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1.
Phys Chem Chem Phys ; 22(4): 2212-2228, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31913367

RESUMO

In this work, the interaction of a bioactive tea polyphenol (-)-epigallocatechin gallate (EGCG) with bovine hemoglobin (BHb) along with its anti-oxidative behavior and the anti-glycation property have been explored using multi-spectroscopic and computational techniques. The binding affinity for EGCG towards BHb was observed to be moderate in nature with an order of 104 M-1, and the fluorescence quenching mechanism was characterized by an unusual static quenching mechanism. The binding constant (Kb) showed a continuous enhancement with temperature from 3.468 ± 0.380 × 104 M-1 at 288 K to 6.017 ± 0.601 × 104 M-1 at 310 K. The fluorescence emission measurements along with molecular docking studies indicated that EGCG binds near the most dominant fluorophore of BHb (ß2-Trp37, at the interface of α1 and ß2 chains) within the pocket formed by the α1, α2 and ß2 chains. The sign and magnitude of the thermodynamic parameters, changes in enthalpy (ΔH = +17.004 ± 1.007 kJ mol-1) and in entropy (ΔS = +146.213 ± 2.390 J K-1 mol-1), indicate that hydrophobic forces play a major role in stabilizing the BHb-EGCG complex. The micro-environment around the EGCG binding site showed an increase in hydrophobicity upon ligand binding. The binding of EGCG with BHb leads to a decrease in the α-helical content, whereas that of the ß-sheet increased. FTIR studies also indicated that the secondary structure of BHb changed upon binding with EGCG, along with providing further support for the presence of hydrophobic forces in the complexation process. Molecular docking studies indicated that EGCG binds within the cavity of α1, α2, and ß2 chains surrounded by residues such as α1- Lys99, α1-Thr134, α1-Thr137, α1-Tyr140, α2-Lys127 and ß2-Trp37. Molecular dynamics simulation studies indicated that EGCG conferred additional stability to BHb. Furthermore, moving away from the binding studies, EGCG was found to prevent the glyoxal (GO)-mediated glycation process of BHb, and it was also found to act as a potent antioxidant against the photo-oxidative damage of BHb.


Assuntos
Catequina/análogos & derivados , Hemoglobinas/química , Hemoglobinas/metabolismo , Polifenóis/metabolismo , Animais , Catequina/química , Bovinos , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Polifenóis/química , Ligação Proteica , Análise Espectral
2.
Adv Exp Med Biol ; 1232: 215-221, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893413

RESUMO

Patients with hematological malignancy might already have decreased muscle oxygen saturation at rest and exercise capacity before undergoing hematopoietic stem cell transplantation (HSCT). However, to date, no studies have investigated the relationship between exercise capacity and muscle oxygen saturation at rest in these patients. Therefore, purpose of this study was to investigate the relationship between exercise capacity and muscle oxygen-hemoglobin (O2Hb) saturation (SmO2) at rest and patients' hemoglobin level before undergoing HSCT. METHODS: This study included 60 men with hematologic disease who underwent allo-HSCT. Patients performed a 6-minute walk test (6MWT) to determine exercise capacity, and muscle O2Hb saturation at rest was evaluatabed using near-infrared spectroscopy (BOM-L1TRW, Omegawave Inc., Japan); hemoglobin levels in hematological malignancy patients before undergoing HSCT were also evaluated. RESULTS: There was a significant correlation between the 6MWT and muscle O2Hb saturation at rest in hematological malignancy patients (p < 0.05). Additionally, the 6MWT was significantly correlated to the hemoglobin level (p < 0.05). Furthermore, muscle O2Hb saturation at rest was significantly related to hemoglobin level (p < 0.05). CONCLUSION: In patients with hematological malignancy, a relationship exists between exercise capacity, muscle O2Hb saturation, and hemoglobin level before they undergo HSCT. Therefore, rehabilitation staff, nurses, and physicians should recognize these relationships in patients who undergo allo-HSCT. Moreover, physiotherapists may need to promote muscle oxidative metabolism through exercise to increase exercise capacity in these patients.


Assuntos
Tolerância ao Exercício , Transplante de Células-Tronco Hematopoéticas , Hemoglobinas , Músculo Esquelético , Adolescente , Adulto , Hemoglobinas/metabolismo , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Adulto Jovem
3.
Adv Exp Med Biol ; 1232: 105-112, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893401

