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AIMS: We report associations between different formulae for estimating plasma volume status (PVS) and clinical and ultrasound markers of congestion in patients with chronic heart failure (CHF) enrolled in the Hull Lifelab registry. METHODS AND RESULTS: Cohort 1 comprised patients with data on signs and symptoms at initial evaluation (n = 3505). Cohort 2 included patients with ultrasound assessment of congestion [lung B-line count, inferior vena cava (IVC) diameter, jugular vein distensibility (JVD) ratio] (N = 341). Two formulae for PVS were used: (a) Hakim (HPVS) and (b) Duarte (DPVS). Results were compared with clinical and ultrasound markers of congestion. Outcomes assessed were mortality and the composite of heart failure (HF) hospitalisation and all-cause mortality. In cohort 1, HPVS was associated with mortality [hazard ratio (HR) per unitary increase = 1.02 (1.01-1.03); P < 0.001]. In cohort 2, HPVS was associated with B-line count (HR) = 1.05 [95% confidence interval (CI) (1.01-1.08); P = 0.02] and DPVS with the composite outcome [HR = 1.26 (1.01-1.58); P = 0.04]. HPVS and DPVS were strongly related to haemoglobin concentration and HPVS to weight. After multivariable analysis, there were no strong or consistent associations between PVS and measures of congestion, severity of symptoms, or outcome. By contrast, log[NTproBNP] was strongly associated with all three. CONCLUSION: Amongst patients with CHF, HPVS and DPVS are not strongly or consistently associated with clinical or ultrasound evidence of congestion, nor clinical outcomes after multivariable adjustment. They appear only to be surrogates of the variables from which they are calculated with no intrinsic clinical utility.
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Insuficiencia Cardíaca , Volumen Plasmático , Humanos , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/diagnóstico , Enfermedad Crónica , HospitalizaciónRESUMEN
The majority of beef cattle in the United States often receive at least one anabolic implant resulting in improved growth, feed efficiency, and environmental and economic sustainability. However, the physiological and molecular mechanisms through which anabolic implants increase skeletal muscle growth of beef cattle remain elusive. The objective of this study was to identify transcriptional changes occurring in skeletal muscle of steers receiving anabolic implants containing different steroid hormones. Forty-eight steers were stratified by weight into 1 of 4 (n = 12/treatment) implant treatment groups: (1) estradiol (ImpE2; 25.7 mg E2; Compudose, Elanco Animal Health, Greenfield, IN), (2) trenbolone acetate (ImpTBA; 200 mg TBA; Finaplix-H, Merck Animal Health, Madison, NJ), (3) combination (ImpETBA; 120 mg TBA + 24 mg E2; Revalor-S, Merck Animal Health), or (4) no implant (CON). Skeletal muscle biopsies were taken from the longissimus 2 and 10 d post-implantation. The mRNA abundance of 94 genes associated with skeletal muscle growth was examined. At 10 d post-implantation, steers receiving ImpETBA had greater (P = 0.02) myoblast differentiation factor 1 transcript abundance than CON. Citrate synthase abundance was increased (P = 0.04) in ImpETBA steers compared to CON steers. In ImpE2 steers 10 d post-implantation, muscle RING finger protein 1 decreased (P = 0.05) compared to CON steers, and forkhead box protein O4 decreased (P = 0.05) in ImpETBA steers compared to CON steers. Interleukin-6 abundance tended to be increased (P = 0.09) in ImpE2 steers compared to both ImpETBA and CON steers. Furthermore, interleukin-10 mRNA abundance tended to be increased (P = 0.06) in ImpTBA steers compared to ImpETBA steers. Leptin receptor abundance was reduced (P = 0.01) in both ImpE2 and ImpTBA steers when compared to CON steers. Abundance of phosphodiesterase 4B was increased (P = 0.04) in ImpTBA steers compared to CON steers 2 d post-implantation. Taken together, the results of this research demonstrate that estradiol increases skeletal muscle growth via pathways related to nutrient partitioning and mitochondria function, while trenbolone acetate improves steer skeletal muscle growth via pathways related to muscle growth.
