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The outpatient forensic aftercare department of the Charité Berlin treated 32 paraphilic sex offenders with GnRH analogues within the past 5 years. Out of those patients, three men suffered from urolithiasis and were in need of treatment. All 3 patients had previously developed osteopenia/osteoporosis while on antiandrogen treatment.This article describes these 3 cases and suggests an intense consideration of the possible occurrence of urolithiasis in sex offenders on antiandrogen treatment.
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Acetato de Ciproterona/efectos adversos , Hormona Liberadora de Gonadotropina/agonistas , Leuprolida/efectos adversos , Trastornos Parafílicos/tratamiento farmacológico , Pamoato de Triptorelina/efectos adversos , Urolitiasis/inducido químicamente , Adulto , Oxalato de Calcio/orina , Acetato de Ciproterona/uso terapéutico , Preparaciones de Acción Retardada , Estudios de Seguimiento , Humanos , Cálculos Renales/inducido químicamente , Cálculos Renales/orina , Leuprolida/uso terapéutico , Cuidados a Largo Plazo , Masculino , Persona de Mediana Edad , Trastornos Parafílicos/orina , Recurrencia , Pamoato de Triptorelina/uso terapéutico , Cálculos Ureterales/inducido químicamente , Cálculos Ureterales/orina , Urolitiasis/terapia , Urolitiasis/orinaRESUMEN
BACKGROUND: The Forensic Therapeutic Outpatient Clinic (FTA) in Berlin targets the professional aftercare treatment of classified high-risk violent and sexual offenders released from prison or forensic psychiatric hospitals. PATIENTS AND METHODS: A comparison sample (n = 32) matched to the patients of the FTA (complete survey n = 32) according to similar criminal histories and diagnoses (ICD-10) was collected from offenders released from prison and forensic psychiatry at a time before the FTA was established. The focus of the study was on recidivism measured by complaints received by police departments during the follow-up period. RESULTS: Sexual recidivism occurred significantly later in the case of released offenders with aftercare treatment compared to those without. Moreover, for the duration of aftercare treatment the general risk of recidivism was approximately 85 % lower; however, after termination of treatment the recidivism rates of both samples converged to almost the same level. CONCLUSION: Individually adapted measures should be maintained after finishing aftercare treatment; however, because prisoners released from prison are frequently less prepared than patients from forensic psychiatric hospitals, the therapeutic work often reaches its limits in these cases. Therefore, social work should be taken into account right from the start.
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Cuidados Posteriores/psicología , Instituciones de Atención Ambulatoria , Criminales/psicología , Prisioneros/psicología , Delitos Sexuales/prevención & control , Violencia/prevención & control , Adulto , Cuidados Posteriores/métodos , Psiquiatría Forense/métodos , Alemania , Encuestas de Atención de la Salud , Hospitales Psiquiátricos , Humanos , Masculino , Alta del Paciente , Prevención Secundaria/métodos , Delitos Sexuales/psicología , Resultado del Tratamiento , Violencia/psicologíaRESUMEN
BACKGROUND: We sought to define the frequency of falls in early PD and assess potential risk factors for falls in this population. METHODS: We analyzed the data from two randomized, placebo controlled trials (NET-PD FS1 and FS-TOO) of 413 individuals with early PD over 18 months of follow-up in FS1 and 12 months in FS-TOO. Falls were defined as any report of falls on the UPDRS or the adverse event log. We assessed the frequency of falls overall and by age. The relationship between prespecified fall risk markers and the probability of falling was assessed using logistic and multiple logistic regression. A hurdle Poisson model was used to jointly model the probability of remaining fall-free and the number of falls. RESULTS: During the follow-up period, 23% of participants fell, and 11% were habitual fallers. In a multiple logistic regression model, age, baseline UPDRS Falling score, and baseline PDQ-39 scores were associated with subsequent fall risk (p < 0.001). Similarly, in a hurdle Poisson regression model, age, baseline UPDRS falling item, and baseline PDQ-39 were all significantly related to the probability of falling, but only UPDRS falling >0 was associated with the number of falls. CONCLUSION: Falls are frequent and are associated with impaired quality of life, even in early PD. Current standard rating scales do not sufficiently explain future fall risk in the absence of a prior fall history. New assessment methods for falls and postural instability are required to better evaluate this important problem in clinical trials and clinical practice.
