RESUMEN
BACKGROUND: The concurrent presence or manifestation of multiple chronic conditions, i.e. multimorbidity, poses a challenge to affected patients and their relatives, physicians, and practitioners, and to the health care system in general. Aiming to improve medical care for different chronic diseases, the Chronic Care Model also appears to be suited for multimorbidity. The established research consortium PRISCUS is trying to create some of the prerequisites for a new care model for multimorbid, elderly patients oriented along the lines of the Chronic Care Model. METHODS AND RESULTS: Four out of seven subprojects of the research consortium provide an overview of some of their findings. Topics in a sports medicine subproject were the assessment of physical activity by means of a newly developed questionnaire and the development and feasibility testing of an exercise program for elderly people with chronic conditions and mobility impairment. Partners from family medicine implemented geriatric assessment in a primary care setting and evaluated its consequences. In a pharmacological subproject, potentially inappropriate medication as well as drug-drug interactions and dosing errors were addressed. The health economic subproject investigated quality of life impairment due to multiple chronic diseases and the effects of multimorbidity on costs. CONCLUSIONS: The results of the PRISCUS research consortium allow a better description of consequences of multimorbidity and illustrate at least some new approaches towards prevention, diagnosis, and treatment of patients suffering from multimorbidity. Ongoing projects will test the efficacy of a physical activity program and a new complex intervention to reduce potentially inappropriate medication in the elderly. With this, the research consortium will create some prerequisites for a new health care model for patients with multimorbidity comparable to the Chronic Care Model.
Asunto(s)
Enfermedad Crónica/epidemiología , Ensayos Clínicos como Asunto , Comorbilidad , Medicina Basada en la Evidencia , Investigación sobre Servicios de Salud/organización & administración , Servicios de Salud para Ancianos , Modelos Organizacionales , Anciano , Anciano de 80 o más Años , Alemania , HumanosRESUMEN
AIMS: The characteristic histological feature of autoimmune hepatitis (AIH) is interface hepatitis with predominant portal lymphoplasmacytic necroinflammatory infiltration. Centrilobular necrosis (CN), reminiscent of toxic or circulatory liver injury, has been reported in AIH. The aim of this study was to assess the frequency of CN in patients with AIH and its correlation with laboratory and clinical data. METHODS: Liver biopsies were obtained from 114 patients (90 women, 24 men, mean (SD) age 45.4 (19.4) years) with AIH and were evaluated under code by a single pathologist according to the modified Knodell score. RESULTS: CN was found in 20 (17.5%) patients with virtually unaffected portal areas in four cases. Patients with AIH with CN had a higher total hepatic activity index (median (range) 11 (6 to 15) v 5 (2 to 10)) and presented less frequently with cirrhosis (10% v 38%). Patients with CN had a higher frequency of acute onset (87% v 32%), higher bilirubin (median (range) 12.0 (0.43 to 40.0) v 1.9 (0.36 to 46)) and higher ALT levels (median (range) 25.6 (2.7 to 63.9) v 7.2 (0.7 to 62.6)), than did patients with AIH without centrizonal injury. CONCLUSION: CN with sparing of the portal areas represents a rare histological pattern in AIH. CN is associated with an acute clinical presentation and might reflect an early lesion preceding portal involvement. Recognition of this particular histological appearance enables early diagnosis of AIH and a timely initiation of immunosuppressive therapy.
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Hepatitis Autoinmune/patología , Hígado/patología , Enfermedad Aguda , Adolescente , Adulto , Conductos Biliares/patología , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Femenino , Fibrosis , Hepatocitos/patología , Humanos , Masculino , Persona de Mediana Edad , Necrosis , Estadísticas no ParamétricasRESUMEN
Extracellular stimuli are often encoded in the frequency, amplitude and duration of spikes in the intracellular concentration of calcium ([Ca2+]i). However, the timing of individual [Ca2+]i-spikes in relation to the dynamics of an extracellular stimulus is still an open question. To address this question, we use a systems biology approach combining experimental and theoretical methods. Using computer simulations, we predict that more naturalistic pulsed stimuli generate precisely-timed [Ca2+]i-spikes in contrast to the application of constant stimuli of the same dose. These computational results are confirmed experimentally in single primary rat hepatocytes upon alpha1-adrenergic stimulation. Hormonal signalling in analogy to neuronal signalling thus has the potential to make use of temporal coding on the level of single cells. The [Ca2+]i-signalling cascade provides a first example for increasing the information capacity of an intracellular regulatory signal beyond the known coding mechanisms of amplitude (AM) and frequency modulation (FM).
