RESUMEN
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that is predominantly caused by alterations of the methyl-CpG-binding protein 2 (MECP2) gene. Disease severity and the presence of comorbidities such as gastrointestinal distress vary widely across affected individuals. The gut microbiome has been implicated in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) as a regulator of disease severity and gastrointestinal comorbidities. Although the gut microbiome has been previously characterized in humans with RTT compared to healthy controls, the impact of MECP2 mutation on the composition of the gut microbiome in animal models where the host and diet can be experimentally controlled remains to be elucidated. By evaluating the microbial community across postnatal development as behavioral symptoms appear and progress, we have identified microbial taxa that are differentially abundant across developmental timepoints in a zinc-finger nuclease rat model of RTT compared to WT. We have additionally identified p105 as a key translational timepoint. Lastly, we have demonstrated that fecal SCFA levels are not altered in RTT rats compared to WT rats across development. Overall, these results represent an important step in translational RTT research.
Asunto(s)
Microbioma Gastrointestinal/fisiología , Proteína 2 de Unión a Metil-CpG/genética , Mutación , Síndrome de Rett/microbiología , Animales , Modelos Animales de Enfermedad , Ácidos Grasos Volátiles/metabolismo , Femenino , Proteína 2 de Unión a Metil-CpG/metabolismo , Ratas , Síndrome de Rett/genética , Síndrome de Rett/metabolismoRESUMEN
A subset of neurons in the retrotrapezoid nucleus (RTN) function as respiratory chemoreceptors by regulating depth and frequency of breathing in response to changes in tissue CO2/H+. The activity of chemosensitive RTN neurons is also subject to modulation by CO2/H+-dependent purinergic signaling. However, mechanisms contributing to purinergic regulation of RTN chemoreceptors are not entirely clear. Recent evidence suggests adenosine inhibits RTN chemoreception in vivo by activation of A1 receptors. The goal of this study was to characterize effects of adenosine on chemosensitive RTN neurons and identify intrinsic and synaptic mechanisms underlying this response. Cell-attached recordings from RTN chemoreceptors in slices from rat or wild-type mouse pups (mixed sex) show that exposure to adenosine (1 µM) inhibits chemoreceptor activity by an A1 receptor-dependent mechanism. However, exposure to a selective A1 receptor antagonist (8-cyclopentyl-1,3-dipropylxanthine, DPCPX; 30 nM) alone did not potentiate CO2/H+-stimulated activity, suggesting activation of A1 receptors does not limit chemoreceptor activity under these reduced conditions. Whole-cell voltage-clamp from chemosensitive RTN neurons shows that exposure to adenosine activated an inward rectifying K+ conductance, and at the network level, adenosine preferentially decreased frequency of EPSCs but not IPSCs. These results show that adenosine activation of A1 receptors inhibits chemosensitive RTN neurons by direct activation of a G-protein-regulated inward-rectifier K+ (GIRK)-like conductance, and presynaptically, by suppression of excitatory synaptic input to chemoreceptors.
Asunto(s)
Adenosina/metabolismo , Células Quimiorreceptoras/fisiología , Receptores Purinérgicos P1/metabolismo , Centro Respiratorio/citología , Transducción de Señal/fisiología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Adenosina/farmacología , Animales , Animales Recién Nacidos , Bario/farmacología , Dióxido de Carbono/farmacología , Células Quimiorreceptoras/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Plasticidad Neuronal/efectos de los fármacos , Neurotransmisores/farmacología , Bloqueadores de los Canales de Potasio/farmacología , Purinérgicos/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Purinérgicos P1/genética , Transducción de Señal/efectos de los fármacos , Bloqueadores de los Canales de Sodio/farmacología , Tetrodotoxina/farmacologíaRESUMEN
Autoantibodies to phospholipids (APA) occur frequently in systemic lupus erythematosus (SLE) and other autoimmune disorders and predispose to intravascular thromboses. Major histocompatibility complex (MHC) class II alleles (HLA-DR and DQ) were determined by restriction fragment length polymorphisms (RFLP) in 20 patients with APA (lupus anticoagulant). HLA-DQw7 (DQB1*0301), linked to HLA-DR5 and -DR4 haplotypes, occurred in 70% and was significantly increased compared to 139 race-matched normal controls (P = 0.002, P corrected [pc] = 0.05, odds ratio [OR] = 5.1). Moreover, the frequency of HLA-DQw7 was significantly higher in SLE patients with APA as compared with patients without APA but with other autoantibodies, including anti-Ro and La (P = 0.0001, pc = 0.002, OR = 10.7), anti-Ro alone (P = 0.001, pc = 0.02, OR = 11.2), anti-dsDNA (P = 0.001, pc = 0.02, OR = 7.1), and possibly anti-Sm (P = 0.04, pc = NS, OR = 6.8) and anti-nRNP (U1-RNP) (P = 0.01, pc = NS, OR = 7.8). The DQB1*0301 allele of DQw7 showed the strongest association, while the frequencies of the DQA1*0301 (45%) and DQA1*0501 (50%) alleles did not differ from the controls. Among the HLA-DQB1*0301 (DQw7) negative patients, all possessed HLA-DQw8 (DQB1*0302) and/or HLA-DQw6 (DQB1*0602 or DQB1*0603) alleles. The HLA-DQB1*0301 chain shares an identical seven amino acid sequence with DQB1*0302, *0602, and *0603 chains in the third hypervariable region of the HLA-DQ molecule. This candidate "epitope" may play a role in mediating an autoimmune response to APA.