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Accidentes por Caídas , Enfermedad de Parkinson/fisiopatología , Equilibrio Postural/fisiología , Accidentes por Caídas/estadística & datos numéricos , Estudios de Seguimiento , Humanos , Incidencia , Modelos Logísticos , Examen Neurológico , Medición de Riesgo , Factores de Riesgo , Encuestas y CuestionariosRESUMEN
We present a broadband (460 - 980 nm) analysis of the nonlinear absorption processes in bulk ZnO, a large-bandgap material with potential blue-to-UV photonic device applications. Using an optical parametric amplifier we generated tunable 1-kHz repetition rate laser pulses and employed the Z-scan technique to investigate the nonlinear absorption spectrum of ZnO. For excitation wavelengths below 500 nm, we observed reverse saturable absorption due to one-photon excitation of the sample, agreeing with rate-equation modeling. Two- and three-photon absorption were observed from 540 to 980 nm. We also determined the spectral regions exhibiting mixture of nonlinear absorption mechanisms, which were confirmed by photoluminescence measurements.
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BACKGROUND: Every third person with intellectual disability suffers from additional mental health problems, among others phobic disorders. Yet we do not know whether psychotherapeutic methods that are effective in the normal population are applicable to people with intellectual disabilities. PATIENTS AND METHODS: We give a survey of the development and the present state of the art of psychotherapy, particularly with regard to phobic disorders in intellectual disability. Therapeutic recommendations described in the literature will be evaluated in a case study of one patient. RESULTS: The confrontation with the phobic stimulus is the basis of behavior therapy for people with intellectual disability as well. However, with respect to the special needs of these people, some modifications need to be considered in the treatment strategy. In addition to some general rules like simple language or the use of visual materials, some techniques of intervention turned out to be particularly effective, e.g., graduated in vivo exposure, involving significant others, contingency management, and coping strategies. CONCLUSION: Specific phobias in intellectual disability can be treated with behavior therapy as well. However, the special needs of these people need to be considered.
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Discapacidad Intelectual/psicología , Discapacidad Intelectual/terapia , Modelos Psicológicos , Trastornos Fóbicos/psicología , Trastornos Fóbicos/terapia , Psicoterapia/métodos , Alemania , Humanos , Discapacidad Intelectual/complicaciones , Trastornos Fóbicos/complicacionesRESUMEN
We report on the photoluminescence properties of ZnO nanowires treated with a mild Ar plasma. The nanowires exhibited stable and strong enhancement of the near-band-edge emission and quenching of the deep level emission. The low temperature PL revealed a strong hydrogen donor-bound-exciton line in the plasma-treated samples indicating unintentional incorporation of hydrogen during the plasma treatment. To confirm the results, hydrogen was implanted into the ZnO nanowires with a low ion energy of 600 eV and different fluences. The observed result can be related to the passivation of deep centers by hydrogen. The absolute photoluminescence intensity measured by an integrating sphere showed stable and strong UV emission from the treated samples even after several weeks.
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Self-organized and highly ordered GaN nanorods were grown without catalyst on r-plane sapphire using a combination of molecular beam epitaxy and metal-organic vapor-phase epitaxy. AlN nucleation centers for the nanorods were prepared by nitridation of the sapphire in a metal-organic vapor-phase epitaxy reactor, while the nanorods were grown by molecular beam epitaxy. A coalesced two-dimensional GaN layer was observed between the nanorods. The nanorods are inclined by 62 degrees towards the [Formula: see text]-directions of the a-plane GaN layer. The high degree of ordering and the structural perfection were confirmed by micro-photoluminescence measurements.
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We report the influence of an Al(2)O(3) shell on the photoluminescence emission of ZnO nanowires. At room temperature, the spectrum of the core-shell nanowires shows a strong reduction of the relative intensity of the green defect emission with respect to the near-band-edge emission. At 5 K an increase of the relative intensity of the surface exciton band with respect to the donor-bound exciton emission is observed. Annealing the core-shell nanowires at 500 °C does not increase the green defect luminescence at 5 K. We propose a model explaining the spectral changes.
