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BACKGROUND: It has been shown that the interleukin (IL)-23/IL-17 axis is critical in the pathogenesis of psoriasis. OBJECTIVES: To present the primary end point (week 12) and safety and efficacy data up to week 24 from a head-to-head trial (IXORA-S) of the IL-17A inhibitor ixekizumab (IXE) vs. the IL-12/23 inhibitor ustekinumab (UST). METHODS: Randomized patients received IXE (160-mg starting dose, then 80 mg every 2 weeks for 12 weeks, then 80 mg every 4 weeks, n = 136) or UST (45 mg or 90 mg weight-based dosing per label, n = 166). The primary end point was the proportion of patients reaching ≥ 90% Psoriasis Area and Severity Index improvement (PASI 90). Hommel-adjusted key secondary end points at week 12 included PASI 75, PASI 100, static Physician's Global Assessment (sPGA) score of 0 or 1, sPGA score of 0, Dermatology Life Quality Index (DLQI) score of 0 or 1, ≥ 4-point reduction on the itch numerical rating scale (NRS) and changes in itch NRS and skin pain visual analogue scale. RESULTS: At week 12, IXE (n = 99, 72·8%) was superior to UST (n = 70, 42·2%) in PASI 90 response (response difference 32·1%, 97·5% confidence interval 19·8-44·5%, P < 0·001). Response rates for PASI 75, PASI 100 and sPGA (0,1) were significantly higher for IXE than for UST (adjusted P < 0·05). At week 24, IXE-treated patients had significantly higher response rates than UST-treated patients for PASI, sPGA and DLQI (unadjusted P < 0·05). No deaths were reported, and the treatments did not differ with regard to overall incidences of adverse events (P = 0·299). CONCLUSIONS: The superior efficacy of IXE demonstrated at week 12 persisted up to week 24. The safety profiles were consistent with those previously reported for both treatments.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Psoriasis/tratamiento farmacológico , Ustekinumab/administración & dosificación , Adulto , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Medición de Resultados Informados por el Paciente , Resultado del TratamientoRESUMEN
Background: Baseline clinical variables are prognostic for overall survival (OS) in patients with castration-resistant prostate cancer (CRPC). Their prognostic and predictive value with agents targeting bone metastases, such as radium-223, is not established. Patients and methods: The radium-223 ALSYMPCA trial enrolled patients with CRPC and symptomatic bone metastases. Prognostic potential of baseline variables was assessed using Cox models. Percentage changes in biomarker levels from baseline were evaluated during the trial period; changes from baseline to week 12 were evaluated for association with OS and surrogacy. Results: Eastern Cooperative Oncology Group performance status, total alkaline phosphatase (tALP), lactate dehydrogenase (LDH), and prostate-specific antigen (PSA) at baseline were associated with OS (P ≤ 0.0003) in the intent-to-treat population (radium-223, N = 614; placebo, N = 307). tALP declined from baseline within 4 weeks after beginning radium-223, by week 12 declining in 87% of radium-223 and 23% of placebo patients (P < 0.001). LDH declined in 51% and 34% (P = 0.003), whereas PSA declined in 27% and 14% (P = 0.160). Mean tALP change from baseline was 32.2% decrease with radium-223 and 37.2% increase with placebo. Radium-223 patients with tALP decline from baseline to week 12 (confirmed ≥3 weeks from week 12) had 55% lower risk of death (hazard ratio = 0.45; 95% CI 0.34-0.61) versus those with no confirmed tALP decline. Proportional treatment effect (PTE) values for tALP, LDH, and PSA changes from baseline at week 12 as OS surrogate markers were 0.34 (95% CI: 0-0.746), 0.07 (95% CI: 0-0.211), and 0 (95% CI: 0-0.082), respectively. Conclusions: Significant tALP declines (versus placebo) occurred as early as 4 weeks after beginning radium-223 therapy. tALP or LDH declines at 12 weeks correlated with longer OS, but did not meet statistical surrogacy requirements. Dynamic changes in tALP and LDH during radium-223 treatments may be useful to monitor, but do not serve as surrogates for survival.
