RESUMEN
The clinical severity of sickle cell disease (SCD) is strongly influenced by the level of fetal haemoglobin (HbF) persistent in each patient. Three major HbF loci (BCL11A, HBS1L-MYB, and Xmn1-HBG2) have been reported, but a considerable hidden heritability remains. We conducted a genome-wide association study for HbF levels in 1006 Nigerian patients with SCD (HbSS/HbSß0), followed by a replication and meta-analysis exercise in four independent SCD cohorts (3,582 patients). To dissect association signals at the major loci, we performed stepwise conditional and haplotype association analyses and included public functional annotation datasets. Association signals were detected for BCL11A (lead SNP rs6706648, ß = -0.39, P = 4.96 × 10-34) and HBS1L-MYB (lead SNP rs61028892, ß = 0.73, P = 1.18 × 10-9), whereas the variant allele for Xmn1-HBG2 was found to be very rare. In addition, we detected three putative new trait-associated regions. Genetically, dissecting the two major loci BCL11A and HBS1L-MYB, we defined trait-increasing haplotypes (P < 0.0001) containing so far unidentified causal variants. At BCL11A, in addition to a haplotype harbouring the putative functional variant rs1427407-'T', we identified a second haplotype, tagged by the rs7565301-'A' allele, where a yet-to-be-discovered causal DNA variant may reside. Similarly, at HBS1L-MYB, one HbF-increasing haplotype contains the likely functional small indel rs66650371, and a second tagged by rs61028892-'C' is likely to harbour a presently unknown functional allele. Together, variants at BCL11A and HBS1L-MYB SNPs explained 24.1% of the trait variance. Our findings provide a path for further investigation of the causes of variable fetal haemoglobin persistence in sickle cell disease.
Asunto(s)
Anemia de Células Falciformes , Proteínas de Unión al GTP , Estudio de Asociación del Genoma Completo , Haplotipos , Femenino , Humanos , Masculino , Alelos , Anemia de Células Falciformes/genética , Anemia de Células Falciformes/sangre , Predisposición Genética a la Enfermedad , Nigeria , Proteínas Nucleares/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas Represoras/genéticaRESUMEN
Not available.
Asunto(s)
Anemia de Células Falciformes , Enfermedad de la Hemoglobina SC , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/genética , Infarto Cerebral/genética , Estudio de Asociación del Genoma Completo , Hemoglobina Falciforme/genética , HumanosRESUMEN
Silent cerebral infarction is the most common neurological abnormality in children with sickle cell anemia, affecting 30-40% of 14 year olds. There are no known biomarkers to identify children with silent cerebral infarcts, and the pathological basis is also unknown. We used an unbiased proteomic discovery approach to identify plasma proteins differing in concentration between children with and without silent cerebral infarcts. Clinical parameters and plasma samples were analysed from 51 children (mean age 11.8 years, range 6-18) with sickle cell anemia (HbSS). A total of 19 children had silent cerebral infarcts and 32 normal MRI; the children with silent infarcts had lower HbF levels (8.6 vs 16.1%, P=0.049) and higher systolic blood pressures (115 vs 108.6, P=0.027). Plasma proteomic analysis showed 13 proteins increased more than 1.3 fold in the SCI patients, including proteins involved in hypercoagulability (α2-antiplasmin, fibrinogen-γ chain, thrombospondin-4), inflammation (α2-macroglobulin, complement C1s and C3), and atherosclerosis (apolipoprotein B-100). Higher levels of gelsolin and retinol-binding protein 4 were also found in the population with silent infarcts, both of which have been linked to stroke. We investigated the genetic basis of these differences by studying 359 adults with sickle cell disease (199 with silent cerebral infarcts, 160 normal MRIs), who had previously undergone a genome-wide genotyping array. None of the genes coding for the differentially expressed proteins were significantly associated with silent infarction. Our study suggests that silent cerebral infarcts in sickle cell anemia may be associated with higher systolic blood pressure, lower HbF levels, hypercoagulability, inflammation and atherosclerotic lipoproteins.