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We report on the investigation of correlated spectral properties of two different surface-related photoluminescence bands in ZnO nanowires. We show that the spectral position and the temperature-dependent intensity of the surface-related emission band A are directly correlated with the emission of the surface-exciton band SX. We measure the thermal activation energies of both emission bands and present time-resolved photoluminescence data to deduce the photoluminescence decay time of the A emission band. We propose a model to explain the experimental observations and assign the A emission band to excitons bound to structural defects in the surface layer of the nanowires.
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AIMS: The aim of this study was to characterize the properties of synthetic double-stranded RNA to induce fever and circulating cytokines in guinea pigs with special emphasis on the route of administration and on a putative development of tolerance to this pyrogen. METHODS: Changes in abdominal temperature were recorded in unrestrained animals by use of intra-abdominally implanted radiotransmitters. Circulating concentrations of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured by use of specific bioassays. RESULTS: The pyrogenic effect of double-stranded RNA at a dose of 500 microg kg(-1) depended on the route of its administration. Intra-arterial (i.a.) or intraperitoneal injections of double-stranded RNA induced pronounced fevers and strong elevations of circulating TNF-alpha and IL-6. Intramuscular injections of the synthetic pyrogen caused rather moderate febrile and cytokine responses. Administration of synthetic RNA into artificial subcutaneously implanted Teflon chambers had no pyrogenic and cytokine-inducing effects. I.a. injections of double-stranded RNA, repeated five times at intervals of 3 days, resulted in fevers of similar shape and duration and similar cytokine response patterns. However, the strength of fever and cytokine formation was significantly reduced, although not abolished, in response to the repeated injections compared with the first injection, indicating a partial development of tolerance. CONCLUSIONS: The modulation of the strength of RNA-induced fever, dependent on the route of administration, or the state of partial tolerance to this pyrogen, may thus be related to the formation of pyrogenic cytokines.
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Citocinas/sangre , Fiebre/inducido químicamente , Pirógenos/efectos adversos , ARN Bicatenario/efectos adversos , Animales , Relación Dosis-Respuesta a Droga , Cobayas , Inyecciones Intraarteriales , Inyecciones Intramusculares , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Interleucina-6/sangre , Masculino , Pirógenos/administración & dosificación , ARN Bicatenario/administración & dosificación , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Self-diffusion of implanted (31)Si and (71)Ge in relaxed Si(0.20)Ge(0.80) layers has been studied in the temperature range 730-950 degrees C by means of a modified radiotracer technique. The temperature dependences of the diffusion coefficients were found to be Arrhenius-type with activation enthalpies of 3.6 eV and 3.5 eV and preexponential factors of 7.5 x 10(-3) m(2) s(-1) and 8.1 x 10(-3) m(2) s(-1) for (31)Si and (71)Ge , respectively. These results suggest that, as in Ge, in Si(0.20)Ge(0.80) both (31)Si and (71)Ge diffuse via a vacancy mechanism. Since in Si(0.20)Ge(0.80) (71)Ge diffuses only slightly faster than (31)Si , in self-diffusion studies on Si-Ge (71)Ge radioisotopes may be used as substitutes for the "uncomfortably" short-lived (31)Si radiotracer atoms.
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The genes of the gibberellin (GA) biosynthesis pathway in Gibberella fujikuroi are organized in a gene cluster consisting of at least seven genes. Here we report the cloning and characterization of smt, a gene encoding a membrane transporter of the major facilitator super-family 1, which is located next to the GA gene cluster. Since pathway-specific transporters occur frequently in prokaryotic and fungal antibiotic and toxin clusters, smt was thought to be involved in GA secretion. The gene is expressed in mycelium grown under GA-production conditions, but not when the GA biosynthesis is repressed by high amounts of ammonium. To investigate the function of SMT, gene replacement experiments were performed. The smt-mutants did not show any reduction in the GA yield; and gibberellic acid or its precursors did not influence the gene expression. However, sugar alcohols, such as myo-inositol, sorbitol and mannitol, induced the expression of smt. The results demonstrate that the smt gene does not play an essential role in biosynthesis and secretion of GAs in G. fujikuroi, despite the location adjacent to the GA gene cluster.