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Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Radiofármacos/uso terapéutico , Radio (Elemento)/uso terapéutico , Fosfatasa Alcalina/metabolismo , Biomarcadores de Tumor/metabolismo , Humanos , Calicreínas/metabolismo , Estimación de Kaplan-Meier , L-Lactato Deshidrogenasa/metabolismo , Masculino , Análisis Multivariante , Pronóstico , Modelos de Riesgos Proporcionales , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/enzimología , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Resultado del TratamientoRESUMEN
The rational design of brighter upconversion nanoparticles (UCNPs) requires a better understanding of the radiationless deactivation pathways in these materials. Here, we demonstrate the potential of excitation power density (P)-dependent studies of upconversion (UC) luminescence intensities, slope factors, and absolute quantum yields (ΦUC) of popular ß-NaYF4:20% Yb3+,2% Er3+ UCNPs of different surface chemistries in organic solvents, D2O, and water as a tool to gain deeper insight into the UC mechanism including population and deactivation pathways particularly of the red emission. Our measurements, covering a P regime of three orders of magnitude, reveal a strong difference of the P-dependence of the ratio of the green and red luminescence bands (Ig/r) in water and organic solvents and P-dependent population pathways of the different emissive energy levels of Er3+. In summary, we provide experimental evidence for three photon processes in UCNPs, particularly for the red emission. Moreover, we demonstrate changes in the excited population dynamics via bi- and triphotonic processes dependent on the environment, surface chemistry, and P, and validate our findings theoretically.
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BACKGROUND: Biologics are effective for the treatment of psoriasis. However, treatment outcomes may differ among biologic-naive patients and those switched from previous biological therapies. OBJECTIVES: The study's objective was to investigate efficacy and safety of ixekizumab, a high-affinity anti-interleukin-17A antibody, in patients with psoriasis with and without previous exposure to biologics. METHODS: Data were integrated from the 12-week induction phase of two etanercept-controlled Phase III trials. Patients received 80 mg ixekizumab every 2 weeks (IXE Q2W; N = 736) or every 4 weeks (IXE Q4W; N = 733) following a 160-mg starting dose, or placebo (N = 361). Etanercept (50 mg twice weekly; N = 740) was administered as active control. Psoriasis Area and Severity Index (PASI) 75, PASI 90 and PASI 100 response rates at week 12 were evaluated in patients with or without previous exposure to biologics. Treatment effects were analysed with the Cochran-Mantel-Haenszel test stratified by study; missing values were imputed as non-response. RESULTS: Overall, 497 (19.3%) patients had prior exposure to biologics and 2073 (80.7%) were naive to biologic therapy. PASI 75 was achieved by 91.5% of biologic-experienced patients and 87.7% of biologic-naive patients for IXE Q2W, 76.2% and 82.2% for IXE Q4W, respectively, and 34.6% and 50.7%, respectively, for etanercept. Higher response rates favouring each ixekizumab dose over etanercept within subgroups were also seen regarding PASI 90 and PASI 100. CONCLUSIONS: Contrary to etanercept, the efficacy of ixekizumab was similarly high in patients with and without previous exposure to biologics when administered 80 mg every 2 weeks.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Etanercept/uso terapéutico , Psoriasis/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Ensayos Clínicos Fase III como Asunto , Fármacos Dermatológicos/administración & dosificación , Fármacos Dermatológicos/efectos adversos , Método Doble Ciego , Sustitución de Medicamentos , Etanercept/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Índice de Severidad de la Enfermedad , Evaluación de Síntomas , Resultado del TratamientoRESUMEN
OBJECTIVE: This study has two aims: 1. Validate a non-invasive malocclusion model of mouse temporomandibular joint (TMJ) osteoarthritis (OA) that we developed and 2. Confirm role of inflammation in TMJ OA by comparing the disease in the presence and absence of the receptor for advanced glycation end products (RAGE). DESIGN: The malocclusion procedure was performed on eight week old mice, either wild type (WT) or without RAGE. RESULTS: We observed TMJ OA at two weeks post-misalignment/malocclusion. The modified Mankin score used for the semi-quantitative assessment of OA showed an overall significantly higher score in mice with malocclusion compared to control mice at all times points (2, 4, 6 and 8 weeks). Mice with malocclusion showed a decrease in body weight by the first week after misalignment but returned to normal weight for their ages during the following weeks. The RAGE knock out (KO) mice had statistically lower modified Mankin scores compared to WT mice of the same age. The RAGE KO mice had statistically lower levels of Mmp-13 and HtrA1 but higher Tgf-ß1, as measured by immunohistochemistry, compared to WT mice at eight weeks post malocclusion. CONCLUSIONS: We demonstrate an inexpensive, efficient, highly reproducible and non-invasive model of mouse TMJ OA. The mechanical nature of the malocclusion resembles the natural development of TMJ OA in humans, making this an ideal model in future studies that aim to elucidate the pathogenesis of the disease leading to the discovery of a treatment. The RAGE plays a role in mouse TMJ OA.