Asunto(s)
Alelos , Autoanticuerpos/genética , Factores de Coagulación Sanguínea/inmunología , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Lupus Eritematoso Sistémico/inmunología , Factores de Coagulación Sanguínea/genética , Humanos , Inhibidor de Coagulación del Lupus , Lupus Eritematoso Sistémico/genética , Fosfolípidos/inmunología , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
The aim of the study was to evaluate angiogenesis in different subtypes of non-Hodgkin's lymphoma (NHL) and to correlate angiogenic scores to clinical endpoints. Pre-therapeutic lymph node biopsies from 308 patients with NHL [107 follicular B-cell lymphoma (FL), 94 diffuse large B-cell lymphoma (DLBCL), 107 peripheral T-cell lymphoma (PTCL)] were studied. Microvessels were scored according to the Chalkley and microvessel density method (MVD) methods. Vascular endothelial growth factor (VEGF) protein expression was evaluated by immunohistochemistry. Both Chalkley and MVD methods showed, that the lymphoma subtypes differed significantly in angiogenic scores (P < 0.001). Angiogenic scores in tumor area were highest in PTCL, and lowest in FL. However, a remarkable high microvessel density was found in interfollicular areas of FL. In FL, high interfollicular MVD scores predicted progressive disease and poorer overall and event-free survival (P = 0.024 and 0.013). High interfollicular Chalkley scores correlated with transformation to DLBCL (P = 0.01). VEGF expression was detected in all NHL subtype, and the strongest expression was found in PTCL. In FL, patients with diffuse VEGF expression in lymphoma cells had poorer overall survival than those with focal expression.
Asunto(s)
Linfoma de Células B/metabolismo , Linfoma Folicular/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células T Periférico/metabolismo , Neovascularización Patológica/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Anciano , Biomarcadores de Tumor/metabolismo , Femenino , Humanos , Técnicas para Inmunoenzimas , Linfoma de Células B/patología , Linfoma Folicular/patología , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células T Periférico/patología , Masculino , Microcirculación , Persona de Mediana Edad , Neovascularización Patológica/patología , Pronóstico , Tasa de SupervivenciaRESUMEN
Voltage-gated chloride channels have recently been implicated as being important for cell proliferation and invasive cell migration of primary brain tumors cells. In the present study we provide several lines of evidence that glioma Cl- currents are primarily mediated by ClC-2 and ClC-3, two genes that belong to the ClC superfamily. Transcripts for ClC-2 thru ClC-7 were detected in a human glioma cell line by PCR, whereas only ClC-2, ClC-3, and ClC-5 protein could be identified by Western blot. Prominent ClC-2, -3, and -5 channel expression was also detected in acute patient biopsies from low- and high-grade malignant gliomas. Immunogold electron microscopic studies as well as digital confocal imaging localized a portion of these ClC channels to the plasma membrane. Whole-cell patch-clamp recordings show the presence of two pharmacologically and biophysically distinct Cl- currents that could be specifically reduced by 48 hr exposure of cells to channel-specific antisense oligonucleotides. ClC-3 antisense selectively and significantly reduced the expression of outwardly rectifying current with pronounced voltage-dependent inactivation. Such currents were sensitive to DIDS (200-500 microm) and 5-nitro-2-(3-phenylpropylamino) benzoic acid (165 microm). ClC-2 antisense significantly reduced expression of inwardly rectifying currents, which were potentiated by hyperpolarizing prepulses and inhibited by Cd2+ (200-500 microm). Currents that were mediated by ClC-5 could not be demonstrated. We suggest that ClC-2 and ClC-3 channels are specifically upregulated in glioma membranes and endow glioma cells with an enhanced ability to transport Cl-. This may in turn facilitate rapid changes in cell size and shape as cells divide or invade through tortuous extracellular brain spaces.
