RESUMO
OBJECTIVE: In chronic kidney disease (CKD), both anemia and deregulated phosphate metabolism are common and predictive of adverse outcome. Previous studies suggest that iron status influences phosphate metabolism by modulating proteolytic cleavage of FGF23 into C-terminal fragments. Red cell distribution width (RDW) was recently identified as a strong prognostic determinant for cardiovascular morbidity and mortality, independently of iron status. We assessed whether RDW is associated with FGF23 cleaving in CKD patients with heart failure. MATERIALS AND METHODS: The associations between RDW and either intact FGF23 (iFGF23), C-terminal FGF23 (cFGF23, reflecting iFGF23 and C-terminal fragments together) and the iFGF23/cFGF23 ratio were analyzed in 52 patients with CKD (eGFR 34,9 ± 13.9 ml/min/1.73m2) and chronic heart failure (CHF). Associations between RDW and FGF23 forms were studied by linear regression analysis adjusted for parameters of renal function, iron metabolism, phosphate metabolism and inflammation. RESULTS: Median cFGF23 levels were 197.5 [110-408.5] RU/ml, median iFGF23 levels were 107.3 [65.1-162.2] pg/ml and median FGF23 ratio was 0.80 [0.37-0.86]. Mean RDW was 14.1 ± 1.2%. cFGF23 and RDW were associated (ß = 1.63 x 10(-3), P < 0.001), whereas iFGF23 and RDW were not (ß = -1.38 x 10(-3), P = 0.336). The iFGF23/cFGF23 ratio was inversely associated with RDW. The difference between cFGF23 and iFGF23 (cFGF23- iFGF23) was positively associated with RDW (ß = 1.74 x 10(-3), P < 0.001). The association between cFGF23 and RDW persisted upon multivariable linear regression analysis, adjusted for parameters of renal function, phosphate metabolism, iron metabolism and inflammation (ß = 0.97 x 10(-3), P = 0.047). CONCLUSION: RDW is associated with cFGF23 but not with iFGF23 levels in patients with CKD and CHF. This suggests a connection between RDW and FGF23 catabolism, independent of iron status and inflammation. Future studies are needed to unravel underlying mechanisms and whether these pertain to the link between RDW and outcome.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/complicações , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Índices de Eritrócitos , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Insuficiência Cardíaca/metabolismo , Humanos , Masculino , Análise Multivariada , Insuficiência Renal Crônica/metabolismoRESUMO
AIM: Iron deficiency is an important child health problem. Its diagnosis in areas of high infection exposure remains complicated as inflammation may interfere with the accuracy of peripheral iron markers. With this study, we aimed to validate the conventional iron markers and two novel iron markers, hepcidin and Red blood cell Size Factor (RSf), against the reference standard of iron status, bone marrow iron, in children living in an infectious setting. METHODS: We compared ferritin, soluble transferrin receptor, Soluble Transferrin Log-Ferritin Index (sTfR-F), mean cellular volume, mean cellular haemoglobin concentration, hepcidin and RSf, against bone marrow iron in 87 healthy Malawian children (6-66â months) scheduled for elective surgery. RESULTS: Of all children, 44.8% had depleted bone marrow iron stores. Using optimised cut-offs, ferritin (<18â µg/L) and sTfR-F (>1.85) best predicted depleted iron stores with a sensitivity/specificity of 73.7%/77.1% and 72.5%/75.0%, respectively. Hepcidin (<1.4â nmol/L) was a moderate sensitive marker (73.0%) although specificity was 54.2%; RSf poorly predicted depleted iron stores. CONCLUSIONS: We provide the first bone marrow-validated data on peripheral iron markers in African children, and showed ferritin and sTfR-F best predicted iron status. Using appropriately defined cut-offs, these indicators can be applied in surveillance and research. As their accuracy is limited for clinical purposes, more reliable iron biomarkers are still required in African children.