RESUMO

BACKGROUND: We have repeatedly observed a right-left asymmetry (RLA) of prefrontal cerebral oxygenation of subjects during the resting state. AIM: To clarify if the RLA is a reliably observable phenomenon at the group level and whether it is associated with systemic physiology, absolute tissue oxygen saturation (StO2) or total hemoglobin concentration ([tHb]). MATERIAL AND METHODS: StO2 and [tHb] values at the right and left prefrontal cortex (PFC) were calculated for two 5- min resting phases based on data from 76 single measurements (24 healthy adults, aged 22.0 ± 6.4 years). StO2 and [tHb] were measured with an ISS OxiplexTS frequency domain near-infrared spectroscopy device. In addition, end-tidal CO2 (PETCO2), heart rate (HR), respiration rate (RR) and the pulse-respiration quotient (PRQ = HR/RR) were measured and analyzed for the two phases. RESULTS: On the group level it was found that i) StO2 was higher at the right compared to the left PFC (for both phases), ii) RLA of StO2 (∆StO2 = StO2 (right)-StO2 (left) was independent of PETCO2, HR and PRQ, and iii) ∆StO2 was associated with absolute StO2 and [tHb] values (positively and negatively, respectively). DISCUSSION AND CONCLUSION: This study shows that i) RLA of StO2 at the PFC is a real phenomenon, and that ii) ∆StO2 at the group level does not depend on PETCO2, HR, RR or PRQ, but on absolute StO2 and [tHb]. We conclude that the RLA is a real effect, independent of systemic physiology, and most likely reflects genuine properties of the brain, i.e. different activity states of the two hemispheres.


Assuntos
Hemoglobinas , Oxigênio , Córtex Pré-Frontal , Espectroscopia de Luz Próxima ao Infravermelho , Adolescente , Adulto , Hemoglobinas/metabolismo , Humanos , Oxigênio/metabolismo , Consumo de Oxigênio , Córtex Pré-Frontal/metabolismo , Adulto Jovem
4.
Adv Exp Med Biol ; 1232: 121-127, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893403

RESUMO

Changes in NIRS signals are related to changes in local cerebral blood flow or oxy-Hb concentration. On the other hand, recent studies have revealed the effect of chewing gum on cognitive performance, stress control etc. which accompanied brain activity in the prefrontal cortex (PFC). However, these relationships are still controversial. To evaluate the chewing effect on PFC, NIRS seems to be a suitable method of imaging such results. When measuring NIRS on PFC, blood volume in superficial tissues (scalp, skin, muscle) might have some affect. The aim of the present study was to clarify the effect of the anterior temporal muscle on NIRS signals during gum chewing. Eight healthy volunteers participated. Two-channel NIRS (HOT-1000, NeU, Japan), which can distinguish total-Hb concentrations in deep tissue and superficial tissue layers, was used. In addition to a conventional optode separation distance of 3.0 cm, Hot 1000 has a short distance of 1.0 cm (NEAR channel) to measure NIRS signals that originate exclusively from surface tissues. NIRS probes were placed at Fp1 and Fp2 in the normal probe setting. The headset was displaced to the left in order to allow the left probe to be placed over the left anterior temporal muscle. In the normal setting, the superficial signal curve shows no notable change; however, the neural (calculated and defined in HOT-1000) and deep curves show an increase during the gum chewing task. At the deviated setting, all three signals show marked changes during the task. Total-Hb concentration in the deviated probe setting is significantly large (p < 0.05) than that of in the normal probe setting. When using gum chewing as a task, it would be better to consider a probe position carefully so that the influence of muscle activity on NIRS signal can be distinguished.


Assuntos
Mastigação , Córtex Pré-Frontal , Espectroscopia de Luz Próxima ao Infravermelho , Adulto , Hemoglobinas/metabolismo , Humanos , Japão , Projetos Piloto , Córtex Pré-Frontal/fisiologia , Adulto Jovem
5.
Adv Exp Med Biol ; 1232: 201-207, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893411

RESUMO

Our previous research confirmed that patients with malignant hematopoietic disease already had a low hemoglobin level before allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, no study has determined whether a correlation exists between exercise load, hemoglobin level, and muscle oxygen saturation (SmO2), during exercise. Therefore, the purpose of this study was to investigate whether near-infrared spectroscopy (NIRS)-derived SmO2 is associated with exercise load, as determined by a dynamometer, before allo-HSCT. This study included 19 male patients who received allo-HSCT in Hyogo College of Medicine Hospital (Japan) between November 2009 and October 2012. Patients performed isometric repeated dorsiflexion at 50% maximum voluntary contraction for 180 s to determine exercise load, and SmO2 was evaluated during exercise at the same time using NIRS (BOM-L1TRW, Omega Wave, Inc., Japan). The hemoglobin level was also evaluated before allo-HSCT. Patients with hematopoietic disease before allo-HSCT already had a low hemoglobin level. There was a significant correlation between exercise load and ∆SmO2; however, the hemoglobin level was not correlated with exercise load. In these patients, exercise load might be affected by muscle oxygen consumption rather than by the hemoglobin level. This finding shows that NIRS can used to assess fatigue in patients with malignant hematopoietic disease.


