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BACKGROUND: Mechanical waves produced by ultrasound pulses have been shown to activate mechanosensitive ion channels and modulate peripheral nerves. However, while peripheral ultrasound neuromodulation has been demonstrated in vitro and in pre-clinical models, there have been few reports of clinical tests. AIM: We modified a diagnostic imaging system for ultrasound neuromodulation in human subjects. We report the first safety and feasibility outcomes in subjects with type 2 diabetes (T2D) mellitus and discuss these outcomes in relation to previous pre-clinical results. DESIGN: The study was performed as an open label feasibility study to assess the effects of hepatic ultrasound (targeted to the porta hepatis) on glucometabolic parameters in subjects with T2D. Stimulation (peripheral focused ultrasound stimulation treatment) was performed for 3 days (i.e. 15 min per day), preceded by a baseline examination and followed by a 2-week observation period. METHODS: Multiple metabolic assays were employed including measures of fasting glucose and insulin, insulin resistance and glucose metabolism. The safety and tolerability were also assessed by monitoring adverse events, changes in vital signs, electrocardiogram parameters and clinical laboratory measures. RESULTS AND CONCLUSION: We report post-pFUS trends in several outcomes that were consistent with previous pre-clinical findings. Fasting insulin was lowered, resulting in a reduction of HOMA-IR scores (P-value 0.01; corrected Wilcoxon signed-rank test). Additional safety and exploratory markers demonstrated no device-related adverse impact of pFUS. Our findings demonstrate that pFUS represents a promising new treatment modality that could be used as a non-pharmaceutical adjunct or even alternative to current drug treatments in diabetes.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Insulina , Glucosa , Hígado/diagnóstico por imagen , Homeostasis , Glucemia/metabolismoRESUMEN
BACKGROUND: Hop performance evaluation in children after anterior cruciate ligament (ACL) reconstruction may benefit from comparison to healthy controls. Thus, the purpose was to investigate the hop performance in children one year after ACL reconstruction with a comparison to healthy controls. METHODS: Hop performance data from children with ACL reconstruction one year post-surgery and healthy children were compared. Four one-legged hop test data were analyzed: 1) single hop (SH), 2) 6 m timed hop (6 m-timed), 3) triple hop (TH), and 4) cross-over hop (COH). Outcomes were the best result (longest/fastest hop) from each leg and limb asymmetry. Differences in hop performance between-limbs (operated versus non-operated) and between-groups were estimated. RESULTS: 98 children with ACL reconstruction and 290 healthy children were included. Few statistically significant group differences were observed. Girls with ACL reconstruction outperformed healthy controls in two tests on the operated leg SH, COH) and in three tests on the non-operated leg (SH, TH, COH). However, the girls performed 4-5% worse on the operated leg when compared to the non-operated leg in all hop tests. No statistically significant between-group differences in the limb asymmetry were found. CONCLUSION: The hop performance in children with ACL reconstruction one year post-surgery was largely comparable to the level of healthy controls. Despite this, we cannot exclude that neuromuscular deficits exist among the children with ACL reconstruction. The inclusion of a healthy control group for evaluating hop performance evoked complex findings regarding the ACL reconstructed girls. Thus, they may represent a selected group.
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Lesiones del Ligamento Cruzado Anterior , Reconstrucción del Ligamento Cruzado Anterior , Femenino , Humanos , Niño , Lesiones del Ligamento Cruzado Anterior/cirugía , Estudios Transversales , Estado de SaludRESUMEN
Alterations in the nitric oxide (NO) pathway play a major role in pulmonary arterial hypertension (PAH). L-arginine (LA) and tetrahydrobiopterin (BH4) are main substrates in the production of NO, which mediates pulmonary vasodilation. Administration of either LA or BH4 decrease pulmonary artery pressure (PAP). A combined administration of both may have synergistic effects in the therapy of PAH. In a telemetrically monitored model of unilateral pneumonectomy and monocrotaline-induced PAH, male Sprague-Dawley rats received either LA (300 mg/kg; n = 15), BH4 (20 mg/kg; n = 15), the combination of LA and BH4 (300 mg/kg, 20 mg/kg; n = 15), or vehicle (control group; n = 10) from day 28 after monocrotaline induction. Therapy was orally administered once daily over consecutive 14 days. LA, BH4, or both equally lowered PAP, increased pulmonary vascular elasticity, restored spontaneous locomotoric activity, prevented body weight loss and palliated small vessel disease of severely pulmonary hypertensive rats. BH4 substitution lowered asymmetric dimethylarginine levels sustainably at 60 min after administration and downregulated endothelial NO synthase mRNA expression. No significant survival, macro- and histomorphologic or hemodynamic differences were found between therapy groups at the end of the study period. Administration of LA and BH4 both mediated a decrease of mean PAP, attenuated right ventricular hypertrophy and small vessel disease in monocrotaline-induced pulmonary hypertensive rats, though a combined administration of both substances did not reveal any synergistic therapy effects in our animal model.