Assuntos
Anemia Ferropriva/diagnóstico , Medula Óssea/química , Hepcidinas/sangue , Ferro/análise , Anemia Ferropriva/sangue , Biomarcadores/sangue , Pré-Escolar , Índices de Eritrócitos , Feminino , Ferritinas/sangue , Humanos , Lactente , Ferro/sangue , Deficiências de Ferro , Malaui , Masculino , Receptores da Transferrina/sangue , TransferrinaRESUMO
INTRODUCTION: A reliable diagnostic biomarker of iron status is required for severely anemic children living in malarious areas because presumptive treatment with iron may increase their infection risk if they are not iron deficient. Current biomarkers are limited because they are altered by host inflammation. In this study hepcidin concentrations were assessed in severely anemic children living in a highly malarious area of Malawi and evaluated against bone marrow iron in order to determine the usefulness of hepcidin as a point of care test. METHODS: 207 severely anemic children were assessed for levels of hepcidin, ferritin, serum transferrin receptor, erythropoietin, hematological indices, C-reactive protein, interleukin-6, malaria parasites and HIV infection. Deficiency of bone marrow iron stores was graded and erythroblast iron incorporation estimated. Interaction of covariates was assessed by structural-equation-modeling. RESULTS AND CONCLUSION: Hepcidin was a poor predictor of bone marrow iron deficiency (sensitivity 66.7%; specificity 48.5%), and of iron incorporation (sensitivity 54.2%; specificity 61.8%), and therefore would have limitations as a point of care test in this category of children. As upregulation of hepcidin by inflammation and iron status was blunted by erythropoietin in this population, enhanced iron absorption through the low hepcidin values may increase infection risk. Current recommendations to treat all severely anemic children living in malarious areas with iron should therefore be reconsidered.
Assuntos
Anemia/sangue , Anemia/epidemiologia , Medula Óssea/metabolismo , Doenças Transmissíveis/sangue , Doenças Transmissíveis/epidemiologia , Hepcidinas/sangue , Deficiências de Ferro , Pré-Escolar , Eritropoese , Feminino , Humanos , Hipóxia/sangue , Incidência , Lactente , Malaui/epidemiologia , Masculino , Análise MultivariadaRESUMO
BACKGROUND: Low-molecular-weight heparins (LMWHs) are frequently used to treat arterial and venous thrombo-embolic events. LMWHs accumulate with renal failure, but only limited clinical data regarding appropriate dosage adjustments are available. Nevertheless, LMWHs are routinely used in these patients worldwide. Although many clinics apply renal function-based dosage reductions, anti-factor Xa (anti-Xa) activity is not measured routinely. METHODS: We determined anti-Xa activity in 51 patients with MDRD-eGFR <60 mL/min/1.73 m(2), treated with therapeutic doses of nadroparin according to a standard, renal function-based guideline. RESULTS: An a priori dosage reduction resulted in anti-Xa activity within, below and above the reference range in 51, 30 and 19% of the measurements, respectively. Treatment resulted in different anti-Xa activities compared with dosages that were not given according to official advice (P < 0.001). Anti-Xa values increased with longer treatment duration (P = 0.038). CONCLUSIONS: A preemptive fixed reduction (25%) of the nadroparin dosage in all patients with renal failure seems appropriate. However, because target anti-Xa activities were reached in only half of the patients, we submit that the use of nadroparin, dosage reduction and monitoring of anti-Xa activity in combination with clinical outcome monitoring in this patient population urgently needs further investigation.
RESUMO
BACKGROUND: The efficacy of preventive zinc supplementation against diarrhea and respiratory illness may depend on simultaneous supplementation with other micronutrients. We aimed to assess the effect of supplementation with zinc and multiple micronutrients on diarrhea and other causes of non-malarial morbidity. METHODS AND FINDINGS: Rural Tanzanian children (nâ=â612) aged 6-60 months and with height-for-age z-score < -1.5 SD were randomized to daily supplementation with zinc (10 mg) alone, multi-nutrients without zinc, multi-nutrients with zinc, or placebo. Children were followed for an average of 45 weeks. During follow-up, we recorded morbidity episodes. We found no evidence that concurrent supplementation with multi-nutrients influenced the magnitude of the effect of zinc on rates of diarrhea, respiratory illness, fever without localizing signs, or other illness (guardian-reported illness with symptoms involving skin, ears, eyes and abscesses, but excluding trauma or burns). Zinc supplementation reduced the hazard rate of diarrhea by 24% (4%-40%). By contrast, multi-nutrients seemed to increase this rate (HR; 95% CI: 1.19; 0.94-1.50), particularly in children with asymptomatic Giardia infection at baseline (2.03; 1.24-3.32). Zinc also protected against episodes of fever without localizing signs (0.75; 0.57-0.96), but we found no evidence that it reduced the overall number of clinic visits. CONCLUSIONS: We found no evidence that the efficacy of zinc supplements in reducing diarrhea rates is enhanced by concurrent supplementation with other micronutrients. By reducing rates of fever without localizing signs, supplementation with zinc may reduce inappropriate drug use with anti-malarial medications and antibiotics. TRIAL REGISTRATION: ClinicalTrials.gov NCT00623857.