Assuntos
Exercício , Doenças Hematológicas , Neoplasias Hematológicas , Hemoglobinas , Músculo Esquelético , Consumo de Oxigênio , Doenças Hematológicas/metabolismo , Doenças Hematológicas/fisiopatologia , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/fisiopatologia , Hemoglobinas/metabolismo , Humanos , Japão , Masculino , Músculo Esquelético/metabolismo , Oxigênio/metabolismo
6.
Ann Hematol ; 99(1): 7-19, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31650290

RESUMO

Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies associated with an erythroid maturation defect, resulting in anemia. Treatments for MDS include erythropoiesis-stimulating agents (ESAs). The identification of prognostic markers is important to help predict response and improve outcomes. Various scoring systems have been developed to help predict response to ESAs. Despite limitations in its assessment, serum erythropoietin (sEPO) level is an important predictor of hematologic response to ESAs in patients with lower-risk MDS. Numerous studies have reported significantly lower sEPO levels among responders versus non-responders. Furthermore, treatment response is significantly more likely among those with sEPO levels below versus those above various cutoffs. Other prognostic indicators for response to ESAs include lower transfusion requirement, fewer bone marrow blasts, higher hemoglobin, lower serum ferritin, lower-risk MDS, and more normal cytogenetics. Studies of other MDS therapies (e.g., lenalidomide and luspatercept) have also reported that lower sEPO levels are indicative of hematologic response. In addition, lower sEPO levels (up to 500 IU/L) have been included in treatment algorithms for patients with lower-risk MDS to define whether ESAs are indicated. Lower sEPO levels are predictive of hematologic response-particularly to ESAs. Further, clinical trials should use sEPO thresholds to ensure more homogeneous cohorts.


Assuntos
Receptores de Activinas Tipo II/uso terapêutico , Eritropoetina/sangue , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Lenalidomida/uso terapêutico , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Feminino , Ferritinas/sangue , Hemoglobinas/metabolismo , Humanos , Masculino , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/patologia , Prognóstico , Fatores de Risco
7.
Ann Hematol ; 99(1): 57-63, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31811360

RESUMO

Recent studies in iron-depleted women have challenged the current approach of treating iron-deficiency anemia (IDA) with oral iron in divided daily doses. Alternate day dosing leads to more fractional absorption of iron. In this randomized controlled trial, we looked at the efficacy and safety of alternate-day (AD) versus twice-daily (BD) oral iron in all severity of IDA. Total of 62 patients were randomized, 31 patients in BD arm received 60 mg elemental iron twice daily while 31 patients in AD arm received 120 mg iron on alternate days. The primary endpoint of 2 g/dl rise in hemoglobin was met in significantly more patients in the BD arm at 3 weeks (32.3% vs. 6.5%, p < 0.0001) and 6 weeks (58% vs. 35.5%, p = 0.001). There was a significant rise in the median hemoglobin at 3 (1.6 vs. 1.1, p = 0.02) and 6 weeks (2.9 vs. 2.0 g/dl, p = 0.03) in the BD arm. However, the median hemoglobin rise in the AD arm at 6 weeks was not significantly different than the BD arm at 3 weeks. Alternate-day dosing for 6 weeks and twice-daily dosing for 3 weeks resulted in the provision of the same total amount of iron. There were more reports of nausea in the BD arm (p = 0.03). In conclusion, the choice of twice-daily or alternate-day oral iron therapy should depend on the severity of anemia, the rapidity of response desired, and patient preference to either regimen due to adverse events. Trial Registration: CTRI reg. no. CTRI/2018/07/015106 http://ctri.nic.in/Clinicaltrials/login.php.


Assuntos
Anemia Ferropriva/tratamento farmacológico , Ferro/administração & dosagem , Administração Oral , Idoso , Anemia Ferropriva/sangue , Feminino , Hemoglobinas/metabolismo , Humanos , Ferro/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
8.
Toxicol Lett ; 318: 92-98, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31678399

RESUMO

Sulfur mustard (SM) is a vesicant chemical warfare agent. Recent studies reported alleged use of SM by non-state actors in Syria and Iraq. It has been shown that SM induced immunological and hematological complications. The aim of this study was to determine acute toxic effects of SM exposure on hematological parameters. Blood samples from a group of Syrian exposed to SM in 2016 were taken daily during the follow-up of the patients in intensive care unit. Initial leukocytosis was observed in all patients (100%) on the first 48 h after exposure. Following leukocytosis, isolated lymphopenia was observed in all patients (100%) between 2nd and 4th days. A decrease in hemoglobin level was noted in five patients (62.5%) between 4th and 5th days. Thrombocytopenia was observed in 75% of patients between 4th and 6th days for mild cases and between 9th and 11th days for severe cases. Three patients (37.5%) developed distinct leucopenia/neutropenia on 11th and 12th days. It was observed that human exposure to high dose of SM has direct toxic effect on hematological cells and bone marrow. New strategies on treatment of SM-induced myelosuppression could reduce the effects of hematological complications and could increase the survival rate in these patients.