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Algoritmos , Relojes Biológicos/fisiología , Señalización del Calcio/fisiología , Calcio/metabolismo , Hepatocitos/fisiología , Modelos Biológicos , Animales , Células Cultivadas , Simulación por Computador , Masculino , Ratas , Ratas Endogámicas Lew , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Galectin-3, a member of beta-galactoside-binding lectins, is expressed and secreted by a variety of cell types including human intestinal epithelial cells. The presence of anti-galectin-3 antibody in the sera of patients was analyzed by immunoblotting using recombinant human galectin-3. A substantially higher percentage of sera from Crohn's disease patients contained anti-galectin-3 IgG autoantibodies than from patients with ulcerative colitis, primary biliary cirrhosis, or autoimmune hepatitis and of apparently healthy control volunteers. In Crohn's disease patients the titer of autoantibodies was high and interestingly correlated negatively with disease activity. To characterize and generate artificial epitopes (mimotopes), the anti-galectin-3 monoclonal antibodies A3A12 and B2C10 were used for biopannings of phage display nonapeptide libraries. These mimotopes interfered with the binding of autoantibodies to recombinant and native intestinal epithelial galectin-3. Our data may suggest that galectin-3 mimotopes could be used for the induction of IgG with desired specificity to regulate immune responses in Crohn's disease patients.
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Antígenos de Diferenciación/inmunología , Autoanticuerpos/sangre , Autoantígenos/inmunología , Enfermedad de Crohn/sangre , Lectinas/inmunología , Secuencia de Aminoácidos , Anticuerpos Monoclonales/inmunología , Autoanticuerpos/inmunología , Unión Competitiva , Extractos Celulares/inmunología , Línea Celular , Enfermedad de Crohn/inmunología , Epítopos de Linfocito B/genética , Epítopos de Linfocito B/inmunología , Galectina 3 , Humanos , Immunoblotting , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Datos de Secuencia Molecular , Biblioteca de Péptidos , Péptidos/síntesis química , Péptidos/genética , Péptidos/inmunología , Análisis de Secuencia de ADNRESUMEN
Uridine diphosphate glucuronosyltransferase (UGT) was identified as an antigenic target in a subgroup of liver-kidney microsomal autoantibodies and was termed LKM-3. To evaluate the nature of LKM-3 antibodies, we screened sera from 80 untreated patients with autoimmune hepatitis (AIH) type 1 and 2, primary biliary cirrhosis (PBC), AIH/PBC, hepatitis C virus (HCV) infection, and 12 healthy individuals (controls) against 7 recombinant human UGT isoenzymes (UGT1A1, UGT1A4, UGT1A6, UGT1A7, UGT1A9, UGT1A10, and UGT2B7). Autoantibodies reacting against various UGT isoenzymes were observed in sera from 3 of 18 AIH type 2 and 1 of 27 of the HCV patients. The anti-UGT-positive sera from AIH type 2 patients revealed the strongest immunoreactivity against UGT1A1, the main UGT-isoform involved in the bilirubin glucuronidation. Additionally, these sera were able to block UGT-mediated substrate glucuronidation in vitro. The prevalence for UGT1A1 was shown by 2 independent techniques: (1) UGT1A1 was identified as the main antigen by Western blotting. Preabsorption of sera with UGT1A1 prevented reaction against all tested UGT-isoforms. (2) In vitro immunoinhibition experiments showed that glucuronidation of the anticancer drug flavopiridol by UGT1A1 was more strongly inhibited than its UGT1A9-mediated biotransformation. In contrast, the serum from the HCV-patient reacted predominately with UGT1A6, and moreover, the immunoreactivity pattern was different from that of the AIH group. To summarize, we show the subtype preference of antibodies against UGT1A1 in a subgroup of AIH type 2 patients. These autoantibodies inhibit UGT-mediated glucuronidation in vitro, but it is unlikely that anti-UGT antibodies will have a marked effect on the patients capacity for drug biotransformation, as serum bilirubin levels in patients remained within the normal range.