Asunto(s)
Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/complicaciones , Proteínas Sanguíneas , Infarto Cerebral/etiología , Proteómica , Adulto , Enfermedades Asintomáticas , Biomarcadores , Infarto Cerebral/diagnóstico , Niño , Preescolar , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Proteómica/métodos , Evaluación de Síntomas , Adulto JovenRESUMEN
In order to identify very early prognostic factors that can provide insights into subsequent clinical complications, we performed a comprehensive longitudinal multi-center cohort study on 57 infants with sickle cell anemia (55 SS; 2 Sß°) during the first 2 years of life (ClinicalTrials.gov: NCT01207037). Time to first occurrence of a severe clinical event-acute splenic sequestration (ASS), vaso-occlusive (VOC) event requiring hospitalization, transfusion requirement, conditional/ abnormal cerebral velocities, or death-was used as a composite endpoint. Infants were recruited at a mean age of 4.4 ±1 months. Median follow-up was 19.4 months. During the study period, 38.6% of infants experienced ≥1 severe event: 14% ASS, 22.8% ≥ 1 VOC (median age: 13.4 and 12.8 months, respectively) and 33.3% required transfusion. Of note, 77% of the cohort was hospitalized, with febrile illness being the leading cause for admission. Univariate analysis of various biomarkers measured at enrollment showed that fetal hemoglobin (HbF) was the strongest prognostic factor of subsequent severe outcome. Other biomarkers measured at enrolment including absolute neutrophil or reticulocyte counts, expression of erythroid adhesion markers, % of dense red cells, cellular deformability or Ï-globin genetic variants, failed to be associated with severe clinical outcome. Multivariate analysis demonstrated that higher Hb concentration and HbF level are two independent protective factors (adjusted HRs (95% CI) 0.27 (0.11-0.73) and 0.16 (0.06-0.43), respectively). These findings imply that early measurement of HbF and Hb levels can identify infants at high risk for subsequent severe complications, who might maximally benefit from early disease modifying treatments.
Asunto(s)
Anemia de Células Falciformes/diagnóstico , Índice de Severidad de la Enfermedad , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/terapia , Biomarcadores/análisis , Transfusión Sanguínea , Estudios de Cohortes , Femenino , Hemoglobina Fetal/análisis , Hemoglobinas/análisis , Hospitalización , Humanos , Lactante , Estudios Longitudinales , Masculino , PronósticoRESUMEN
We explored transient elastography (TE) and enhanced liver fibrosis (ELF™ ) score with standard markers of liver function to assess liver damage in 193 well patients with sickle cell disease (SCD). Patients with HbSS or HbSß0 thalassaemia (sickle cell anaemia, SCA; N = 134), had significantly higher TE results and ELF scores than those with HbSC (N = 49) disease (TE, 6·8 vs. 5·3, P < 0·0001 and ELF, 9·2 vs. 8·6 P < 0·0001). In SCA patients, TE and ELF correlated significantly with age and all serum liver function tests (LFTs). Additionally, (weak) positive correlation was found with lactate dehydrogenase (TE: r = 0·24, P = 0·004; ELF: r = 0·26 P = 0·002), and (weak) negative correlation with haemoglobin (TE: r = -0·25, P = 0·002; ELF: r = -0·25 P = 0·004). In HbSC patients, correlations were weaker or not significant between TE or ELF, and serum LFTs. All markers of iron loading correlated with TE values when corrected for sickle genotype (serum ferritin, ß = 0·25, P < 0·0001, total blood transfusion units, ß = 0·25, P < 0·0001 and LIC ß = 0·32, P = 0·046). The exploratory study suggests that, while TE could have a role, the utility of ELF score in monitoring liver damage in SCD, needs further longitudinal studies.