Assuntos
Medula Óssea/efeitos dos fármacos , Terrorismo Químico , Substâncias para a Guerra Química/envenenamento , Leucocitose/induzido quimicamente , Leucopenia/induzido quimicamente , Linfopenia/induzido quimicamente , Gás de Mostarda/envenenamento , Trombocitopenia/induzido quimicamente , Adolescente , Adulto , Biomarcadores/sangue , Medula Óssea/patologia , Feminino , Hemoglobinas/metabolismo , Humanos , Leucocitose/sangue , Leucocitose/patologia , Leucopenia/sangue , Leucopenia/patologia , Linfopenia/sangue , Linfopenia/patologia , Masculino , Síria , Trombocitopenia/sangue , Trombocitopenia/patologia , Adulto Jovem
9.
Toxicol Lett ; 321: 1-11, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31846690

RESUMO

Upon entering the body, nerve agents can bind active amino acid residues to form phosphonylated adducts. Tabun derivatives (O-alkyl-N,N-dialkyl phosphoroamidocyanidates) have strikingly different structural features from other G-series nerve agents, such as sarin and soman. Here, we investigate the binding mechanism for the phosphonylated adducts of nerve agents of tabun derivatives. Binding sites for three tabun derivatives, O-ethyl-N,N- dimethyl phosphoramidocyanidate (GA), O-ethyl-N,N-ethyl(methyl) phosphoramidocyanidate, and O-ethyl-N,N-diethylphosphoramidocyanidate were studied. Quadrupole-orbitrap mass spectrometry (Q-Orbitrap-MS) coupled to proteomics was used to screen adducts between tabun derivatives and albumin, immunoglobulin, and hemoglobin. The results reveal that all three tabun derivatives exhibit robust selectivity to lysine residues, rather than other amino acid residue types. A set of 10 lysine residues on human serum albumin are labeled by tabun derivatives in vitro, with K525 (K*QTALVELVK) and K199 (LK*CASLQK) peptides displaying the most reactivity. Tabun derivatives formed stable adducts on K525 and K414 (K*VPQVSTPTLVEVSR) for at least 7 days and on K351 (LAK*TYETTLEK) for at least 5 days in a rabbit model. Three of these peptides-K525, K414, and K351-have the highest homology with human serum albumin of all 5 lysine residues that bound to examined rabbit blood proteins in vivo. Molecular simulation of the tabun-albumin interaction using structural analysis and molecular docking provided theoretical evidence supporting lysine residue reactivity to phosphonylation by tabun derivatives. K525 has the lowest free binding energy and the strongest hydrogen bonding to human albumin. In summary, these findings identify unique binding properties for tabun derivatives to blood proteins.


Assuntos
Substâncias para a Guerra Química/metabolismo , Organofosfatos/metabolismo , Albumina Sérica Humana/metabolismo , Animais , Sítios de Ligação , Substâncias para a Guerra Química/química , Feminino , Hemoglobinas/metabolismo , Humanos , Ligações de Hidrogênio , Imunoglobulina G/metabolismo , Lisina , Masculino , Espectrometria de Massas , Simulação de Dinâmica Molecular , Organofosfatos/química , Ligação Proteica , Conformação Proteica , Coelhos , Albumina Sérica Humana/química , Relação Estrutura-Atividade
10.
Pan Afr Med J ; 33: 262, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692740

RESUMO

Hyperbilirubinemia is one of the most widely seen cause of neonatal morbidity. Besides ABO and Rh isoimmunization, minor blood incompatibilities have been also been identified as the other causes of severe newborn jaundice. We report a newborn with indirect hyperbilirubinemia caused by minor blood group incompatibilities (P1, M, N, s and Duffy) whose hemolysis was successfully managed with intravenous immunoglobulin therapy. A thirty-two gestational weeks of preterm male baby became severely icteric on postnatal day 11, with a total bilirubin level of 14.66 mg/dl. Antibody screening tests revealed incompatibility on different minor groups (P1, M, N, s and Duffy (Fya ve Fyb)). On postnatal day thirteen, the level of bilirubin increased to 20.66 mg/dl although baby was under intensive phototherapy. After the administration of intravenous immunoglobulin and red blood cell transfusion, hemoglobin and total bilirubin levels became stabilised. Minor blood incompatibilities should be kept in mind during differential diagnosis of hemolytic anemia of the newborn. They share the same treatment algorithm with the other types hemolytic anemia. New studies revealed that intravenous immunoglobulin treatment in hemolytic anemia have some attractive and glamorous results. It should be seriously taken into consideration for treatment of minor blood incompatibilities.


Assuntos
Anemia Hemolítica/etiologia , Bilirrubina/metabolismo , Hiperbilirrubinemia/etiologia , Imunoglobulinas Intravenosas/administração & dosagem , Anemia Hemolítica/diagnóstico , Incompatibilidade de Grupos Sanguíneos/complicações , Diagnóstico Diferencial , Transfusão de Eritrócitos/métodos , Hemoglobinas/metabolismo , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Icterícia Neonatal/etiologia , Masculino
11.
Pan Afr Med J ; 34: 6, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31762875