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Maloclusión/patología , Osteoartritis/patología , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Articulación Temporomandibular/patología , Animales , Desviación Ósea , Cartílago Articular/patología , Condrocitos/patología , Modelos Animales de Enfermedad , Productos Finales de Glicación Avanzada/metabolismo , Serina Peptidasa A1 que Requiere Temperaturas Altas , Inmunohistoquímica , Maloclusión/fisiopatología , Metaloproteinasa 13 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Alambres para Ortodoncia , Osteoartritis/fisiopatología , Serina Endopeptidasas/metabolismo , Trastornos de la Articulación Temporomandibular/patología , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
BACKGROUND: To investigate baseline demographics and disease characteristics as predictors of the analgesic effect of duloxetine and pregabalin on diabetic peripheral neuropathic pain (DPNP). METHODS: Based on data from the COMBO-DN study, a multinational clinical trial in DPNP, the potential impact of baseline characteristics on pain relief after 8-week monotherapy with 60 mg/day duloxetine or 300 mg/day pregabalin was assessed using analyses of covariance. Subgroups of interest were characterized regarding their baseline characteristics and efficacy outcomes. RESULTS: A total of 804 patients were evaluated at baseline. A significant interaction with treatment was observed in the mood symptom subgroups with a larger pain reduction in duloxetine-treated patients having no mood symptoms [Hospital Anxiety and Depression Scale (HADS) depression or anxiety subscale score <11; -2.33 (duloxetine); -1.52 (pregabalin); p = 0.024]. There were no significant interactions between treatment for subgroups by age (<65 or ≥65 years), gender, baseline pain severity [Brief Pain Inventory Modified Short Form (BPI-MSF) average pain <6 or ≥6], diabetic neuropathy duration (≤2 or >2 years), baseline haemoglobin A1c (HbA1c) (<8% or ≥8%), presence of comorbidities and concomitant medication use. CONCLUSIONS: Our analyses suggest that the efficacy of duloxetine and pregabalin for initial 8-week treatment in DPNP was consistent across examined subgroups based on demographics and disease characteristics at baseline except for the presence of mood symptoms. Duloxetine treatment appeared to be particularly beneficial in DPNP patients having no mood symptoms.