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Enfermedades de los Bovinos , Acetato de Trembolona , Animales , Bovinos , ARN Mensajero/genética , Acetato de Trembolona/farmacología , Inflamación/veterinaria , Músculo Esquelético , EstradiolRESUMEN
INTRODUCTION: Iron deficiency (ID) is common in patients with chronic heart failure (CHF) and is associated with worse symptoms and prognosis regardless of whether anemia is also present. However, randomized controlled trials (RCT) of intravenous (IV) iron in patients with CHF have produced inconsistent results. This review considers the past, present, and future of defining and treating ID in patients with CHF. AREAS COVERED: The current guideline definition of ID is a serum ferritin <100 µg/L or serum ferritin 100-299 µg/L and transferrin saturation (TSAT) <20% derived from trials of IV iron in patients with end-stage renal failure. Ferritin synthesis and secretion is promoted by inflammatory cytokines which are raised in patients with CHF; thus, using ferritin to define iron deficiency in patients with CHF may be flawed. Observational data suggest that the current definition of iron deficiency in CHF does not identify a high-risk population. EXPERT OPINION: Alternative indicators of ID such as low serum iron concentrations or TSAT may better identify patients with ID who are at greater risk of adverse outcome and thus, possibly, more likely to benefit from IV iron.
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Anemia Ferropénica , Insuficiencia Cardíaca , Deficiencias de Hierro , Anemia Ferropénica/diagnóstico , Anemia Ferropénica/etiología , Enfermedad Crónica , Ferritinas , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/diagnóstico , Humanos , HierroRESUMEN
AIMS: Hypochloraemia is common in patients hospitalized with heart failure (HF) and associated with a high risk of adverse outcomes during admission and following discharge. We assessed the significance of changes in serum chloride concentrations in relation to serum sodium and bicarbonate concentrations during admission in a cohort of 1002 consecutive patients admitted with HF and enrolled into an observational study based at a single tertiary centre in the UK. METHODS AND RESULTS: Hypochloraemia (<96 mmol/L), hyponatraemia (<135 mmol/L), and metabolic alkalosis (bicarbonate >32 mmol/L) were defined by local laboratory reference ranges. Outcomes assessed were all-cause mortality, all-cause mortality or all-cause readmission, and all-cause mortality or HF readmission. Cox regression and Kaplan-Meier curves were used to investigate associations with outcome. During a median follow-up of 856 days (interquartile range 272-1416), discharge hypochloraemia, regardless of serum sodium, or bicarbonate levels was associated with greater all-cause mortality [hazard ratio (HR) 1.44, 95% confidence interval (CI) 1.15-1.79; P = 0.001], all-cause mortality or all-cause readmission (HR 1.26, 95% CI 1.04-1.53; P = 0.02), and all-cause mortality or HF readmission (HR 1.41, 95% CI 1.14-1.74; P = 0.002) after multivariable adjustment. Patients with concurrent hypochloraemia and natraemia had lower haemoglobin and haematocrit, suggesting congestion; those with hypochloraemia and normal sodium levels had more metabolic alkalosis, suggesting decongestion. CONCLUSION: Hypochloraemia is common at discharge after a hospitalization for HF and is associated with worse outcome subsequently. It is an easily measured clinical variables that is associated with morbidity or mortality of any cause.