Assuntos
Diarreia , Suplementos Nutricionais , Micronutrientes/administração & dosagem , Doenças Respiratórias , População Rural , Zinco/administração & dosagem , Pré-Escolar , Diarreia/mortalidade , Diarreia/prevenção & controle , Feminino , Humanos , Lactente , Malária , Masculino , Doenças Respiratórias/mortalidade , Doenças Respiratórias/prevenção & controle , Saúde da População Rural , TanzâniaRESUMO
BACKGROUND: It is uncertain to what extent oral supplementation with zinc can reduce episodes of malaria in endemic areas. Protection may depend on other nutrients. We measured the effect of supplementation with zinc and other nutrients on malaria rates. METHODS AND FINDINGS: In a 2×2 factorial trial, 612 rural Tanzanian children aged 6-60 months in an area with intense malaria transmission and with height-for-age z-score≤-1.5 SD were randomized to receive daily oral supplementation with either zinc alone (10 mg), multi-nutrients without zinc, multi-nutrients with zinc, or placebo. Intervention group was indicated by colour code, but neither participants, researchers, nor field staff knew who received what intervention. Those with Plasmodium infection at baseline were treated with artemether-lumefantrine. The primary outcome, an episode of malaria, was assessed among children reported sick at a primary care clinic, and pre-defined as current Plasmodium infection with an inflammatory response, shown by axillary temperature ≥37.5°C or whole blood C-reactive protein concentration ≥ 8 mg/L. Nutritional indicators were assessed at baseline and at 251 days (median; 95% reference range: 191-296 days). In the primary intention-to-treat analysis, we adjusted for pre-specified baseline factors, using Cox regression models that accounted for multiple episodes per child. 592 children completed the study. The primary analysis included 1,572 malaria episodes during 526 child-years of observation (median follow-up: 331 days). Malaria incidence in groups receiving zinc, multi-nutrients without zinc, multi-nutrients with zinc and placebo was 2.89/child-year, 2.95/child-year, 3.26/child-year, and 2.87/child-year, respectively. There was no evidence that multi-nutrients influenced the effect of zinc (or vice versa). Neither zinc nor multi-nutrients influenced malaria rates (marginal analysis; adjusted HR, 95% CI: 1.04, 0.93-1.18 and 1.10, 0.97-1.24 respectively). The prevalence of zinc deficiency (plasma zinc concentration <9.9 µmol/L) was high at baseline (67% overall; 60% in those without inflammation) and strongly reduced by zinc supplementation. CONCLUSIONS: We found no evidence from this trial that zinc supplementation protected against malaria. TRIAL REGISTRATION: ClinicalTrials.gov NCT00623857
Assuntos
Suplementos Nutricionais/efeitos adversos , Ferro/efeitos adversos , Malária Falciparum/tratamento farmacológico , Micronutrientes/uso terapêutico , Zinco/uso terapêutico , Antimaláricos/administração & dosagem , Combinação Arteméter e Lumefantrina , Artemisininas/administração & dosagem , Pré-Escolar , Suplementos Nutricionais/análise , Combinação de Medicamentos , Etanolaminas , Feminino , Fluorenos/administração & dosagem , Seguimentos , Humanos , Incidência , Lactente , Ferro/administração & dosagem , Ferro/uso terapêutico , Deficiências de Ferro , Malária/classificação , Malária/tratamento farmacológico , Malária/epidemiologia , Malária/prevenção & controle , Malária Falciparum/classificação , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Masculino , Desnutrição/sangue , Desnutrição/epidemiologia , Micronutrientes/administração & dosagem , Micronutrientes/deficiência , Prevalência , Análise de Regressão , Tanzânia/epidemiologia , Zinco/administração & dosagem , Zinco/deficiênciaRESUMO
BACKGROUND: It is controversial to what degree α(+)-thalassaemia protects against episodes of uncomplicated malaria and febrile disease due to infections other than Plasmodium. METHODS: In Tanzania, in children aged 6-60 months and height-for-age z-score < -1.5 SD (n = 612), rates of fevers due to malaria and other causes were compared between those with heterozygous or homozygotes α(+)-thalassaemia and those with a normal genotype, using Cox regression models that accounted for multiple events per child. RESULTS: The overall incidence of malaria was 3.0/child-year (1, 572/526 child-years); no differences were found in malaria rates between genotypes (hazard ratios, 95% CI: 0.93, 0.82-1.06 and 0.91, 0.73-1.14 for heterozygotes and homozygotes respectively, adjusted for baseline factors that were predictive for outcome). However, this association strongly depended on age: among children aged 6-17 months, those with α(+)-thalassaemia experienced episodes more frequently than those with a normal genotype (1.30, 1.02-1.65 and 1.15, 0.80-1.65 for heterozygotes and homozygotes respectively), whereas among their peers aged 18-60 months, α(+)-thalassaemia protected against malaria (0.80, 0.68-0.95 and 0.78, 0.60-1.03; p-value for interaction 0.001 and 0.10 for hetero- and homozygotes respectively). No effect was observed on non-malarial febrile episodes. CONCLUSIONS: In this population, the association between α(+)-thalassaemia and malaria depends on age. Our data suggest that protection by α(+)-thalassaemia is conferred by more efficient acquisition of malaria-specific immunity.