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Analgésicos/uso terapéutico , Anticonvulsivantes/uso terapéutico , Antidepresivos/uso terapéutico , Neuropatías Diabéticas/complicaciones , Neuropatías Diabéticas/tratamiento farmacológico , Dolor/tratamiento farmacológico , Afecto , Factores de Edad , Anciano , Analgésicos/efectos adversos , Anticonvulsivantes/efectos adversos , Antidepresivos/efectos adversos , Ansiedad/complicaciones , Ansiedad/psicología , Depresión/complicaciones , Depresión/psicología , Neuropatías Diabéticas/psicología , Clorhidrato de Duloxetina/efectos adversos , Clorhidrato de Duloxetina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dolor/psicología , Pregabalina/efectos adversos , Pregabalina/uso terapéutico , Escalas de Valoración Psiquiátrica , Resultado del TratamientoRESUMEN
Although body image is central to the etiological models of anorexia nervosa and body dysmorphic disorder, studies comparing body image and beliefs about attractiveness between the disorders are rare. Sixty-nine individuals (anorexia nervosa: n=24, body dysmorphic disorder: n=23, healthy controls: n=22) completed self-report measures (body image and general psychopathology), diagnostic interviews, and Go/No-Go Association tasks measuring implicit associations. Compared to controls, both clinical groups exhibited greater negative body image, a more negative attitude toward their physical selves, and more dysfunctional coping strategies (ps<.001). Also, both clinical groups shared greater explicit beliefs about the importance of attractiveness (ps<.001). In addition to supporting previous research with regard to comparable body image disturbance, this study also showed that beliefs regarding the importance of appearance (e.g., "one must be attractive to be successful") might be a fruitful target for therapy across both disorders.
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Anorexia Nerviosa/diagnóstico , Anorexia Nerviosa/psicología , Belleza , Trastorno Dismórfico Corporal/diagnóstico , Trastorno Dismórfico Corporal/psicología , Imagen Corporal , Cultura , Adaptación Psicológica , Adulto , Anorexia Nerviosa/terapia , Trastorno Dismórfico Corporal/terapia , Femenino , Humanos , Control Interno-Externo , Entrevista Psicológica , Masculino , Psicometría/estadística & datos numéricos , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
Pruritic skin diseases are common in cats and demand rigorous diagnostic workup for finding an underlying etiology. Measurement of a serum allergen-specific IgE in a pruritic cat is often used to make or confirm the diagnosis of a skin hypersensitivity disease, although current evidence suggests that elevated allergen-specific IgE do not always correlate with a clinical disease and vice versa. The aim of the study was to to assess the possible influence of age, deworming status, lifestyle, flea treatment, and gender on allergen-specific IgE levels and to evaluate the reliability of IgE testing in predicting the final diagnosis of a pruritic cat. For this purpose sera of 179 cats with pruritus of different causes and 20 healthy cats were evaluated for allergen-specific IgE against environmental, food and flea allergens using the Fc-epsilon receptor based enzyme-linked immunosorbent assay (ELISA) test. The results of the study showed positive correlation between age, outdoor life style, absence of deworming, absence of flea control measures and levels of allergen-specific IgE. Gender and living area (urban versus rural) did not seem to affect the formation of allergen-specific IgE. According to these findings, evaluating allergen-specific IgE levels, is not a reliable test to diagnose hypersensitivity to food or environmental allergens in cats. On the contrary, this test can be successfully used for diagnosing feline flea bite hypersensitivity.
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Alérgenos/inmunología , Enfermedades de los Gatos/inmunología , Inmunoglobulina E/sangre , Prurito/veterinaria , Animales , Enfermedades de los Gatos/sangre , Gatos , Ensayo de Inmunoadsorción Enzimática/veterinaria , Femenino , Inmunoglobulina E/inmunología , Masculino , Prurito/sangre , Prurito/inmunología , Receptores de IgE/inmunología , Estadísticas no ParamétricasRESUMEN
Corticosterone (CORT) levels in seabirds fluctuate across breeding stages and in different foraging conditions. Here we use a ten-year data set to examine whether CORT levels in Atlantic puffins differ in years with high or low availability of capelin, the preferred forage species. Female puffins had higher CORT levels than males, possibly related to cumulative costs of egg production and higher parental investment. Puffins had higher CORT levels and body mass during pre-breeding than during chick rearing. Yearly mean chick growth rates were higher in years when adults had higher body mass and in years where adults brought chicks a lower percentage of non-fish (invertebrates/larval fish) food. Unlike most results from seabird species with shorter chick-rearing periods, higher CORT levels in puffins were not associated with lower capelin abundance. Puffins may suppress CORT levels to conserve energy in case foraging conditions improve later in the prolonged chick-rearing period. Alternatively, CORT levels may be lowest both when food is very abundant (years not in our sample) or very scarce (e.g., 2009 in this study), and increase when extra foraging effort will increase foraging efficiency (most years in this study). If these data primarily represent years with medium to poor foraging, it is possible that CORT responses to variation in foraging conditions are similar for puffins and other seabirds.