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Insuficiencia Cardíaca , Hiponatremia , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/epidemiología , Hospitalización , Hospitales , Humanos , Hiponatremia/epidemiología , Hiponatremia/etiología , Readmisión del Paciente , PronósticoRESUMEN
STUDY DESIGN: Randomized controlled trial with single-blinded primary outcome assessment. OBJECTIVES: To determine the efficacy and safety of autologous incubated macrophage treatment for improving neurological outcome in patients with acute, complete spinal cord injury (SCI). SETTING: Six SCI treatment centers in the United States and Israel. METHODS: Participants with traumatic complete SCI between C5 motor and T11 neurological levels who could receive macrophage therapy within 14 days of injury were randomly assigned in a 2:1 ratio to the treatment (autologous incubated macrophages) or control (standard of care) groups. Treatment group participants underwent macrophage injection into the caudal boundary of the SCI. The primary outcome measure was American Spinal Injury Association (ASIA) Impairment Scale (AIS) A-B or better at ≥6 months. Safety was assessed by analysis of adverse events (AEs). RESULTS: Of 43 participants (26 treatment, 17 control) having sufficient data for efficacy analysis, AIS A to B or better conversion was experienced by 7 treatment and 10 control participants; AIS A to C conversion was experienced by 2 treatment and 2 control participants. The primary outcome analysis for subjects with at least 6 months follow-up showed a trend favoring the control group that did not achieve statistical significance (P=0.053). The mean number of AEs reported per participant was not significantly different between the groups (P=0.942). CONCLUSION: The analysis failed to show a significant difference in primary outcome between the two groups. The study results do not support treatment of acute complete SCI with autologous incubated macrophage therapy as specified in this protocol.
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Macrófagos/trasplante , Traumatismos de la Médula Espinal/cirugía , Enfermedad Aguda , Adolescente , Adulto , Tratamiento Basado en Trasplante de Células y Tejidos/efectos adversos , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Método Simple Ciego , Traumatismos de la Médula Espinal/epidemiología , Traumatismos de la Médula Espinal/patología , Trasplante Autólogo/efectos adversos , Trasplante Autólogo/métodos , Trasplante Autólogo/patología , Insuficiencia del Tratamiento , Adulto JovenRESUMEN
Formalin preserved ocular-associated anterior adnexa tissues from five necropsied Asian elephants (Elephas maximus) were dissected with attention to the palpebrae, conjunctiva, nictitating membranes, nasolacrimal ducts, and periocular glandular tissues. Gross and histologic examination revealed that lacrimal and tarsal glands were not present. Evidence of the lacrimal drainage apparatus, including lacrimal punctae or any remnant of lacrimal sacs, was also absent. In contrast, well-developed sebaceous glands associated with accessory hairs along the palpebrae were exceptionally abundant. Mixed-secreting accessory lacrimal glands were noted in the deep stroma posterior to the tarsus of both palpebrae and the gland of the nictitating membrane. Apparently, the Asian elephant has developed a novel tear system in the absence of lacrimal and tarsal (meibomian) glands. Clinical examinations and bacterial cultures of the visible periocular tissues were performed on eight living adult Asian elephants to confirm the postmortem anatomic findings and provide guidance to the clinician during examination of the elephant conjunctiva.
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Elefantes/anatomía & histología , Ojo/anatomía & histología , Membrana Nictitante/anatomía & histología , Animales , Cadáver , FemeninoRESUMEN
The hepatitis A virus (HAV), a picornavirus, is a common cause of hepatitis worldwide. Spread of infection is generally person to person or by oral intake after fecal contamination of skin or mucous membranes; less commonly, there is fecal contamination of food or water. Hepatitis A is endemic in developing countries, and most residents are exposed in childhood. In contrast, the adult population in developed countries demonstrates falling rates of exposure with improvements in hygiene and sanitation. The export of food that cannot be sterilized, from countries of high endemicity to areas with low rates of infection, is a potentially important source of infection. After ingestion and uptake from the gastrointestinal tract, the virus replicates in the liver and is excreted into the bile. Cellular immune responses to the virus lead to destruction of infected hepatocytes with consequent development of symptoms and signs of disease. Humoral immune responses are the basis for diagnostic serologic assays. Acute HAV infection is clinically indistinguishable from other causes of acute viral hepatitis. In young children the disease is often asymptomatic, whereas in older children and adults there may be a range of clinical manifestations from mild, anicteric infection to fulminant hepatic failure. Clinical variants include prolonged, relapsing, and cholestatic forms. Management of the acute illness is supportive, and complete recovery without sequelae is the usual outcome. Research efforts during World War II led to the development of passive immunoprophylaxis. Pooled immune serum globulin is efficacious in the prevention and attenuation of disease in exposed individuals. More recently, active immunoprophylaxis by vaccination has been accomplished. Future eradication of this disease can now be contemplated.