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La ecografía es una técnica que permite una exploración bastante completa del aparato urinario, alcanzando una alta sensibilidad para la detección de enfermedades relevantes, sobre todo a nivel renal, vesical y prostático. La detección temprana de afecciones como los tumores o la obstrucción de la vía urinaria, en ocasiones incluso antes de presentar expresión clínica, ha mejorado su manejo y pronóstico en muchas ocasiones. Esto, junto con su bajo coste e inocuidad, convierte a la ecografía en la técnica idónea para el abordaje inicial y el seguimiento de un número amplio de enfermedades del aparato urinario. En el presente artículo se revisan las características ecográficas de las principales afecciones que se pueden diagnosticar con esta técnica en el aparato urinario (AU)
Ultrasound techniques are able to provide a fairly complete examination of the urinary system, achieving a high sensitivity in relevant-pathology detection, especially in the kidney, bladder and prostate. Early detection of pathologies such as tumors or urinary tract obstructions, sometimes even before their clinical manifestation, has improved their management and prognosis in many cases. This, added to its low cost and harmlessness, makes ultrasound ideal for early approaches and follow-up of a wide number of urinary system pathologies. In this article, the ultrasound characteristics of the main urinary system pathologies that can be diagnosed by this technique, are reviewed (AU)
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Humanos , Masculino , Femenino , Sistema Urinario , Riñón/patología , Riñón , Uréter , Vejiga Urinaria , Próstata , Neoplasias , Cálculos Ureterales , Cálculos Urinarios , Anomalías Congénitas , Urolitiasis , HidronefrosisRESUMEN
INTRODUCTION: Haemophilia A is an X-linked bleeding disorder characterized by a deficiency of coagulation protein factor VIII (FVIII). A challenging complication of therapeutic FVIII infusions is the formation of neutralizing alloantibodies against the FVIII protein defined as inhibitors. The development of FVIII inhibitors drastically alters the quality of life of the patients and is associated with tremendous increases in morbidity as well as treatment costs. AIM: Current clinical immune tolerance induction protocols to reverse inhibitors are lengthy, costly and not effective in all patients. Prophylactic protocols to prevent inhibitor formation have not yet been developed in the clinical setting. However, there has been ample progress towards this goal in recent years in preclinical studies using animal models of haemophilia. METHODS: Here, we review the mechanisms that lead to inhibitor formation against FVIII and two promising new strategies for antigen-specific tolerance induction. RESULTS: CD4+ T cells play an important role in the FVIII-specific B cell response. Immune tolerance can be induced based on transplacental delivery of FVIII domains fused to Fc or on oral delivery of leaf cells from chloroplast transgenic crop plants. CONCLUSIONS: Recent literature suggests that prophylactic tolerance induction protocols for FVIII may be feasible in haemophilia A patients.
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Hemofilia A/inmunología , Tolerancia Inmunológica , Animales , Anticuerpos Neutralizantes/sangre , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Modelos Animales de Enfermedad , Factor VIII/inmunología , Factor VIII/uso terapéutico , Femenino , Hemofilia A/tratamiento farmacológico , Humanos , Fragmentos Fc de Inmunoglobulinas/genética , Fragmentos Fc de Inmunoglobulinas/metabolismo , Intercambio Materno-Fetal , Plantas Modificadas Genéticamente/inmunología , EmbarazoRESUMEN
Ultrasound techniques are able to provide a fairly complete examination of the urinary system, achieving a high sensitivity in relevant-pathology detection, especially in the kidney, bladder and prostate. Early detection of pathologies such as tumors or urinary tract obstructions, sometimes even before their clinical manifestation, has improved their management and prognosis in many cases. This, added to its low cost and harmlessness, makes ultrasound ideal for early approaches and follow-up of a wide number of urinary system pathologies. In this article, the ultrasound characteristics of the main urinary system pathologies that can be diagnosed by this technique, are reviewed.