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Autoanticuerpos/análisis , Glucuronosiltransferasa/inmunología , Hepatitis Autoinmune/inmunología , Isoenzimas/inmunología , Autoanticuerpos/farmacología , Niño , Reacciones Cruzadas , Femenino , Flavonoides/antagonistas & inhibidores , Flavonoides/metabolismo , Glucurónidos/antagonistas & inhibidores , Glucurónidos/biosíntesis , Glucuronosiltransferasa/metabolismo , Hepatitis C Crónica/inmunología , Hepatitis Autoinmune/terapia , Humanos , Himecromona/metabolismo , Inmunosupresores/uso terapéutico , Cirrosis Hepática Biliar/inmunología , Masculino , Piperidinas/antagonistas & inhibidores , Piperidinas/metabolismo , Proteínas Recombinantes/inmunología , Valores de ReferenciaRESUMEN
BACKGROUND/AIMS: Antibodies against nuclear pore complexes (NPCs) have been detected in primary biliary cirrhosis (PBC), but their clinical relevance is still unsettled. METHODS: We tested sera from 171 consecutive PBC patients and 230 control subjects (149 with autoimmune or viral liver diseases, 28 with systemic lupus erythematosus, and 53 healthy) by immunoblotting for antibodies against purified human NPCs. RESULTS: Antibodies to NPCs were detected in 27% of the patients with PBC, were highly specific (97%), and were not associated with antimitochondrial antibodies. Their prevalence was higher in symptomatic patients (36 vs. 16%, P < 0.01) and was associated (P < 0.001) with more severe disease, as assessed by the presence of cirrhosis or its complications (13% prevalence in patients without cirrhosis, 31% in uncomplicated, and 54% in complicated cirrhosis), or by the application of the Mayo prognostic model (12% in the lowest, 21% in the median, 47% in the highest score tertile). Positive patients had higher levels of serum bilirubin (2.2 +/- 3.7 vs. 1.0 +/- 1.1 mg/dl, P < 0.01) and more marked inflammatory infiltrates on liver biopsy (P < 0.05). CONCLUSIONS: Autoantibodies to NPCs are more prevalent in PBC patients than in controls and are strongly associated with more active and severe disease.
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Autoanticuerpos/análisis , Cirrosis Hepática Biliar/inmunología , Cirrosis Hepática Biliar/patología , Poro Nuclear/inmunología , Bilirrubina/sangre , Humanos , Hígado/patología , Cirrosis Hepática Biliar/sangre , Cirrosis Hepática Biliar/complicaciones , Hepatopatías/inmunología , Lupus Eritematoso Sistémico/inmunología , Persona de Mediana Edad , Modelos Teóricos , Pronóstico , Valores de Referencia , Índice de Severidad de la EnfermedadRESUMEN
A 61-year-old man presented with diffuse abdominal pain, diarrhea, vomiting and fever. On the initial diagnosis of gastroenteritis the patient received the antibiotic ofloxacine for one week. On admission plain abdominal radiograph suggested a mechanic intestinal obstruction. In computed tomography a conglomerate tumor in the ileocecal region was seen and the patient underwent laparotomy. The conglomerate tumor was mobilized and an abscess opened, which was caused by a perforated appendicitis. After the operation the patient improved immediately and had an uneventful postoperative course. He was released and did not suffer from gastrointestinal symptoms the following 16 months of follow-up. The present case shall set forth that perforated appendicitis can clinically present as intestinal obstruction. Although a rare complication, perforated appendicitis should therefore even be considered in cases of mechanic intestinal obstruction of unknown cause.
Asunto(s)
Absceso/diagnóstico , Apendicitis/diagnóstico , Enfermedades del Íleon/diagnóstico , Obstrucción Intestinal/diagnóstico , Perforación Intestinal/diagnóstico , Absceso/cirugía , Apendicitis/cirugía , Diagnóstico Diferencial , Humanos , Enfermedades del Íleon/cirugía , Obstrucción Intestinal/cirugía , Perforación Intestinal/cirugía , Masculino , Persona de Mediana Edad , Rotura Espontánea/diagnóstico , Tomografía Computarizada por Rayos XRESUMEN
OBJECTIVE: We investigated the prevalence of hepatitis G-RNA (GBV-C/HGV-RNA), a recently cloned new flavivirus, and of antibodies to the envelope 2 antigen (anti-E2), a marker of past infection, in patients with autoimmune hepatitis, and compared it with the prevalence in patients with chronic viral hepatitis and healthy control individuals. METHODS: Sera of 63 patients with autoimmune hepatitis were studied for the presence of GBV-C/HGV-RNA by reverse-transcription polymerase chain reaction and for anti-E2 by enzyme-linked immunosorbent assay. GBV-C/HGV genotypes were determined by genome sequencing. RESULTS: Patients with autoimmune hepatitis had a similar high prevalence of GBV-C/HGV-RNA and anti-E2 antibodies as patients with chronic viral hepatitis B or C. GBV-C/HGV-RNA was found significantly more often in patients with autoimmune hepatitis (11%, p = 0.045), hepatitis B (16%, p = 0.004), or hepatitis C (21%, p = 0.001) than in healthy controls (2%). The prevalence of anti-E2 antibodies in patients with autoimmune hepatitis was not different from healthy controls (17% vs 13%, NS). The various subtypes of autoimmune hepatitis had similar prevalence rates of GBV-C/HGV-RNA as patients with liver-kidney microsomal antibody-positive hepatitis C. All of our anti-E2+ (GBV-C/HGV-RNA-) patients were positive for anti-smooth-muscle antibody, whereas only 29% of GBV-C/HGV-RNA+ (anti-E2-) patients were positive (p = 0.025). All seven of the GBV-C/HGV-RNA+ patients with autoimmune hepatitis had genotype 2a, which is also the most prevalent genotype in our region. CONCLUSION: The prevalence of GBV-C/HGV-RNA is significantly increased in patients with autoimmune hepatitis, compared with healthy controls, and is similar to the increased prevalence seen in chronic hepatitis B or C patients. Anti-E2 positivity was associated with antibodies against smooth-muscle antigen in all cases. All GBV-C/HGV+ autoimmune hepatitis patients were infected with genotype 2a.