Assuntos
Febre de Causa Desconhecida/epidemiologia , Malária/epidemiologia , Malária/patologia , Talassemia alfa/complicações , Fatores Etários , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Incidência , Lactente , Masculino , Modelos Estatísticos , Estudos Prospectivos , Tanzânia/epidemiologiaRESUMO
BACKGROUND: Studies have shown that red cell distribution width (RDW) is related to outcome in chronic heart failure (CHF). The pathophysiological process is unknown. We studied the relationship between RDW and erythropoietin (EPO) resistance, and related factors such as erythropoietic activity, functional iron availability and hepcidin. METHODS AND RESULTS: In the Mechanisms of Erythropoietin Action in the Cardiorenal Syndrome (EPOCARES) study, which investigates the role of EPO in 54 iron-supplemented anemic patients with CHF and chronic kidney disease (CKD) (n = 35 treated with 50 IU/kg/wk Epopoetin beta, n = 19 control), RDW was not associated with EPO resistance. We defined EPO resistance by EPO levels (r = 0.12, P = .42), the observed/predicted log EPO ratio (r = 0.12, P = .42), the increase in reticulocytes after 2 weeks of EPO treatment (r = -0.18, P = .31), and the increase of hemoglobin after 6 months of EPO treatment (r = 0.26, P = .35). However, RDW was negatively correlated with functional iron availability (reticulocyte hemoglobin content, r = -0.48, P < .001, and transferrin saturation, r = -0.39, P = .005) and positively with erythropoietic activity (soluble transferrin receptor, r = 0.48, P < .001, immature reticulocyte fraction, r = 0.36, P = .01) and positively with interleukin-6 (r = 0.48, P < .001). No correlation existed between hepcidin-25 and RDW. CONCLUSIONS: EPO resistance was not associated with RDW. RDW was associated with functional iron availability, erythropoietic activity, and interleukin-6 in anemic patients with CHF and CKD.
Assuntos
Resistência a Medicamentos/fisiologia , Índices de Eritrócitos/fisiologia , Eritrócitos/patologia , Eritropoetina/uso terapêutico , Insuficiência Cardíaca/sangue , Falência Renal Crônica/sangue , Idoso , Idoso de 80 Anos ou mais , Anemia/sangue , Anemia/tratamento farmacológico , Anemia/patologia , Tamanho Celular/efeitos dos fármacos , Resistência a Medicamentos/efeitos dos fármacos , Índices de Eritrócitos/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Eritropoetina/farmacologia , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/patologia , Humanos , Falência Renal Crônica/tratamento farmacológico , Falência Renal Crônica/patologia , Masculino , Estudos ProspectivosRESUMO
BACKGROUND: Severe anaemia is a major cause of morbidity and mortality in African children. The aetiology is multi-factorial, but interventions have often targeted only one or a few causal factors, with limited success. METHODS AND FINDINGS: We assessed the contribution of different pathophysiological mechanisms (red cell production failure [RCPF], haemolysis and blood loss) to severe anaemia in Malawian children in whom etiological factors have been described previously. More complex associations between etiological factors and the mechanisms were explored using structural equation modelling. In 235 children with severe anaemia (haemoglobin<3.2 mMol/L [5.0 g/dl]) studied, RCPF, haemolysis and blood loss were found in 48.1%, 21.7% and 6.9%, respectively. The RCPF figure increased to 86% when a less stringent definition of RCPF was applied. RCPF was the most common mechanism in each of the major etiological subgroups (39.7-59.7%). Multiple aetiologies were common in children with severe anaemia. In the final model, nutritional and infectious factors, including malaria, were directly or indirectly associated with RCPF, but not with haemolysis. CONCLUSION: RCPF was the most common pathway leading to severe anaemia, from a variety of etiological factors, often found in combination. Unlike haemolysis or blood loss, RCPF is a defect that is likely to persist to a significant degree unless all of its contributing aetiologies are corrected. This provides a further explanation for the limited success of the single factor interventions that have commonly been applied to the prevention or treatment of severe anaemia. Our findings underline the need for a package of measures directed against all of the local aetiologies of this often fatal paediatric syndrome.