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Sistema Urinario/diagnóstico por imagen , Enfermedades Urológicas/diagnóstico por imagen , Humanos , Masculino , Enfermedades de la Próstata/diagnóstico por imagen , Sensibilidad y Especificidad , Ultrasonografía , Sistema Urinario/anomalías , Sistema Urinario/anatomía & histologíaRESUMEN
The reported IgG seroprevalence against hepatitis E virus (HEV) in German blood donations is 6.8%, and HEV RNA detected in 0.08%, but documented evidence for HEV transmission is lacking. We identified two donations from a single donor containing 120 IU HEV RNA/mL plasma and 490 IU/mL. An infectious dose of 7,056 IU HEV RNA was transmitted via apheresis platelets to an immunosuppressed patient who developed chronic HEV. Further, transmission was probable in an immunocompetent child.
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Virus de la Hepatitis E/aislamiento & purificación , Hepatitis E/sangre , ARN Viral/sangre , Reacción a la Transfusión , Adulto , Anticuerpos Antivirales/sangre , Donantes de Sangre , Niño , Trazado de Contacto , Alemania , Anticuerpos Antihepatitis/sangre , Hepatitis E/transmisión , Hepatitis E/virología , Virus de la Hepatitis E/genética , Virus de la Hepatitis E/inmunología , Humanos , Inmunoglobulina G/sangre , ARN Viral/genética , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
HISTORY AND ADMISSION FINDINGS: A 43-year-old man presented at our emergency room with progressive dyspnea and productive cough. He was in moderate respiratory distress. Symptomatic treatment had so far not led to clinical improvement. He had suffered from similar episodes since adolescence. INVESTIGATIONS: An intensive diagnostic investigation was started to evaluate the source of infection and dyspnea. CRP levels were elevated to 26â mg/l. Arterial blood gas analysis showed a moderate hypoxemia with a pO2 of 8.35kPa (63â mmHg) and a pCO2 of 3.84kPa (29â mmHg). DIAGNOSIS, TREATMENT AND COURSE: Computed tomography of the chest revealed the diagnosis of trachebobronchomegaly. This rare cause of recurrent bronchitis is named after Mounier-Kuhn who established this diagnosis for the first time. The patient improved under a course with antibiotics and inhaled bronchodilators. CONCLUSION: In patients with recurrent bronchitis, an underlying disease of the tracheobronchial system has to be suspected. The Mounier-Kuhn syndrome is only rarely diagnosed because the diagnosis cannot be established by conventional chest x-ray. Computed tomography is the gold standard for diagnosis. Mounier-Kuhn syndrome is likely to lead to severe venilatory failure and death, if untreated.
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Bronquitis/diagnóstico , Bronquitis/etiología , Disnea/diagnóstico , Disnea/etiología , Traqueobroncomegalia/complicaciones , Traqueobroncomegalia/diagnóstico , Adulto , Diagnóstico Diferencial , Humanos , Masculino , Enfermedades Raras/complicaciones , Enfermedades Raras/diagnóstico , Recurrencia , Tomografía Computarizada por Rayos X/métodosRESUMEN
The purpose of this study was to devise a simple but reliable radiological method of identifying a lumbosacral transitional vertebra (LSTV) with a solid bony bridge on sagittal MRI, which could then be applied to a lateral radiograph. The vertical mid-vertebral angle (VMVA) and the vertical anterior vertebral angle (VAVA) of the three most caudal segments of the lumbar spine were measured on MRI and/or on a lateral radiograph in 92 patients with a LSTV and 94 controls, and the differences per segment (Diff-VMVA and Diff-VAVA) were calculated. The Diff-VMVA of the two most caudal vertebrae was significantly higher in the control group (25° (sd 8) than in patients with a LSTV (type 2a+b: 16° (SD 9), type 3a+b: -9° (SD 10), type 4: -5° (SD 7); p < 0.001). A Diff-VMVA of ≤ +10° identified a LSTV with a solid bony bridge (type 3+4) with a sensitivity of 100% and a specificity of 89% on MRI and a sensitivity of 94% and a specificity of 74% on a lateral radiograph. A sensitivity of 100% could be achieved with a cut-off value of 28° for the Diff-VAVA, but with a lower specificity (76%) on MRI than with Diff-VMVA. Using this simple method (Diff-VMVA ≤ +10°), solid bony bridging of the posterior elements of a LSTV, and therefore the first adjacent mobile segment, can be easily identified without the need for additional imaging.