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Antígenos Virales/análisis , Flaviviridae/genética , Hepatitis Autoinmune/virología , Glicoproteínas de Membrana/análisis , ARN Viral/genética , Proteínas del Envoltorio Viral/análisis , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos/análisis , Anticuerpos Antivirales/análisis , Ensayo de Inmunoadsorción Enzimática , Femenino , Flaviviridae/inmunología , Genotipo , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/virología , Hepatitis C Crónica/inmunología , Hepatitis C Crónica/virología , Hepatitis Autoinmune/inmunología , Humanos , Riñón/inmunología , Masculino , Microsomas/inmunología , Microsomas Hepáticos/inmunología , Persona de Mediana Edad , Músculo Liso/inmunología , Reacción en Cadena de la Polimerasa , Prevalencia , Análisis de Secuencia de ARNRESUMEN
OBJECTIVE: To assess the prevalence and potential pathogenetic factors of hypertransaminasaemia in patients with coeliac disease prior to initiation of a gluten-free diet (GFD) and to assess the course of transaminases on a GFD. PATIENTS: A retrospective study was made of 178 patients with coeliac disease (130 women, 48 men; median age 36 years; range 17-84 years) at the gastroenterological department of a university hospital. METHODS: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured prior to initiation of a GFD and at 3, 6 and 12 months of GFD. Intestinal permeability, a test for functional integrity of the small bowel, was investigated before starting a GFD in 116 patients by an oral test using lactulose and mannitol. RESULTS: In 72 patients (40.4%) AST and/or ALT were increased prior to initiation of a GFD. Within 1 year on a GFD ALT and AST normalized except in eight cases (4.6%). The intestinal permeability index (% lactulose/% mannitol in 5 h urine) was higher in patients with elevated (median 0.34; range 0.03-1.43) than in patients with normal transaminases (0.11; 0.02-1.28) (P < 0.0001) and correlated with AST (tau = 0.34; P < 0.0001) and ALT (tau = 0.32; P < 0.0001). In five cases with hypertransaminasaemia a liver biopsy was performed prior to initiation of a GFD. Two patients had mild to moderate hepatitis with septal fibrosis. The other three had minimal lymphocytic infiltrates of the portal tracts. Inflammatory alterations of the bile ducts were not found. CONCLUSION: Hypertransaminasaemia before GFD is frequent in coeliac patients, correlates with intestinal permeability and normalizes on a GFD in most patients. In cases of persistently elevated liver function tests of unknown origin underlying coeliac disease should be considered.
Asunto(s)
Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Enfermedad Celíaca/enzimología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Enfermedad Celíaca/sangre , Enfermedad Celíaca/dietoterapia , Enfermedad Celíaca/metabolismo , Dieta con Restricción de Proteínas , Proteínas en la Dieta/administración & dosificación , Diuréticos Osmóticos , Femenino , Estudios de Seguimiento , Fármacos Gastrointestinales , Glútenes/administración & dosificación , Hepatitis/patología , Humanos , Intestino Delgado/metabolismo , Lactulosa , Hígado/patología , Cirrosis Hepática/patología , Masculino , Manitol , Persona de Mediana Edad , Permeabilidad , Prevalencia , Estudios RetrospectivosRESUMEN
AIMS/BACKGROUND: Autoimmune cholangitis/cholangiopathy (AIC) is an enigmatic disease marked by chronic cholangitis, antinuclear antibodies (ANA) and sero-negativity for conventionally detected antimitochondrial antibodies (AMA). We examined whether AIC is a distinct entity, an AMA-negative variant of primary biliary cirrhosis (PBC), or a cholangiopathic variant of autoimmune hepatitis (AIH) by comparing the clinical, laboratory and autoantibody profiles of 21 cases of AIC, 37 cases PBC and 16 cases of AIH from selected Japanese patients. METHODS: The specificities of AMA and ANA were determined by immunofluorescence, immunoblotting and enzyme inhibition assays using various mitochondrial and nuclear autoantigens, and the frequencies for these groups were compared. RESULTS: By clinical, biochemical and histological data, AIC and PBC were similar and both were clearly distinct from AIH. Serologically, by immunofluorescence of AMA and ANA, there was polarisation. By immunoblotting, and notwithstanding the negative test for AMA, a proportion of the AIC sera reacted with the E2 subunits of the 2-oxo-acid dehydrogenase enzyme complexes, but more particularly with the lower molecular weight E2 subunits. The antinuclear reactivity in AIC was with centromere, Sp100 and nuclear pore complex proteins as in PBC, but preferentially with the nuclear pore complex. CONCLUSION: Our results demonstrate that AIC and PBC are similar diseases. However this duo is of interest because, usually, among sets of autoimmune syndromes, differences in serological targetting are matched by differences in clinical presentation: AIC and PBC are an exception to this.
