RESUMEN
El Niño and La Niña events, the extremes of ENSO climate variability, influence river flow and flooding at the global scale. Estimates of the historical probability of extreme (high or low) precipitation are used to provide vital information on the likelihood of adverse impacts during extreme ENSO events. However, the nonlinearity between precipitation and flood magnitude motivates the need for estimation of historical probabilities using analysis of hydrological data sets. Here, this analysis is undertaken using the ERA-20CM-R river flow reconstruction for the twentieth century. Our results show that the likelihood of increased or decreased flood hazard during ENSO events is much more complex than is often perceived and reported; probabilities vary greatly across the globe, with large uncertainties inherent in the data and clear differences when comparing the hydrological analysis to precipitation.
RESUMEN
Treatment of neural cells with calix[n]arenes featuring sulphonate moieties and linked to Ag nanoparticles results in reduced reactive species. For Gram+ bacteria there is an inverse correlation between anti-bacterial activity and ROS reduction whereas for Gram- bacteria only calix[6]arenes bearing O-alkyl sulphonate functions act as ROS inhibitors and anti-bacterial agents.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Calixarenos/química , Calixarenos/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Ácido Glutámico/toxicidad , Bacterias Gramnegativas/efectos de los fármacos , Nanopartículas del Metal/química , Neuronas/citología , Neuronas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Células PC12 , Ratas , Especies Reactivas de Oxígeno/metabolismo , Plata/químicaRESUMEN
The resection of a low-lying rectal cancer can lead to the creation of an ostomy to discharge fecal material. In view of this reconfiguration of anatomy and life-changing modification of daily bodily functions, it is not surprising that a rapidly growing literature has examined ostomy patients' psychosocial challenges. The current study was designed (1) to systematically review the published literature on these psychosocial challenges and (2) to explore, in a single-institution setting, whether medical oncologists appear to acknowledge the existence of an ostomy during their post-operative evaluations of rectal cancer patients. This systematic review identified that social isolation, sleep deprivation; financial concerns; sexual inhibition; and other such issues are common among patients. Surprisingly, however, in our review of 66 consecutive rectal cancer patients, in 17%, the ostomy was not mentioned at all in the medical record during the first medical oncology visit; and, in one patient, it was never mentioned at all during months of adjuvant chemotherapy. Even in the setting of ostomy complications, the ostomy was not always mentioned. This study underscores the major psychosocial issues cancer patients confront after an ostomy and suggests that healthcare providers of all disciplines should work to remain sensitive to such issues.
Asunto(s)
Colostomía/psicología , Ileostomía/psicología , Pautas de la Práctica en Medicina , Neoplasias del Recto/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Masculino , Oncología Médica , Persona de Mediana Edad , Neoplasias del Recto/psicología , Estudios RetrospectivosRESUMEN
Neuronal differentiation from expanded human ventral mesencephalic neural precursor cells (NPCs) is very limited. Astrocytes are known to secrete neurotrophic factors, and so in order to enhance neuronal survival from NPCs, we tested the effect of regional astrocyte-conditioned medium (ACM) from the rat cortex, hippocampus and midbrain on this process. Human NPC's were expanded in FGF-2 before differentiation for 1 or 4 weeks in ACM. The results show that ACM from the hippocampus and midbrain increase the number of neurons from expanded human NPCs, an effect that was not observed with cortical ACM. In addition, both hippocampal and midbrain ACM increased the number and length of phosphorylated neurofilaments. MALDI-TOF analysis used to determine differences in media revealed that although all three regional ACMs had cystatin C, α-2 macroglobulin, extracellular matrix glycoprotein and vimentin, only hippocampal and midbrain ACM also contained clusterin, which when immunodepleted from midbrain ACM eliminated the observed effects on neuronal differentiation. Furthermore, clusterin is a highly glycosylated protein that has no effect on cell proliferation but decreases apoptotic nuclei and causes a sustained increase in phosphorylated extracellular signal-regulated kinase, implicating its role in cell survival and differentiation. These findings further reveal differential effects of regional astrocytes on NPC behavior and identify clusterin as an important mediator of NPC-derived neuronal survival and differentiation.