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Vértebras Lumbares/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Sacro/diagnóstico por imagen , Enfermedades de la Columna Vertebral/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radiografía , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Adulto JovenRESUMEN
Non-physiological components of peritoneal dialysis fluids (PDF) lead to the injury of peritoneal mesothelial cells resulting in the failure of peritoneal dialysis (PD) potentially via inadequate induction of the protective heat shock response (HSR). Glycogen synthase kinase-3ß (GSK-3ß) is a negative regulator of cell survival partly by suppression of the HSR and is influenced by stress stimuli also present in conventional PDF. The effects of PDF on GSK-3ß activation and the impact of GSK-3ß inhibition with lithium (LiCl) were investigated on cell survival with special regard to HSR, in particular to heat shock transcription factor 1 (HSF-1) activation and Hsp72 production in an in vitro model of PD using MeT-5A and primary mesothelial cells. Incubation of cells with the PDF Dianeal® (glucose-based, low pH, high glucose degradation products (GDP)) and Extraneal® (icodextrin-based, low pH, low GDP) caused activation of GSK-3ß compared to the other tested PDF, i.e. Balance®, Physioneal® (normal pH, glucose-based, low GDP) and Nutrineal® (moderately acidic, amino acid-based). Inhibition of GSK-3ß with LiCl in Dianeal® and Extraneal®-treated cells dose-dependently decreased cell damage and death rate and was paralleled by higher HSF-1 activation and Hsp72 expression. GSK-3ß is activated by low pH GDP containing PDF with and without glucose as osmotic agent, indicating that GSK-3ß is involved in mesothelial cell signalling in response to experimental PD. Inhibition of GSK-3ß with LiCl ameliorated cell injury and improved HSR upon PDF exposure. Thus, GSK-3ß inhibitors likely have therapeutic potential as cytoprotective additive for decreasing PDF toxicity.
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Soluciones para Diálisis/toxicidad , Células Epiteliales/efectos de los fármacos , Glucanos/toxicidad , Glucosa/toxicidad , Glucógeno Sintasa Quinasa 3/metabolismo , Respuesta al Choque Térmico/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Proteínas de Unión al ADN/metabolismo , Células Epiteliales/metabolismo , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Guanosina Difosfato/farmacología , Proteínas del Choque Térmico HSP72/metabolismo , Factores de Transcripción del Choque Térmico , Humanos , Concentración de Iones de Hidrógeno , Icodextrina , Cloruro de Litio/farmacología , Diálisis Peritoneal , Peritoneo/citología , Fosforilación , Factores de Transcripción/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
INTRODUCTION: Rupture of the Arteria ovarica is a rare but life-threatening injury and occurs primarily in pregnancy. Most previously described ruptures of the Arteria ovarica were in the early postpartum period and in women who were older than 45 years. We report on a two-stage rupture of the Arteria ovarica after a high energy trauma, which has not previously been described in the literature. PATIENT AND METHOD: A 66-year-old female patient was admitted to the emergency room after a car accident. Initial treatment was performed in a regional hospital. Initial clinical and radiological examinations were without any pathologies and the patient was discharged home after ambulatory treatment. Six days later, the patient was referred to our hospital because of increasing headache. A computed tomography of the head showed a subdural haematoma. A follow-up CT scan after three days showed no further progression of the haematoma. RESULTS AND CONCLUSIONS: During the hospital stay, the patient developed abdominal pain, nausea and cardiovascular decompensation. An ultrasound of the abdomen showed free fluids, while a performed CT scan of the abdomen confirmed an arterial bleeding from a pseudoaneurysm of the left ovarian artery. An emergency operation was performed. Postoperative management included ICU monitoring, diuresis control and blood transfusion. The patient was discharged home after 19 days in a good condition. The indication for performing a CT scan and primary hospitalisation after a high energy trauma should be applied generously.