Assuntos
Anemia/fisiopatologia , Anemia/metabolismo , Pré-Escolar , Eritrócitos/metabolismo , Feminino , Hemoglobinas/metabolismo , Hemólise , Humanos , Lactente , Malaui , MasculinoRESUMO
AIMS: Erythropoietin (EPO) resistance, an important cause of anaemia in patients with heart and renal failure, is associated with increased mortality. The hypothesis of the present study was that exogenous EPO decreases hepcidin levels and that the decrease in hepcidin levels upon EPO treatment is related to the bone marrow response. METHODS AND RESULTS: In the EPOCARES trial, patients with renal failure (glomerular filtration rate 20-70 mL/min), heart failure, and anaemia were randomized to receive 50 IU/kg/week EPO (n = 20) or not (n = 13). Haemoglobin (Hb), hepcidin-25, ferritin, reticulocytes, serum transferrin receptor (sTfR), IL-6, and high-sensitivity C-reactive protein were measured at baseline and during treatment. Hepcidin-25 was measured by weak cation exchange chromatography/matrix assisted laser desorption ionization time-of-flight mass spectrometry. Baseline hepcidin levels were increased compared with a healthy reference population and were inversely correlated with Hb (r(2) = 0.18, P = 0.02), and positively with ferritin (r(2) = 0.51, P < 0.001), but not with renal function, high-sensitivity C-reactive protein or IL-6. Erythropoietin treatment increased reticulocytes (P < 0.001) and sTfR (P < 0.001), and decreased hepcidin (P < 0.001). Baseline hepcidin levels and the magnitude of the decrease in hepcidin correlated with the increase in reticulocytes (r(2) = 0.23, P = 0.03) and sTfR (r(2) = 0.23, P = 0.03) and also with the Hb response after 6 months (r(2) = 0.49, P = 0.001). CONCLUSION: In this group of patients with combined heart and renal failure and anaemia, increased hepcidin levels were associated with markers of iron load and not with markers of inflammation. The (change in) hepcidin levels predicted early and long-term bone marrow response to exogenous EPO. In our group hepcidin seems to reflect iron load and response to EPO rather than inflammation and EPO resistance.
Assuntos
Anemia/tratamento farmacológico , Peptídeos Catiônicos Antimicrobianos/sangue , Eritropoetina/uso terapêutico , Insuficiência Cardíaca/sangue , Falência Renal Crônica/sangue , Idoso , Idoso de 80 Anos ou mais , Anemia/sangue , Anemia/complicações , Biomarcadores/sangue , Resistência a Medicamentos , Eritropoetina/administração & dosagem , Feminino , Seguimentos , Insuficiência Cardíaca/complicações , Hemoglobinas/metabolismo , Hepcidinas , Humanos , Falência Renal Crônica/complicações , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Prognóstico , Proteínas RecombinantesRESUMO
BACKGROUND: Anemia is common in patients with the combination of chronic heart failure and chronic kidney disease and is associated with increased mortality. Recent clinical studies suggest that recombinant human erythropoietin (EPO) treatment has desirable as well as undesirable effects, related to its hematopoietic or nonhematopoietic effects. Therefore a translational study is needed to elucidate mechanistic aspects of EPO treatment. METHODS: In this open-label randomized 12-month trial (the Mechanisms of Erythropoietin Action in the Cardiorenal Syndrome [EPOCARES]), patients with the combination of chronic heart failure and chronic kidney disease (glomerular filtration rate 20-70 ml/min) and mild anemia (hemoglobin 10.3-12.6 g/dL in men, and 10.3-11.9 g/dL in women) are being randomized into 3 groups: 1 group (n=25) receives a fixed dose of 50 IU/kg per week EPO to increase hemoglobin level to a maximum of 13.7 g/dL for men and 13.4 g/dL for women; another group (n=25) is treated with 50 IU/kg per week EPO maintaining baseline hemoglobin levels for the first 6 months by phlebotomy. The control group (n=25) receives standard care without EPO. RESULTS: Cardiac and renal function as well as a panel of biomarkers and iron parameters are being assessed. Furthermore, the effects of EPO on monocyte gene expression profiles and on endothelial progenitor cells are being evaluated. CONCLUSION: This translational study is designed primarily to discern hematopoietic from nonhematopoietic effects of EPO in cardiorenal patients. The study will add insights into the mechanisms that could explain the fragile balance between desirable and undesirable effects of EPO (Trial registration: ClinicalTrials.gov identifier NCT00356733).