RESUMO

Introduction: Heart Failure (HF) is a growing public health concern in Morocco and there is a striking paucity on determinants of severe HF (SHF) in this population. The aim of this study was to identify patients admitted with HF at Ibn Rochd Hospital, Casablanca from 2011 onwards, when electronic record keeping began. Methods: A total of 105 patients underwent a series of cardiological examinations between July 2011 and January 2014. The New York Heart Association (NYHA) criteria was used to evaluate the severity of HF. Patients with NYHA classification gradings of I and II were defined as having moderate HF (MHF) and those graded as III and IV were defined as having a SHF. Univariable and multivariable risk factors associated with SHF were explored using logistic regression. The results were reported following the RECORD (Reporting of studies Conducted using Observational Routinely-collected Data) statement. Results: A total of 24 (33%) patients were identified as having a SHF. Four predictors of SHF were identified in univariate analysis: haemoglobin <12g/dL, neutrophil-to-lymphocyte ratio (NLR) >3, mean corpuscular haemoglobin concentration (MCHC) <32 picolitre, and high density lipoprotein (HDL) <0.35 (mmol/L). Only NLR>3 and HDL <0.35 mmol/L remained independent predictors in multivariable analysis. Patients with NLR >3 were at 6-fold increased odds of SHF [adjusted odds ratio (AOR): 6.78, 95% confidence interval (CI): 1.40-32.80, p=0.017], and those with HDL<0.35 (mmol/L) were at 10-fold increased odds of SHF [AOR: 10.11, 95% CI: 2.26-45.27, p=0.002]. Conclusion: The independent biomarkers of SHF identified in this study provide valuable information to ward clinicians in resource-constrained facilities to identify patients vulnerable to developing severe heart complications.


Assuntos
Insuficiência Cardíaca/epidemiologia , Hemoglobinas/metabolismo , Linfócitos/metabolismo , Neutrófilos/metabolismo , Idoso , Biomarcadores/metabolismo , Registros Eletrônicos de Saúde , Feminino , Insuficiência Cardíaca/fisiopatologia , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Marrocos , Fatores de Risco , Índice de Gravidade de Doença
12.
BMC Public Health ; 19(1): 1395, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31660924

RESUMO

BACKGROUND: Studies have demonstrated that high or low haemoglobin increases the risk of stroke. Previous studies, however, performed only a limited number of haemoglobin measurements, while there are dynamic haemoglobin changes over the course of a lifetime. This longitudinal cohort study aimed to classify the long-term trajectory of haemoglobin and examine its association with stroke incidence. METHODS: The cohort consisted of 11,431 participants (6549 men) aged 20 to 50 years whose haemoglobin was repeatedly measured 3-9 times during 2004-2015. A latent class growth mixture model (LCGMM) was used to classify the long-term trajectory of haemoglobin concentrations, and hazard ratios (HRs) and 95% confidence intervals (95% CI) according to the Cox proportional hazard model were used to investigate the association of haemoglobin trajectory types with the risk of stroke. RESULTS: Three distinct trajectory types, high-stable (n = 5395), normal-stable (n = 5310), and decreasing (n = 726), were identified, with stroke incidence rates of 2.7, 1.9 and 3.2 per 1000 person-years, respectively. Compared to the normal-stable group, after adjusting for the baseline covariates, the decreasing group had a 2.94-fold (95% CI 1.22 to 7.06) increased risk of developing stroke. Strong evidence was observed in men, with an HR (95% CI) of 4.12 (1.50, 11.28), but not in women (HR = 1.66, 95% CI 0.34, 8.19). Individuals in the high-stable group had increased values of baseline covariates, but the adjusted HR (95% CI), at 1.23 (0.77, 1.97), was not significant for the study cohort or for men and women separately. CONCLUSIONS: This study revealed that a decreasing haemoglobin trajectory was associated with an increased risk of stroke in men. These findings suggest that long-term decreasing haemoglobin levels might increase the risk of stroke.


Assuntos
Hemoglobinas/metabolismo , Acidente Vascular Cerebral/epidemiologia , Adulto , Feminino , Humanos , Incidência , Estudos Longitudinais , Masculino , Fatores de Risco
13.
Nat Commun ; 10(1): 4260, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534126

RESUMO

Iron is essential for growth of Mycobacterium tuberculosis (Mtb), but most iron in the human body is stored in heme within hemoglobin. Here, we demonstrate that the substrate-binding protein DppA of the inner membrane Dpp transporter is required for heme and hemoglobin utilization by Mtb. The 1.27 Å crystal structure of DppA shows a tetrapeptide bound in the protein core and a large solvent-exposed crevice for heme binding. Mutation of arginine 179 in this cleft eliminates heme binding to DppA and prevents heme utilization by Mtb. The outer membrane proteins PPE36 and PPE62 are also required for heme and hemoglobin utilization, indicating that these pathways converge at the cell surface of Mtb. Albumin, the most abundant blood protein, binds heme specifically and bypasses the requirements for PPE36, PPE62 and Dpp. Thus, our study reveals albumin-dependent and -independent heme uptake pathways, highlighting the importance of iron acquisition from heme for Mtb.