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Astrocitos/metabolismo , Diferenciación Celular , Clusterina/metabolismo , Células-Madre Neurales/citología , Neuronas/citología , Animales , Supervivencia Celular , Células Cultivadas , Corteza Cerebral/citología , Clusterina/farmacología , Medios de Cultivo Condicionados , Cistatina C/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Hipocampo/citología , Humanos , Mesencéfalo/citología , Proteínas de Neurofilamentos/metabolismo , Neuronas/metabolismo , Fosforilación , Ratas , Tubulina (Proteína)/metabolismo , Vimentina/metabolismo , alfa-Macroglobulinas/metabolismoRESUMEN
BACKGROUND: Bleeding after cardiopulmonary bypass (CPB) is a major cause of morbidity and mortality and consumes large amounts of blood. Identifying patients at increased risk of bleeding secondary to hemostatic impairment may improve clinical outcomes by allowing early intervention. METHODS: This present study recruited 77 patients undergoing CPB and measured coagulation screens, coagulation factors, TEG(®), Rotem(®) and thrombin generation (TG) before surgery and 30 min after heparin reversal. The tests were analyzed to investigate whether they identified patients at increased risk of excess bleeding (defined as > 1000 mL) in the first 24 h postoperatively. RESULTS: Patients who bled > 1000 mL had a lower: platelet count (P < 0.02), factors (F)IX, X and XI (P < 0.005), endogenous thrombin potential (ETP) and an initial rate of TG (P < 0.02) and higher activated partial thromboplastin time (aPTT) (P < 0.001) than patients who bled < 1000 mL. Receiver operating characteristic (ROC) analysis was significant for post-operative TG and aPTT (P < 0.001). Furthermore, reduced pre-operative TG was associated with increased postoperative bleeding (P < 0.02). Pre- and postoperative TG were correlated (ρ = 0.7, P < 0.001). TEG(®), Rotem(®) and prothrombin time (PT) at either time point were not associated with increased bleeding. CONCLUSION: These data suggest that pre-operative defects in the propagation phase of hemostasis are exacerbated during CPB, contributing to bleeding post-CPB. TG taken both pre- and postoperatively could potentially be used to identify patients at an increased risk of bleeding post-CPB.
Asunto(s)
Puente de Arteria Coronaria , Hemorragia Posoperatoria , Trombina/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Pruebas de Coagulación Sanguínea , Calibración , Hemostasis , Humanos , Persona de Mediana Edad , Curva ROCRESUMEN
Patients with haemophilia requires different amounts of FVIII to prevent and treat bleeds. We hypothesise that this is because FVIII has variable effects on individual patients' global haemostasis. Twelve patients with severe haemophilia A were infused with 50 IU/kg FVIII and thrombin generation in platelet rich (PRP) and platelet poor plasma (PPP) and velocity of changing clot elasticity were measured preinfusion and at nine subsequent time points over 72 h. Despite a close correlation between median FVIII and median initial rate of thrombin generation (R(2) 0.94), endogenous thrombin potential (ETP; R(2) 0.94) and peak thrombin (R(2) 0.91) in PPP, there was wide inter-patient variability at each time point. There was, however, a highly predictable intra-patient relationship between FVIII level and thrombin generation. Inter-patient variability was due to both differences in FVIII levels and the variable effect FVIII had on an individuals' thrombin generation. The utility of PRP was limited because, at low-FVIII levels, only rate of thrombin generation was measurable. At low-FVIII concentrations, the rate of thrombin generation in PPP was the most useful test whilst at higher levels ETP and peak thrombin could also be used.