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Vacunas contra la Hepatitis A , Virus de la Hepatitis A Humana/inmunología , Hepatitis A , Hepatitis A/diagnóstico , Hepatitis A/etiología , Hepatitis A/fisiopatología , Hepatitis A/terapia , Virus de la Hepatitis A Humana/clasificación , Virus de la Hepatitis A Humana/patogenicidad , Humanos , Control de Infecciones , Factores de RiesgoRESUMEN
Transcription of the LDL receptor gene is markedly enhanced in the Jurkat T cell line by stimulation with the combination of the phorbol ester phorbol 12-myristate 13-acetate (PMA) and the protein synthesis inhibitor cycloheximide (CHX). The DNA sequences necessary for this response were identified by analysis of Jurkat T cells permanently transfected with reporter gene expression vectors containing fragments of the LDL receptor promoter extending from 68 bp to 1472 bp 5' of the major transcription start site. The magnitude of the response of this array of promoter fragments to stimulation with PMA and CHX was similar to that previously observed with a approximately 6.5 kb promoter fragment. However, the various promoter fragments differed with regard to the role of the sterol regulatory element-1 (SRE-1) sequence. Thus, whereas a 142 bp promoter mediated transcription stimulated by PMA and CHX independently of SRE-1, a shorter 115 bp promoter was absolutely dependent on SRE-1. Furthermore, internal deletion of promoter sequences from -142 bp to -113 bp from longer promoter constructs in which the SRE-1 was mutated prevented the induction of transcription by PMA and CHX. Electrophoretic mobility shift assays (EMSAs) demonstrated sequence-specific, stimulus-independent binding by Jurkat nuclear proteins to the novel response element mapped between -142 and -115. Even though the minimal 115 bp or 68 bp promoter fragment required an intact SRE-1 to respond to PMA and CHX, transcriptional induction persisted when nuclear levels of sterol regulatory element binding proteins (SREBPs) were made undetectable by culture in suppressive sterols. Taken together, these data indicate that non-sterol stimuli such as the combination of PMA and CHX induce LDL receptor gene transcription through at least two distinct promoter elements, neither of which requires the presence of SREBPs. However, the element proximal to the transcription start site is dependent on the SRE-1.
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Proteínas Potenciadoras de Unión a CCAAT , Proteínas de Unión al ADN/metabolismo , Proteínas Nucleares/metabolismo , Receptores de LDL/genética , Factores de Transcripción , Secuencia de Bases , Cicloheximida/farmacología , Sondas de ADN/genética , Genes Reguladores , Genes Reporteros , Humanos , Células Jurkat , Datos de Secuencia Molecular , Mutación , Regiones Promotoras Genéticas , Inhibidores de la Síntesis de la Proteína/farmacología , Eliminación de Secuencia , Proteína 1 de Unión a los Elementos Reguladores de Esteroles , Acetato de Tetradecanoilforbol/farmacología , Transcripción Genética/efectos de los fármacosRESUMEN
Stimulation with phorbol 12-myristate 13-acetate (PMA) and the calcium ionophore ionomycin increased native low density lipoprotein (LDL) receptor gene expression in the human leukemic T cell line Jurkat when cells were cultured in the absence of sterols and also increased nuclear accumulation of sterol regulatory element binding protein (SREBP)-1. PMA and ionomycin likewise increased LDL receptor mRNA levels when cells were cultured in the presence of suppressive concentrations of sterols, when neither SREBP-1 nor SREBP-2 was detectable in the nucleus. These findings indicated that mitogen-induced up-regulation of the LDL receptor gene could be independent of sterol-regulated transcription factors. The involvement of sterol regulatory element (SRE)-1 was analyzed by transfection of LDL receptor promoter constructs. Promoter fragments of either the 5' 1472 or 142 base pairs induced reporter gene expression after mitogenic stimulation when cells were cultured in the absence or presence of sterols. Mutation of the SRE-1 sequence in either construct abolished sterol-mediated regulation of transcription. However, mutation of the SRE-1 sequence in the 1472 base pair promoter fragment did not alter mitogenic induction of transcription, whereas mutation of SRE-1 in the 142 base pair promoter fragment completely prevented up-regulation of transcription. Taken together, these results demonstrate that the LDL receptor promoter contains at least one 5' SRE-independent as well as an SRE-dependent response element. Furthermore, the data suggest that the SRE-dependent response may not involve the action of either SREBP-1 or -2. Thus, mitogen-induced transcription of the LDL receptor promoter is regulated by diverse sterol-independent mechanisms.