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Enfermedades Autoinmunes/inmunología , Colangitis/inmunología , Hepatitis Autoinmune/inmunología , Cirrosis Hepática Biliar/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antinucleares/análisis , Autoanticuerpos/análisis , Catálisis , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Immunoblotting , Masculino , Persona de Mediana Edad , Mitocondrias/inmunología , Músculo Liso/inmunología , Proteínas Nucleares/inmunología , Complejo Piruvato Deshidrogenasa/antagonistas & inhibidoresRESUMEN
BACKGROUND & AIMS: Elevated hepatic iron concentration may affect the response to antiviral therapy in chronic hepatitis C. This study explored the contribution of genetic hemochromatosis to iron accumulation in chronic hepatitis C. METHODS: HFE mutations (C282Y and H63D) were assessed in 184 patients with chronic hepatitis C virus and 487 controls. Liver biopsy specimens were available in 149 patients. Hepatic iron content was measured in 114 patients by atom-absorption spectrophotometry. RESULTS: The C282Y and H63D allele frequencies were 7.06 and 11.6 in patients and 4.83 and 11.09 in controls, respectively. Eight patients were homozygotes (5 C282Y [2.7%] and 3 H63D [1.6%]), 2 compound heterozygotes (1%), and 49 heterozygotes (14 C282Y [7.6%] and 35 H63D [19%]). Biochemical evidence of iron overload was more common in patients with HFE mutations (28 of 47) than in those without (34 of 102; P = 0.0045). Histological iron grading and hepatic iron content overlapped among patients with or without mutations. A hepatic iron index of >1.9 was observed only in 1 of the 4 C282Y homozygotes and 1 of the 3 H63D homozygotes. CONCLUSIONS: HFE mutations contribute to but do not fully explain hepatic iron accumulation in chronic hepatitis C. Furthermore, C282Y or H63D homozygosity in chronic hepatitis C is not necessarily associated with a high hepatic iron content.
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Hemocromatosis/genética , Hepatitis C Crónica/metabolismo , Hierro/metabolismo , Adolescente , Adulto , Anciano , Austria , Femenino , Frecuencia de los Genes , Hemocromatosis/complicaciones , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/enzimología , Hepatitis C Crónica/patología , Homocigoto , Humanos , Sobrecarga de Hierro/complicaciones , Sobrecarga de Hierro/metabolismo , Hígado/enzimología , Hígado/metabolismo , Hígado/patología , Masculino , Persona de Mediana Edad , Mutación Missense , Reacción en Cadena de la PolimerasaRESUMEN
BACKGROUND: Recently, the serotonin antagonist ondansetron has been reported to have a positive effect on cholestasis-associated pruritus. OBJECTIVES: To study the effect of orally administered ondansetron on pruritus in chronic liver disease in a randomized, placebo-controlled, double-blind, cross-over study. METHODS: Subjective severity of pruritus was assessed using a visual analogue scale (VAS) recorded four times daily by the patients. After a one week pretreatment baseline period the patients were randomized to receive ondansetron tablets 8 mg tds or placebo tablets tds for one week. Following a one week wash-out period patients were switched to the other treatment for one week. The study was ended by an additional follow-up week without medication. For each day peak VAS values were determined and the mean value of the last five days of each week was calculated and referred to as the composite peak VAS score. RESULTS: We observed a significant but moderate reduction of the composite peak VAS score of 1.34 points (CI(95%): 0.12-2.56; P=0.033) during treatment with ondansetron as compared to placebo (treatment effect). In addition, a period effect was observed: a reduction of composite peak VAS score by 1.26 points (C1(95%): 0.04-2.48; P=0.044) was seen in the second treatment period as compared to the first period, irrespective of the kind of treatment. Although under treatment with ondansetron a significant improvement of itching as assessed by the VAS score was demonstrated, this treatment was not preferred over placebo by the patients. CONCLUSIONS: The 5-hydroxytryptamine receptor type 3 antagonist ondansetron has a small, but significant positive effect on pruritus in chronic liver disease as compared to placebo.