Asunto(s)
Anemia de Células Falciformes/complicaciones , Hepatopatías/etiología , Adolescente , Adulto , Anciano , Anemia de Células Falciformes/patología , Diagnóstico por Imagen de Elasticidad , Femenino , Enfermedad de la Hemoglobina SC , Hemoglobina Falciforme , Humanos , Sobrecarga de Hierro/diagnóstico , Cirrosis Hepática/diagnóstico , Hepatopatías/patología , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: Intracranial aneurysms and aneurysmal subarachnoid hemorrhage may occur more frequently in sickle-cell disease (SCD), and this could be related to the sickle genotype and moyamoya syndrome seen in SCD. METHODS: Records from a total of 1002 patients with SCD attending 2 specialized adult hematologic services were retrospectively reviewed. We analyzed data of a cohort of 767 patients attending 1 SCD clinic between 2002 and 2013 and of 235 patients from the other clinic who have had neurovascular imaging between 2007 and 2014. RESULTS: We identified 4 patients in the cohort who had an aneurysmal subarachnoid hemorrhage during 9063 patient-years. The highest incidence rate was seen among women in the age group 30 to 39 years with the hemoglobin SS (HbSS) genotype (440 per 100 000 patient-years). Unruptured intracranial aneurysms were found in 20 of the 324 patients, who had imaging data; the prevalence was significantly higher in patients with HbSS genotype compared with other sickle genotypes with the highest prevalence (15%) observed in women in the age group 30 to 39 years. Fifty-one HbSS patients had a moyamoya vasculopathy, but only 3 of these had concomitant intracranial aneurysms. CONCLUSIONS: Intracranial aneurysms are common in HbSS SCD. There was also a trend toward more common occurrence of aneurysmal subarachnoid hemorrhage in HbSS; women in the age group 30 to 39 years were most at risk. There was no correlation between the occurrence of intracranial aneurysms and moyamoya syndrome.
Asunto(s)
Anemia de Células Falciformes/epidemiología , Genotipo , Hemoglobina Falciforme/genética , Aneurisma Intracraneal/epidemiología , Enfermedad de Moyamoya/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anemia de Células Falciformes/diagnóstico por imagen , Anemia de Células Falciformes/genética , Encéfalo/diagnóstico por imagen , Angiografía Cerebral , Niño , Preescolar , Comorbilidad , Femenino , Predisposición Genética a la Enfermedad , Humanos , Incidencia , Lactante , Recién Nacido , Aneurisma Intracraneal/diagnóstico por imagen , Aneurisma Intracraneal/genética , Angiografía por Resonancia Magnética , Masculino , Persona de Mediana Edad , Enfermedad de Moyamoya/diagnóstico por imagen , Enfermedad de Moyamoya/genética , Prevalencia , Estudios Retrospectivos , Adulto JovenRESUMEN
Sickle cell disease (SCD) has evolved into a debilitating disorder with emerging end-organ damage. One of the organs affected is the liver, causing "sickle hepatopathy," an umbrella term for a variety of acute and chronic pathologies. Prevalence of liver dysfunction in SCD is unknown, with estimates of 10%. Dominant etiologies include gallstones, hepatic sequestration, viral hepatitis, and sickle cell intrahepatic cholestasis (SCIC). In addition, causes of liver disease outside SCD must be identified and managed. SCIC is an uncommon, severe subtype, with outcome of its acute form having vastly improved with exchange blood transfusion (EBT). In its chronic form, there is limited evidence for EBT programs as a therapeutic option. Liver transplantation may have a role in a subset of patients with minimal SCD-related other organ damage. In the transplantation setting, EBT is important to maintain a low hemoglobin S fraction peri- and posttransplantation. Liver dysfunction in SCD is likely to escalate as life span increases and patients incur incremental transfusional iron overload. Future work must concentrate on not only investigating the underlying pathogenesis, but also identifying in whom and when to intervene with the 2 treatment modalities available: EBT and liver transplantation.
Asunto(s)
Anemia de Células Falciformes/complicaciones , Hepatopatías/etiología , Hepatopatías/cirugía , Trasplante de Hígado , Adolescente , Niño , Preescolar , Humanos , Masculino , Adulto JovenRESUMEN
INTRODUCTION: People with a disability living in rural areas commonly experience difficulty in accessing therapy services. Information and Communication Technologies (ICT) may have the potential to provide occupational therapy services remotely through two-way visual interactions. The aim of this qualitative study was to understand the perspectives of carers of a person with a disability living in rural New South Wales (NSW) on the use of ICT for occupational therapy service delivery. METHODS: Individual semi-structured telephone interviews were conducted with 11 carers of persons with a disability living in rural NSW. Participants were asked about their use of technology, therapy experiences and their attitudes towards using ICT to receive occupational therapy for their son/daughter. Data were analysed via constant comparison and thematic analysis. RESULTS: Participants were willing to use ICT to enhance their current access to therapy based on their in-depth knowledge of their son or daughter and their prior experiences with therapy and technology. For ICT to work for occupational therapy, participants identified the need for support and access prior to, during and between ICT sessions. CONCLUSION: From the carers' perspectives, ICT has the potential to increase access to occupational therapy services for people with a disability who live in rural NSW. Occupational therapists could benefit from eliciting the experiences, knowledge and willingness of rural carers to deliver therapy via ICT, thereby supplementing and enhancing in-person service delivery.