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Proteínas Potenciadoras de Unión a CCAAT , Receptores de LDL/genética , Receptores de LDL/metabolismo , Esteroles/metabolismo , Secuencia de Bases , Cloranfenicol O-Acetiltransferasa/biosíntesis , Cloranfenicol O-Acetiltransferasa/genética , ADN/genética , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Ionomicina/farmacología , Ionóforos/farmacología , Células Jurkat , Mutación , Proteínas Nucleares/metabolismo , Regiones Promotoras Genéticas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles , Proteína 2 de Unión a Elementos Reguladores de Esteroles , Acetato de Tetradecanoilforbol/farmacología , Factores de Transcripción/metabolismo , TransfecciónRESUMEN
This study was undertaken to determine the effect of transient overexpression of hepatic cholesterol 7alpha-hydroxylase on low density lipoprotein (LDL) cholesterol transport in mice lacking LDL receptors (LDL receptor-/-). Primary overexpression of hepatic 7alpha-hydroxylase in LDL receptor-/- mice was accompanied by a dose-dependent decrease in the rate of LDL cholesterol appearance in plasma (whole body LDL cholesterol transport) and a corresponding reduction in circulating LDL cholesterol levels. The increase in hepatic 7alpha-hydroxylase activity necessary to achieve a 50% reduction in plasma LDL cholesterol concentrations was approximately 10-fold. In comparison, cholestyramine increased hepatic 7alpha-hydroxylase activity approximately 3-fold and reduced plasma LDL cholesterol concentrations by 17%. This study demonstrates that augmentation of hepatic 7alpha-hydroxylase expression is an effective strategy for lowering plasma LDL concentrations even in animals with a genetic absence of LDL receptors.
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Colesterol 7-alfa-Hidroxilasa/genética , Lipoproteínas LDL/metabolismo , Receptores de LDL/genética , Animales , Transporte Biológico , Femenino , Técnicas de Transferencia de Gen , Lipoproteínas LDL/sangre , Hígado/enzimología , Ratones , Ratones NoqueadosRESUMEN
In Wilson's disease, a genetic defect in a copper transporter causes defective incorporation of copper into apo-ceruloplasmin and the failure to excrete copper into bile. Copper accumulated in hepatocytes generates damage via reactive oxygen species. Release of copper from necrotic hepatocytes leads to damage of other tissues, including the brain, urinary tract, red blood cells, heart, endocrine glands, skin, pancreas, bones, and joints. Treatment is designed to chelate the excess copper for urinary excretion, prevent copper absorption, and render tissue copper nontoxic. Liver transplantation, with replacement of the defective hepatic gene, may be necessary in some cases.