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Proteínas Fúngicas/genética , Gibberella/genética , Giberelinas/genética , ADN de Hongos/genética , Genes Fúngicos , Filogenia , ARN de Hongos/genética , Mapeo Restrictivo , Transformación GenéticaRESUMEN
The distribution of the CD15 antigen (CD15, 3-fucosyl-N-acetyl-lactosamine, Lewis x) has been studied immunohistochemically in the fetal human thalamus. Its changing patterns could be related to three successive, but overlapping, periods primarily due to its association with radial glial cells, neuropil, and neural cell bodies, respectively. From 9 weeks of gestation (wg), a subset of CD15-positive radial glial cells distinguished the neuroepithelium of the ventral thalamus, a characteristic also seen in the developing mouse. Distal processes of the radial glial cells converged at the root of the forebrain choroid tenia, which was also CD15 positive. From 13 wg until approximately 20 wg, CD15-positive neuropil labeling marked the differentiation areas of prospective nuclei within the dorsal thalamus and progressively outlined their territories in a time sequence, which appeared specific for each nucleus. CD15 labeling of differentiating nuclei of the ventral, medial, anterior, and intralaminar thalamic divisions showed a transient topographic relationship with restricted areas of the ventricular wall. After 26 wg, CD15 immunoreactivity was observed in subpopulations of glial cells and neurons. Transient CD15 immunoreactivity was also found in delimited compartments within the subventricular region. The time of CD15 expression, its location, and cellular association suggest that CD15 is involved in segmentation of diencephalon, in the specification of differentiating nuclear areas and initial processes regarding the formation of intercellular contacts and cellular maturation.
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Antígeno Lewis X/análisis , Proteínas del Tejido Nervioso/análisis , Tálamo/anatomía & histología , Biomarcadores , Calbindina 2 , Regulación del Desarrollo de la Expresión Génica , Edad Gestacional , Humanos , Recién Nacido , Antígeno Lewis X/biosíntesis , Antígeno Lewis X/genética , Morfogénesis , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Neuroglía/química , Neuronas/química , Neurópilo/química , Proteína G de Unión al Calcio S100/análisis , Núcleos Talámicos/anatomía & histología , Núcleos Talámicos/embriología , Núcleos Talámicos/crecimiento & desarrollo , Tálamo/embriología , Tálamo/crecimiento & desarrolloRESUMEN
We have investigated the suitability of proteomics for identification of tumor-associated antigens. First, we compared the proteomes of nontumorous kidney and renal cell carcinoma (RCC) by two-dimensional gel electrophoresis (2-DE) and silver staining. Protein patterns were markedly different (approximately 800 spots in RCCs versus approximately 1400 spots in kidney). 2-DE immunoblotting revealed five RCC-specific spots, reproducibly reactive with RCC-patient but not healthy donor control sera. Two of these antigens were isolated by preparative 2-DE, and identified by Edman sequencing of tryptic peptides. The first antigen, smooth muscle protein 22-alpha (SM22-alpha), is an actin-binding protein of unknown function predominantly expressed in smooth muscle cells. In situ hybridization revealed that SM22-alpha is not expressed in the malignant cells but in mesenchymal cells of the tumor stroma. The second antigen represents carbonic anhydrase I (CAI), an isoform usually not expressed in kidney. Interestingly, a different isoform (CAXII) has previously been identified by serological expression cloning as an antigen overexpressed in some RCCs. In additional assays, antibodies to recombinant CAI or SM22-alpha were detected in sera from 3/11 or 5/11 RCC patients, respectively, whereas sera from 13 healthy individuals did not react. In conclusion, serological proteome analysis may be a new tool for the identification of tumor-associated antigens.