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Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Pruebas de Coagulación Sanguínea , Plaquetas/fisiología , Factor VIII/farmacología , Hemofilia A/sangre , Hemostasis/efectos de los fármacos , Humanos , Activación Plaquetaria , Trombina/biosíntesis , Activador de Tejido Plasminógeno/farmacologíaRESUMEN
BACKGROUND: In the context of post-transplant immunosuppression, cyclosporine A (CSA) is dose adjusted in accordance with whole blood drug monitoring. While currently available immunoassay systems primarily target the parent drug, cross-reactivity results in the detection of the major circulating CSA metabolites, though their contribution to both immunosuppression and toxicity remain unclear. This study examines the relationship of CSA metabolites to hepatic and renal dysfunction and the incidence of graft-versus-host disease (GvHD) through parallel assaying of parent drug and drug/metabolites expressed as a metabolite ratio (Cp:mR). METHOD: Sequential pre-treatment (trough) whole blood samples (n=527) were collected from 31 allo-stem cell transplantation (SCT) recipients. Both parent drug and drug/metabolite levels were determined using the Abbott fluorescence polarization immunoassay. RESULTS: The average mean Cp:mR was significantly higher in patients with hepatic (P=0.004) and renal dysfunction (P=0.004) than in those without. Significantly higher Cp:mR were also found in patients with grades II-IV GvHD (P=0.001) than were observed in patients who did not experience significant GvHD. When measured prospectively, an increasing Cp:mR predated the rise in serum creatinine concentration by a median of two weeks. CONCLUSIONS: This study demonstrates a clinically useful CSA metabolite ratio that shows association with hepatic and renal dysfunction and with GvHD. The measure can be used to predict those patients on CSA therapy who are likely to develop renal dysfunction.
Asunto(s)
Ciclosporina/sangre , Inmunoensayo de Polarización Fluorescente/métodos , Enfermedades Renales/sangre , Trasplante de Células Madre , Adolescente , Adulto , Niño , Preescolar , Ciclosporina/metabolismo , Ciclosporina/uso terapéutico , Monitoreo de Drogas/métodos , Femenino , Enfermedad Injerto contra Huésped/sangre , Enfermedad Injerto contra Huésped/diagnóstico , Humanos , Inmunosupresores/sangre , Inmunosupresores/metabolismo , Inmunosupresores/uso terapéutico , Enfermedades Renales/diagnóstico , Enfermedades Renales/fisiopatología , Hepatopatías/sangre , Hepatopatías/diagnóstico , Hepatopatías/fisiopatología , Masculino , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
Here, we describe partial calibration of a parsimonious mathematical model of growth hormone (GH) secretion. From first principles, we derived a model of the effects on GH secretion from pituitary somatotrophs of stimulation by GH-releasing factor (GRF) or GH secretagogue, and of inhibition by somatostatin. We obtained a concise model by collapsing the many processes of the signal transduction cascade into a single step broadly reflecting the initial binding of GRF to its receptors. In the model, GH secretion is proportional to the rate of binding of GRF to activatable receptors. Desensitization occurs because of reduction of free receptors/available effector units, and resensitization occurs as those lost are replaced. This replacement is speeded up in the presence of somatostatin, which also inhibits GH secretion by reducing the constant of proportionality between the rate of GH secretion and the rate of GRF binding. We derived simple mathematical equations for the rate of GH secretion and cumulative secretion. Using these, we tested the model against data obtained from experiments performed in vitro, and made it quantitative using rigorous statistical approaches to optimize parameter estimates. The behaviour of the calibrated model matches experimental observations closely.
Asunto(s)
Hormona Liberadora de Hormona del Crecimiento/metabolismo , Hormona del Crecimiento/metabolismo , Modelos Biológicos , Hipófisis/metabolismo , Algoritmos , Animales , Células Cultivadas , Masculino , Hipófisis/citología , Valores de Referencia , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
UNAIDS/WHO estimates that 42 million people are living with HIV/AIDS worldwide and 50% of all adults with HIV infection are women predominantly infected via heterosexual transmission. Women with HIV infection, like other women, may wish to plan pregnancy, limit their family, or avoid pregnancy. Health professionals should enable these reproductive choices by counselling and appropriate contraception provision at the time of HIV diagnosis and during follow up. The aim of this article is to present a global overview of contraception choice for women living with HIV infection including effects on sexual transmission risk.
