RESUMEN
OBJECTIVE: To report two cases of cranial multineuritis after severe acute respiratory syndrome caused by coronavirus-2. METHODS: Patients' data were obtained from medical records of the clinical chart of dell'Angelo Hospital, Venice, Italy. RESULTS: The first patient is a 42-year-old male patient who developed, 10 days after the resolution of coronavirus-2 pneumonia and intensive care unit hospitalization with hyperactive delirium, a cranial multineuritis with asymmetric distribution (bilateral hypoglossus involvement and right Claude Bernard Horner syndrome). No albumin-cytologic dissociation was found in cerebrospinal fluid; severe bilateral denervation was detected in hypoglossus nerve, with normal EMG of other cranial muscles, blink reflex, and cerebral magnetic resonance with gadolinium. He presented a striking improvement after intravenous human immunoglobulin therapy. The second case is a 67-year-old male patient who developed a cranial neuritis (left hypoglossus paresis), with dyslalia and deglutition difficulties. He had cerebrospinal fluid abnormalities (albumin-cytologic dissociation), no involvement of ninth and 10th cranial nerves, diffuse hyporeflexia, and brachial diparesis. DISCUSSION: Cranial neuritis is a possible neurological manifestation of coronavirus-2 pneumonia. Etiology is not clear: it is possible a direct injury of the nervous structures by the virus through olfactory nasopharyngeal terminations. However, the presence of albumin-cytological dissociation in one patient, the sparing of the sense of smell, and the response to human immunoglobulin therapy suggests an immune-mediated genesis of the disorder.
Asunto(s)
COVID-19 , Enfermedades de los Nervios Craneales , Neuritis , Adulto , Anciano , Enfermedades de los Nervios Craneales/complicaciones , Humanos , Italia , Masculino , SARS-CoV-2RESUMEN
TGF-beta1 has been shown to induce autophagy in certain cells but whether and how this action is exerted in muscle and whether this activity relates to TGF-beta1 control of muscle cell differentiation remains unknown. Here, we show that expression of the autophagy-promoting protein phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (PED/PEA-15) progressively declines during L6 and C2C12 skeletal muscle cell differentiation. PED/PEA-15 underwent rapid induction upon TGF-beta1 exposure of L6 and C2C12 myoblasts, accompanied by impaired differentiation into mature myotubes. TGF-beta1 also induced autophagy in the L6 and C2C12 cells through a PP2A/FoxO1-mediated mechanism. Both the TGF-beta1 effect on differentiation and that on autophagy were blocked by specific PED/PEA-15 ShRNAs. Myoblasts stably overexpressing PED/PEA-15 did not differentiate and showed markedly enhanced autophagy. In these same cells, the autophagy inhibitor 3-methyladenine rescued TGF-beta1 effect on both autophagy and myogenesis, indicating that PED/PEA-15 mediates TGF-beta1 effects in muscle. Muscles from transgenic mice overexpressing PED/PEA-15 featured a significant number of atrophic fibers, accompanied by increased light chain 3 (LC3)II to LC3I ratio and reduced PP2A/FoxO1 phosphorylation. Interestingly, these mice showed significantly impaired locomotor activity compared with their non-transgenic littermates. TGF-beta1 causes transcriptional upregulation of the autophagy-promoting gene PED/PEA-15, which in turn is capable to induce atrophic responses in skeletal muscle in vivo.
Asunto(s)
Autofagia/efectos de los fármacos , Músculo Esquelético/citología , Fosfoproteínas/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Adenina/análogos & derivados , Adenina/farmacología , Animales , Proteínas Reguladoras de la Apoptosis , Astrocitos/citología , Astrocitos/metabolismo , Hidrolasas de Éster Carboxílico/metabolismo , Línea Celular , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/metabolismo , Ratones , Ratones Transgénicos , Proteínas Asociadas a Microtúbulos/metabolismo , Desarrollo de Músculos , Músculo Esquelético/metabolismo , Mioblastos/citología , Mioblastos/metabolismo , Fosfoproteínas/antagonistas & inhibidores , Fosfoproteínas/genética , Fosforilación , Interferencia de ARN , ARN Interferente Pequeño/metabolismoRESUMEN
AIMS/HYPOTHESIS: Overproduction of phosphoprotein enriched in diabetes (PED, also known as phosphoprotein enriched in astrocytes-15 [PEA-15]) is a common feature of type 2 diabetes and impairs insulin action in cultured cells and in mice. Nevertheless, the potential role of PED in diabetic complications is still unknown. METHODS: We studied the effect of PED overproduction and depletion on kidney function in animal and cellular models. RESULTS: Transgenic mice overexpressing PED (PEDTg) featured age-dependent increases of plasma creatinine levels and urinary volume, accompanied by expansion of the mesangial area, compared with wild-type littermates. Serum and kidney levels of TGF-beta1 were also higher in 6- and 9-month-old PEDTg. Overexpression of PED in human kidney 2 cells significantly increased TGF-beta1 levels, SMAD family members (SMAD)2/3 phosphorylation and fibronectin production. Opposite results were obtained following genetic silencing of PED in human kidney 2 cells by antisense oligonucleotides. Inhibition of phospholipase D and protein kinase C-beta by 2-butanol and LY373196 respectively reduced TGF-beta1, SMAD2/3 phosphorylation and fibronectin production. Moreover, inhibition of TGF-beta1 receptor activity and SMAD2/3 production by SB431542 and antisense oligonucleotides respectively reduced fibronectin secretion by about 50%. TGF-beta1 circulating levels were significantly reduced in Ped knockout mice and positively correlated with PED content in peripheral blood leucocytes of type 2 diabetic patients. CONCLUSIONS/INTERPRETATION: These data indicate that PED regulates fibronectin production via phospholipase D/protein kinase C-beta and TGF-beta1/SMAD pathways in kidney cells. Raised PED levels may therefore contribute to the abnormal accumulation of extracellular matrix and renal dysfunction in diabetes.