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Cruzamiento , Charadriiformes/metabolismo , Corticosterona/sangre , Animales , Charadriiformes/sangre , Charadriiformes/fisiología , Femenino , Masculino , Estaciones del Año , Factores SexualesRESUMEN
A six-year-old Rottweiler with chronic ascites and moderate panhypoproteinaemia that had been treated with large volume paracentesis over several months duration was diagnosed with a large bi-atrial mass and hepatic fibrosis. For palliative treatment, a peritoneo-vesical automated fluid shunt system with an integrated chargeable battery and an integrated computer to control pump function and to transmit data transcutaneously was implanted by coeliotomy. The pump was left in place for 10 weeks, eliminating the need for further paracentesis during this time. At the end of this period, no ascites was discernible and serum protein concentrations had returned to their respective reference intervals. As a complication, decubitus with skin perforation had developed above the pump. Besides palliative treatment of chronic refractory ascites, this pump may have application in other conditions characterised by chronic cavity effusion or in peritoneal dialysis.
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Ascitis/veterinaria , Enfermedades de los Perros/terapia , Drenaje/veterinaria , Animales , Ascitis/terapia , Perros , Drenaje/instrumentación , Drenaje/métodos , Masculino , Cuidados PaliativosRESUMEN
Canine and human atopic dermatitis are multifaceted diseases whose clinical development may be influenced by several factors, such as genetic background, environment, secondary infections, food and psychological effects. The role of the environment has been extensively examined in humans but remains unclear in dogs. The aim of this study was to examine environmental factors in two genetically close breeds, Labrador and golden retrievers. Using standard criteria, atopic dogs in Switzerland and Germany were selected and compared with healthy individuals. Information on environmental factors was collected using a 46-question survey encompassing date and place of birth, way of life at the breeder's and owner's home, food and treatments. Univariate and multivariate logistic regression were used to assess the association between potential risk factors and disease status. The following parameters were associated with an increased risk of disease development: living in a shed during puppyhood, adoption at the age of 8-12 weeks and washing the dog regularly. In contrast, the following factors were associated with a lower risk: living in a rural environment, living in a household with other animals and walking in a forest. These associations do not prove causality but support the primary hypothesis that certain environmental factors may influence the development of canine atopic dermatitis. Further studies are warranted to confirm these results and conclusions.
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Dermatitis Atópica/veterinaria , Enfermedades de los Perros/etiología , Exposición a Riesgos Ambientales/efectos adversos , Alérgenos/efectos adversos , Alimentación Animal , Crianza de Animales Domésticos , Animales , Dermatitis Atópica/etiología , Perros , Ambiente , Alemania , Vivienda para Animales , Análisis Multivariante , Factores de Riesgo , Estaciones del Año , SuizaRESUMEN
An 8 year old male castrated Russian Blue cat with polyuria, polydipsia, polyphagia, abdominal enlargement, unkempt and easily epilated hair coat and abdominal alopecia is described. As a first step diabetes mellitus was diagnosed. Further work-up by ultrasonography revealed severe bilateral enlargement of the adrenal glands. Hypercortisolism was suspected and therefore ACTH stimulation test and dexamethasone suppression test were performed. In all samples cortisol concentrations were below the detection limit of the assay used. Various precursor hormones were measured and high progesterone concentrations were found. Histologically, the adrenal masses were characterised as bilateral adrenal carcinomas of the adrenal cortex. The case report demonstrates that adrenal gland tumors are also capable to secrete sex hormones instead of cortisol. Clinical signs of hyperprogesteronism are identical to those of hypercortisolism.