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Conducta de Elección , Conducta Anticonceptiva , Infecciones por VIH/psicología , Adolescente , Adulto , Condones/estadística & datos numéricos , Condones Femeninos/estadística & datos numéricos , Anticonceptivos Hormonales Orales , Consejo , Femenino , Humanos , Dispositivos Intrauterinos , Persona de Mediana Edad , EspermicidasRESUMEN
Simian immunodeficiency virus has been shown to cause acquired immunodeficiency syndrome in macaque monkeys. Data gathered from clinical examination and fundus photography have shown that the lentivirus is capable of the induction of choroidal lesions and retinal hemorrhages in the macaque. These findings demonstrate the potential value of the macaque monkey eye as a model of the retinal pathology routinely seen in human AIDS patients.
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Oftalmopatías/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Virus de la Inmunodeficiencia de los Simios , Animales , Oftalmopatías/patología , Fondo de Ojo , Macaca mulatta , Retina/patología , Retina/virologíaRESUMEN
Even though the role of fetal hyperinsulinemia in the pathogenesis of fetal macrosomia in patients with overt diabetes and gestational diabetes mellitus seems plausible, the molecular mechanisms of action of hyperinsulinemia remain largely enigmatic. Recent indications that hyperinsulinemia "primes" various tissues to the mitogenic influence of growth factors by increasing the pool of prenylated Ras proteins prompted us to investigate the effect of fetal hyperinsulinemia on the activitiy of farnesyltransferase (FTase) and the amounts of farnesylated p21 Ras in fetal tissues in the ovine experimental model. Induction of fetal hyperinsulinemia by direct infusion of insulin into the fetus and by either fetal or maternal infusions of glucose resulted in significant increases in the activity of FTase and the amounts of farnesylated p21 Ras in fetal liver, skeletal muscle, fat, and white blood cells. An additional infusion of somatostatin into hyperglycemic fetuses blocked fetal hyperinsulinemia and completely prevented these increases, specifying insulin as the causative factor. We conclude that the ability of fetal hyperinsulinemia to increase the size of the pool of farnesylated p21 Ras may prime fetal tissues to the action of other growth factors and thereby constitute one mechanism by which fetal hyperinsulinemia could induce macrosomia in diabetic pregnancies.
Asunto(s)
Enfermedades Fetales/metabolismo , Hiperinsulinismo/metabolismo , Prenilación de Proteína/efectos de los fármacos , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/embriología , Tejido Adiposo/metabolismo , Transferasas Alquil y Aril/metabolismo , Animales , Modelos Animales de Enfermedad , Farnesiltransferasa , Femenino , Enfermedades Fetales/inducido químicamente , Peso Fetal/efectos de los fármacos , Feto , Glucosa/administración & dosificación , Hiperinsulinismo/inducido químicamente , Infusiones Intravenosas , Insulina , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Hígado/efectos de los fármacos , Hígado/embriología , Hígado/metabolismo , Intercambio Materno-Fetal , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/embriología , Músculo Esquelético/metabolismo , Embarazo , Ovinos , Somatostatina/administración & dosificaciónRESUMEN
Previous studies have shown that passage of nonpathogenic SHIV-4 through a series of macaques results in the selection of variants of the virus that are capable of causing rapid subtotal loss of CD4(+) T cells and AIDS within 6-8 months following inoculation into pig-tailed macaques. Using a pathogenic variant of SHIV-4 known as SHIV(KU-1bMC33), we reported that a mutant of this virus with the majority of the vpu deleted was still capable of causing profound CD4(+) T cell loss and neuroAIDS in pig-tailed macaques (McCormick-Davis et al., 2000, Virology 272, 112-116). In this study, we have analyzed the tissue-specific changes in the env and nef in one macaque that developed neuroAIDS (macaque 50 O) and in three macaques that developed only a moderate or no significant loss of CD4(+) T cells and no neurological disease (macaques 50 Y, 20220, 20228) following inoculation with DeltavpuSHIV(KU-1bMC33). Sequence analysis of the gp120 region of env isolated from lymphoid tissues (lymph node and spleen) of macaques 50 Y, 20220, and 20228 revealed no consensus amino acid substitutions. In