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Accidentes de Tránsito , Aneurisma Falso/diagnóstico , Arterias/lesiones , Ovario/irrigación sanguínea , Lesiones del Sistema Vascular/diagnóstico , Anciano , Aneurisma Falso/cirugía , Arterias/cirugía , Diagnóstico Diferencial , Femenino , Hematoma Subdural/diagnóstico , Hemoperitoneo/diagnóstico , Hemoperitoneo/cirugía , Humanos , Tomografía Computarizada por Rayos X , Ultrasonografía , Lesiones del Sistema Vascular/cirugíaRESUMEN
BACKGROUND: Formation of inhibitory antibodies is a frequent and serious complication of factor (F) VIII replacement therapy for the X-linked bleeding disorder hemophilia A. Similarly, hemophilia A mice develop high-titer inhibitors to recombinant human FVIII after a few intravenous injections. OBJECTIVE: Using the murine model, the study sought to develop a short regimen capable of inducing tolerance to FVIII. METHODS: A 1-month immunomodulatory protocol, consisting of FVIII administration combined with oral delivery of rapamycin, was developed. RESULTS: The protocol effectively prevented formation of inhibitors to FVIII upon subsequent intravenous treatment (weekly for 3.5 months). Control mice formed high-titer inhibitors and had CD4(+) T effector cell responses characterized by expression of IL-2, IL-4 and IL-6. Tolerized mice instead had a CD4(+)CD25(+)FoxP3(+) T cell response to FVIII that suppressed antibody formation upon adoptive transfer, indicating a shift from Th2 to Treg if FVIII antigen was introduced to T cells during inhibition with rapamycin. CD4(+) T cells from tolerized mice also expressed TGF-ß1 and CTLA4, but not IL-10. The presence of FVIII antigen during the time of rapamycin administration was required for specific tolerance induction. CONCLUSIONS: The study shows that a prophylactic immune tolerance protocol for FVIII can be developed using rapamycin, a drug that is already widely in clinical application. Immune suppression with rapamycin was mild and highly transient, as the mice regained immune competence within a few weeks.
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Anticuerpos/sangre , Linfocitos T CD4-Positivos/efectos de los fármacos , Coagulantes/administración & dosificación , Factor VIII/administración & dosificación , Hemofilia A/tratamiento farmacológico , Tolerancia Inmunológica/efectos de los fármacos , Inmunosupresores/administración & dosificación , Sirolimus/administración & dosificación , Traslado Adoptivo , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/trasplante , Antígeno CTLA-4/metabolismo , Células Cultivadas , Coagulantes/inmunología , Modelos Animales de Enfermedad , Esquema de Medicación , Factor VIII/inmunología , Factores de Transcripción Forkhead/metabolismo , Hemofilia A/sangre , Hemofilia A/inmunología , Humanos , Interleucina-2/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Proteínas Recombinantes/administración & dosificación , Factores de Tiempo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Recently the relevance of femoroacetabular impingement as a cause of hip and groin pain in sportsmen has been recognized. The entity often poses diagnostic and therapeutic problems to the sports physician. The patients go through an odyssey of different diagnostic and therapeutic modalities before the correct diagnosis is made and an adequate therapy is implemented. Not seldom, patients get even operated at another site which is thought to cause the problems. The present review analyzes the current literature concerning diagnostic standards and therapy of femoroacetabular impingement focussing on their relevance for sports medicine. It is aimed to help the sports physician to recognise this entity as a cause for groin and hip pain in the athlete and realise its importance for the short term performance of the athlete and its long term significance in terms of development of early hip osteoarthrosis.