Asunto(s)
Astrocitoma/metabolismo , Canales de Cloruro/biosíntesis , Glioblastoma/metabolismo , Glioma/metabolismo , Anticuerpos/farmacología , Astrocitoma/patología , Biopsia , Western Blotting , Canales de Cloruro CLC-2 , Membrana Celular/metabolismo , Canales de Cloruro/antagonistas & inhibidores , Canales de Cloruro/genética , Cloruros/metabolismo , Glioblastoma/patología , Glioma/patología , Humanos , Inmunohistoquímica , Oligonucleótidos Antisentido/farmacología , Técnicas de Placa-Clamp , Reacción en Cadena de la Polimerasa , ARN Mensajero/biosíntesis , Células Tumorales Cultivadas , Regulación hacia ArribaRESUMEN
Nine aminoacyl-tRNA synthetases from Ehrlich ascites cells were examined with respect to their ability to be isolated as high molecular weight complexes, soluble enzymes, and ribosome-bound enzymes. Several different methods were employed for cell homogenization and enzyme isolation, with particular attention paid to the effects of hypotonic, isotonic, and hypertonic buffers on enzyme isolation. The binding of all synthetases to ribosomes was eliminated if the low ionic strength of the isolation buffer was raised to isotonic levels. In contrast, neither the ionic strength or composition of the buffers, nor the procedures used for cell homogenization or enzyme isolation had any significant effect on the isolation of the high molecular weight synthetase complex. Certain enzymes (lysyl-, methionyl- and isoleucyl-tRNA synthetases) formed very stable complexes and high molecular weight species were the predominant forms of these enzymes under all conditions of cell homogenization and enzyme isolation. Other enzymes (glycyl-, tyrosinyl- and threonyl-tRNA synthetases) formed complexes very weakly, if at all, and always appeared predominately in the soluble enzyme fraction. Isolated soluble forms of the lysyl-, methionyl- and isoleucyl-tRNA synthetases did not associate to form significant amounts of complex upon re-isolATION, SUGGESTING THAT A COMPONENT NECESSARY FOR COMPLEX FORMATION WAS MISSING FROM THE SOLUBLE ENZYME FRACTION. However, the soluble forms of these enzymes, but not the glycyl-, tyrosinyl- and threonyl-tRNA synthetases, did for complexes when mixed with ribosomal RNA or polyuridylic acid. Preliminary experiments showed no significant differences between the complexed and soluble forms of the lysyl-, methionyl- and isoleucyl-tRNA synthetases with respect to Km values or ability to charge different isoaccepting tRNAs.
Asunto(s)
Aminoacil-ARNt Sintetasas/metabolismo , Carcinoma de Ehrlich/enzimología , Aminoacil-ARNt Sintetasas/aislamiento & purificación , Animales , Sitios de Unión , Estabilidad de Medicamentos , Sustancias Macromoleculares , Ratones , Peso Molecular , Polirribonucleótidos , Unión Proteica , Ribosomas/enzimologíaRESUMEN
First pregnancies are known to have higher oestrogen levels than later ones and first-born women are at increased breast cancer risk compared with later-born women. We hypothesized that a birth order effect might be even more evident in male breast cancer patients, in whom oestrogens in adult life are generally low. In a population-based study in Denmark involving 77 male breast cancer patients and 288 population controls, first-born men compared with later-born men had a relative risk of 1.71 for the disease (95% confidence interval (CI) 1.00-2.92). This result is in line with that seen in female breast cancer cases and indicates that male breast cancer may have roots in the intrauterine life, oestrogens being a likely mediator.
Asunto(s)
Orden de Nacimiento , Neoplasias de la Mama Masculina/etiología , Estrógenos/efectos adversos , Efectos Tardíos de la Exposición Prenatal , Neoplasias de la Mama Masculina/epidemiología , Estudios de Casos y Controles , Dinamarca/epidemiología , Femenino , Humanos , Masculino , Embarazo , Factores de RiesgoRESUMEN
BACKGROUND/AIMS: We examined the risk of non-calculus suppurative cholangitis in patients with inflammatory bowel disease in the entire Danish population. METHODOLOGY: The study included all patients discharged from Danish hospitals with a diagnosis of Crohn's disease or ulcerative colitis as registered in the Danish National Registry of Patients from January 1, 1977 to December 31, 1992. We compared the observed number of patients hospitalized with suppurative cholangitis with expected numbers on the basis of age, gender, and calendar-specific incidence rates in the general population. RESULTS: Overall, 15,317 eligible patients with inflammatory bowel disease were discharged during the study period. Among these were 52 cases of non-calculus suppurative cholangitis. The incidence rate of non-calculus suppurative cholangitis in the cohort with inflammatory bowel disease was 46.1 per 100,000 person-years. The standardized incidence ratio (SIR) for suppurative cholangitis was increased similarly for patients with Crohn's disease [SIR=6.7, 95% confidence interval (CI): 3.1-12.7] and for patients with ulcerative colitis (SIR=6.6, 95% CI: 4.7-9.1). The highest relative risk was found in male patients younger than 40 years of age, for both Crohn's disease and ulcerative colitis (SIR=70.5 and 78.7, respectively). CONCLUSIONS: Patients with inflammatory bowel disease have an increased risk of non-calculus suppurative cholangitis.