Asunto(s)
Cuidadores/psicología , Personas con Discapacidad/rehabilitación , Terapia Ocupacional/organización & administración , Servicios de Salud Rural/organización & administración , Telerrehabilitación/organización & administración , Adolescente , Adulto , Anciano , Niño , Niños con Discapacidad , Femenino , Accesibilidad a los Servicios de Salud/organización & administración , Humanos , Entrevistas como Asunto , Masculino , Persona de Mediana Edad , Nueva Gales del Sur , Investigación Cualitativa , Población Rural , Adulto JovenRESUMEN
Transfusion therapy is effective in the prevention and treatment of many complications of sickle cell disease (SCD). However, its benefits must be balanced against its risks, including delayed haemolytic transfusion reactions (DHTR). Not only is the relative rate of alloimmunization higher in patients with SCD than in other patient populations, but attendant risks associated with DHTR are even greater in SCD. Clinicians' awareness of DHTR events is poor because symptoms of DHTR mimic acute vaso-occlusive pain and immunohaematology findings are often negative. Transfusions delivered in the acute rather than elective setting appear to confer a higher risk of DHTR. Management of DHTR in SCD depends on the clinical severity, ranging from supportive care to immunosuppression, and optimization of erythropoiesis. DHTR must be considered in any recently transfused patient presenting with acute sickle cell pain. Meticulous documentation of transfusion and immunohaematology history is key. We anticipate an increase in DHTR events in SCD patients with the increasing use of red blood cell transfusion therapy.
Asunto(s)
Anemia de Células Falciformes/complicaciones , Reacción a la Transfusión , Reacción a la Transfusión/etiología , Reacción a la Transfusión/terapia , Adolescente , Anemia de Células Falciformes/epidemiología , Anemia de Células Falciformes/terapia , Manejo de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Reacción a la Transfusión/diagnóstico , Reacción a la Transfusión/epidemiologíaRESUMEN
Delayed haemolytic transfusion reactions (DHTR) are potentially life-threatening complications in patients with sickle cell disease (SCD). Between 1 August 2008 and 31 December 2013, 220 of 637 adult patients in our centre had at least one red blood cell (RBC) transfusion in 2158 separate transfusion episodes. Twenty-three DHTR events occurred in 17 patients (13 female) including 15 HbSS, one HbSC and one HbSß(0) thalassaemia, equating to a DHTR rate of 7·7% of patients transfused. Mean interval from RBC transfusion to DHTR event was 10·1 ± 5·4 d, and typical presenting features were fever, pain and haemoglobinuria. Twenty of the 23 (87·0%) DHTR episodes occurred following transfusion in the acute setting. Notably, 11/23 (47·8%) of DHTRs were not diagnosed at the time of the event, most were misdiagnosed as a vaso-occlusive crisis. 16/23 DHTRs had 'relative reticulocytopenia', which was more common in older patients. Seven of 23 episodes resulted in alloantibody formation, and three caused autoantibody formation. DHTRs are a severe but uncommon complication of RBC transfusion in SCD and remain poorly recognized, possibly because they mimic an acute painful crisis. Most of the DHTRs are triggered by RBC transfusion in the acute setting when patients are in an inflammatory state.