Assuntos
Anemia/tratamento farmacológico , Eritropoetina/uso terapêutico , Insuficiência Cardíaca/fisiopatologia , Falência Renal Crônica/fisiopatologia , Anemia/fisiopatologia , Biomarcadores , Eritropoetina/efeitos adversos , Feminino , Insuficiência Cardíaca/sangue , Humanos , Falência Renal Crônica/sangue , Masculino , Proteínas RecombinantesRESUMO
BACKGROUND: Urine microscopic analysis is hampered by its lack in standardisation and semi-quantitative reports, resulting in limited reliability. Automation of urinalysis could overcome these problems. METHODS: We compared the performance of the iQ200 with traditional microscopy and strip analysis in routine urinalysis. A total of 1482 routine samples, positive in dipstick testing, were evaluated for erythrocytes, leukocytes, casts, dysmorphic erythrocytes and bacteria using the iQ200 and traditional microscopy. The results of 320 of these samples were linked to underlying urological pathology as well as results from bacterial culturing. RESULTS: Analytically, the iQ200 surpasses traditional microscopy. The identification of casts and dysmorphic erythrocytes in routine samples improves when using the iQ200, although the sub-classification of casts required well-trained technicians. The auto-classification of particles was least reliable for yeast and bacterial cocci. The quantitative reports, and therefore the use of precise cut-off points allowed earlier and improved detection of urinary tract pathology. CONCLUSIONS: The performance of the iQ200 is equal to traditional microscopy, but it strongly improves the reliability of urinalysis by standardisation, quantitative reports and improved workflow. From a clinical point of view, renewed attention and improvement of routine urinalysis aids in the efficient detection of renal and urinary tract pathology.
Assuntos
Microscopia/métodos , Urinálise/instrumentação , Urinálise/métodos , Autoanálise/instrumentação , Autoanálise/métodos , Bactérias/citologia , Bactérias/isolamento & purificação , Erros de Diagnóstico/estatística & dados numéricos , Eritrócitos/citologia , Hematúria/diagnóstico , Hematúria/urina , Humanos , Leucócitos/citologia , Masculino , Doenças Prostáticas/diagnóstico , Doenças Prostáticas/urina , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/urina , Infecções Urinárias/diagnóstico , Infecções Urinárias/urina , Urina/química , Urina/citologia , Urina/microbiologia , Urolitíase/diagnóstico , Urolitíase/urinaRESUMO
BACKGROUND: In hospital-based studies, alpha(+)-thalassemia has been found to protect against severe, life-threatening falciparum malaria. alpha(+)-Thalassemia does not seem to prevent infection or high parasite densities but rather limits progression to severe disease--in particular, severe malarial anemia. We assessed to what extent alpha(+)-thalassemia influences the association between mild, asymptomatic Plasmodium falciparum infection and hemoglobin concentration. METHODS: The study was based on 2 community-based surveys conducted among afebrile children (0.5-8 years old; n=801) in Kenya and Tanzania. RESULTS: Among children without inflammation (whole-blood C-reactive protein concentration Assuntos
Anemia/prevenção & controle
, Imunidade Inata
, Malária/complicações
, Malária/imunologia
, Talassemia alfa
, Animais
, Criança
, Pré-Escolar
, Globinas/genética
, Hemoglobinas/análise
, Humanos
, Lactente
, Quênia/epidemiologia
, Tanzânia/epidemiologia
RESUMO
BACKGROUND: alpha(1)-Antitrypsin (alpha(1)AT) deficiency predisposes individuals to chronic obstructive pulmonary disease (COPD) and/or liver disease. Phenotyping of the protein by isoelectric focusing is often used to characterize alpha(1)AT deficiency, but this method may lead to misdiagnosis (e.g., by missing null alleles). We evaluated a workup that included direct sequencing of the relevant parts of the gene encoding alpha(1)AT, SERPINA1 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1], for patients with alpha(1)AT concentrations < or =1.0 g/L. METHODS: During a 5-year period, we identified 66 patients with alpha(1)AT concentrations < or =1.0 g/L and amplified and sequenced exons 2, 3, and 5 of the alpha(1)AT gene in these patients. To ensure that no relevant genotypes were missed, we sequenced the same exons in 48 individuals with alpha(1)AT concentrations between 1.0 and 1.5 g/L. RESULTS: Sequence analysis revealed 18 patients with combinations of disease-associated alpha(1)AT alleles: 8 homozygous for the deficient Z allele and 10 compound heterozygotes for various deficient or null alleles. We identified and named 2 new null alleles, Q0(soest) (Thr(102)-->delA, which produces a TGA stop signal at codon 112) and Q0(amersfoort) (Tyr(160)-->stop). No relevant disease-associated allele combinations were missed at a 1.0-g/L threshold. CONCLUSIONS: Up to 22% of the alleles in disease-associated alpha(1)AT allele combinations may be missed by conventional methods. Genotyping by direct sequencing of samples from patients with alpha(1)AT concentrations < or =1.0 g/L detected these alleles and identified 2 new null alleles.