Assuntos
Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Heme/metabolismo , Ferro/metabolismo , Mycobacterium tuberculosis/metabolismo , Proteínas Periplásmicas de Ligação/metabolismo , Albuminas/metabolismo , Cristalografia por Raios X , Hemoglobinas/metabolismo , Humanos , Mycobacterium tuberculosis/genética , Proteínas Periplásmicas de Ligação/genética , Ligação Proteica/fisiologia , Estrutura Secundária de Proteína
14.
Nat Commun ; 10(1): 4020, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488841

RESUMO

Timely perception of adverse environmental changes is critical for survival. Dynamic changes in gases are important cues for plants to sense environmental perturbations, such as submergence. In Arabidopsis thaliana, changes in oxygen and nitric oxide (NO) control the stability of ERFVII transcription factors. ERFVII proteolysis is regulated by the N-degron pathway and mediates adaptation to flooding-induced hypoxia. However, how plants detect and transduce early submergence signals remains elusive. Here we show that plants can rapidly detect submergence through passive ethylene entrapment and use this signal to pre-adapt to impending hypoxia. Ethylene can enhance ERFVII stability prior to hypoxia by increasing the NO-scavenger PHYTOGLOBIN1. This ethylene-mediated NO depletion and consequent ERFVII accumulation pre-adapts plants to survive subsequent hypoxia. Our results reveal the biological link between three gaseous signals for the regulation of flooding survival and identifies key regulatory targets for early stress perception that could be pivotal for developing flood-tolerant crops.


Assuntos
Arabidopsis/metabolismo , Etilenos/metabolismo , Etilenos/farmacologia , Hipóxia , Óxido Nítrico/metabolismo , Estresse Fisiológico/fisiologia , Aclimatação/genética , Aclimatação/fisiologia , Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Inundações , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Hemoglobinas/metabolismo , Oxigênio/metabolismo , Proteólise , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética , Fatores de Transcrição/metabolismo
15.
N Engl J Med ; 381(10): 933-944, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31483964

RESUMO

BACKGROUND: Pyruvate kinase deficiency is caused by mutations in PKLR and leads to congenital hemolytic anemia. Mitapivat is an oral, small-molecule allosteric activator of pyruvate kinase in red cells. METHODS: In this uncontrolled, phase 2 study, we evaluated the safety and efficacy of mitapivat in 52 adults with pyruvate kinase deficiency who were not receiving red-cell transfusions. The patients were randomly assigned to receive either 50 mg or 300 mg of mitapivat twice daily for a 24-week core period; eligible patients could continue treatment in an ongoing extension phase. RESULTS: Common adverse events, including headache and insomnia, occurred at the time of drug initiation and were transient; 92% of the episodes of headache and 47% of the episodes of insomnia resolved within 7 days. The most common serious adverse events, hemolytic anemia and pharyngitis, each occurred in 2 patients (4%). A total of 26 patients (50%) had an increase of more than 1.0 g per deciliter in the hemoglobin level. Among these patients, the mean maximum increase was 3.4 g per deciliter (range, 1.1 to 5.8), and the median time until the first increase of more than 1.0 g per deciliter was 10 days (range, 7 to 187); 20 patients (77%) had an increase of more than 1.0 g per deciliter in the hemoglobin level at more than 50% of visits during the core study period, with improvement in markers of hemolysis. The response was sustained in all 19 patients remaining in the extension phase, with a median follow-up of 29 months (range, 22 to 35). Hemoglobin responses were observed only in patients who had at least one missense PKLR mutation and were associated with the red-cell pyruvate kinase protein level at baseline. CONCLUSIONS: The administration of mitapivat was associated with a rapid increase in the hemoglobin level in 50% of adults with pyruvate kinase deficiency, with a sustained response during a median follow-up of 29 months during the extension phase. Adverse effects were mainly low-grade and transient. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02476916.).


Assuntos
Anemia Hemolítica Congênita não Esferocítica/tratamento farmacológico , Hemoglobinas/metabolismo , Piperazinas/administração & dosagem , Piruvato Quinase/deficiência , Erros Inatos do Metabolismo dos Piruvatos/tratamento farmacológico , Quinolinas/administração & dosagem , Administração Oral , Adolescente , Adulto , Anemia Hemolítica Congênita não Esferocítica/sangue , Anemia Hemolítica Congênita não Esferocítica/genética , Catecóis , Esquema de Medicação , Feminino , Seguimentos , Cefaleia/induzido quimicamente , Humanos , Masculino , Mutação , Piperazinas/efeitos adversos , Piruvato Quinase/sangue , Piruvato Quinase/genética , Erros Inatos do Metabolismo dos Piruvatos/sangue , Erros Inatos do Metabolismo dos Piruvatos/genética , Quinolinas/efeitos adversos , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Tirfostinas , Adulto Jovem
16.
Ann Clin Lab Sci ; 49(4): 513-518, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31471342

RESUMO

BACKGROUND: Multiple myeloma (MM) is one of the most common types of hematological malignancies, but its pathogenesis is poorly understood. Interleukin-9 (IL-9) is a growth factor, mainly produced by helper T cells. A series of observations suggested that IL-9 might act as a factor promoting oncogenesis. This study was aimed at detecting the serum concentrations of IL-9 in patients with MM, and to investigate its potential clinical significance. METHODS: The serum IL-9 levels in 34 patients with MM and 15 normal controls were quantified by using the Enzyme Linked Immunosorbent Assay (ELISA). RESULTS: Our results showed that the serum IL-9 concentration in MM patients was significantly higher than that in the controls (p<0.0001). Interestingly, the IL-9 level in serum was found to be negatively associated with the hemoglobin concentration among the newly diagnosed MM patients (p=0.0108, r=-0.5850). Moreover, MM patients with renal dysfunction showed a significant increase in serum IL-9 concentration over those with normal renal function (p=0.0395). CONCLUSION: These findings may imply a novel role of IL-9 in anemia and/or renal dysfunction development in MM.