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Traumatismos en Atletas/diagnóstico , Pinzamiento Femoroacetabular/diagnóstico , Ingle , Cadera , Dolor/etiología , Acetábulo/lesiones , Acetábulo/fisiopatología , Acetábulo/cirugía , Adulto , Artrografía , Artroscopía , Traumatismos en Atletas/epidemiología , Traumatismos en Atletas/fisiopatología , Traumatismos en Atletas/cirugía , Fenómenos Biomecánicos , Estudios Transversales , Diagnóstico Precoz , Pinzamiento Femoroacetabular/epidemiología , Pinzamiento Femoroacetabular/fisiopatología , Pinzamiento Femoroacetabular/cirugía , Articulación de la Cadera/fisiopatología , Articulación de la Cadera/cirugía , Humanos , Imagen por Resonancia Magnética , Masculino , Osteoartritis de la Cadera/diagnóstico , Osteoartritis de la Cadera/epidemiología , Osteoartritis de la Cadera/fisiopatología , Osteoartritis de la Cadera/cirugía , Rango del Movimiento Articular/fisiología , Resultado del Tratamiento , Adulto JovenRESUMEN
The beta-angle is a radiological tool for measuring the distance between the pathological head-neck junction and the acetabular rim with the hip in 90 degrees of flexion in patients with femoroacetabular impingement. Initially it was measured using an open-chamber MRI. We have developed a technique to measure this angle on plain radiographs. Correlation analysis was undertaken to determine the relationship between the range of movement and the beta-angle in 50 patients with femoroacetabular impingement and 50 asymptomatic control subjects. Inter- and intra-observer reliability of the beta-angle was also evaluated. Patients with femoroacetabular impingement had a significantly smaller (p < 0.001) mean beta-angle (15.6 degrees, 95% confidence interval (CI) 13.3 to 17.7) compared with the asymptomatic group (38.7 degrees, 95% CI 36.5 to 41.0). Correlation between internal rotation and the beta-angle was high in the impingement group and moderate in the asymptomatic group. The beta-angle had excellent inter- and intra-observer reliability in both groups. Our findings suggest that the measurement of the beta-angle on plain radiography may represent a valid, reproducible and cost-effective alternative to open MRI in the assessment of the pathological bony anatomy in patients with cam, pincer and mixed femoroacetabular impingement.
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Acetábulo/diagnóstico por imagen , Cabeza Femoral/diagnóstico por imagen , Articulación de la Cadera/anomalías , Articulación de la Cadera/patología , Inestabilidad de la Articulación/diagnóstico por imagen , Adolescente , Adulto , Femenino , Humanos , Artropatías/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Radiografía , Rango del Movimiento Articular , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
BACKGROUND: Elevation of the gastric pH increases the risk for sensitization against food allergens by hindering protein breakdown. This can be caused by acid-suppressing medication like sucralphate, H2-receptor blockers and proton pump inhibitors, as shown in recent murine experimental and human observational studies. OBJECTIVE: The aim of the present study was to assess the sensitization capacity of the dietary supplement base powder and of over-the-counter antacids. METHODS: Changes of the pH as well as of protein digestion due to base powder or antacids were measured in vitro. To examine the in vivo influence, BALB/c mice were fed codfish extract with one of the acid-suppressing substances. Read-out of antibody levels in the sera, of cytokine levels of stimulated splenocytes and of intradermal skin tests was performed. RESULTS: The pH of hydrochloric acid was substantially increased in vitro by base powder as well as antacids in a time- and dose-dependent manner. This elevation hindered the digestion of codfish proteins in vitro. A significant increase in codfish-specific IgE antibodies was found in the groups fed codfish combined with Rennie Antacidum or with base powder; the latter also showed significantly elevated IgG1 and IgG2a levels. The induction of an anaphylactic immune response was proven by positive results in intradermal skin tests. CONCLUSIONS: Antacids and dietary supplements influencing the gastric pH increase the risk for sensitization against allergenic food proteins. As these substances are commonly used in the general population without consulting a physician, our data may have a major practical and clinical impact.