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Hepatopatías/complicaciones , Ondansetrón/uso terapéutico , Prurito/tratamiento farmacológico , Antagonistas de la Serotonina/uso terapéutico , Administración Oral , Adulto , Anciano , Enfermedad Crónica , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ondansetrón/administración & dosificación , Dimensión del Dolor , Prurito/complicaciones , Antagonistas de la Serotonina/administración & dosificación , Resultado del TratamientoRESUMEN
Autoimmune cholangitis (AIC) is characterised by clinical and/or laboratory features of cholestasis, the presence of antinuclear antibodies and the lack of antimitochondrial antibodies. Histologically, changes largely identical to those found in primary biliary cirrhosis (PBC) are typically found. It is not possible to differentiate between AIC and PBC on conventional morphological grounds, and we therefore wished to find whether there is a difference between these entities in the composition of the inflammatory infiltrate leading to bile duct destruction. In liver biopsies from ten patients with confirmed AIC and ten patients with PBC the inflammatory infiltrate was characterised with antibodies against CD 3, OPD 4 CD 8, GB 7, L 26, CD 56 and CD 57. In AIC, T cells were predominant in the portal inflammatory infiltrate in nine cases. Granzyme B-positive activated cytolytic T lymphocytes were found in the bile duct epithelium in five cases. All these five cases showed inflammatory bile duct destruction. No significant differences between the immunohistochemical findings in AIC and in PBC were found. We suggest that AIC is a subgroup of PBC, antimitochondrial antibody-negative type.
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Enfermedades Autoinmunes/patología , Movimiento Celular , Colangitis/patología , Adulto , Anciano , Antígenos de Superficie/análisis , Femenino , Humanos , Inmunohistoquímica , Hígado/patología , Cirrosis Hepática Biliar/patología , Subgrupos Linfocitarios/patología , Masculino , Persona de Mediana Edad , Síndrome de Sjögren/patologíaRESUMEN
BACKGROUND & AIMS: Autoimmmune hepatitis (AIH), a chronic liver disorder, can be classified into two subtypes on the basis of the specificities of circulating autoantibodies. Type I AIH is defined by antibodies to nuclear and/or smooth muscle antigens (SMA), and type II is characterized by antibodies to cytochrome P450IID6. There is an additional type of AIH characterized by antibodies to a cytosolic soluble liver antigen (SLA), which can occur alone or in combination with antinuclear antibodies and SMA. The aim of this study was to identify the reactive antigen in SLA, a heterogenous cytosolic fraction consisting of at least 100 extremely soluble proteins. METHODS: Sera from 31 patients with AIH reacting with SLA and from 30 disease controls were tested. The immunoreactive antigens were determined using immunoprecipitation and immunoblotting after one- and two-dimensional polyacrylamide gel electrophoresis. The antigens were identified by microsequencing of the corresponding protein spots. RESULTS: Twenty-five of 31 anti-SLA-positive sera (80, 7%) reacted with a set of proteins ranging from 25 to 27 kilodaltons that were identified as three subunits of glutathione S-transferases: Ya, Yb1, and Yc. CONCLUSIONS: Glutathione S-transferase subunit proteins represent the major autoantigen in anti-SLA-positive AIH. This new finding permits the establishment of standardized immunoassays for routine diagnosis.
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Autoantígenos/análisis , Glutatión Transferasa/inmunología , Hepatitis Autoinmune/inmunología , Adolescente , Adulto , Animales , Niño , Citosol/inmunología , Femenino , Glutatión Transferasa/genética , Humanos , Hígado/inmunología , Masculino , Persona de Mediana Edad , RatasRESUMEN
Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver, frequently associated with thrombocytopenia. As various immune abnormalities have been described in PBC, we hypothesized that thrombocytopenia is also an autoimmune phenomenon in these patients. We therefore assessed the frequency of platelet antibodies and their target platelet glycoprotein (GP) specificities. We investigated 66 PBC patients with a median disease duration of 25 months. Twenty-two patients with alcoholic liver disease and thrombocytopenia served as controls. Specificities of platelet antibodies were determined by the monoclonal antibody-specific immobilization of platelet antigens (MAIPA) assay using monoclonal antibodies directed against GPIIb/IIIa and GPIb/IX. The notion that immunoglobulins are nonspecifically bound to platelets was further evaluated by the production of eluates from antibody-coated platelets. The specificities of antibodies in these eluates were again determined by the MAIPA assay. Twenty-six PBC patients had platelet antibodies, whereas antibodies were not detectable in control alcoholic patients. Seven of 13 thrombocytopenic PBC patients had detectable antibodies. Overall, GP Ib/IX and GP IIb/IIIa served in a similar frequency as target antigens. Antibody specificities were confirmed by the production of eluates from platelets. These studies provide evidence that antibodies are specifically bound to platelets in patients with PBC and that the development of immune phenomena in PBC may also involve immuno-mediated platelet destruction.