Asunto(s)
Colangitis/etiología , Colitis Ulcerosa/complicaciones , Enfermedad de Crohn/complicaciones , Adulto , Distribución por Edad , Colangitis/epidemiología , Estudios de Cohortes , Colitis Ulcerosa/epidemiología , Enfermedad de Crohn/epidemiología , Dinamarca/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Medición de Riesgo , Distribución por Sexo , Supuración/epidemiología , Supuración/etiologíaRESUMEN
PURPOSE: To determine the prevalence and spectrum of underlying rheumatic diseases, especially Sjögren's syndrome (SS) and the antiphospholipid syndrome, and the prevalence of the lupus anticoagulant, antinuclear antibody (ANA), and rheumatoid factor (RF) within a neurologic patient population. PATIENTS AND METHODS: The study design entailed a prospective, consecutive sample of patients admitted to a university-affiliated neurology service for 72 hours or more. Study patients were obtained from a sequential evaluation of 100 inpatients with a wide spectrum of neurologic diseases. Another 31 eligible patients were not included due to refusal (n = 4), inability to give consent (n = 12), or an incomplete database (n = 15). All patients underwent a physical examination and responded to a rheumatic disease questionnaire (administered by one rheumatologist) assessing signs and symptoms relevant to rheumatic disease. All had lupus anticoagulant, ANA, and RF determinations. An independent patient evaluation was done by the attending neurologist. RESULTS: Eleven patients had a rheumatic or autoimmune disorder directly related to their neurologic admission: three patients with SS (one each with embolic stroke, dementia, and hemiparetic somatization); three patients with lupus anticoagulant syndrome (all with stroke, recurrent in two); one patient with systemic lupus erythematosus accompanied by migraine headache and the lupus anticoagulant; and one patient each with isolated central nervous system (CNS) angiitis, neuro-Behçet's disease, CNS Whipple's disease, and HLA-B27-associated spondyloarthropathy. Nineteen patients had one or more autoantibodies: ANA greater than or equal to 1:80 (n = 10); RF greater than or equal to 1:80 (n = 6); and positive lupus anticoagulant (n = 7). The seroreactivity of 10 of these patients remained unexplained. CONCLUSIONS: This neurologic population demonstrated significant seroreactivity and rheumatic disease associations, with SS and lupus anticoagulant-related neurologic disease the most common. Since SS and the antiphospholipid syndrome can be overlooked, it is recommended that a formal evaluation for SS and a direct lupus anticoagulant assay should be considered in the examination of patients with neuropsychiatric symptoms.
Asunto(s)
Anticuerpos Antinucleares/análisis , Factores de Coagulación Sanguínea/inmunología , Enfermedades Reumáticas/inmunología , Factor Reumatoide/análisis , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antinucleares/inmunología , Factores de Coagulación Sanguínea/análisis , Femenino , Humanos , Inhibidor de Coagulación del Lupus , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Enfermedades Reumáticas/sangre , Enfermedades Reumáticas/diagnóstico , Síndrome de Sjögren/sangre , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/inmunología , Encuestas y CuestionariosRESUMEN
Cogan's syndrome is a rare autoimmune disease characterized by the presence of interstitial keratitis and audiovestibular symptoms. The audiovestibular symptoms include fluctuating sensory hearing impairment, tinnitus, vertigo, and reduced vestibular response. Immediate diagnosis and medical intervention provides optimum auditory recovery. Frequent audiologic assessments are necessary to monitor the disease activity and to aid in the therapeutic levels of steroidal medications. Amplification is often required on a temporary or permanent basis. Two case studies are presented to illustrate the audiologist's role in the identification and management of patients with Cogan's syndrome.
Asunto(s)
Enfermedades Autoinmunes/diagnóstico , Sordera/diagnóstico , Queratitis/diagnóstico , Vértigo/diagnóstico , Corticoesteroides/administración & dosificación , Corticoesteroides/uso terapéutico , Adulto , Amplificadores Electrónicos , Audiometría , Percepción Auditiva , Enfermedades Autoinmunes/terapia , Sordera/complicaciones , Diagnóstico Diferencial , Femenino , Humanos , Queratitis/complicaciones , Queratitis/terapia , Síndrome , Vértigo/complicacionesRESUMEN
Neuronal activity in the spinal cord results in extracellular potassium accumulation that is significantly higher in the dorsal horn than in the ventral horn. This is suggestive of differences in K(+) clearance, widely thought to involve diffusional K(+) uptake by astrocytes. We previously identified the inward rectifying K(+) channel Kir4.1 as the major K(+) conductance in spinal cord astrocytes in situ and hence hypothesized that different expression levels of Kir4.1 may account for the observed differences in potassium dynamics in spinal cord. Our results with immunohistochemical staining demonstrated highest Kir4.1 channel expression in the ventral horn and very low levels of Kir4.1 in the apex of the dorsal horn. Western blots from tissue of these two regions similarly confirmed much lower levels of Kir4.1 in the apex of the dorsal horn. Whole cell patch-clamp recordings from astrocytes in rat spinal cord slices also showed a difference in inwardly rectifying currents in these two regions. However, no statistical difference in either fast-inactivating (Ka) or delayed rectifying potassium currents (Kd) was observed, suggesting these differences were specific to Kir currents. Importantly, when astrocytes in each region were challenged with high [K(+)](o), astrocytes from the dorsal horn showed significantly smaller (60%) K(+) uptake currents than astrocytes from the ventral horn. Taken together, these data support the conclusion that regional differences in astrocytic expression of Kir4.1 channels result in marked changes in potassium clearance rates in these two regions of the spinal cord.