Assuntos
Hemoglobinas/metabolismo , Interleucina-9/sangue , Rim/fisiopatologia , Mieloma Múltiplo/sangue , Mieloma Múltiplo/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Regulação para Cima
17.
Clin Lab ; 65(8)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31414755

RESUMO

BACKGROUND: The instructions of manufacturers of methodologies for anti-HIV-1/2 antibodies screening tests re-commend avoiding analyzing blood samples with hemolysis or lipemia, but they do not mention references about scientific studies evaluating their interference. The increased need for an opportune detection of HIV infection to avoid its spread has led to public health institutions including routine HIV screening even in internal medicine and emergency rooms. Nevertheless, these blood samples are usually associated with the presence of lipemia and/ or hemolysis, leaving doubt for probable misinterpretations. This fact highlights the need for applying verification techniques, established under the internal methodological conditions of each laboratory, in order to increase the coverage of HIV screening and to ensure the reliability of their results. METHODS: Following the ethics committee approval and patient's informed consent, a confirmed anti-HIV-1 positive human serum (undetectable viral load and p24 antigen, and stable total lymphocytes > 30%) was obtained. This work describes techniques for the semiquantitative analysis of anti-HIV antibodies of three commercial HIV-screening methodologies (immunochromatography, enzyme-immunoassay and chemiluminescence) and to deter-mine the detection limit of these screening tests, as well as evaluating the maximum concentration of total lipids and of free hemoglobin that do not interfere in the detection limits. RESULTS: The highest analyzed concentration of total lipid (870 mg/dL) did not interfere with the detection limits of anti-HIV-1 antibodies in any of the evaluated methodologies. Free hemoglobin presented interference at different concentrations depending on the methodology: immunochromatography (0.57 g/dL)), enzyme-immunoassay (8.6 g/dL), and chemiluminescence (11.5 g/dL)). CONCLUSIONS: Concentrations of lipemia above postprandial levels or hemolysis induced by experimental manipulation might not interfere with HIV-serological screening. Determining the maximum permissible limits of lipemia and hemolysis by each manufacturer or laboratory based on an internal evaluation of their serological methodology would increase the reliability of HIV-diagnosis in internal medicine and emergency rooms and in patients with dyslipidemia or physiological hemolysis.


Assuntos
Anticorpos Anti-HIV/imunologia , Infecções por HIV/diagnóstico , Soropositividade para HIV/diagnóstico , HIV-1/imunologia , Sorodiagnóstico da AIDS/métodos , Anticorpos Anti-HIV/sangue , Infecções por HIV/sangue , Infecções por HIV/virologia , Soropositividade para HIV/sangue , Soropositividade para HIV/virologia , HIV-1/fisiologia , Hemoglobinas/imunologia , Hemoglobinas/metabolismo , Hemólise/imunologia , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/imunologia , Limite de Detecção , Lipídeos/sangue , Lipídeos/imunologia , Sensibilidade e Especificidade
18.
Sex Reprod Healthc ; 21: 21-25, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31395229

RESUMO

INTRODUCTION: Retained placenta can be defined as lack of expulsion of the placenta within 30 min of delivery of the infant. It is a significant cause of maternal mortality and morbidity throughout the developing world. AIM OF THE WORK: The aim of this study was to compare the efficacy of intra-umbilical vein injection of carbetocin versus oxytocin in the management of retained placenta. PATIENTS AND METHODS: A total of 200 women were included in this study. They were divided into two groups; each 100 women. The first group received intra-umbilical vein injection of 1 mL carbetocin (containing 100 µg carbetocin) diluted in 20 mL normal saline 0.9% and the second group received intra-umbilical vein injection of 20 IU oxytocin diluted in 20 mL normal saline 0.9%. RESULTS: Total blood loss (ml) and duration of the third stage of labor (minutes) were significantly lower in carbetocin group when compared to oxytocin group. Postoperative Hb concentration (g/dl) was significantly higher in carbetocin group. Also there was a highly significant difference between both groups as regard change in Hb concentration (g/dl) with less change in the carbetocin group. The need for additional uterotonic drugs following placental delivery and the occurrence of postpartum hemorrhage and the need for blood transfusion were significantly lower in the carbetocin group. CONCLUSION: Intra-umbilical carbetocin is more effective than intra-umbilical oytocin as a method for management of retained placenta. Intra-umbilical carbetocin seems to have more acceptable hemodynamic safety profile when compared to intra-umbilical oxytocin in the management of retained placenta.