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Antígenos de Neoplasias/análisis , Carcinoma de Células Renales/química , Carcinoma de Células Renales/inmunología , Neoplasias Renales/química , Neoplasias Renales/inmunología , Proteoma/análisis , Proteoma/inmunología , Pruebas Serológicas/métodos , Secuencia de Aminoácidos , Antígenos de Neoplasias/genética , Secuencia de Bases , Northern Blotting , Anhidrasa Carbónica I/análisis , Anhidrasa Carbónica I/genética , Anhidrasa Carbónica I/inmunología , Carcinoma de Células Renales/genética , ADN Complementario/genética , ADN de Neoplasias/genética , Electroforesis en Gel Bidimensional , Humanos , Riñón/química , Riñón/inmunología , Neoplasias Renales/genética , Proteínas de Microfilamentos/análisis , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/inmunología , Datos de Secuencia Molecular , Proteínas Musculares/análisis , Proteínas Musculares/genética , Proteínas Musculares/inmunología , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/aislamiento & purificación , Proteoma/genética , ARN Mensajero/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunologíaRESUMEN
IGF-I-dependent decreases in endogenous GH mRNA expression were studied in individual rat MtT/S somatotroph cells using in situ hybridization. It was first shown that increasing IGF-I concentrations (0-90 nM) decreased GH mRNA levels in a ultrasensitive manner when averaged over the entire population, such that the decrease occurred over a narrow range of IGF-I concentration with an EC50 of 7.1 nM. The degree of ultrasensitivity of the population average was expressed by calculating the Hill coefficient (nA), which had a value of -2.0. GH mRNA levels in individual dispersed cells from these cultures were then measured. These results were first summed for all cells to show that the average response of the population remained ultrasensitive (nA = -2.6, EC50 = 8.1 nM). Then, parameters for individual cells of the population were calculated using mathematical modeling of the distribution of individual cell GH mRNA levels after treatment with 0-90 nM IGF-I. Solution of the data from the individual cells yielded a Hill coefficient (nI = -0.65) and a heterogeneity coefficient (mI = -1.2) indicative of individual cell responsiveness to IGF-I that was not ultrasensitive and very heterogeneous. These results suggested that ultrasensitivity in the population may likely be caused by an extracellular mechanism regulating IGF-I concentrations, such as IGF binding proteins. Increasing concentrations of long (Arg)3IGF-1, an analog that binds the IGF type-1 receptor but not IGF binding proteins, showed a linear inhibition of GH mRNA levels. Treatment with IGF binding protein ligand inhibitor, an IGF-I analog that binds to IGF binding proteins but not the IGF type-1 receptor, decreased GH mRNA levels in the absence of exogenous IGF-I. Thus, IGF binding proteins provide the extracellular sequestration of IGF-I necessary for the precise and ultrasensitive regulation of GH mRNA levels in the entire cell population, although expression within individual cells is regulated in a graded fashion.
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Hormona del Crecimiento/genética , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Animales , Células Cultivadas , Regulación de la Expresión Génica/fisiología , Hormona del Crecimiento/metabolismo , Humanos , Hibridación in Situ , Cinética , Modelos Biológicos , Unión Proteica , ARN Mensajero/genética , ARN Mensajero/metabolismo , RatasRESUMEN
The MtT/S somatotroph cell line should be a growth hormone-releasing hormone (GHRH)-responsive model system for the study of physiological control of growth hormone (GH) transcription because GH secretion from these cells is stimulated by GHRH. To examine the GH transcriptional activity of these cells, endogenous GH mRNA levels were measured using a ribonuclease protection assay following treatment under a variety of hormonal conditions. While omission of serum led to reduction of GH mRNA to 22% of control levels by 2 days and to 8% by 5 days (P<0.05 for both), GH mRNA levels were maintained at control values in serum-free medium containing 5 nM dexamethasone and 30 pM triiodothyronine (TDM). However, the addition of 10 nM GHRH under any treatment condition did not significantly alter GH mRNA levels. Characterization of the MtT/S cells showed that GHRH-receptor (GHRH-R) mRNA was detectable by reverse transcription-polymerase chain reaction (RT-PCR) amplification. Measurement of extracellular cAMP showed that the MtT/S cells have basal levels of > or =20 nmol/10(6) cells per h in both serum-containing and serum-free media, and that GHRH had no effect on cAMP levels, suggesting constitutive activation. To rule out the possibility of autocrine stimulation by GHRH produced endogenously, GHRH mRNA was not detectable in MtT/S cells using RT-PCR amplification. The stimulatory G-protein alpha subunit, mutations of which are known to activate adenylate cyclase constitutively in acromegaly, was sequenced but found not to differ from normal pituitary in the regions most commonly mutated. Finally, treatment with 10 microM forskolin, to directly activate adenylate cyclase, increased GH mRNA to 140% of controls in TDM, and to 163% in serum-free medium after 2 days, and to 166% in TDM-treated cells and 174% in serum-free culture after 5 days (all P<0.05). Taken together, these data indicate that although MtT/S cells express the GHRH-R, GHRH cannot stimulate adenylate cyclase to increase GH transcription due to constitutive elevation of cAMP levels, by a means that may be similar to that in cases of acromegaly not caused by oncogenic gsp mutations.