Asunto(s)
Astrocitos/fisiología , Homeostasis/fisiología , Canales de Potasio de Rectificación Interna/metabolismo , Potasio/metabolismo , Médula Espinal/citología , Potenciales de Acción/fisiología , Animales , Animales Recién Nacidos , Bario/farmacología , Transportador 2 de Aminoácidos Excitadores/metabolismo , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Homeostasis/efectos de los fármacos , Técnicas In Vitro , Masculino , Técnicas de Placa-Clamp/métodos , Fosfopiruvato Hidratasa/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Spinal cord astrocytes (SCA) have a high permeability to K+ and hence have hyperpolarized resting membrane potentials. The underlying K+ channels are believed to participate in the uptake of neuronally released K+. These K+ channels have been studied extensively with regard to their biophysics and pharmacology, but their molecular identity in spinal cord is currently unknown. Using a combination of approaches, we demonstrate that channels composed of the Kir4.1 subunit are responsible for mediating the resting K+ conductance in SCA. Biophysical analysis demonstrates astrocytic Kir currents as weakly rectifying, potentiated by increasing [K+]o, and inhibited by micromolar concentrations of Ba2+. These currents were insensitive to tolbutemide, a selective blocker of Kir6.x channels, and to tertiapin, a blocker for Kir1.1 and Kir3.1/3.4 channels. PCR and Western blot analysis show prominent expression of Kir4.1 in SCA, and immunocytochemistry shows localization Kir4.1 channels to the plasma membrane. Kir4.1 protein levels show a developmental upregulation in vivo that parallels an increase in currents recorded over the same time period. Kir4.1 is highly expressed throughout most areas of the gray matter in spinal cord in vivo and recordings from spinal cord slices show prominent Kir currents. Electrophysiological recordings comparing SCA of wild-type mice with those of homozygote Kir4.1 knockout mice confirm a complete and selective absence of Kir channels in the knockout mice, suggesting that Kir4.1 is the principle channel mediating the resting K+ conductance in SCA in vitro and in situ.
Asunto(s)
Astrocitos/metabolismo , Canales de Potasio de Rectificación Interna/biosíntesis , Médula Espinal/metabolismo , Animales , Astrocitos/efectos de los fármacos , Western Blotting , Células Cultivadas , Electrofisiología , Genotipo , Inmunohistoquímica , Ratones , Ratones Noqueados , Técnicas de Placa-Clamp , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio de Rectificación Interna/efectos de los fármacos , Canales de Potasio de Rectificación Interna/genética , ARN/biosíntesis , ARN/genética , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Médula Espinal/citología , Médula Espinal/efectos de los fármacosRESUMEN
BACKGROUND: Use of antipsychotics has been linked with an adverse cardiovascular risk factor profile and an increased risk of dysrhythmia and sudden cardiac death. However, detailed data on the association between use of antipsychotics and development of atherosclerotic disease are limited. OBJECTIVE: To examine risk of hospitalization for myocardial infarction (MI) amongst users of antipsychotics compared with non-users. DESIGN AND SUBJECTS: A population-based case-control study using data from hospital discharge registries in the counties of North Jutland, Viborg and Aarhus, Denmark, and the Danish Civil Registration System. We identified 21,377 cases of first-time hospitalization for MI and 106,885 sex- and age-matched non-MI population controls in the period 1992-2004. All prescriptions for antipsychotics filled prior to the date of admission for MI were retrieved from population-based prescription databases. We used conditional logistic regression to adjust for a wide range of covariates. RESULTS: Current users of atypical [adjusted relative risk: 0.98, 95% confidence interval (CI): 0.88-1.09] and typical antipsychotics (adjusted relative risk: 0.99, 95% CI: 0.96-1.03) had no increased overall risk of being admitted to hospital for MI when compared with non-users of antipsychotics. These findings were consistent in all examined subgroups. Further, we found no association between the cumulative dose of antipsychotics and the risk of hospitalization for MI. CONCLUSION: These findings do not support the hypothesis that use of antipsychotics and in particular atypical antipsychotics is associated with increased risk of MI.
