This novel glucan is water soluble and having (1, 4)-α-D-glycosidic linkages in the main chain and (1, 6)-α-D-glycosidic linked side chains at an interval of 6, 7 glucose units. The signaling mechanism of the novel (1,4)-a-D-glucan (RR1) was investigated in macrophages to evaluate its immunostimulating properties. When RAW264.7 macrophages were incubated with RR1 at 4°C, the novel glucan inhibited the phagocytosis of unopsonized zymosan A bioparticles in a dose-dependent manner. RR1 also inhibited the binding and internalization of opsonized zymosan A bioparticles, although at a lower level than laminarin. Incubation of macrophages with anti-CD11b mAb followed by RR1 failed to show any inhibitory effect on RR1-induced TNF-α synthesis confirming that complement receptor 3 (CR3) is not involved in the opsonic binding and internalization of RR1 in macrophages unlike zymosan A. The anti-CD11b mAb has significant inhibitory effect on the zymosan A-induced tumor necrosis factor (TNF)-α synthesis. RR1 induced TNF-α synthesis in macrophages in a dose-dependent manner which can be completely inhibited by the NF-κB inhibitor caffeic acid phenethyl ester (CAPE) or curcumin. RR1 activated NF-κB in a time- and dose-dependent manner and this modulation of nuclear NF-κB activity is associated with the degradation of I-κB a thus facilitating the translocation of NF-κB into the nucleus. RR1-induced NF-κB activity peaks at 8 h of RR1 stimulation while I-κB a degradation occurred within 1 h of stimulation. RR1-induced NF-κB activation occurred through TLR6 signaling as evidenced by the synthesis of IL-8 in TLR6-transfected HEK293 cells. These results show that the novel (1,4)-α-D glucan from Tinospora cordifolia activates the immune system through the activation of macrophages that occurs through TLR6 signaling, NF-κB translocation and cytokine production. (Supported by Miami Children’s Hospital Foundation research funds).
Haplotype Block for Inflammatory Cytokine Gene Polymorphisms in Fabry Disease.
Authors: Elstein Deborah , Safyan Rachael , Whybra Catharina , Beck Michael , Altarescu Gheona 
Published: October 2019

Abstract
Fabry disease is an X-linked disorder associated with early-onset stroke, cardiomiopathy, and progression to end-stage renal failure. Correlations between IL-6 inflammatory cytokine gene polymorphisms and Mainz Severity Score Index (MSSI) scores have been shown. Therefore, polymorphisms of other key pro- and anti-inflammatory cytokines and correlation to clinical manifestations (MSSI scores) were attempted in order to build haplotype descriptions for Fabry disease. Genotyping for IL-10[819C/T;-592C/A]; IL-1b[+3954 C/T; -511C/T]; IL-1α[-889C/T]; and TNF-α[–308G/A] was performed in 76 patients and correlated with MSSI sub-scores and with enzyme (alpha-galactosidase A) levels. Fifty normal volunteers, age- and sex-matched, were also genotyped. Of 76 patients, 31(41%) were males and 45 (59%) were females. There was no correlation between enzyme levels and any cytokine levels. Statistically significant differences were found in prevalence of TNF-α [–308G/A] genotypes: 84%GG in patients versus 63%GG in controls (p=0.038) and for IL–1α [–889C/T] genotypes: 94%CC in patients versus 21%CC in controls (p<0.001). Statistically significant differences were found in the ratio between the two polymorphisms of IL-10 (p<0.0001), between the two polymorphisms of IL-1b (p=0.001); between IL-1α [–889C/T] and IL-1beta [3954C/T] (p=0.002); and between IL-10[–592C/T] and IL-1b [3954C/T] (p=0.041). Correlations between TNF-α [–308G/A] and both kidney and neurological MSSI sub-score (both: p=0.06) and between IL-10[-819C/T] and the MSSI neurological score (p=0.03) were noted. The relationship between inflammation and Fabry disease appears to exist on several levels. There was a multiplicity of associations among the two IL-10 polymorphisms and the two IL-1b polymorphisms and the one IL-1a polymorphism. These seem to indicate that the majority of patients have at least one C allele (but more often two C alleles) for each of the five polymorphic sites. On the other hand, the majority of patients had the GG genotype of the TNF-a[−308] polymorphism which is associated with decreased production of this pro-inflammatory cytokine. We speculate that sequence variations in regulatory DNA of genes coding for important members of the interleukin inflammatory family are associated with differential effects in Fabry disease and with increased sample size, haplotype blocks might be constructed.
The Spanish Gaucher Registry. An Observatoire To Detect Neurological Manifestations in Patients and Relatives.
Authors: Giraldo Pilar , Alfonso Pilar , Latre Paz , Fernandez-Galan Angeles M. , Alonso Dora , Ruiz Angeles M. , Vasco Ana , Masana Luis , Leon Pilar , Guzman Jose L. , Sanjurjo Pablo , Hernandez-Rivas Jesus M. , Albadalejo Jose , Loyola Ines , Martin-Hernandez Elena , Pocovi Miguel 
Published: October 2019