Assuntos
Ocitócicos/uso terapêutico , Ocitocina/análogos & derivados , Ocitocina/uso terapêutico , Placenta Retida/tratamento farmacológico , Hemorragia Pós-Parto/prevenção & controle , Adulto , Transfusão de Sangue , Volume Sanguíneo , Método Duplo-Cego , Feminino , Hemoglobinas/metabolismo , Humanos , Injeções Intravenosas , Ocitócicos/administração & dosagem , Ocitocina/administração & dosagem , Ocitocina/efeitos adversos , Gravidez , Estudos Prospectivos , Veias Umbilicais , Adulto Jovem
19.
Eur J Med Res ; 24(1): 28, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31405381

RESUMO

BACKGROUND: Preoperative anemia is relatively common in patients undergoing primary total knee arthroplasty (TKA), and is associated with higher medical costs due to blood transfusions. METHODS: We aimed to discuss the efficiency of tranexamic acid (TXA) administration for blood loss control in preoperatively anemic patients undergoing primary TKA. We retrospectively reviewed the clinical data regarding a consecutive series of primary unilateral TKA patients with preoperative anemia. Patients were divided into TXA group (received TXA peri-operatively) and control group (did not receive TXA). Outcome measures included drainage volume; hemoglobin, and hematocrit levels recorded preoperatively and over the first 5 days postoperatively; amount of allogeneic blood transfusion; and prevalence of thrombosis. RESULTS: Ninety-six patients from 996 cases were included in the study. Demographics, general health condition, and preoperative conditions were comparable between the two groups. However, significantly lower drainage volume (P < 0.001), hidden blood loss (P < 0.001), and allogeneic blood transfusion volume (χ = 4.00, P = 0.046) were noted in TXA group. The hemoglobin and hematocrit levels were significantly higher in TXA group on the first postoperative day (P = 0.006), but overall the drop in hemoglobin and hematocrit levels over the first 5 days postoperatively was similar between the groups (P = 0.763), as was the incidence of thromboembolism events (P = 0.794). CONCLUSION: TXA has a positive role for patients with preoperative anemia in primary total knee arthroplasty. In patients with mild preoperative anemia, TXA decreases hidden blood loss and the need for allogeneic blood transfusion, which mainly appears effective on the first postoperative day of TKA.


Assuntos
Anemia/tratamento farmacológico , Anemia/etiologia , Artroplastia do Joelho/efeitos adversos , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Ácido Tranexâmico/uso terapêutico , Idoso , Perda Sanguínea Cirúrgica , Distribuição de Qui-Quadrado , Feminino , Hematócrito , Hemoglobinas/metabolismo , Humanos , Masculino , Ácido Tranexâmico/administração & dosagem
20.
Biomed Res Int ; 2019: 8534752, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31428649

RESUMO

Anaemia and high haemoglobin levels are common in ST elevation myocardial infarction (STEMI) patients, but the effect of the haemoglobin level on the prognosis of STEMI patients remains in dispute. This study aimed to evaluate the prognostic value of the haemoglobin level combined with the CAMI-STEMI score in STEMI patients after percutaneous coronary intervention (PCI). We included 360 STEMI patients who underwent PCI. The patients were divided into 3 groups according to the first haemoglobin value after PCI. Clinical characteristics and the incidence of major adverse cardiovascular and cerebral events (MACCE) during the follow-up period were recorded. The incidence of MACCE in the 3 groups increased with a decrease in the haemoglobin level. Multivariate regression analysis showed that the CAMI-STEMI score was an independent predictor of MACCE incidence at 30 days after PCI and that anaemia was an independent predictor of MACCE incidence at 6 months and 1 year after PCI. A high haemoglobin level was an independent predictor of MACCE incidence at 1 year after PCI. The area under receiver operating characteristic curves (AUCs) of the haemoglobin level, CAMI-STEMI score, and haemoglobin level combined with CAMI-STEMI score predicting the occurrence of MACCE in STEMI patients within 30 days after PCI were 0.604, 0.614, and 0.639, respectively. In conclusion, The CAMI-STEMI score was an independent predictor of MACCE incidence at 30 days after PCI. The haemoglobin level combined with the CAMI-STEMI score improved the predictive value of MACCE in STEMI patients within 30 days after PCI. Trial Registration. This trial was a prospective cohort study and registered with ChiCTR-ROC-17011542.


Assuntos
Transtornos Cerebrovasculares , Hemoglobinas/metabolismo , Intervenção Coronária Percutânea , Complicações Pós-Operatórias , Infarto do Miocárdio com Supradesnível do Segmento ST , Idoso , Idoso de 80 Anos ou mais , Transtornos Cerebrovasculares/sangue , Transtornos Cerebrovasculares/epidemiologia , Transtornos Cerebrovasculares/etiologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/epidemiologia , Valor Preditivo dos Testes , Estudos Prospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/epidemiologia , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia
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