Asunto(s)
Proteína Quinasa C/genética , Factor de Crecimiento Transformador beta1/genética , Actinas/genética , Animales , Astrocitos/metabolismo , Presión Sanguínea , Cartilla de ADN , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/fisiopatología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatología , Nefropatías Diabéticas/epidemiología , Ácidos Grasos no Esterificados/sangre , Fibronectinas/genética , Regulación de la Expresión Génica , Frecuencia Cardíaca , Humanos , Insulina/sangre , Riñón/fisiología , Fallo Renal Crónico/etiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Fenotipo , Fosfoproteínas/biosíntesis , Fosfoproteínas/genética , Proteína Quinasa C beta , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína Smad2/genética , Regulación hacia ArribaRESUMEN
We tested in vitro the effect of recombinant human erythropoietin (rhEPO) plus recombinant human G-CSF (rhG-CSF) on purified human CD34+ haemopoietic progenitors (HP) and in vivo in patients who had undergone anti-cancer chemotherapy for advanced ovarian cancer. In this preliminary experience we found that, in vitro, rhEPO potentiates the effect of rhG-CSF on HP growth and differentiation toward the granulocyte-macrophage lineage. rhEPO plus rhG-CSF produced in vitro a proliferative stimulus of HP which represents 26% of the maximum stimulation obtained using IL-1, IL-3, IL-6, G-CSF, GM-CSF and stem cell factor in combination. In the patients treated with rhEPO plus rhG-CSF after chemotherapy, we observed a favourable trend for platelet and neutrophil recoveries compared with a control group treated with rhG-CSF alone and a significantly higher haematocrit nadir was observed in the rhEPO plus rhG-CSF series. In the patients treated with rhEPO plus rhG-CSF we observed a significant increase of circulating colony-forming unit granulocyte-macrophage (CFU-GM) and burst forming unit-erythroid (BFU-e) compared with the rhG-CSF series. Our results, in vitro and in vivo, encourage the in vivo use of rhEPO plus rhG-CSF to improve blood cell recoveries of patients who have undergone conventional or high-dose chemotherapy. Moreover, rhEPO plus rhG-CSF was demonstrated to be a good HP mobilising treatment for blood stem cell collection after chemotherapy.
Asunto(s)
Eritropoyetina/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Células Madre Hematopoyéticas/efectos de los fármacos , Adulto , Antineoplásicos/administración & dosificación , Recuento de Células Sanguíneas , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Ensayo de Unidades Formadoras de Colonias , Sinergismo Farmacológico , Femenino , Células Madre Hematopoyéticas/citología , Humanos , Técnicas In Vitro , Persona de Mediana Edad , Neoplasias Ováricas/sangre , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Proteínas Recombinantes/administración & dosificaciónRESUMEN
We evaluated the HLA-DR, CD33 and CD13 antigen expression on CD34+ haematopoietic progenitor cells (HPC) isolated from the bone marrow (BM) and peripheral blood (PB) of normal donors. The majority of both BM and PB CD34+ HPC expressed CD13 and HLA-DR. The coexpression of CD34 and CD33 was found in a minor CD34+ subset. After 7 d of culture in the presence of interleukin-3 and granulocyte-macrophage colony-stimulating factor, CD33 expression was detected in about 50% of HPC. At this point CD34 antigen expression was lost and CD13 and HLA-DR expression was partially lost. After 14 d of culture, the majority of HPC were CD33+. HPC maintained the capacity to generate colony forming unit granulocyte-macrophage but they lost the capacity to generate burst forming unit-erythroid. A correlation was found between the percentage of CD34+/HLA-DR+ cells and the total number of colony forming cells in unfractionated samples from BM and PB of patients with malignancies. These studies demonstrate that, in normal conditions, only a minor subset of CD34+ cells coexpress CD33 antigen either in BM or in PB and CD33 antigen is a lineage marker which is coexpressed with HLA-DR and CD13 on a progenitor committed to the granulocytic-macrophagic lineage.