Abstract
Background: The Spanish Gaucher Foundation (FEETEG) is an independent and non-profit organization that keeps the Spanish Gaucher Registry (SGR) established in 1993. This SGR contains demographic, genetic, clinical, analytical and image data from a cohort of 306 Gaucher Disease (GD) patients (269 GD1, 22 GD2, 16 GD3), and 751 relatives. The SGR is a useful tool to perform epidemiological-genetic studies and analyse associated comorbilities. Patients and
Methods: From January to July 2006 an epidemiological survey to physicians and to the patients through GD Associations was conducted to ascertain the incidence of neurological symptoms in patients and their relatives as well as analyse genotype-phenotype relationship. The statistical analysis was performed in a SPSS 12.0 database using descriptive parameters, ANOVA, t-test and correlation study including Pearson coefficient.
Results: Twenty-four (38.7%) out of 62 GD1 patient respondents from 56 families have neurological symptoms, 8 (12.5%) tremor, 8 (12.5%) uncoordinated movements, 11 (17.7%) concentration defects, 3 (4.8%) strabismus and 8 (12.5%) deafness, 3 (4.8%) Parkinson Disease (PD). Twenty-one out of 56 families have one or more relatives with neurological manifestations. There were 29(8.6%) out of 336 relatives with neurological symptoms:13 (3.8%) PD, 5 (1.5%) epilepsy, 6 (1.8%) essential tremor, 5 (1.5%) others. Subjects with PD were carriers of mutations:: S364R, G202R, V398I, R47X, L336P, L444P, G195W, recNci and insertion alleles. In families with epilepsy the predominant carrier mutations were: L444P, G195W, R130W and in essential tremor: L444P.
Comments: There is a high incidence of neurological symptoms between GD1 patients and carriers. These manifestations appear frequently in carriers of rare mutations. It is very recommendable to perform a systematic neurological exam in GD1 patients and in carriers with risk mutations.
HMGB1 Derived from Macrophages Acts as an Angiogenic Factor.
Authors: Maruyama Ikuro , Kawahara Ko-ichi , Ito Takashi , Oyama Yoko , Takenouchi Kazunori , Shimizu Toshiaki , Kikuchi Kiyoshi , Hashiguchi Teruto 
Published: October 2019

Abstract
High Mobility Group Box-1 (HMGB1) protein, released from the most of necrotic cells and activated macrophages, has been identified as a novel cytokine through the receptor for advanced glycation endproducts (RAGE) and Toll-like receptor(TLR)-2 and -4. The HMGB1-RAGE and TLRs-2, -4 interactions contribute to cellular migration and the production of proinflammatory cytokines, and participate in pathomechanisms in tumor growth and invasion, in which an angiogenesis development is an important aspect.
We here show that HMGB1 stimulates the expression of Vascular Endothelial Growth Factor (VEGF), the most potent angiogenic factor in tumors, through the HMGB1-RAGE, but neither TLR-2 nor TLR-4 in macrophage-lineage cells in vitro. The mechanism of VEGF production is mediated through the Akt pathway, which is linked to tumor growth and invasion. Furthermore, HMGB1 induced angiogenesis was also observed in an in vivo rabbit corneal assay (Fig). These results suggest that HMGB1, released from the tumor-associated macrophages, may act as a key cytokine in the development of angiogenesis by producing VEGF in tumor growth and invasion. Thus the tumor-associated HMGB1/RAGE system may contribute to our understanding of the mechanism of cancer cell escape from macrophage-associated acceleration of inflammation.