Asunto(s)
Anemia de Células Falciformes/complicaciones , Reacción a la Transfusión , Reacción a la Transfusión/etiología , Adolescente , Adulto , Anemia de Células Falciformes/terapia , Femenino , Humanos , Hipersensibilidad Tardía/diagnóstico , Hipersensibilidad Tardía/tratamiento farmacológico , Hipersensibilidad Tardía/etiología , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Reacción a la Transfusión/diagnóstico , Reacción a la Transfusión/tratamiento farmacológico , Resultado del Tratamiento , Adulto JovenAsunto(s)
Anemia/diagnóstico , Betacoronavirus , Infecciones por Coronavirus/diagnóstico , Hemoglobinopatías/diagnóstico , Neumonía Viral/diagnóstico , Encuestas y Cuestionarios , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anemia/epidemiología , COVID-19 , Niño , Preescolar , Infecciones por Coronavirus/epidemiología , Femenino , Hemoglobinopatías/epidemiología , Humanos , Lactante , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/epidemiología , SARS-CoV-2 , Adulto JovenAsunto(s)
Anemia de Células Falciformes/diagnóstico , Anemia de Células Falciformes/genética , Mutación con Ganancia de Función , Canales Iónicos/genética , Eliminación de Secuencia , Alelos , Anemia de Células Falciformes/sangre , Biomarcadores , Índices de Eritrocitos , Eritrocitos/metabolismo , Genotipo , Humanos , FenotipoRESUMEN
BACKGROUND: Caesarean section rates in Australia have risen to >30%, with repeat caesarean delivery the most common indication. One method of reducing caesarean delivery rates is to increase rates of vaginal birth after caesarean section (VBAC). AIMS: To determine the combined effect of two management strategies on the rates of successful VBAC in women experiencing their first pregnancy following primary caesarean section. METHODS: Prospective cohort study from May 2009 to October 2010 at a metropolitan Australian teaching hospital. The strategies studied were (i) allocating responsibility for VBAC candidates attempting labour to the hospital's three high-risk obstetric consultants and (ii) implementing a next birth after caesarean (NBAC) antenatal clinic designed to counsel and support women deciding on mode of birth for their next pregnancy after a primary caesarean section. Data were collected from Obstetrix, a NBAC logbook and medical records of 396 eligible women who gave birth during the study period. RESULTS: Overall VBAC rates improved from 17.2% in 2006 prior to implementation of the combined strategies, to 27.0% over the studied period (P < 0.001). Of those women who desired and attempted a VBAC, the success rate was 64.4%. Regression analysis identified an increased likelihood of attempted vaginal birth where malpresentation was the indication for previous caesarean, while Eastern Asian ethnicity was associated with increased likelihood of choosing repeat caesarean. CONCLUSIONS: A dedicated NBAC clinic and more consistent approach to labour management can help improve VBAC rates. Further targeted counselling towards women with previous malpresentation and/or East Asian descent may further improve VBAC attempt rates.
Asunto(s)
Cesárea Repetida/estadística & datos numéricos , Parto Vaginal Después de Cesárea/tendencias , Adulto , Australia , Toma de Decisiones , Asia Oriental/etnología , Femenino , Humanos , Presentación en Trabajo de Parto , Embarazo , Estudios Prospectivos , Medición de Riesgo/organización & administración , Esfuerzo de Parto , Parto Vaginal Después de Cesárea/estadística & datos numéricos , Adulto JovenAsunto(s)
Anemia de Células Falciformes/economía , Anemia de Células Falciformes/mortalidad , Factores Socioeconómicos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Renta/estadística & datos numéricos , Esperanza de Vida , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Adulto JovenRESUMEN
The COVID-19 pandemic spurred some regulators in the USA to require occupational health and safety programs to prevent COVID-19 transmission in workplaces. The objective of this study was to describe such state and federal regulations enacted between January 2020 and January 2022. Regulations, including emergency temporary standards (ETS) and permanent standards, were identified through a search of Nexis Uni and Bloomberg Law and review of US OSHA websites and the Federal Register. Full texts were reviewed for regulatory scope, hazard and exposure definitions, determination of exposure or risk levels, and control strategies. Four state (California, Michigan, Virginia, and Oregon) and two federal regulations were identified. All regulations described respiratory aerosols as the primary source of SARS-CoV-2 and recognized person-to-person transmission by droplet, airborne, and contact routes. Only the US OSHA ETS for healthcare explicitly stated that inhalation of respiratory particles was the most likely method of COVID-19 transmission. The Virginia, Michigan, and Oregon regulations described different categories of risk defined by exposure frequency and duration or specific workplace activities. California described exposure as places and times when employees come into contact or congregate with other people. The US OSHA ETS for healthcare described exposure as involving close contact with suspected or confirmed COVID-19 patients. While all of the state regulations required strategies from across the hierarchy, only the Virginia regulations specifically incorporated the hierarchy of controls. Only the California and Virginia regulations explicitly linked control strategies to the transmission route, while Virginia demarcated control strategies by risk level. Oregon linked risk level to occupancy levels and physical distancing requirements and referred to the use of a layered approach for transmission control. The US OSHA ETS for healthcare defined droplet and airborne precautions but made no mention of the hierarchy of controls or risk levels. Respirators were discussed in most of the regulations. The first Michigan regulation explicitly required respirators appropriate to exposure risk. The California regulations noted that respirators protect the wearer while face coverings protect people around the wearer. These regulations offer insights for a permanent US OSHA infectious disease regulation, such as the need to consider a range of transmission modes including near- and far-range aerosol inhalation, endemic and novel pathogens, workplaces beyond healthcare settings, factors that contribute to exposure and risk, the hierarchy of controls, the role of vaccination, and the importance of written exposure assessment and infection prevention plans.