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Neoplasias de la Corteza Suprarrenal/veterinaria , Carcinoma Corticosuprarrenal/veterinaria , Hiperfunción de las Glándulas Suprarrenales/veterinaria , Enfermedades de los Gatos/sangre , Progesterona/sangre , Pruebas de Función de la Corteza Suprarrenal/veterinaria , Neoplasias de la Corteza Suprarrenal/complicaciones , Neoplasias de la Corteza Suprarrenal/metabolismo , Carcinoma Corticosuprarrenal/complicaciones , Carcinoma Corticosuprarrenal/metabolismo , Hiperfunción de las Glándulas Suprarrenales/sangre , Hiperfunción de las Glándulas Suprarrenales/etiología , Animales , Gatos , Complicaciones de la Diabetes/sangre , Complicaciones de la Diabetes/veterinaria , MasculinoRESUMEN
Canine atopic dermatitis sensu stricto and food-induced allergic dermatitis are common canine skin conditions, which are often considered clinically undistinguishable. Several attempts have been made to describe populations of atopic dogs and determine breed predisposition but the results were often biased by the use of hospital populations as control group. The present study aims to describe a population of Swiss atopic and food-allergic dogs and to compare it with a data set representing more than 85% of all Swiss dogs. The study, which was carried out during 1 year in several practices and teaching hospital in Switzerland, describes a group of 259 allergic dogs, determines breed predisposition for atopic dermatitis and food-induced allergic dermatitis, compares the clinical signs and features of both conditions, and outlines the clinical picture of five frequently affected breeds.
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Dermatitis Atópica/veterinaria , Enfermedades de los Perros/epidemiología , Enfermedades de los Perros/genética , Hipersensibilidad a los Alimentos/veterinaria , Linaje , Animales , Dermatitis Atópica/epidemiología , Dermatitis Atópica/etiología , Dermatitis Atópica/genética , Enfermedades de los Perros/etiología , Perros , Femenino , Hipersensibilidad a los Alimentos/epidemiología , Hipersensibilidad a los Alimentos/etiología , Hipersensibilidad a los Alimentos/genética , Predisposición Genética a la Enfermedad , Masculino , Estudios Prospectivos , Suiza/epidemiologíaRESUMEN
Vesicoacetabular cutaneous fistula is a rare but severe complication after total hip replacement. Diagnosis is based on clinical symptoms as well as radiologic and endoscopic findings. Therapy, however, requires an interdisciplinary approach. Anuria was the leading symptom in this case. After verifying the diagnosis, the prosthesis was completely removed, the fistula was excised, and the bladder was closed in multiple layers using an omentum majus flap. The patient was mobilized early and is content to date with the situation.
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Acetábulo , Fístula Cutánea/etiología , Prótesis de Cadera , Complicaciones Posoperatorias/etiología , Falla de Prótesis , Infecciones Estafilocócicas/etiología , Enfermedades de la Vejiga Urinaria/etiología , Fístula Urinaria/etiología , Anciano , Anuria/etiología , Cistoscopía , Extravasación de Materiales Terapéuticos y Diagnósticos/etiología , Extravasación de Materiales Terapéuticos y Diagnósticos/cirugía , Femenino , Estudios de Seguimiento , Migración de Cuerpo Extraño/etiología , Migración de Cuerpo Extraño/cirugía , Humanos , Resistencia a la Meticilina , Complicaciones Posoperatorias/cirugía , Reoperación , Infecciones Estafilocócicas/cirugía , Vejiga Urinaria/cirugía , Enfermedades de la Vejiga Urinaria/cirugía , Fístula Urinaria/cirugía , UrografíaRESUMEN
The mean and range of concentrations of mercury in crude oil processed by U.S. refineries in 2004 were determined using two analytical methods. One hundred seventy separate crude oil streams were sampled repetitively to obtain 328 individual samples. Samples were retrieved immediately upstream of refinery tank farms. Losses of mercury during production, separation, and transportation were not examined. The arithmetic mean and median of 170 oil streams were 7.3 and 1.5 microg/kg in total mercury, respectively. The total mercury concentration of oil processed in the United States in year 2004, including all species and both dissolved and suspended forms, expressed as a volume-weighted mean was calculated to be 3.5 +/- 0.6 microg/kg. The range of measured concentrations extended from below the analytical detection limit (0.5 microg/kg) to approximately 600 microg/kg. Good agreement was found with other recent and independent studies of mercury in crude oil refined in North America. The total amount of mercury in crude oil processed in the U.S annually is less than five percent of the amount contained in U.S. coal produced annually.