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Degeneración Hepatolenticular , Animales , Transporte Biológico , Cobre/farmacocinética , Femenino , Degeneración Hepatolenticular/genética , Humanos , Hígado/metabolismo , MasculinoRESUMEN
Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl (HMG) CoA reductase, and 6-fluoromevalonate (Fmev), an inhibitor of diphosphomevalonate decarboxylase, blocked the synthesis of downstream mevalonate products, including prenyl-derived lipids, and prevented membrane localization of Ras in the myeloid cell line U-937. In contrast to lovastatin, which induced cytosol localization of Ras in U-937 cells, Fmev failed to increase cytosolic Ras and also completely prevented the proliferation of U-937 cells. Growth of U-937 cells was restored by the addition of lovastatin to Fmev-blocked cells. These results implied that a product of mevalonate metabolism proximal to isopentenyl diphosphate was responsible for the suppression of proliferation. To delineate the action of this endogenous inhibitor of cell proliferation and determine the relationship between its impact on Ras localization and cell proliferation, the effect of Fmev on a variety of leukemia- and lymphoma-derived cells was examined. Whereas Fmev blocked the growth of these cell lines, there were more than 50-fold differences in the concentrations required to inhibit the growth of individual cell lines by 90%. Regardless of its effect on cell proliferation, the biochemical effect of Fmev was similar. Thus, Fmev uniformly prevented the conversion of radiolabeled mevalonate to isopentenyl diphosphate and other downstream products, including synthesis of sterol and nonsterol lipids and prenylation of proteins. A correlation was noted between higher intrinsic rates of mevalonate synthesis by a cell and susceptibility to inhibition by Fmev. Thus, sensitivity of a cell line to inhibition by Fmev was associated with markedly increased rates of HMG CoA reductase activity that were further increased by incubation with Fmev. Whereas Fmev depleted cellular levels of the prenylated protein Ras in the sensitive cell line U-937, there was no depletion of cellular Ras levels in the resistant cell line EL-4, but rather, there was a shift of Ras from membrane to cytosol, as expected for inhibition of prenylation. These results suggest that leukemic cells with increased HMG CoA reductase activity produce increased levels of an endogenous mevalonate-derived inhibitor that leads to Ras depletion and suppression of cell growth. As a result, inhibition of the growth of these transformed cells might be specifically accomplished by Fmev.
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Acilcoenzima A/metabolismo , Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Lovastatina/farmacología , Ácido Mevalónico/análogos & derivados , Ácido Mevalónico/metabolismo , Proteínas de Neoplasias/efectos de los fármacos , Proteínas ras/efectos de los fármacos , Acilcoenzima A/antagonistas & inhibidores , División Celular/efectos de los fármacos , Línea Celular Transformada/efectos de los fármacos , Línea Celular Transformada/metabolismo , Membrana Celular/química , Humanos , Leucemia/metabolismo , Leucemia/patología , Linfoma/metabolismo , Linfoma/patología , Proteínas de Neoplasias/metabolismo , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/metabolismo , Proteínas ras/metabolismoRESUMEN
Patients presenting with clinical and laboratory features consistent with a diagnosis of acute non-A, non-B hepatitis were evaluated for evidence of hepatitis C or hepatitis E infection and for evidence of severe or prolonged disease. Antibody to hepatitis C virus (anti-HCV) was detected in 75 of 108 (69%) patients, antibody to hepatitis E virus (anti-HEV) in three patients (3%), and neither antibody in 31 (29%) patients. One patient had both anti-HCV and anti-HEV. HCV RNA was not detected in sera from any of 20 patients with seronegative (non-ABCDE) hepatitis, but in all 10 patients with anti-HCV who were tested by polymerase chain reaction (PCR). Compared with patients with acute hepatitis C, those with non-ABCDE hepatitis had a lower incidence of parenteral risk factors (6% vs. 70%; P < .001), higher peak serum bilirubin levels (45% vs. 5% with peak levels > 15 mg/dL; P < .001), more prolonged jaundice (25% vs. 0% with peak bilirubin >5 weeks after onset; P < .01), more severe prothrombin time abnormalities (26% vs. 0% with >3 second prolongation; P < .001), more severe hypoalbuminemia (39% vs. 9% with albumin <3 g/dL; P < .01), and more frequent major clinical complications (13% vs. 0% with encephalopathy; P < .01; 10% vs. 0% with death or transplant; P = .024). Patients with acute non-ABCDE hepatitis were less likely to develop chronic hepatitis than those with acute hepatitis C (23% vs. 68%; P < .05). Thus, patients with acute non-ABCDE hepatitis are epidemiologically distinct from those with acute hepatitis C and have a significantly more severe acute illness.