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Colforsina/farmacología , Hormona Liberadora de Hormona del Crecimiento/farmacología , Hormona del Crecimiento/genética , ARN Mensajero/efectos de los fármacos , Adenilil Ciclasas/metabolismo , Adenilil Ciclasas/farmacología , Animales , Línea Celular , AMP Cíclico/metabolismo , Hormona Liberadora de Hormona del Crecimiento/genética , Proteínas de Unión al GTP Heterotriméricas/genética , ARN Mensajero/metabolismo , Ratas , Receptores de Neuropéptido/metabolismo , Receptores de Hormona Reguladora de Hormona Hipofisaria/metabolismo , Hormonas Tiroideas/farmacologíaRESUMEN
Pathogenic Escherichia coli strains are known to cause edema disease (ED) and postweaning diarrhea (PWD) in piglets. Although the exact mechanisms of pathogenicity that lead to ED-PWD remain to be elucidated, E. coli-borne Shiga-like toxin and adhesion-mediating virulence factors such as F18 adhesin or F4 fimbriae are believed to play a central role in ED-PWD. In light of these observations we investigated whether another E. coli adhesin, the plasmid-encoded AIDA (adhesin involved in diffuse adherence) might also be present in ED-PWD-causing E. coli isolates. For rapid screening for the AIDA system in large numbers of isolates, a multiplex PCR method along with a duplex Western blot procedure was developed. When screening 104 strains obtained from pigs with or without ED-PWD, we observed a high prevalence of the AIDA operon in porcine E. coli isolates, with over 25% of all strains being AIDA positive, and we could demonstrate a significant association of the intact AIDA gene (orfB) with ED-PWD, while defects in orfB were associated with the absence of disease. Although our data hint toward a contribution of AIDA to ED-PWD, further studies will be necessary since the presence of the AIDA genes was also associated with the presence of the Shiga-like toxin and F18 adhesin genes, two reported virulence factors for ED-PWD.
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Adhesinas de Escherichia coli/genética , Antígenos Bacterianos , Proteínas Bacterianas/genética , Diarrea/veterinaria , Edematosis Porcina/microbiología , Infecciones por Escherichia coli/veterinaria , Proteínas de Escherichia coli , Escherichia coli/genética , Proteínas Fimbrias , Toxina Shiga II/genética , Animales , Western Blotting/métodos , Diarrea/microbiología , Escherichia coli/aislamiento & purificación , Infecciones por Escherichia coli/microbiología , Genes Bacterianos , Ligamiento Genético , Variación Genética , Operón , Reacción en Cadena de la Polimerasa/métodos , Serotipificación , Porcinos , Factores de TiempoRESUMEN
The development of human cancer is caused by complex molecular perturbations leading to variable clinical behavior often even in single disease entities. To prove that expression profiling on the protein level can be correlated with clinical data we systematically compared in a pilot study the protein expression patterns obtained by 2-dimensional gel electrophoresis with clinical features in human B-cell chronic lymphocytic leukemia (B-CLL), a disease characterized by broad clinical variability. Statistical methods were devised to analyze the spot pattern from 24 patient samples. This analysis allowed the identification of proteins that clearly discriminated between the patient groups with defined chromosomal characteristics or whose expression levels did correlate with clinical parameters such as patient survival. This report demonstrates that the correlation of large-scale protein expression profiles with clinical data can be used to gain new insights into molecular aspects of a disease. The data described here show that B-CLL patient populations with shorter survival times exhibit changed levels of redox enzymes, heat shock protein 27 and protein disulfide isomerase. These molecules may be potentially involved in drug resistance.