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Mercurio/análisis , Petróleo/análisis , Estándares de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Incertidumbre , Estados UnidosRESUMEN
Activating internal tandem duplication (ITD) insertions in the juxtamembrane domain of the FLT3 tyrosine kinase are found in about one fourth of patients with acute myeloid leukemia and have been shown to be an independent negative prognostic factor for survival. We show that sorafenib (BAY 43-9006, Nexavar) potently inhibits FLT3 enzymatic and signaling activities. In HEK293 cells stably transfected with FLT3-WT or FLT3-ITD, sorafenib blocked basal and ligand dependent FLT3-mediated tyrosine autophosphorylation as well as extracellular signal-regulated kinase1/2 and Stat5 phosphorylation. In leukemia cell lines MV4-11 and EOL-1, sorafenib treatment resulted in decreased cell proliferation and inhibition of FLT3 signaling. The growth of the FLT3-independent RS4-11 cell line was only weakly inhibited by sorafenib. Cell cycle arrest and induction of apoptosis were observed upon treatment with sorafenib in MV4-11 and EOL-1 cells. The antitumor efficacy of sorafenib was evaluated against the MV4-11 leukemia grown subcutaneously in NCr nu/nu mice. Doses of 3 and 10 mg/kg administered orally for 14 days resulted in six and nine out of 10 animals with complete responses, respectively. The demonstration that sorafenib exhibits potent target inhibition and efficacy in FLT3-driven models suggests that this compound may have a therapeutic benefit for patients with FLT3-driven leukemias.
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Antineoplásicos/farmacología , Bencenosulfonatos/farmacología , Leucemia Mieloide/tratamiento farmacológico , Proteínas Mutantes/fisiología , Proteínas de Neoplasias/fisiología , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Tirosina Quinasa 3 Similar a fms/fisiología , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Bencenosulfonatos/uso terapéutico , Ciclo Celular/efectos de los fármacos , Línea Celular , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Riñón , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patología , Ratones , Ratones Desnudos , Proteínas Mutantes/antagonistas & inhibidores , Proteínas Mutantes/genética , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Proteínas Recombinantes de Fusión/fisiología , Sorafenib , Secuencias Repetidas en Tándem , Transfección , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
This study aims to provide information on the occurrence of spotted fever rickettsiae in Ixodes ricinus ticks in southern Germany. A total of 2,141 I. ricinus ticks was collected in Bavaria. Pools of 5-10 ticks were studied by a PCR targeting the rickettsial citrate synthase gene gltA. The average prevalence rate was 12% (257 of 2,141). Sequencing data exclusively identified Rickettsia helvetica DNA. Results and other data demonstrate the possible role of R. helvetica in I. ricinus as a source of human infections in southern Germany.