contrast, analysis of the gp120 sequences isolated from lymphoid and CNS tissues (parietal cortex, basal ganglia, and pons) of macaque 50 O revealed numerous amino acid substitutions. The significance of the amino acid substitutions in gp120 was supported by neutralization assays which showed that the virus isolated from the lymph node of macaque 50 O was neutralization resistant compared to the parental SHIV(KU-1bMC33). Analysis of changes in the nef gene from macaque 50 O revealed in-frame deletions in Nef that ranged from 4 to 13 amino acids in length, whereas the nef genes isolated from the other three macaques revealed no deletions or consensus amino acid substitutions. Inoculation of the virus isolated from the lymph node of the macaque which developed neuroAIDS, SHIV(50OLNV), into four pig-tailed macaques resulted in a severe loss of the circulating CD4(+) T cells within 2 weeks postinoculation, which was maintained for up to 20 weeks postinoculation, confirming that this virus had indeed become more pathogenic in pig-tailed macaques. Taken together, these observations suggest that DeltavpuSHIV(KU-1bMC33) has a low pathogenic phenotype in macaques but that individual pig-tailed macaques can select for additional mutations within the Env and Nef which can compensate for the lack of an intact Vpu and ultimately increase its pathogenicity.
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Síndrome de Inmunodeficiencia Adquirida/virología , Productos del Gen env/genética , Virus Reordenados/patogenicidad , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Proteínas Reguladoras y Accesorias Virales/genética , Síndrome de Inmunodeficiencia Adquirida/inmunología , Secuencia de Aminoácidos , Animales , Ganglios Basales/virología , Encéfalo/virología , Recuento de Linfocito CD4 , Infecciones del Sistema Nervioso Central/virología , Secuencia de Consenso , Modelos Animales de Enfermedad , Productos del Gen nef/genética , Proteína gp120 de Envoltorio del VIH/genética , VIH-1/patogenicidad , Proteínas del Virus de la Inmunodeficiencia Humana , Leucocitos Mononucleares/virología , Ganglios Linfáticos/virología , Macaca nemestrina , Datos de Secuencia Molecular , Virus de la Inmunodeficiencia de los Simios/genética , Bazo/virología , Proteínas Reguladoras y Accesorias Virales/aislamiento & purificación , Productos del Gen nef del Virus de la Inmunodeficiencia HumanaRESUMEN
Necrobiosis lipoidica diabeticorum (NLD) is a rare skin condition associated with diabetes, which characteristically occurs in the pretibial region of the lower limbs (Boulton et al., 1988). The lesions generally appear as well-circumscribed reddish plaques, which are most often asymptomatic, resulting primarily in cosmetic disability. Currently, there is no reliable form of treatment for NLD, although many regimens have been tried (Shall et al., 1990)
Asunto(s)
Diabetes Mellitus Tipo 1/complicaciones , Necrobiosis Lipoidea/tratamiento farmacológico , Factor de Crecimiento Derivado de Plaquetas/uso terapéutico , Administración Tópica , Becaplermina , Humanos , Pierna , Proyectos Piloto , Factor de Crecimiento Derivado de Plaquetas/administración & dosificación , Factor de Crecimiento Derivado de Plaquetas/efectos adversos , Proteínas Proto-Oncogénicas c-sis , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Cicatrización de Heridas/efectos de los fármacosRESUMEN
We compared the Vif sequences from more than 100 group M and O strains of HIV-1 isolated from diverse geographical regions and various subtypes, in order to identify regions of high variability and those amino acid residues that were highly conserved or invariant. Our analysis found that there were 10 highly conserved domains with additional invariant residues located throughout the protein. Our analysis revealed that in the highly conserved amino-terminal domain, all subtype C isolates examined had a methionine-to-leucine substitution at position 8 and most subtype C isolates had an arginine-to-lysine substitution at position 17 of the protein. Our analysis revealed that the MAP kinase phosphorylation sites, and the cysteine residues at positions 114 and 133, were conserved in Vif sequences from group M, group O, and SIV cpz isolates. Our analysis also shows that the RKKR motif at positions 90--93, proposed as a nuclear transport inhibition signal (NTIS), was conserved neither in different geographical group M and O HIV-1 isolates nor in SIVcpz.