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Hepacivirus/inmunología , Hepatitis C/inmunología , Hepatitis C/virología , Virus de la Hepatitis E/inmunología , Hepatitis E/inmunología , Hepatitis E/virología , Adolescente , Adulto , Anciano , Bilirrubina/sangre , Demografía , Femenino , Hepatitis C/sangre , Hepatitis E/sangre , Humanos , Masculino , Persona de Mediana EdadRESUMEN
AIMS: To look for differences in levels of various plasma constituents between pair-matched controls and patients who had cataracts classified by location and appearance of lens opacity and nuclear colour in order to identify systemic risk factors. METHODS: One thousand patients were taken from the cataract waiting list of a specialist eye hospital. For each patient, a matched control of the same sex and half-decade of age but without cataract was taken from the patient-list of the family doctor of the patient; the control was the next alphabetically after the patient on the doctor's list. At an early morning visit to the homes of both patients and controls, fasting, a team of nurses performed venepunctures and collected information for a questionnaire. Eye examinations were performed by a team of ophthalmologists. RESULTS: Predominantly nuclear cataract was significantly associated with raised plasma alanine aminotransferase and bilirubin, posterior subcapsular cataract with increased calcium and urea, cuneiform with reduced potassium, mature/hypermature with raised potassium and reduced total carbon dioxide. The following were consistently significantly associated with all forms of cataract; diabetes and raised plasma glucose (not in non-diabetics), use of steroid medication, raised levels of cortisol (steroid users excluded), albumin, alkaline phosphatase, gamma-glutamyl transpeptidase, sodium and total protein and reduced levels of cholesterol and albumin/(total protein-albumin) ratio (an approximation for the albumin/globulin ratio). The multivariate analysis indicated that the most important non-specific cataractogenic effects were those of increased total protein, diabetes and use of steroid medication. CONCLUSION: This and other studies support, broadly, the conclusions that senile or age-related cataract is not merely caused by increasing age and also that various morphological types have different risk factors. The mechanisms underlying the biochemical associations with different patterns of lens opacification and the identification of the ultimate risk factors remain to be elucidated.
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Proteínas Sanguíneas/metabolismo , Catarata/clasificación , Núcleo del Cristalino/patología , Anciano , Envejecimiento/metabolismo , Glucemia/metabolismo , Calcio/sangre , Estudios de Casos y Controles , Catarata/sangre , Catarata/patología , Femenino , Humanos , Núcleo del Cristalino/metabolismo , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Potasio/sangre , Factores de Riesgo , Triglicéridos/sangre , Urea/sangreAsunto(s)
Antígenos HLA/genética , Hemocromatosis/genética , Antígenos de Histocompatibilidad Clase I/genética , Hierro/metabolismo , Proteínas de la Membrana , Animales , Modelos Animales de Enfermedad , Hemocromatosis/metabolismo , Hemocromatosis/patología , Hemocromatosis/prevención & control , Hemocromatosis/terapia , Proteína de la Hemocromatosis , Humanos , Complejo Mayor de Histocompatibilidad , Proteínas/metabolismoRESUMEN
Hepatic 7alpha-hydroxylase activity appears to be regulated at the transcriptional level by the quantity of bile salts fluxing through the enterohepatic circulation. Whether bile salts directly suppress 7alpha-hydroxylase expression at the level of the hepatocyte or do so indirectly by promoting the release or absorption of an intestinal factor has not been resolved. We have investigated the ability of primary bile salts to suppress hepatic 7alpha-hydroxylase expression in bile-diverted hamsters. Biliary diversion was accompanied by derepression of both hepatic 7alpha-hydroxylase activity (4-5-fold) and bile salt secretion (approximately 3-fold). Derepression of hepatic 7alpha-hydroxylase expression could be prevented by several interventions that increase the availability of bile salts within the hepatocyte including 1) overexpression of an exogenous 7alpha-hydroxylase gene by adenovirus-mediated gene transfer, 2) obstruction of the common bile duct, and 3) intravenous infusions of taurocholate. In contrast, none of these interventions prevented derepression of hepatic cholesterol synthesis or significantly down-regulated hepatic low density lipoprotein receptor expression over the relatively short time course (24 h) of these studies. Together, these data indicate that primary bile salts contribute to the regulation of bile salt synthesis through feedback repression of 7alpha-hydroxylase expression at the level of the hepatocyte.