Asunto(s)
COVID-19 , Exposición Profesional , Humanos , COVID-19/prevención & control , SARS-CoV-2 , Pandemias/prevención & control , Exposición Profesional/prevención & control , Aerosoles y Gotitas Respiratorias , Formulación de PolíticasRESUMEN
BACKGROUND: Provider and patient reminders can be effective in increasing rates of preventive screenings and vaccinations. However, the effect of patient-directed electronic reminders is understudied. OBJECTIVE: To determine whether providing reminders directly to patients via an electronic Personal Health Record (PHR) improved adherence to care recommendations. DESIGN: We conducted a cluster randomized trial without blinding from 2005 to 2007 at 11 primary care practices in the Partners HealthCare system. PARTICIPANTS: A total of 21,533 patients with access to a PHR were invited to the study, and 3,979 (18.5%) consented to enroll. INTERVENTIONS: Patients in the intervention arm received health maintenance (HM) reminders via a secure PHR "eJournal," which allowed them to review and update HM and family history information. Patients in the active control arm received access to an eJournal that allowed them to input and review information related to medications, allergies and diabetes management. MAIN MEASURES: The primary outcome measure was adherence to guideline-based care recommendations. KEY RESULTS: Intention-to-treat analysis showed that patients in the intervention arm were significantly more likely to receive mammography (48.6% vs 29.5%, p = 0.006) and influenza vaccinations (22.0% vs 14.0%, p = 0.018). No significant improvement was observed in rates of other screenings. Although Pap smear completion rates were higher in the intervention arm (41.0% vs 10.4%, p < 0.001), this finding was no longer significant after excluding women's health clinics. Additional on-treatment analysis showed significant increases in mammography (p = 0.019) and influenza vaccination (p = 0.015) for intervention arm patients who opened an eJournal compared to control arm patients, but no differences for any measure among patients who did not open an eJournal. CONCLUSIONS: Providing patients with HM reminders via a PHR may be effective in improving some elements of preventive care.
Asunto(s)
Conductas Relacionadas con la Salud , Registros de Salud Personal , Atención Primaria de Salud/métodos , Sistemas Recordatorios , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atención Primaria de Salud/normas , Sistemas Recordatorios/normasRESUMEN
A recent paper in Malaria Journal suggests that a high proportion of Plasmodium falciparum isolates found in travellers returning from a range of African countries carry the PfATP6 A623E S769N haplotype, and that this genotype is associated with artemether resistance. Such a finding would represent a substantial departure from the extensive literature reporting these individual mutations to be very rare, with the double mutation never documented. The number of isolates screened to obtain these double mutants is unstated, but highly relevant, not least because selection of isolates could have introduced significant confounders, such as timing of in vitro testing. An additional concern relates to the location of sequencing primers used to assess these positions. In the absence of clear information on these fundamental questions it would be appropriate to treat the findings with caution.
Asunto(s)
Antimaláricos/farmacología , Artemisininas/farmacología , ATPasas Transportadoras de Calcio/genética , Resistencia a Medicamentos , Malaria Falciparum/parasitología , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Plasmodium falciparum/efectos de los fármacos , Animales , HumanosRESUMEN
Acute pain, the most prominent complication of sickle cell disease (SCD), results from vaso-occlusion triggered by sickling of deoxygenated red blood cells (RBCs). Concentration of 2,3-diphosphoglycerate (2,3-DPG) in RBCs promotes deoxygenation by preferentially binding to the low-affinity T conformation of HbS. 2,3-DPG is an intermediate substrate in the glycolytic pathway in which pyruvate kinase (gene PKLR, protein PKR) is a rate-limiting enzyme; variants in PKLR may affect PKR activity, 2,3-DPG levels in RBCs, RBC sickling, and acute pain episodes (APEs). We performed a candidate gene association study using 2 cohorts: 242 adult SCD-HbSS patients and 977 children with SCD-HbSS or SCD-HbSß0 thalassemia. Seven of 47 PKLR variants evaluated in the adult cohort were associated with hospitalization: intron 4, rs2071053; intron 2, rs8177970, rs116244351, rs114455416, rs12741350, rs3020781, and rs8177964. All 7 variants showed consistent effect directions in both cohorts and remained significant in weighted Fisher's meta-analyses of the adult and pediatric cohorts using P < .0071 as threshold to correct for multiple testing. Allele-specific expression analyses in an independent cohort of 52 SCD adults showed that the intronic variants are likely to influence APE by affecting expression of PKLR, although the causal variant and mechanism are not defined.