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Antiácidos/efectos adversos , Suplementos Dietéticos/efectos adversos , Hipersensibilidad a los Alimentos/complicaciones , Hipersensibilidad a los Alimentos/inmunología , Alérgenos/inmunología , Animales , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Femenino , Proteínas de Peces/inmunología , Humanos , Concentración de Iones de Hidrógeno , Ratones , Medicamentos sin Prescripción/efectos adversos , Úlcera Gástrica/complicacionesRESUMEN
Viral vectors are potent gene delivery platforms used for the treatment of genetic and acquired diseases. However, just as viruses have evolved to infect cells efficiently, the immune system has evolved to fight off what it perceives as invading pathogens. Therefore, innate immunity and antigen-specific adaptive immune responses against vector-derived antigens reduce the efficacy and stability of in vivo gene transfer. In addition, a number of vectors are derived from parent viruses that humans encounter through natural infection, resulting in preexisting antibodies and possibly in memory responses against vector antigens. Similarly, antibody and T-cell responses may be directed against therapeutic gene products that often differ from the endogenous nonfunctional or absent protein that is being replaced. As details and mechanisms of such immune reactions are uncovered, novel strategies are being developed, and vectors are being specifically engineered to avoid, suppress or manipulate the response, ideally resulting in sustained expression and immune tolerance to the transgene product. This review provides a summary of our current knowledge of the interactions between the immune system adeno-associated virus, adenoviral and lentiviral vectors, and their transgene products.
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Adenoviridae/inmunología , Dependovirus/inmunología , Terapia Genética , Vectores Genéticos/inmunología , Lentivirus/inmunología , Animales , Anticuerpos Antivirales/inmunología , Antígenos Virales/inmunología , Proteínas del Sistema Complemento/inmunología , Humanos , Tolerancia Inmunológica , Inmunidad Innata , Ratones , Linfocitos T/inmunología , Receptor Toll-Like 9/inmunologíaRESUMEN
BACKGROUND: Gene and protein replacement therapies for inherited protein deficiencies such as hemophilia or lysosomal storage disorders are limited by deleterious immune responses directed against their respective therapeutic proteins. Therefore, the development of protocols preventing such responses is key to providing successful long-term therapy. OBJECTIVES: We sought to develop a protocol, utilizing a drug/peptide cocktail, that would effectively shift the antigen-specific CD4+ T-cell population, tipping the balance from effector T cells (Teffs) towards regulatory T cells (Tregs). METHODS: Treg-deficient (DO11.10-tg Rag2(-/-)) BALB/c mice were used to screen for an optimal protocol addressing the aforementioned goal and to study the mechanisms underlying in vivo changes in T-cell populations. Muscle-directed gene transfer to hemophilia B mice was also performed in order to test the optimal protocol in a therapeutically relevant setting. RESULTS: Specific antigen administration (4-week repeated dosing) combined with rapamycin and interleukin-10 led to substantial reductions in Teffs, via activation-induced cell death, and induced CD4+CD25+FoxP3+ Tregs to a large extent in multiple organs. The proportion of apoptotic T cells also increased over time, whereas Teffs and Tregs were differentially affected. When applied to a model of protein deficiency (gene therapy for hemophilia B), the protocol successfully prevented inhibitor formation, whereas non-specific immunosuppression was only marginally effective. CONCLUSIONS: It is feasible to provide a short-term, prophylactic protocol allowing for the induction of immune tolerance. This protocol may provide a marked advance in efforts seeking to improve clinical outcomes in disorders involving therapeutic protein replacement.
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Antígenos/química , Factor IX/genética , Terapia Genética/métodos , Hemofilia A/genética , Tolerancia Inmunológica , Sirolimus/farmacología , Linfocitos T Reguladores/inmunología , Animales , Linfocitos T CD4-Positivos/citología , Factores de Transcripción Forkhead/biosíntesis , Hemofilia A/metabolismo , Humanos , Interleucina-10/metabolismo , Subunidad alfa del Receptor de Interleucina-2/biosíntesis , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3HRESUMEN
The immune response to coagulation factors VIII or IX, in particular formation of inhibitory antibodies, complicates treatment of hemophilia. Therefore, a number of recent studies in animal models have explored novel approaches toward induction of immune tolerance in protein or gene replacement therapy. Strong evidence has emerged that regulatory T cells (Treg) are an important component of the mechanism by which tolerance is maintained and inhibitor formation, a T help dependent response, is prevented. Limited data in patients also support this concept. In particular, CD4+ CD25+ FoxP3+ Treg, whether naturally occurring or induced, have been invoked in suppression of antibody and of cytotoxic T lymphocyte responses to the therapeutic clotting factor. This review summarizes the data on this emerging concept of Treg-mediated regulation of the immune response in treatment of hemophilia, strategies and mechanisms of Treg induction and function, and the implications for development of immune tolerance protocols.