Asunto(s)
Productos del Gen vif/genética , VIH-1/genética , Virus de la Inmunodeficiencia de los Simios/genética , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Arginina/genética , Transporte Biológico , Núcleo Celular/metabolismo , Núcleo Celular/virología , Secuencia de Consenso , Productos del Gen vif/metabolismo , Variación Genética , Proteínas del Virus de la Inmunodeficiencia Humana , Humanos , Leucina/genética , Lisina/genética , Metionina/genética , Datos de Secuencia Molecular , Pan troglodytes , Fragmentos de Péptidos/metabolismo , Alineación de Secuencia , Proteínas Reguladoras y Accesorias Virales/genética , Productos del Gen vif del Virus de la Inmunodeficiencia HumanaRESUMEN
Loxosceles spiders, of which the brown recluse is the best known, are indigenous to southcentral and southwestern regions of the United States. Loxosceles spider envenomation frequently results in painful, centrally necrotic, erythematous skin lesions that evolve over 24 to 48 hours and may take several weeks to completely heal. The diagnosis of loxoscelism is typically is based on the presence of the characteristic dermal lesion, because no definitive clinical diagnostic assay exists, and the spider is generally not available for identification. We used a rapid Loxosceles-specific enzyme immunoassay to detect spider venom in a dermal biopsy and hairs plucked from a suspicious skin lesion on the lower extremity of a 52-year-old man. This report indicates that in using a novel Loxosceles-specific immunoassay, venom can be detected in dermonecrotic skin and hair specimens for up to 4 days after envenomation.
Asunto(s)
Técnicas para Inmunoenzimas/métodos , Enfermedades de la Piel/etiología , Picaduras de Arañas/diagnóstico , Venenos de Araña/inmunología , Biopsia/métodos , Cabello/inmunología , Humanos , Necrosis , Piel/inmunología , Piel/patología , Enfermedades de la Piel/diagnóstico , Enfermedades de la Piel/patología , Picaduras de Arañas/complicacionesRESUMEN
A number of chimeric simian-human immunodeficiency virus (SHIV) viruses containing tat, rev, vpu, and env from HIV-1 (strain HXBc2) in a genetic background of simian immunodeficiency virus (SIV(mac)239) have been derived from the parental nonpathogenic SHIV-4 virus. In this article we examine the renal pathology associated with the derivation of these pathogenic SHIV strains. The first of the pathogenic SHIVs, SHIV(KU-1), is associated with rapid CD4(+) T cell loss and opportunistic infections associated with AIDS, but only one of four infected pigtail macaques examined has developed significant renal pathology. The renal pathology in this macaque consists of a diffuse increase in matrix in the core of each lobule with collapsed glomerular capillries, which is similar to the renal changes reported in HIVAN. Passage of this virus into rhesus macaques yielded SHIV(KU-2), which results in renal pathology in three of four inoculated rhesus macaques in which <10% of the glomeruli are involved. A molecular clone of SHIV(KU-2) was derived (SHIV(KU-2MC4)) that causes neurologic and renal pathology with more than 60% of the glomeruli involved and results in uremic level BUN concentrations. These results indicate that SHIV(KU-2MC4) causes severe significant glomerular pathology and should permit a detailed analysis of the molecular determinants associated with the development of SHIV-associated glomerulosclerosis in rhesus macaques.