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Hidrocarburo de Aril Hidroxilasas , Ácidos y Sales Biliares/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Hígado/metabolismo , Esteroide Hidroxilasas/metabolismo , Adenoviridae/genética , Animales , Colesterol/biosíntesis , Cricetinae , Sistema Enzimático del Citocromo P-450/genética , Regulación hacia Abajo , Retroalimentación , Expresión Génica , Técnicas de Transferencia de Gen , Cinética , Lipoproteínas LDL/metabolismo , Hígado/efectos de los fármacos , Masculino , Mesocricetus , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Esteroide Hidroxilasas/genética , Ácido Taurocólico/farmacologíaRESUMEN
Dermatological conditions and treatments were analysed in a study comparing cataract patients and stringently matched controls. One thousand patients were taken from the cataract waiting list of a specialist eye hospital. For each patient a matched control of the same gender, half-decade of age, and family doctor but without cataract was selected. Venepunctures and eye examinations were performed on both patients and controls; in addition, questionnaire information was obtained from each. Age-related cataract is significantly associated with dermatological abnormality and its treatment, the former association being more significant and more pronounced after 69 years of age. The association of hydrocortisone use after 69 years of age and cataract, however, remains significant even after adjustments for dermatological abnormality and steroid use, suggesting that even among steroid medications hydrocortisone is particularly strongly associated with cataract.
Asunto(s)
Catarata/epidemiología , Enfermedades de la Piel/epidemiología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antiinflamatorios/efectos adversos , Antiinflamatorios/uso terapéutico , Estudios de Casos y Controles , Catarata/diagnóstico , Femenino , Humanos , Hidrocortisona/efectos adversos , Hidrocortisona/sangre , Hidrocortisona/uso terapéutico , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Flebotomía , Psoriasis/tratamiento farmacológico , Psoriasis/epidemiología , Factores Sexuales , Enfermedades de la Piel/tratamiento farmacológico , Agudeza VisualRESUMEN
OBJECTIVES: The goals of this study were to examine responses to corticosteroid-containing therapy in non-B chronic hepatitis patients with different anti-hepatitis C virus (HCV), autoantibody, and biochemical test results and to determine what factors correlate with response. METHODS: Patients with a prior or current history of steroid therapy for putative autoimmune or chronic non-A, non-B hepatitis were assessed. Responses during the first 6 months of therapy were categorized as "complete" (normal aminotransferases for > or = 1 month), "partial" ( > 50% reduction), or "no response." RESULTS: Sufficient data available to permit evaluation in 32 patients. Complete responses were noted in 17, partial responses in 12, and no response in three subjects. By multivariate analysis, only absence of anti-HCV and presence of cirrhosis were independent predictors of response. Nonresponders were found to have lower scores in a proposed autoimmune hepatitis scoring system, but scores of complete and partial responders were not significantly different. Despite a lower likelihood of a complete response, 80% (12/15) of patients with multiantigen positive anti-HCV tests had either partial or complete initial responses to corticosteroid-containing therapy, and, in nine patients, aminotransferases fell to < 2 times the upper limit of normal. All 15 anti-HCV-negative patients, but only three of 15 anti-HCV-positive patients, entered complete responses that were sustained (aminotransferases < twofold abnormal) on regimens containing < 20 mg/day or prednisolone or prednisone. CONCLUSIONS: Although anti-HCV-positive patients frequently exhibit partial initial responses to immunosuppressive therapy, the absence of specific anti-HCV antibodies was better as a predictor of completeness of response than assessment of autoantibodies or degree of biochemical abnormalities.