Asunto(s)
Factores de Coagulación Sanguínea/inmunología , Tolerancia Inmunológica/fisiología , Linfocitos T Reguladores/fisiología , Hemofilia A/inmunología , Hemofilia A/terapia , HumanosRESUMEN
OBJECTIVE: To investigate the effects of steady state erythromycin on the pharmacokinetics of roflumilast and its pharmacodynamically active metabolite roflumilast N-oxide in healthy subjects. Both roflumilast and roflumilast N-oxide have similar intrinsic PDE4 inhibitory activity; the total PDE4 inhibition (tPDE4i) in humans is likely due to the combined effect of roflumilast and roflumilast N-oxide. METHODS: Subjects (n = 16) received single oral roflumilast 500 microg once daily (Days 1 and 15), and repeated oral erythromycin 500 mg three times daily (Days 9 - 21). Percent ratios of Test/Reference (Reference: roflumilast alone; Test: roflumilast and steady-state erythromycin) were calculated for the geometric means and their 90% confidence intervals for systemic exposure (AUC), maximum concentration (Cmax) (roflumilast and roflumilast N-oxide), and apparent clearance of roflumilast. RESULTS: After co-administration of erythromycin and roflumilast, the mean AUC and Cmax of roflumilast increased by 70% and 40%, respectively. The mean apparent clearance of roflumilast decreased from 8.2 l/h (Reference) to 4.8 l/h (Test). Steady-state erythromycin did not alter the mean AUC of roflumilast N-oxide, however, the mean Cmax decreased by 34%. The AUCroflumilast N-oxide/AUCroflumilast ratio decreased from 10.6 (Reference) to 6.4 (Test). Co-administration of erythromycin and roflumilast did not influence the integrated total exposure to roflumilast and roflumilast N-oxide, i.e. mean tPDE4i. No clinically relevant adverse events were observed during the study. CONCLUSIONS: Co-administration of erythromycin (a moderate CYP3A4 inhibitor) and roflumilast does not require dose adjustment of roflumilast.
Asunto(s)
Aminopiridinas/farmacocinética , Benzamidas/farmacocinética , Eritromicina/farmacología , Inhibidores de Fosfodiesterasa/farmacocinética , Administración Oral , Adulto , Aminopiridinas/efectos adversos , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Antibacterianos/farmacología , Área Bajo la Curva , Benzamidas/efectos adversos , Estudios Cruzados , Ciclopropanos/efectos adversos , Ciclopropanos/farmacocinética , Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Interacciones Farmacológicas , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacología , Eritromicina/administración & dosificación , Eritromicina/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Fosfodiesterasa 4 , Inhibidores de Fosfodiesterasa/efectos adversos , Adulto JovenRESUMEN
BACKGROUND: Activated factor X (FXa) is a vitamin K-dependent serine protease that plays a pivotal role in blood coagulation by converting prothrombin to thrombin. There are no reports of humans with complete deficiency of FX, and knockout of murine F10 is embryonic or perinatal lethal. OBJECTIVE: We sought to generate a viable mouse model of FX deficiency. METHODS: We used a socket-targeting construct to generate F10-knockout mice by eliminating F10 exon 8 (knockout allele termed F10(tm1Ccmt), abbreviated as '-'; wild-type '+'), and a plug-targeting construct to generate mice expressing a FX variant with normal antigen levels but low levels of FX activity [4-9% normal in humans carrying the defect, Pro343-->Ser, termed FX Friuli (mutant allele termed F10(tm2Ccmt), abbreviated as F)]. RESULTS: F10 knockout mice exhibited embryonic or perinatal lethality. In contrast, homozygous Friuli mice [F10 (F/F)] had FX activity levels of approximately 5.5% (sufficient to rescue both embryonic and perinatal lethality), but developed age-dependent iron deposition and cardiac fibrosis. Interestingly, F10 (-/F) mice with FX activity levels of 1-3% also showed complete rescue of lethality. Further study of this model provides evidence supporting a role of maternal FX transfer in the embryonic survival. CONCLUSIONS: We demonstrate that, while complete absence of FX is incompatible with murine survival, minimal FX activity as low as 1-3% is sufficient to rescue the lethal phenotype. This viable low-FX mouse model will facilitate the development of FX-directed therapies as well as investigation of the FX role in embryonic development.