Asunto(s)
VIH-1/patogenicidad , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Nefropatía Asociada a SIDA/fisiopatología , Nefropatía Asociada a SIDA/virología , Animales , Colágeno/metabolismo , Modelos Animales de Enfermedad , Productos del Gen gag/metabolismo , VIH-1/genética , Humanos , Inmunoglobulinas/análisis , Inmunohistoquímica , Riñón/patología , Macaca mulatta , Macaca nemestrina , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/genéticaRESUMEN
We compared the Vpu sequences from 101 strains of HIV-1 isolated from diverse geographical regions and various subtypes in order to identify regions of high variability, and those amino acid residues that were highly conserved or invariant. In addition to the highly conserved casein kinase II (CKII) phosphorylation sites, our analysis identified additional invariant residues in the transmembrane domain and in the first and second alpha-helical domains. Our analysis revealed that all subtype C sequences had a conserved LRLL motif at the C terminus that was also found in A/C intersubtype recombinants. While our analysis demonstrated the conservation of CKII domains in HIV-1 group M and O isolates, the number of potential CKII phosphorylation sites was variable in SIVcpz sequences. The results of this study will provide a basis for future mutagenesis studies to examine the role of certain amino acid residues in the structure and function of Vpu.
Asunto(s)
Genes vpu , VIH-1/química , VIH-1/aislamiento & purificación , Proteínas Reguladoras y Accesorias Virales/química , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Animales , Variación Genética , Infecciones por VIH/virología , VIH-1/clasificación , VIH-1/genética , Proteínas del Virus de la Inmunodeficiencia Humana , Humanos , Datos de Secuencia Molecular , Pan troglodytes/virología , Análisis de Secuencia de ADN , Virus de la Inmunodeficiencia de los Simios/genética , Proteínas Reguladoras y Accesorias Virales/genéticaRESUMEN
We report on the role of vpu in the pathogenesis of a molecularly cloned simian-human immunodeficiency virus (SHIV(KU-1bMC33)), in which the tat, rev, vpu, env, and nef genes derived from the uncloned SHIV(KU-1b) virus were inserted into the genetic background of parental nonpathogenic SHIV-4. A mutant was constructed (DeltavpuSHIV(KU-1bMC33)) in which 42 of 82 amino acids of Vpu were deleted. Phase partitioning studies revealed that the truncated Vpu was not an integral membrane protein, and pulse-chase culture studies revealed that cells inoculated with DeltavpuSHIV(KU-1bMC33) released viral p27 into the culture medium with slightly reduced kinetics compared with cultures inoculated with SHIV(KU-1bMC33). Inoculation of DeltavpuSHIV(KU-1bMC33) into two pig-tailed macaques resulted in a severe decline of CD4(+) T cells and neurological disease in one macaque and a more moderate decline of CD4(+) T cells in the other macaque. These results indicate that a membrane-bound Vpu is not required for the CD4(+) T cell loss and neurological disease in SHIV-inoculated pig-tailed macaques. Furthermore, because the amino acid substitutions in the Tat and Rev were identical to those previously reported for the nonpathogenic SHIV(PPc), our results indicate that amino acid substitutions in the Env and/or Nef were responsible for the observed CD4(+) T cell loss and neurological disease after inoculation with this molecular clone.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/virología , Linfocitos T CD4-Positivos/inmunología , Proteínas de la Cápside , Enfermedades Virales del Sistema Nervioso Central/virología , VIH-1/patogenicidad , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Proteínas Reguladoras y Accesorias Virales/metabolismo , Síndrome de Inmunodeficiencia Adquirida/inmunología , Síndrome de Inmunodeficiencia Adquirida/patología , Secuencia de Aminoácidos , Sustitución de Aminoácidos/genética , Animales , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/citología , Cápside/metabolismo , Línea Celular , Membrana Celular/metabolismo , Sistema Nervioso Central/patología , Sistema Nervioso Central/virología , Enfermedades Virales del Sistema Nervioso Central/inmunología , Clonación Molecular , ADN Viral/análisis , ADN Viral/genética , Productos del Gen gag/metabolismo , Proteína gp120 de Envoltorio del VIH/metabolismo , VIH-1/genética , VIH-1/fisiología , Proteínas del Virus de la Inmunodeficiencia Humana , Humanos , Tejido Linfoide/inmunología , Tejido Linfoide/patología , Tejido Linfoide/virología , Macaca nemestrina , Datos de Secuencia Molecular , Eliminación de Secuencia/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/fisiología , Carga Viral , Proteínas Reguladoras y Accesorias Virales/química , Proteínas Reguladoras y Accesorias Virales/genética , Productos del Gen gag del Virus de la Inmunodeficiencia HumanaRESUMEN
Cerebrovascular accident (CVA) is a major complication of sickle cell disease during childhood. Long-term transfusion reduces the hemoglobin S level and generally prevents recurrent stroke, but it also results in progressive iron overload that requires regular chelation therapy. Erythrocytapheresis offers an alternative approach aimed at reducing the iron accumulation. We reviewed the results of erythrocytapheresis in eight sickle cell patients (mean age of 12.1 years) at high risk for a first or recurrent stroke. They were maintained at the standard pre-transfusion hemoglobin S (Hb S) level of 30%. Over an average of 9 months of erythrocytapheresis, none of the patients developed complications related to the procedure or to the increased blood use. Ferritin levels decreased by a mean of 26.5% in all patients. When evaluating the ferritin level in five patients, who remained on chelation therapy with deferoxamine (DFO), the level dropped by a mean of 32%. The levels remained stable in the three patients who were not on DFO. The procedure is safe and effective in reducing iron overload and can obviate the need for chelation therapy, even when the target Hb S is maintained at the standard 30% range.
Asunto(s)
Anemia de Células Falciformes/terapia , Citaféresis/métodos , Células Precursoras Eritroides , Hemoglobina Falciforme/metabolismo , Sobrecarga de Hierro/terapia , Reacción a la Transfusión , Adolescente , Niño , Femenino , Humanos , Quelantes del Hierro/uso terapéutico , Masculino , Resultado del TratamientoRESUMEN
Wilson and coworkers (Wilson SB, Kent SC, Patton KT, Orban T, Jackson RA, Exley M, Porcelli S, Schatz DA, Atkinson MA, Balk SP, Strominger JL, Hafler DA: Extreme Th1 bias of invariant V alpha24J alpha Q T-cells in type 1 diabetes. Nature 391:177-181, 1998) have recently reported raised serum levels of interleukin-4 (IL-4) in anti-islet autoantibody-positive first-degree relatives of patients with type 1A diabetes who did not progress to diabetes. Protection from diabetes has been noted for several human lymphocyte antigen (HLA) alleles, such as HLA DR2-DQA1*0102-DQB1*0602. We, therefore, wanted to determine whether this cytokine phenotype was associated with HLA genes protective for type 1A diabetes. We used a two-site fluoroimmunoassay with the same monoclonal antibodies as those reported by Wilson et al. Using this assay, we have found evidence for human heterophile antibodies mimicking serum IL-4: all serum IL-4 reactivity was lost if mouse serum or mouse immunoglobulin were added to the assay; serum IL-4 activity was bound and then eluted by protein A/G chromatography; and levels of anti-mouse antibodies correlated with apparent serum IL-4. This pseudo-IL-4 activity was found in a subset of control subjects, patients with type 1A diabetes, and their relatives and was primarily associated with specific HLA alleles protective for type 1A diabetes (e.g., DQB1*0602). After adjustment for HLA, positive levels of heterophile antibodies were not associated with protection from diabetes. The confounding effect of protective HLA alleles associated with heterophile antibodies could explain the previously reported association between raised serum IL-4 and protection from type 1A diabetes. The mechanism by which specific DQ alleles protect from diabetes and are associated with increased heterophile antibodies is currently unknown.