Assuntos
Doença Pulmonar Obstrutiva Crônica/genética , Deficiência de alfa 1-Antitripsina/genética , alfa 1-Antitripsina/genética , Alelos , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Análise de Sequência de ProteínaRESUMO
BACKGROUND: Moderate and prolonged consumption of red wine is associated with decreased cardiovascular morbidity and mortality. Inhibition of platelet functions by ingredients in red wine is thought to be one of the causes. However, the molecular mechanism of this inhibition has remained unexplained. MATERIALS AND METHODS: We measured aggregation, changes in cytosolic Ca(2+) and tyrosine phosphorylation of the inhibitory receptor platelet endothelial cell adhesion molecule-1 (PECAM-1) in platelets stimulated with thrombin receptor (PAR-1) activating peptide (TRAP) and ADP and investigated the effects of alcohol-free polyphenolic grape extract (PGE), alcohol, and the polyphenols catechin, epi-catechin, resveratrol, trans-resveratrol, and gallic acid. RESULTS: Polyphenolic grape extract induced dose-dependent inhibition of TRAP-induced and ADP-induced platelet aggregation and Ca(2+) mobilization. Inhibition was accompanied by activation of PECAM-1. Apart from a slight inhibition by catechin, ethanol or other individual polyphenols failed to inhibit aggregation or activate PECAM-1. CONCLUSIONS: Red wine inhibits platelet functions through its PGE content, which stimulates the inhibitory receptor PECAM-1, thereby attenuating platelet activation.
Assuntos
Doenças Cardiovasculares/epidemiologia , Flavonoides/farmacologia , Fenóis/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária , Molécula-1 de Adesão Celular Endotelial a Plaquetas/fisiologia , Vitis/química , Vinho , Difosfato de Adenosina/farmacologia , Biotransformação/efeitos dos fármacos , Cálcio/metabolismo , Citosol/metabolismo , Flavonoides/isolamento & purificação , França/epidemiologia , Frutas/química , Humanos , Indicadores e Reagentes , Fenóis/isolamento & purificação , Fosforilação , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Polifenóis , Receptores de Trombina/metabolismo , Tirosina/metabolismoRESUMO
BACKGROUND: Sodium iron edetic acid (NaFeEDTA) might be a more bioavailable source of iron than electrolytic iron, when added to maize flour. We aimed to assess the effect, on children's iron status, of consumption of whole maize flour fortified with iron as NaFeEDTA or electrolytic iron. METHODS: 516 children, aged 3-8 years, from four schools in Marafa, Kenya, were randomly assigned to four groups. All were given the same amount of porridge five times a week. The porridge for one group was made from unfortified whole maize flour; for the other three groups it was fortified with either high-dose NaFeEDTA (56 mg/kg), low-dose NaFeEDTA (28 mg/kg), or electrolytic iron (56 mg/kg). Concentrations of haemoglobin, plasma ferritin, and transferrin receptor were analysed in samples taken at baseline and at the end of the 5-month intervention. The primary outcome was iron-deficiency anaemia. We analysed data on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT00386074. FINDINGS: The prevalence of iron-deficiency anaemia in children given unfortified flour was 10%. Compared with placebo, the prevalence of iron-deficiency anaemia in children given flour fortified with high-dose NaFeEDTA, low-dose NaFeEDTA, and electrolytic iron changed by -89% (95% CI -97% to -49%), -48% (-77% to 20%), and 59% (-18% to 209%), respectively. Consumption of high-dose NaFeEDTA improved all measured iron-status indicators. Low-dose NaFeEDTA decreased the prevalence of iron deficiency but did not noticeably change the prevalence of anaemia. Electrolytic iron did not improve any of these iron-status indicators. Children who were iron-deficient at baseline benefited more from high-dose and low-dose NaFeEDTA than those with sufficient iron at baseline. INTERPRETATION: Consumption of whole maize flour fortified with NaFeEDTA caused modest, dose-dependent improvements in children's iron status. Fortification with electrolytic iron did not improve their iron status. Therefore, in high-phytate flours, NaFeEDTA is more suitable than electrolytic iron for supplementation of iron in the diet.