Asunto(s)
Antipsicóticos/efectos adversos , Infarto del Miocardio/epidemiología , Anciano , Estudios de Casos y Controles , Dinamarca/epidemiología , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/inducido químicamente , Medición de RiesgoRESUMEN
Old sulphonylureas have been linked with adverse cardiovascular effects; however, data on the clinical implications are sparse. We examined the association between use of sulphonylureas and other antidiabetic drugs and the risk and case fatality rate (CFR) of myocardial infarction (MI) in a population-based case-control and follow-up study, respectively. A total of 6738 cases of first-time MI and 67,374 age- and gender-matched population controls were identified from the Hospital Discharge Registry and the Civil Registration System of North Jutland County, Denmark, in the period 1994 through 2002. Prescriptions for antidiabetic drugs before the index date were retrieved from a prescription database. We estimated odds ratios (ORs) of MI (case-control study) and 30-day CFR (follow-up study) associated with antidiabetic drug use adjusted for possible confounding factors and using nondiabetic subjects as the reference group. The risk of MI appeared higher among users of old sulphonylureas (adjusted OR, 2.07; 95% confidence interval (CI), 1.81-2.37) than among users of new sulphonylureas (adjusted OR, 1.36; 95% CI, 1.01-1.84). The adjusted ORs among users of nonsulphonylurea oral antidiabetic drugs, insulin, and patients with diabetes not receiving pharmacotherapy were 1.38 (95% CI, 0.90-2.11), 2.56 (95% CI, 2.16-3.03), and 3.51 (95% CI, 2.92-4.22), respectively. The overall 30-day CFR was 24.6%, but varied between 9.5% and 37.0% among the different categories. New sulphonylureas may be associated with a lower risk of MI than old sulphonylureas. Furthermore, the 30-day CFR may vary according to type of antidiabetic drug. These differences indicate the need for further examination of the cardiovascular safety of antidiabetic drugs.
Asunto(s)
Hipoglucemiantes/efectos adversos , Infarto del Miocardio/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Intervalos de Confianza , Dinamarca/epidemiología , Prescripciones de Medicamentos/estadística & datos numéricos , Femenino , Estudios de Seguimiento , Hospitalización/estadística & datos numéricos , Humanos , Insulina/efectos adversos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Población , Pronóstico , Medición de Riesgo , Compuestos de Sulfonilurea/efectos adversosRESUMEN
Glioma cells show up-regulation and constitutive activation of erbB2, and its expression correlates positively with increased malignancy. A similar correlation has been demonstrated for the expression of gBK, a calcium-sensitive, large-conductance K(+) channel. We show here that glioma BK channels are a downstream target of erbB2/neuregulin signaling. Tyrphostin AG825 was able to disrupt the constituitive erbB2 activation in a dose-dependent manner, causing a 30-mV positive shift in gBK channel activation in cell-attached patches. Conversely, maximal stimulation of erbB2 with a recombinant neuregulin (NRG-1beta) caused a 12-mV shift in the opposite direction. RT-PCR studies reveal no change in the BK splice variants expressed in treated glioma cells. Furthermore, isolation of surface proteins through biotinylation did not show a change in gBK channel expression, and probing with phospho-specific antibodies showed no alteration in channel phosphorylation. However, fura-II Ca(2+) fluorescence imaging revealed a 35% decrease in the free intracellular Ca(2+) concentration after erbB2 inhibition and an increase in NRG-1beta-treated cells, suggesting that the observed changes most likely were due to alterations in [Ca(2+)](i). Consistent with this conclusion, neither tyrphostin AG825 nor NRG-1beta was able to modulate gBK channels under inside-out or whole-cell recording conditions when intracellular Ca(2+) was fixed. Thus, gBK channels are a downstream target for the abundantly expressed neuregulin-1 receptor erbB2 in glioma cells. However, unlike the case in other systems, this modulation appears to occur via changes in [Ca(2+)](i) without changes in channel expression or phosphorylation. The enhanced sensitivity of gBK channels in glioma cells to small, physiological Ca(2+) changes appears to be a prerequisite for this modulation.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Canales de Potasio Calcio-Activados/metabolismo , Receptor ErbB-2/fisiología , Transducción de Señal/fisiología , Benzotiazoles , Calcio/metabolismo , Línea Celular Tumoral , Humanos , Canales de Potasio de Gran Conductancia Activados por el Calcio , Neurregulinas/metabolismo , Canales de Potasio Calcio-Activados/efectos de los fármacos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Receptor ErbB-2/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Tirfostinos/farmacologíaRESUMEN
Inwardly rectifying potassium (K(ir)) channels are a prominent feature of mature, postmitotic astrocytes. These channels are believed to set the resting membrane potential near the potassium equilibrium potential (E(K)) and are implicated in potassium buffering. A number of previous studies suggest that K(ir) channel expression is indicative of cell differentiation. We therefore set out to examine K(ir) channel expression in malignant glia, which are incapable of differentiation. We used two established and widely used glioma cell lines, D54MG (a WHO grade 4 glioma) and STTG-1 (a WHO grade 3 glioma), and compared them to immature and differentiated astrocytes. Both glioma cell lines were characterized by large outward K(+) currents, depolarized resting membrane potentials (V(m)) (-38.5 +/- 4.2 mV, D54 and -28.1 +/- 3.5 mV, STTG1), and relatively high input resistances (R(m)) (260.6 +/- 64.7 MOmega, D54 and 687.2 +/- 160.3 MOmega, STTG1). These features were reminiscent of immature astrocytes, which also displayed large outward K(+) currents, had a mean V(m) of -51.1 +/- 3.7 and a mean R(m) value of 627.5 +/- 164 MOmega. In contrast, mature astrocytes had a significantly more negative resting membrane potential (-75.2 +/- 0.56 mV), and a mean R(m) of 25.4 +/- 7.4 MOmega. Barium (Ba(2+)) sensitive K(ir) currents were >20-fold larger in mature astrocytes (4.06 +/- 1.1 nS/pF) than in glioma cells (0.169 +/- 0.033 nS/pF D54, 0.244 +/- 0.04 nS/pF STTG1), which had current densities closer to those of dividing, immature astrocytes (0.474 +/- 0.12 nS/pF). Surprisingly, Western blot analysis shows expression of several K(ir) channel subunits in glioma cells (K(ir)2.3, 3.1, and 4.1). However, while in astrocytes these channels localize diffusely throughout the cell, in glioma cells they are found almost exclusively in either the cell nucleus (K(ir)2.3 and 4.1) or ER/Golgi (3.1). These data suggest that mislocalization of K(ir) channel proteins to intracellular compartments is responsible for a lack of appreciable K(ir) currents in glioma cells.