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Ixodes/microbiología , Infecciones por Rickettsia/prevención & control , Infestaciones por Garrapatas/prevención & control , Animales , ADN Bacteriano/genética , ADN Bacteriano/aislamiento & purificación , Femenino , Alemania , Humanos , Ixodes/crecimiento & desarrollo , Larva , Masculino , Reacción en Cadena de la Polimerasa , Densidad de Población , Rickettsia/genética , Rickettsia/aislamiento & purificación , Infecciones por Rickettsia/transmisiónRESUMEN
BACKGROUND: Laparoscopic adrenalectomy for small pheochromocytomas, although challenging, is widely accepted. However, its application to pheochromocytomas larger than 6 cm is questioned due to concerns of malignancy and case complexity. Our aim was to examine the impact of pheochromocytoma tumor size (>/=6 cm vs <6 cm) on operative approach and postoperative patient outcomes. METHODS: A retrospective review of adrenalectomies performed at 3 university hospitals over 1 decade was analyzed. All pheochromocytomas were identified and then divided based on size into large (>/=6 cm) and small (<6 cm) groups. We examined patient and tumor demographics, pathologic diagnosis, operative approach (laparoscopic vs open), postoperative complications, and biochemical cure rates. Data were analyzed using the Student t test and Fisher exact test with a P value <.05 considered significant. RESULTS: From 1995 to 2005, 65 pheochromocytomas were resected. Of the total, 38% (n = 25) tumors were >/=6 cm and 62% (n = 40) were <6 cm. For the large tumors, 1 out of 25 (4%) was malignant, whereas no small tumors were malignant. There was no statistically significant increased risk of malignancy in tumors >/=6 cm in size (P = .31). Initial operative approach was based on surgeon preference. Of the adrenalectomies performed, 88% were laparoscopic, with 3 of 25 (12%) large tumors requiring conversion from laparoscopic to open for intraoperative bleeding. None of the small tumors required conversion. No major postoperative complications (eg, stroke or myocardial infarction) occurred in either group. Minor complications (eg, wound infections and hematomas) were noted in 16% of large tumors and 12.5% of small tumors (P = .45). A total of 96% (24 of 25) patients with large tumors and 100% with small tumors showed postoperative biochemical cure. Tumor recurrence was noted in 1 patient with a tumor <6 cm. CONCLUSIONS: Pheochromocytomas >/=6 cm pose a challenge for laparoscopic resection, and concerns have been raised about the validity of this operative approach. This study demonstrates that there is no significant difference in the rate of malignancy for pheochromocytomas >/=6 cm versus <6 cm. There also were no significant differences identified in complication rates, postoperative biochemical cures, or tumor recurrence rates between these groups. Laparoscopic resection of pheochromocytomas can be safely accomplished regardless of size in centers with surgeons experienced in these procedures.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/patología , Neoplasias de las Glándulas Suprarrenales/cirugía , Adrenalectomía/métodos , Feocromocitoma/patología , Feocromocitoma/cirugía , Adulto , Femenino , Humanos , Laparoscopía , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Estudios Retrospectivos , Resultado del TratamientoAsunto(s)
Cefalea , Hematoma Subdural Crónico/diagnóstico , Hematoma Subdural Crónico/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Linfoma de Células T/terapia , Adulto , Encéfalo/patología , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Hemorragia Subaracnoidea/patologíaRESUMEN
Transplantation-associated microangiopathy (TAM) or renal insufficiency (RI) after allogeneic hematopoietic stem cell transplantation is associated with a high mortality. As calcineurin inhibitors (CI) may contribute to TAM or RI, we evaluated the efficacy of replacing CI by daclizumab in patients with graft-versus-host disease (GVHD). Thirteen patients with GVHD-associated TAM and five patients with RI were treated with daclizumab 1 mg/kg intravenous (i.v.)/week, discontinuation of the CI and continuation of the remaining GVHD treatment. All patients had acute GVHD (steroid-sensitive (n=4), steroid-refractory (n=10)) or chronic GVHD (n=4) and were treated with CI before the start of daclizumab. Nine of 13 patients with TAM treated with daclizumab and discontinuation of CI achieved complete remission of TAM, two had stable disease, and one patient did not respond. Patients receiving daclizumab for RI without TAM showed stabilization (2/5) or improvement (3/5) of renal function. Four of 14 patients with acute GVHD achieved CR, two partial remission, eight patients did not respond and 11/14 died at a median of 39 days after start of the daclizumab. Our data demonstrate that replacement of CI by daclizumab can improve TAM and RI. However, mortality remains high in patients with acute GVHD.