Asunto(s)
Dolor Agudo , Anemia de Células Falciformes , Piruvato Quinasa , 2,3-Difosfoglicerato/metabolismo , Dolor Agudo/genética , Dolor Agudo/metabolismo , Adulto , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/genética , Niño , Eritrocitos Anormales/metabolismo , Hemoglobina Falciforme/metabolismo , Humanos , Piruvato Quinasa/genética , Piruvato Quinasa/metabolismoRESUMEN
BACKGROUND: It has been known for over a decade that Plasmodium falciparum proteins are enriched in non-globular domains of unknown function. The potential for these regions of protein sequence to undergo high levels of genetic drift provides a fundamental challenge to attempts to identify the molecular basis of adaptive change in malaria parasites. RESULTS: Evolutionary comparisons were undertaken using a set of forty P. falciparum metabolic enzyme genes, both within the hominid malaria clade (P. reichenowi) and across the genus (P. chabaudi). All genes contained coding elements highly conserved across the genus, but there were also a large number of regions of weakly or non-aligning coding sequence. These displayed remarkable levels of non-synonymous fixed differences within the hominid malaria clade indicating near complete release from purifying selection (dN/dS ratio at residues non-aligning across genus: 0.64, dN/dS ratio at residues identical across genus: 0.03). Regions of low conservation also possessed high levels of hydrophilicity, a marker of non-globularity. The propensity for such regions to act as potent sources of non-synonymous genetic drift within extant P. falciparum isolates was confirmed at chromosomal regions containing genes known to mediate drug resistance in field isolates, where 150 of 153 amino acid variants were located in poorly conserved regions. In contrast, all 22 amino acid variants associated with drug resistance were restricted to highly conserved regions. Additional mutations associated with laboratory-selected drug resistance, such as those in PfATPase4 selected by spiroindolone, were similarly restricted while mutations in another calcium ATPase (PfSERCA, a gene proposed to mediate artemisinin resistance) that reach significant frequencies in field isolates were located exclusively in poorly conserved regions consistent with genetic drift. CONCLUSION: Coding sequences of malaria parasites contain prospectively definable domains subject to neutral or nearly neutral evolution on a scale that appears unrivalled in biology. This distinct evolutionary landscape has potential to confound analytical methods developed for other genera. Against this tide of genetic drift, polymorphisms mediating functional change stand out to such an extent that evolutionary context provides a useful signal for identifying the molecular basis of drug resistance in malaria parasites, a finding that is of relevance to both genome-wide and candidate gene studies in this genus.
Asunto(s)
Evolución Biológica , Plasmodium falciparum/enzimología , Proteínas Protozoarias/genética , Análisis por Conglomerados , Biología Computacional , Flujo Genético , Interacciones Hidrofóbicas e Hidrofílicas , Mutación/genética , Plasmodium falciparum/genética , Polimorfismo de Nucleótido Simple/genética , Especificidad de la EspecieRESUMEN
Sickle cell disease (SCD) patients are perceived to have a high mortality when admitted to the Critical Care Unit (CCU). We performed a retrospective analysis of all adult sickle admissions to CCU at a single centre over an 8-year period (1 January 2000 to 31 December 2007). Thirty-eight patients (14 male) were admitted 46 times to CCU; the commonest reasons for admission were acute chest syndrome (14, 30%), multi-organ failure (8, 17%) and planned post-elective surgery (7, 15%). CCU mortality for SCD patients was 19.6%, comparable to a CCU-wide mortality of 17.6% during the study period in the same institution. Re-admission to CCU was high (16% over the 8-year period) but did not increase mortality risk.