Asunto(s)
Astrocitos/metabolismo , Glioma/metabolismo , Canales de Potasio de Rectificación Interna/metabolismo , Canales de Potasio de Dominio Poro en Tándem , Canales de Potasio/metabolismo , Animales , Astrocitos/citología , Línea Celular Tumoral , Células Cultivadas , Glioma/patología , Líquido Intracelular/metabolismo , Potenciales de la Membrana/fisiología , Canales de Potasio/biosíntesis , Canales de Potasio/genética , Canales de Potasio de Rectificación Interna/biosíntesis , Canales de Potasio de Rectificación Interna/genética , RatasRESUMEN
OBJECTIVE: To find evidence of a potential genetic predisposition to the anti-Sm or anti-RNP precipitin autoantibody responses. METHODS: HLA-DR and DQ alleles determined by restriction fragment length polymorphism and/or oligotyping in 49 subjects with either anti-Sm alone or anti-RNP alone were compared with those in 139 race-matched normal control subjects and 59 race-matched lupus patients without anti-Sm and anti-RNP autoantibodies. RESULTS: Black patients with anti-Sm precipitin had increased frequencies of HLA-DR2 and the DQw6-associated DQA1*0102 (P = 0.007, odds ratio [OR] = 6.7) and DQB1*0602 (P = 0.001, OR = 9.1) chain alleles compared with normal black control subjects. Black patients with anti-RNP precipitin showed significant increases in the DQw5-associated DQA1*0101 (P = 0.03, OR = 5.5) and DQB1*0501 (P = 0.002, OR = 23.3) chain alleles compared with lupus patients without anti-Sm or RNP. While patients with anti-RNP precipitin showed an increased frequency of the DQw8-associated allele DQB1*0302 (P = 0.02, OR = 3.7) compared with normal controls, as well as an increased frequency of the DQw5-associated alleles DQA1*0101 and DQB1*0501 (P = 0.05, OR = 4.2) compared with lupus patients without anti-Sm or RNP. There were no specific HLA-DR2 or DR4 subtype associations found with either anti-Sm or RNP precipitin autoantibodies. CONCLUSION: There are distinct patterns of major histocompatibility complex class II allele associations with the anti-Sm versus the anti-RNP precipitin autoantibody responses, and HLA-DQ associations may be more primary than HLA-DR associations.
Asunto(s)
Autoanticuerpos/biosíntesis , Autoantígenos/inmunología , Antígenos de Histocompatibilidad Clase II/genética , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Ribonucleoproteínas Nucleares Pequeñas , Alelos , Secuencia de Aminoácidos , Secuencia de Bases , Epítopos , Antígenos HLA-DQ/inmunología , Antígenos HLA-DR/inmunología , Humanos , Datos de Secuencia Molecular , Pruebas de Precipitina , Proteínas Nucleares snRNPRESUMEN
A prospective study of 100 consecutive admissions to a university neurology inpatient service was done to assess the prevalence and spectrum of autoimmune rheumatic disorders, most specifically Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), and lupus anticoagulant (LA)-associated disorders. All patients underwent a physical exam (PE), a rheumatic disease questionnaire, and serologic testing (ANA, RF, and LA). The 100 patients consisted of 36 men and 64 women, aged 17 to 98 (mean 60) years and included 47 white, 45 black and eight other. Definite rheumatic diseases were found in 11%. These included three with previously undiagnosed SS and neurologic symptoms of seizures and dementia, psychiatric disease, and embolic cerebrovascular accident (CVA). Also present were three CVA patients with LA; one migraine patient with known SLE and LA; and one each with CNS Whipples disease, Behcet's disease, isolated CNS angiitis, and B27+ spondyloarthritis. With respect to SS questions and PE findings, three groups of patients were identified: --Questionnaire; +PE 14 patients, aged 33-81 (mean 73) years; 13 F, 1 M who were not further evaluated although significant seroreactivity was present in three (RF 2, LA 1). --Questionnaire; -PE 16 patients, aged 32-98 (mean 56) years; 13 F, 3 M. Four patients had further evaluation, diagnostic for SS in three of them (3/3 abnormal lip biopsies, 2/3 KCS, 2/3 anti-Ro). Another four had unexplained seroreactivity (ANA 2, RF 1, LA 1). --Questionnaire; +PE 12 patients, aged 24-77 (mean 54) years; 10 F, 2 M, not further evaluated although four had seroreactivity in the setting of idiopathic neurologic disorders.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Enfermedades Autoinmunes/complicaciones , Enfermedades del Sistema Nervioso/etiología , Síndrome de Sjögren/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Autoanticuerpos/análisis , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/epidemiología , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Examen Físico , Estudios Prospectivos , Enfermedades Reumáticas/complicaciones , Enfermedades Reumáticas/epidemiología , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/epidemiología , Encuestas y Cuestionarios , TexasRESUMEN
