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INTRODUCTION: Contrasting with the lymphopenia classically reported after administration of glucocorticoids, a lymphocytosis has been sometimes observed in patients after glucocorticoid administration. We here determine prospectively the timing and magnitude of methylprednisolone (mPDN)-induced lymphocytosis and study the effects of concomitant propranolol administration on lymphocyte count (Ly). METHODS: Ly was measured before and 24 to 72hours after initiating mPDN treatment in 20 patients with immune-mediated inflammatory disorders (IMID). After one week, patients with increased Ly were divided in two groups receiving, in addition to mPDN, either propranolol or a placebo; Ly was determined 4 days later. Lymphocyte subpopulations and mPDN plasma levels were determined in subsets of the patients. Values are expressed as median with 25%-75% interquartile range. RESULTS: A 73.4% (37-305) increase of Ly was observed in 18/20 patients as soon as 48 (48-72) hours after initiating mPDN (32mg; 16-32). Lymphocytosis (Ly≥4000/µL) was observed in 7 patients and hyperlymphocytosis (Ly≥5000/µL) in 4 of them. The increase in Ly was noted both for B and T cells. Median mPDN plasma levels (n=13) were 97.4ng/mL (IQR 67-489) and 3.2 (IQR 2.1-5.1) respectively 8hours and 24hours after oral mPDN administration. No significant change in Ly was shown under propranolol (p=0.570). CONCLUSION: A morning lymphocytosis observed during mPDN treatment occurs in the very first days of mPDN administration. Our results do not support the hypothesis of an increased adrenergic tone responsible for this phenomenon. Identifying this unexpected etiology of lymphocytosis could mitigate the need for unnecessary supplementary investigations in clinical practice.
Assuntos
Imidazóis , Tetrazóis , Bélgica/epidemiologia , Diarreia , Humanos , Imidazóis/efeitos adversos , Tetrazóis/efeitos adversosRESUMO
Intravascular large B-cell lymphoma is a rare entity characterized by the proliferation of neoplastic lymphocytes in the lumen of small blood vessels and high mortality. Diagnosis of intravascular lymphoma is often delayed or established postmortem. Here, we report the case of a 48-year-old woman presenting hemophagocytic syndrome, with pituitary gland and neurological involvement. Diagnosis of intravascular large B-cell lymphoma was made on perisplenic vessels, while liver and bone marrow biopsy was noncontributive. This case demonstrates the importance of thorough histopathologic investigations in the setting of high suspicion.
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The osmotic demyelination syndrome (ODS) is a non-primary inflammatory disorder of the central nervous system myelin that is often associated with a precipitous rise of serum sodium concentration. To investigate the physiopathology of ODS in vivo, we generated a novel murine model based on the abrupt correction of chronic hyponatremia. Accordingly, ODS mice developed impairments in brainstem auditory evoked potentials and in grip strength. At 24 hr post-correction, oligodendrocyte markers (APC and Cx47) were downregulated, prior to any detectable demyelination. Oligodendrocytopathy was temporally and spatially correlated with the loss of astrocyte markers (ALDH1L1 and Cx43), and both with the brain areas that will develop demyelination. Oligodendrocytopathy and astrocytopathy were confirmed at the ultrastructural level and culminated with necroptotic cell death, as demonstrated by pMLKL immunoreactivity. At 48 hr post-correction, ODS brains contained pathognomonic demyelinating lesions in the pons, mesencephalon, thalamus and cortical regions. These damages were accompanied by blood-brain barrier (BBB) leakages. Expression levels of IL-1ß, FasL, TNFRSF6 and LIF factors were significantly upregulated in the ODS lesions. Quiescent microglial cells type A acquired an activated type B morphology within 24 hr post-correction, and reached type D at 48 hr. In conclusion, this murine model of ODS reproduces the CNS demyelination observed in human pathology and indicates ambiguous causes that is regional vulnerability of oligodendrocytes and astrocytes, while it discards BBB disruption as a primary cause of demyelination. This study also raises new queries about the glial heterogeneity in susceptible brain regions as well as about the early microglial activation associated with ODS.
Assuntos
Astrócitos/fisiologia , Encéfalo/fisiopatologia , Doenças Desmielinizantes/fisiopatologia , Necrose/fisiopatologia , Oligodendroglia/fisiologia , Animais , Astrócitos/patologia , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Permeabilidade Capilar/fisiologia , Conexina 43/metabolismo , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Progressão da Doença , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Membro Anterior/fisiopatologia , Junções Comunicantes/patologia , Junções Comunicantes/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/patologia , Microglia/fisiologia , Força Muscular/fisiologia , Necrose/patologia , Oligodendroglia/patologiaRESUMO
Adequate protein folding is necessary for normal cell function and a tightly regulated process that requires proper intracellular ionic strength. In many cell types, imbalance between protein synthesis and degradation can induce endoplasmic reticulum (ER) stress, which if sustained, can in turn lead to cell death. In nematodes, osmotic stress induces massive protein aggregation coupled with unfolded protein response and ER stress. In clinical practice, patients sustaining rapid correction of chronic hyponatremia are at risk of osmotic demyelination syndrome. The intense osmotic stress sustained by brain cells is believed to be the major risk factor for demyelination resulting from astrocyte death, which leads to microglial activation, blood-brain barrier opening, and later, myelin damage. Here, using a rat model of osmotic demyelination, we showed that rapid correction of chronic hyponatremia induces severe alterations in proteostasis characterized by diffuse protein aggregation and ubiquitination. Abrupt correction of hyponatremia resulted in vigorous activation of both the unfolded protein response and ER stress accompanied by increased autophagic activity and apoptosis. Immunofluorescence revealed that most of these processes occurred in astrocytes within regions previously shown to be demyelinated in later stages of this syndrome. These results identify osmotic stress as a potent protein aggregation stimuli in mammalian brain and further suggest that osmotic demyelination might be a consequence of proteostasis failure on severe osmotic stress.