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Autoanticuerpos/inmunología , Autoantígenos/inmunología , Plaquetas/inmunología , Cirrosis Hepática Biliar/sangre , Cirrosis Hepática Biliar/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales , Especificidad de Anticuerpos , Femenino , Humanos , Hepatopatías Alcohólicas/sangre , Hepatopatías Alcohólicas/inmunología , Masculino , Persona de Mediana Edad , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/inmunología , Complejo GPIb-IX de Glicoproteína Plaquetaria/inmunologíaRESUMEN
We studied the value of additional diagnostic information obtained by detection of hepatitis B virus (HBV) DNA or hepatitis C virus (HCV) RNA using the qualitative polymerase chain reaction (PCR) in patients with serologic markers of hepatitis B or hepatitis C virus infection. In HBV infection, all HBsAg+HBeAg+ patients and all HBsAg+HBeAg- patients with alanine aminotransferase (ALT) levels > 100 U/L were positive for HBV-DNA by PCR, whereas in HBsAg+HBeAg- patients with ALT < 100 U/L 58% and in HBsAg+HBeAg- patients with normal aminotransferase 45% were found to be positive. In HBsAg+ patients no further clinically useful information can be obtained by PCR as the presence of HBsAg proves infection. However in three of 42 (7%) patients with markers of past HBV infection (antiHBs and/or antiHBc+) HBV-DNA was detected in the serum. Similarly, in some patients with acute hepatitis B HBV-DNA was demonstrable up to four months after the disappearance of HBsAg from serum, pointing to persistence of viremia despite the loss of serological markers of ongoing HBV infection. Demonstrating ongoing HBV infection in patients with serological markers of past infection is valuable additional information in only selected patients. In HCV infection, 10% of anti-HCV+ patients with increased ALT levels had a negative serum HCV-RNA. However, in 20% of those patients HCV-RNA was demonstrated in a serum sample collected later during follow-up, indicating that a single negative HCV-RNA determination cannot be taken as evidence for the resolution of infection.
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Genes Virales/genética , Hepacivirus/genética , Virus de la Hepatitis B/genética , Hepatitis B/diagnóstico , Hepatitis C/diagnóstico , Reacción en Cadena de la Polimerasa/métodos , Adolescente , Adulto , Anciano , Niño , ADN Viral/sangre , Diagnóstico Diferencial , Femenino , Hepatitis B/virología , Antígenos de Superficie de la Hepatitis B/sangre , Antígenos e de la Hepatitis B/sangre , Hepatitis C/virología , Humanos , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , ARN Viral/sangreRESUMEN
BACKGROUND AND OBJECTIVE: To evaluate the ability of monitoring laser induced temperature changes in an open, interventional 0.5 T magnet, adopting fast T1-weighted sequences. MATERIALS AND METHODS: A fast gradient echo- (FGRE) and a fast spoiled gradient echo-sequence (FSPGR), both enabling an image update every 2.5 s, were investigated for their ability to visualize laser tissue effects at 5 Watt. Laser induced temperature was fluorooptically measured and correlated with signal intensity (SI) changes depicted by magnetic resonance imaging (MRI). MRI-lesions were compared with macroscopic findings. RESULTS: SI changes on FGRE images appeared as early as 15 s following the onset of laser application and were significantly more pronounced than those seen on FSPGR images (p < .0001). A correlation of r = 0.94 (FGRE) and r = 0.92 (FSPGR) between temperature and SI loss was established. Owing to a steeper slope, the FGRE sequence was considered more sensitive to temperature changes. The areas of macroscopic tissue change correlated with those of SI loss, but lesion size was generally underestimated by MRI. CONCLUSION: Laser monitoring is possible with rapid image updates in a midfield (0.5 T) interventional MRI environment using fast gradient echo sequence designs.