In North America and European Caucasoids with systemic lupus erythematosus (SLE) there is an increased frequency of a C4A, CYP21A gene deletion, largely associated with the HLA-B8,DR3,C4A*QO extended haplotype. There have been no consistent HLA associations reported for SLE in blacks, although an increased frequency of serologically determined C4A null alleles has been reported in two studies. We studied 79 black American SLE patients and 68 black controls by restriction fragment length polymorphism analysis to determine if a C4A gene deletion was a genetic risk factor for SLE. Moreover, the nature of the deletion and any HLA phenotypic associations were sought. Nineteen of 79 (24%) patients compared to 5 of 68 (7.4%) controls had a phenotypic C4A,CYP21A gene deletion (P = .005; RR = 4). A homozygous deletion in four patients gave a genotypic frequency of 23/158 (14.5%) SLE patients vs 5/136 (3.7%) controls (P = .001; RR = 4.5). The deletion was associated with HLA-DR2 (P = .03) and HLA-DR3 (P = .03). Moreover, all subjects with the deletion had HLA-DR2 or DR3 (P = 7.7 x 10(-6). HLA-B44 was also associated with the deletion (P = .02), and eight of the nine HLA-B44 positives also carried HLA-DR2. HLA-B8 approached significance (P = .08) and was always accompanied by HLA-DR3. Finally, this black population demonstrated a unique C4B gene size polymorphism with 80% C4B "short" as compared to the 40% C4B "short" frequency reported in whites. We conclude that a large C4A,CYP21A gene deletion, particularly associated with the HLA-B44, -DR2, and -DR3 alleles, is the strongest genetic risk factor thus far identified for SLE susceptibility in black Americans. Furthermore, the unique preponderance of the C4B "short" gene form may be a factor in the actual formation of the deletion.
Asunto(s)
Población Negra/genética , Deleción Cromosómica , Complemento C4/genética , Antígenos HLA/genética , Lupus Eritematoso Sistémico/genética , Complemento C4/deficiencia , Complemento C4a , Frecuencia de los Genes , Humanos , Lupus Eritematoso Sistémico/etnología , Hibridación de Ácido Nucleico , Polimorfismo de Longitud del Fragmento de Restricción , Factores de Riesgo , Estados UnidosRESUMEN
OBJECTIVE: To examine the association between cumulative CS dose and risk of hip fracture. DESIGN: Population-based case-control design. SUBJECTS AND METHODS: A total of 6660 subjects with hip fracture and 33,272 age-matched population controls were identified using the County Hospital Discharge Registry in North Jutland County, Denmark and the Danish Central Personal Registry, respectively. Data on redeemed prescriptions for CS within the last 5 years before the index date were retrieved from a population-based prescription database, and recalculated to prednisolone equivalents. Cases and controls were categorized according to cumulative CS dose: (i) no use; (ii) <130 mg (e.g. equivalent to 30 mg of prednisolone for 4 days given for an acute exacerbation of asthma); (iii) 130-499 mg (e.g. equivalent to a short course of prednisolone of 450 mg for acute asthma); (iv) 500-1499 mg (e.g. equivalent to 7.5 mg prednisolone daily for 6 months or 800 microg day(-1) of inhaled budesonide for 1 year); and (v) > or =1500 mg (e.g. equivalent to >4.1 mg day(-1) for 1 year, a long-term high dose). Data were analysed using conditional logistic regression adjusted for potential confounders including gender, redeemed prescriptions for hormone replacement therapy, antiosteoporotic, anxiolytic, antipsychotic and antidepressant drugs. RESULTS: Compared with never users, an increased risk of hip fracture was found for CS users, with increasing cumulative doses of any type of CS use during the preceding 5 years [adjusted odds ratio (OR)=0.96, 95% confidence interval (CI)=0.89-1.04] for <130 mg prednisolone; OR=1.17 (CI=1.01-1.35) for 130-499 mg; OR=1.36 (CI=1.19-1.56) for 500-1499 mg; and OR=1.65 (CI=1.43-1.92) for > or =1500 mg. An increased risk was also found when the study population was stratified according to gender, age and type of CS (systemic or topical). CONCLUSIONS: Even a limited daily dose of CS (more than an average dose of approximately 71 microg prednisolone per day) was associated with an increased risk of hip fracture.