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Encefalopatias/etiologia , Doenças Desmielinizantes/etiologia , Homeostase , Hiponatremia/terapia , Neuroglia , Pressão Osmótica , Agregação Patológica de Proteínas/etiologia , Animais , Estresse do Retículo Endoplasmático , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Hyponatremia is a common electrolyte disorder that carries significant morbidity and mortality. However, severe chronic hyponatremia should not be corrected rapidly to avoid brain demyelination. Vasopressin receptor antagonists (vaptans) are now being widely used for the treatment of hyponatremia along with other alternatives like hypertonic saline. Previous reports have suggested that, in some cases, urea can also be used to correct hyponatremia. Correction of severe hyponatremia with urea has never been compared to treatment with a vaptan or hypertonic saline with regard to the risk of brain complications in the event of a too rapid rise in serum sodium. Here, we compared the neurological outcome of hyponatremic rats corrected rapidly with urea, lixivaptan, and hypertonic saline. Despite similar increase in serum sodium obtained by the three drugs, treatment with lixivaptan or hypertonic saline resulted in a higher mortality than treatment with urea. Histological analysis showed that treatment with urea resulted in less pathological change of experimental osmotic demyelination than was induced by hypertonic saline or lixivaptan. This included breakdown of the blood-brain barrier, microglial activation, astrocyte demise, and demyelination. Thus, overcorrection of hyponatremia with urea resulted in significantly lower mortality and neurological impairment than the overcorrection caused by lixivaptan or hypertonic saline.
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Hiponatremia/tratamento farmacológico , Ureia/uso terapêutico , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Benzamidas/uso terapêutico , Barreira Hematoencefálica/efeitos dos fármacos , Encefalopatias/patologia , Encefalopatias/prevenção & controle , Doença Crônica , Doenças Desmielinizantes/prevenção & controle , Hiponatremia/complicações , Masculino , Microglia/efeitos dos fármacos , Microglia/patologia , Pirróis/uso terapêutico , Ratos , Ratos Wistar , Solução Salina Hipertônica/uso terapêuticoRESUMO
Oral urea has been used in the past to treat various diseases like gastric ulcers, liver metastases, sickle cell disease, heart failure, brain oedema, glaucoma, Meniere disease, etc. We have demonstrated for years, the efficacy of urea to treat euvolemic (SIADH) or hypervolemic hyponatremia. We briefly describe the indications of urea use in symptomatic and paucisymptomatic hyponatremic patients. Urea is a non-toxic, cheap product, and protects against osmotic demyelinating syndrome (ODS) in experimental studies. Prospective studies showing the benefit to treat mild chronic hyponatremia due to SIADH and comparing water restriction, urea, high ceiling diuretics, and antivasopressin antagonist antagonist should be done.
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BACKGROUND AND OBJECTIVES: Vaptans (vasopressin V(2)-receptor antagonists) are a new approach for the treatment of hyponatremia. However, their indications remain to be determined, and their benefit compared with that of the usual treatments for the syndrome of inappropriate antidiuretic hormone secretion (SIADH) have not been evaluated. This prospective, long-term study compared the efficacy, tolerability, and safety of two oral vaptans with those of oral urea in patients with SIADH. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with chronic SIADH of various origins were treated first with vaptans for 1 year. After an 8-day holiday period, they received oral urea for an additional 1-year follow-up. Serum sodium was measured every 2 months, and drug doses were adjusted accordingly. RESULTS: Thirteen participants were initially included in the study (serum sodium, 125±3 mEq/L); 12 completed the 2-year treatment period. Treatment with vaptans (satavaptan, 5-50 mg/d, n=10; tolvaptan, 30-60 mg/day, n=2) increased natremia (serum sodium, 135±3 mEq/L) during the 1-year vaptan period without escape. Hyponatremia recurred in the 12 participants when vaptans were stopped (holiday period). Urea improved the natremia with the same efficacy (serum sodium, 135±2 mEq/L) as vaptans during the 1-year urea treatment period. One participant treated with tolvaptan withdrew from the study early because of excessive thirst. Another patient receiving urea developed hypernatremia without complications. CONCLUSIONS: Urea has efficacy similar to that of vaptans for treatment of chronic SIADH. Tolerance is generally good for both agents.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Benzazepinas/uso terapêutico , Síndrome de Secreção Inadequada de HAD/tratamento farmacológico , Morfolinas/uso terapêutico , Compostos de Espiro/uso terapêutico , Ureia/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Benzazepinas/efeitos adversos , Feminino , Humanos , Hiponatremia/sangue , Hiponatremia/tratamento farmacológico , Hiponatremia/etiologia , Síndrome de Secreção Inadequada de HAD/sangue , Síndrome de Secreção Inadequada de HAD/complicações , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Sódio/sangue , Compostos de Espiro/efeitos adversos , Fatores de Tempo , Tolvaptan , Ureia/efeitos adversosRESUMO
Large vessels vasculitis and more specifically, Giant cell arteritis, is characterized by increased inflammatory markers, headaches and altered clinical status. Diagnosis is confirmed by biopsy of temporal arteries showing the presence of granuloma and vasculitis. We hereby report the case of a patient presenting initially as pericarditis and revealing large vessel vasculitis using FDG-PET.