Assuntos
Anemia Ferropriva/tratamento farmacológico , Grão Comestível , Compostos Férricos/uso terapêutico , Alimentos Fortificados , Quelantes de Ferro/uso terapêutico , Ferro/uso terapêutico , Estado Nutricional/efeitos dos fármacos , Anemia Ferropriva/sangue , Anemia Ferropriva/epidemiologia , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Ácido Edético/administração & dosagem , Ácido Edético/uso terapêutico , Feminino , Compostos Férricos/administração & dosagem , Humanos , Ferro/administração & dosagem , Quelantes de Ferro/administração & dosagem , Quênia/epidemiologia , Masculino , PrevalênciaRESUMO
BACKGROUND: Moderate alcohol consumption is associated with decreased mortality from cardiovascular disease. Drinking large amounts in a short period (binge drinking) is associated with increased cardiovascular morbidity. We tested whether rapid consumption of a large dose of alcohol affects platelet aggregation and adhesion. METHODS: Healthy volunteers (n = 20) were asked to drink three glasses of alcohol or red wine in a 45-min period. Thereafter, another 45 min was allowed for absorption of alcohol. Ninety minutes after the start of the experiment, blood was collected. This entire cycle was repeated once, resulting in consumption of six alcohol-containing drinks in 3 hr. Adenosine-diphosphate (ADP)-induced aggregation was measured and platelet adhesion to fibrinogen and collagen was measured in a perfusion chamber at shear rates of 300/sec and 1600/sec. Platelet coverage and aggregate size were measured. RESULTS: Acute alcohol intake significantly increased platelet aggregation in suspension when stimulated with low concentrations of ADP (0.1 and 0.5 microg/ml). This effect was not observed when consuming red wine. In contrast, adhesion to fibrinogen was significantly inhibited by alcohol but not red wine at high shear rate after six drinks (p = 0.025). The inhibition was accompanied by a reduction in aggregate size at 90 and 180 min after the start of the experiment. Adhesion to collagen was not altered by either alcohol or red wine. CONCLUSIONS: Rapid intake of alcohol increases platelet aggregation, which might contribute to the increased mortality associated with binge drinking. Red wine does not show increased platelet aggregation, which might support the reduction of cardiovascular disease in red wine consumers. However, alcohol inhibits platelet adhesion to fibrinogen-coated surface under flow. The diminished adhesion might contribute to the cardioprotective effects of alcohol.
Assuntos
Consumo de Bebidas Alcoólicas/sangue , Etanol/administração & dosagem , Fibrinogênio/metabolismo , Adesividade Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Adulto , Consumo de Bebidas Alcoólicas/efeitos adversos , Análise de Variância , Feminino , Humanos , Masculino , Adesividade Plaquetária/fisiologia , Agregação Plaquetária/fisiologia , Fatores de Tempo , VinhoRESUMO
We assessed whether large-scale expression profiling of leukocytes of patients with essential hypertension reflects characteristics of systemic disease and whether such changes are responsive to antihypertensive therapy. Total RNA from leukocytes were obtained from untreated (n=6) and treated (n=6) hypertensive patients without apparent end-organ damage and from normotensive controls (n=9). RNA was reverse-transcribed and labeled and gene expression analyzed using a 19-K oligonucleotide microarray using dye swaps. Samples of untreated and of treated patients were pooled for each sex and compared with age- and sex-matched controls. In untreated patients, 680 genes were differentially regulated (314 up and 366 down). In the treated patients, these changes were virtually absent (4 genes up, 3 genes down). A myriad of changes was observed in pathways involved in inflammation. Inflammation-dampening interleukin receptors were decreased in expression. Intriguingly, inhibitors of cytokine signaling (the PIAS family of proteins) were differentially expressed. The expression of several genes that are involved in regulation of blood pressure were also differentially expressed: angiotensin II type 1 receptor, ANP-A receptor, endothelin-2, and 3 of the serotonin receptors were increased, whereas endothelin-converting enzyme-1 was decreased. Strikingly, virtually no changes in gene expression could be detected in hypertensive patients who had become normotensive with treatment. This observation substantiates the long-standing idea that hypertension is associated with a complex systemic response involving inflammation-related genes. Furthermore, leukocytes display differential gene expression that is of importance in blood pressure control. Importantly, treatment of blood pressure to normal values can virtually correct such disturbances.
Assuntos
Anti-Hipertensivos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Leucócitos/efeitos dos fármacos , Adulto , Anti-Hipertensivos/uso terapêutico , Feminino , Perfilação da Expressão Gênica , Humanos , Hipertensão/sangue , Inflamação/sangue , Inflamação/genética , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estresse MecânicoRESUMO
Binge drinking is associated with an increased risk of cardiovascular events. Those events often happen within hours after alcohol is consumed. Apart from arrhythmias and changes in blood pressure, these events may be caused by an acute (i.e., occurring within a 24-h period) shift of the hemostatic balance in a thrombogenic direction. Alcohol can influence platelet aggregation and inhibit fibrinolysis, but little is known about its direct effect on coagulation. In the current study, parameters of coagulation, reflecting either stimulation or inhibition, were measured 5 and 15 h after the consumption of four (62.5 g of alcohol) and eight (125 g of alcohol) glasses of red wine. Both doses had no direct effect on activated cephalin time, thrombin-antithrombin complexes, factors VII and VIII, and von Willebrand factor. In contrast with the observed effects on thrombocytes and fibrinolysis, the consumption of large amounts of wine does not influence the coagulation pathway.