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Terapia por Láser/efectos adversos , Rayos Láser/efectos adversos , Monitoreo Fisiológico/métodos , Temperatura , Animales , Técnicas In Vitro , Hígado/patología , Hígado/efectos de la radiación , Imagen por Resonancia Magnética/métodos , Fantasmas de Imagen , Sensibilidad y Especificidad , PorcinosRESUMEN
BACKGROUND/AIMS: Genetic haemochromatosis is the most common autosomal recessive disorder in Northern European populations. A major histocompatibility complex class I-like gene, HLA-H, has been proposed to be responsible for genetic haemochromatosis. The prevalence of HLA-H gene mutations 282(TGC; Cys/TAC; Tyr) and 63(CAT; His/GAT; Asp) was determined in patients of Austrian origin. METHODS: DNA extracted from the blood of 40 Austrian patients and 271 controls was used to amplify HLA-H gene fragments by the polymerase chain reaction method. The base changes responsible for mutations Cys282Tyr and His63Asp alter recognition sites for restriction enzymes SnaB I and Bcl I, respectively. Digestion products were separated by agarose gel electrophoresis and visualised by ethidium bromide staining. RESULTS: Thirty-one (77.5%) genetic haemochromatosis patients were homozygous for mutation Cys282Tyr and three compound heterozygous for mutations Cys282Tyr and His63Asp. One patient was homozygous for mutation His63Asp but normal for mutation Cys282Tyr. Four patients were normal at both genetic loci and one patient was heterozygous for mutation His63Asp. One control subject homozygous for mutation Cys282Tyr was found on investigation to fulfill diagnostic criteria for haemochromatosis. Eight control subjects homozygous for mutation His63Asp showed no biochemical or clinical evidence of haemochromatosis indicating that this variant is not directly responsible for haemochromatosis. Absence of the Cys282Tyr mutation in six genetic haemochromatosis patients with distinct haplotypes indicates mutations within the HLA-H gene or at alternative genetic loci are the cause of genetic haemochromatosis in these patients. CONCLUSIONS: The HLA-H Cys282Tyr defect is likely to play a key role in the pathogenesis of haemochromatosis in most patients. Predominance of a single HLA-H gene mutation in haemochromatosis allows presymptomatic screening by genotypic analysis.
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Antígenos HLA/genética , Hemocromatosis/genética , Antígenos de Histocompatibilidad Clase I/genética , Proteínas de la Membrana , Adulto , Anciano , Femenino , Genotipo , Haplotipos , Proteína de la Hemocromatosis , Humanos , Masculino , Persona de Mediana Edad , Mutación , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo GenéticoRESUMEN
PURPOSE: Evaluation of an interactive, stereotactic biopsy device integrated in an open superconductive 0.5 tesla MR-scanner with a vertical gap. MATERIAL AND METHODS: In addition to "in-vitro" experiments performed on a plexiglas phantom with holes of varying diameters (5-20 mm) biopsies on eleven patients (7 women, 4 men; average age 55 years) were performed in the interventional MR-system. Lesions in the abdomen (n = 6), muscle (n = 1), thyroid (n = 3) and breast (n = 1) were targeted with 18-20 G aspiration biopsy needles of 5-15 cm length. The intervention was interactively guided by a fast T1-weighted 2-D gradient echo sequence. RESULTS: All of the 15 and 20 mm holes of the phantom, but only 83% of the 10 and 5 mm holes were hit. No complications occurred during the MR-guided patient procedures. All lesions (mean size 3.5 cm, distance from the skin 2 cm to 10 cm) were biopsied successfully. The fast image acquisition in combination with the stereotactic technique enables interactive control of the needle. CONCLUSIONS: Stereotactic, interactively controlled biopsies in the interventional MR are technical feasible. However, the range of meaningful indications for MR-guided biopsies is limited.
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Biopsia/instrumentación , Imagen por Resonancia Magnética/métodos , Técnicas Estereotáxicas , Neoplasias Abdominales/patología , Adulto , Anciano , Femenino , Humanos , Imagen por Resonancia Magnética/instrumentación , Masculino , Persona de Mediana Edad , Técnicas Estereotáxicas/instrumentaciónRESUMEN
BACKGROUND & AIMS: Patients with primary biliary cirrhosis (PBC) frequently produce autoantibodies against constituents of the nuclear envelope. We have recently observed a reactivity of PBC sera with a nuclear envelope antigen at approximately 60 kilodaltons. The aim of this study was to characterize the reactive antigen. METHODS: Sera from 103 patients with liver disease were tested by immunoblotting after the separation of proteins by one- and two-dimensional polyacrylamide gel electrophoresis (PAGE) using proteins of whole nuclei and nuclear pore complexes (NPCs). RESULTS: A nuclear immunofluorescence staining with peripheral accentuation was observed in 25 of 43 sera from patients with PBC. In immunoblotting, the sera displaying a peripheral pattern reacted preferentially with two proteins. Twelve sera showed specificity to an antigen of 210 kilodaltons corresponding to gp210, and 14 sera recognized a protein band at 60 kilodaltons. The intensity of the reactive band at 60 kilodaltons was clearly stronger on blots with immobilized proteins of the NPC than on blots with nuclear proteins, thereby indicating that the sera targeted an antigen as being a component of the NPC. Immunoblotting performed after protein separation by two-dimensional PAGE showed that the sera are directed against nucleoporin p62, a functional protein of the NPC. CONCLUSIONS: Anti-p62 antibodies appear to be a novel marker that is specific for PBC.