RESUMEN
INTRODUCTION: Pontocerebellar hypoplasia type 2 (PCH2) is a rare neurodevelopmental disease with a high disease burden. Besides neurological symptoms, somatic symptoms, such as gastroesophageal reflux (GERD) and failure to thrive, are major contributors to this burden. METHODS: We report three patients with genetically confirmed PCH2A and significant gastrointestinal (GI) symptoms. RESULTS: Apart from impaired swallowing and GERD, which are frequently reported in patients with PCH2, all three patients suffered from episodes of spasmodic abdominal pain and restlessness. In one severely affected patient, lack of intestinal alkaline phosphatase (IAP) is demonstrated. CONCLUSION: GI symptoms are common in PCH2. We draw attention to episodes of spasmodic abdominal pain seriously, aggravating the condition of the patients, especially their movement disorder, and discuss the role of IAP.
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Reflujo Gastroesofágico , Atrofias Olivopontocerebelosas , Dolor Abdominal , Reflujo Gastroesofágico/diagnóstico , HumanosAsunto(s)
Ojo/patología , Zoonosis/microbiología , Zoonosis/parasitología , Animales , Enfermedad por Rasguño de Gato/microbiología , Enfermedad por Rasguño de Gato/patología , Enfermedad por Rasguño de Gato/transmisión , Conjuntivitis Bacteriana/microbiología , Conjuntivitis Bacteriana/patología , Conjuntivitis Bacteriana/transmisión , Cisticercosis/parasitología , Cisticercosis/patología , Cisticercosis/transmisión , Ojo/microbiología , Ojo/parasitología , Humanos , Larva Migrans/parasitología , Larva Migrans/patología , Larva Migrans/transmisión , Trastornos de la Motilidad Ocular/microbiología , Trastornos de la Motilidad Ocular/patología , Toxoplasma/patogenicidad , Toxoplasmosis/parasitología , Toxoplasmosis/patología , Toxoplasmosis/transmisión , Zoonosis/transmisiónRESUMEN
Atherosclerosis is an inflammatory response of the arterial wall to "injury", which is prominently driven by cytokines. The inflammatory mediator macrophage migration inhibitory factor (MIF) is a unique cytokine that was recently associated with atherogenesis. Here, we have investigated whether MIF has a role in spontaneous atherosclerosis by studying apolipoprotein E-deficient (ApoE(-/-)) mice treated with neutralizing anti-MIF monoclonal antibody and comparison with isotype IgG-treated controls. After 14 weeks, the aortas and heart valves were analyzed for inflammatory status, macrophage content and plaque areas. MIF expression in the aortic wall was elevated upon spontaneous atherogenesis, with foam cells representing a major source. Of note, MIF blockade led to a marked reduction in intimal Mac-1-positive macrophages. Similarly, treatment with anti-MIF antibody led to a reduction of a variety of inflammatory mediators typically associated with atherosclerosis including the circulating levels of fibrinogen, MIF and IL-6. Importantly, the local aortic expression of ICAM-1, MMP-2, TNF, IL-12, and CD40L was reduced by MIF blockade, as were the levels of the phospho-c-Jun and C/EBPbeta transcription factors. The observed strong reduction of inflammatory parameters by anti-MIF treatment was associated with a small, yet non-significant, reduction in aortic plaque area. Thus, although MIF's role is not directly linked to plaque volume expansion, in this mouse model of spontaneous atherogenesis, MIF plays an important role in intimal inflammation.
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Anticuerpos Monoclonales/uso terapéutico , Aorta Torácica/patología , Aortitis/tratamiento farmacológico , Aterosclerosis/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Factores Inhibidores de la Migración de Macrófagos/antagonistas & inhibidores , Animales , Aorta Torácica/metabolismo , Aortitis/metabolismo , Aortitis/patología , Apolipoproteínas E/deficiencia , Aterosclerosis/metabolismo , Aterosclerosis/patología , Ligando de CD40/metabolismo , Modelos Animales de Enfermedad , Estudios de Seguimiento , Expresión Génica , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Interleucina-12/metabolismo , Factores Inhibidores de la Migración de Macrófagos/genética , Factores Inhibidores de la Migración de Macrófagos/inmunología , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa , ARN/genética , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Atherosclerosis is a chronic inflammatory response of the arterial wall to injury. Macrophage migration inhibitory factor (MIF), a cytokine with potent inflammatory functions, was thus considered to be important in atherosclerotic lesion evolution. METHODS AND RESULTS: We studied the presence and distribution of MIF immunoreactivity (MIF-IR) and MIF mRNA in internal mammary arteries with a normal histology and arteries with plaques in different stages of human atherosclerosis. To address a potential role for the coactivator Jab1 as a cellular mediator of MIF effects in vascular tissue, we correlated the expression of MIF to that of Jab1 by using immunohistochemistry and coimmunoprecipitation. We further sought to determine a potential functional role for endothelium-derived MIF in early atherogenesis by studying the effects of oxidized LDL on MIF expression in cultured human umbilical vascular endothelial cells. The results showed that MIF-IR and Jab1-IR are found in all cell types present in atherosclerotic lesions, that MIF-IR is upregulated during progression of atherosclerosis, that MIF is produced locally in the arterial wall, and that all MIF(+) cells are simultaneously Jab1(+). Coimmunoprecipitation experiments demonstrated in vivo complex formation between MIF and Jab1 in plaques. MIF expression in human umbilical vascular endothelial cells and a macrophage line was upregulated after stimulation with oxidized LDL. CONCLUSIONS: MIF is produced abundantly by various cells in all types of human atherosclerotic lesions and thus may play an important role in early plaque development and advanced complicated lesions. MIF-Jab1 complexes could serve critical regulatory functions in atherosclerotic lesion evolution.