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OBJECTIVE: To compare the clinical phenotype of patients with chronic migraine (CM) to patients with new daily persistent headache of the chronic migraine subtype (NDPH-CM). METHODS: A study was conducted of CM (n = 257) and NDPH-CM (n = 76) from a tertiary headache center in the UK, and in the US of patients with daily CM (n = 60) and NDPH-CM (n = 22). RESULTS: From the UK cohort, the age of first headache onset was lower in CM (mean ± SD: 16 ± 12 years) than in NDPH-CM (mean ± SD: 23 ± 14 years; p < 0.001). There was a greater number of associated migrainous symptoms in CM compared to NDPH-CM (median and interquartile range: 6, 5-8 vs. 5, 4-7; p < 0.001). A family history of headache was more common in CM compared to NDPH-CM (82%, 202/248, vs. 53%, 31/59; p < 0.001). In the US cohort there were no differences. Osmophobia (B = -1.08; p = 0.002) and older age at presentation to the clinic (B = -0.06; p = 0.001) were negative predictors of NDPH-CM. CONCLUSION: NDPH-CM is relatively less migrainous than CM in the UK cohort. Family history of headache is less common in NDPH-CM, with negative predictors for NDPH-CM including osmophobia and older age of presentation to the clinic. More work is required to understand the chronic migraine phenotype of new daily persistent headache.
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Trastornos de Cefalalgia , Trastornos Migrañosos , Cefalea/diagnóstico , Cefalea/epidemiología , Cefalea/etiología , Trastornos de Cefalalgia/diagnóstico , Trastornos de Cefalalgia/epidemiología , Humanos , Trastornos Migrañosos/complicaciones , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/epidemiología , FenotipoRESUMEN
Introduction: Abuse of nitrous oxide (N2O) has an unusually high lifetime prevalence in developed countries and represents a serious concern worldwide. Myeloneuropathy following the inhalant abuse is commonly attributed to the disturbance of vitamin B12 metabolism, with severe motor deficits are often noted. The present study aims to elucidate its underlying pathophysiology. Methods: Eighteen patients with N2O abuse or vitamin B12 deficiency were recruited. Comprehensive central and peripheral neuro-diagnostic tests were performed, including whole spine MRI, and thermal quantitative sensory testing (QST). Specifically, paired motor and sensory nerve excitability tests were performed in order to obtain a complete picture of the sensorimotor axonal damage. Results: The mean duration of N2O exposure for the N2O abuse patients was 17.13 ± 7.23 months. MRI revealed T2 hyperintensity in 87.5% of the N2O abuse patients and 50% of the vitamin B12 deficiency patients. In N2O abuse patients, the motor nerve excitability test showed decreased in peak response (7.08 ± 0.87 mV, P = 0.05), increased latency (7.09 ± 0.28 ms, P < 0.01), increased superexcitability (-32.95 ± 1.74%, P < 0.05), and decreased accommodation to depolarizing current [TEd (40-60 ms) 56.53 ± 0.70%, P < 0.05]; the sensory test showed only decreased peak response (30.54 ± 5.98 µV, P < 0.05). Meanwhile, motor test in vitamin B12 deficiency patients showed only decreased accommodation to depolarizing current [TEd (40-60 ms) 55.72 ± 1.60%, P < 0.01]; the sensory test showed decreased peak response (25.86 ± 3.44 µV, P < 0.05) increased superexcitability (-28.58 ± 3.71%, P < 0.001), increased subexcitability (8.31 ± 1.64%, P < 0.05), and decreased accommodation to depolarizing current [TEd (peak) 67.31 ± 3.35%, P < 0.001]. Conclusion: Compared to vitamin B12 deficiency, N2O abuse patients showed prominent motor superexcitability changes and less prominent sensory superexcitability changes, hinting a unique pathological process different from that of vitamin B12 deficiency. N2O abuse might cause axonal dysfunction not only by blocking methionine metabolism but also by toxicity affecting the paranodal region.
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Background Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) are two rare headache syndromes classified broadly as Trigeminal Autonomic Cephalalgias (TACs). Methods Here, 65 SUNCT (37 males) and 37 SUNA (18 males) patients were studied to describe their clinical manifestations and responses to treatment. Results Pain was almost always unilateral and side-locked. There were three types of attack: Single stabs, stab groups, and a saw-tooth pattern, with some patients experiencing a mixture of two types. As to cranial autonomic symptoms, SUNA patients mainly had lacrimation (41%) and ptosis (40%). Most cases of the two syndromes had attack triggers, and the most common triggers were touching, chewing, or eating for SUNCT, and chewing/eating and touching for SUNA. More than half of each group had a personal or family history of migraine that resulted in more likely photophobia, phonophobia and persistent pain between attacks. For short-term prevention, both syndromes were highly responsive to intravenous lidocaine by infusion; for long-term prevention, lamotrigine and topiramate were effective for SUNCT, and lamotrigine and gabapentin were efficacious in preventing SUNA attacks. A randomized placebo-controlled cross-over trial of topiramate in SUNCT using an N-of-1 design demonstrated it to be an effective treatment in line with clinical experience. Conclusions SUNCT and SUNA are rare primary headache disorders that are distinct and very often tractable to medical therapy.
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Analgésicos/administración & dosificación , Anticonvulsivantes/administración & dosificación , Cefalea/tratamiento farmacológico , Fenotipo , Síndrome SUNCT/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios Cruzados , Femenino , Estudios de Seguimiento , Gabapentina/administración & dosificación , Cefalea/diagnóstico por imagen , Humanos , Lamotrigina/administración & dosificación , Masculino , Persona de Mediana Edad , Síndrome SUNCT/diagnóstico por imagen , Topiramato/administración & dosificación , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Postural headaches are commonly associated with spontaneous intracranial hypotension and cerebrospinal fluid (CSF) leakage from the spine. A subarachnoid-pleural fistula (SPF) is a very rare and serious type of CSF fistula that has mostly been reported following traumatic causes. CASE REPORT: Here, the case of a 36-year-old woman who suffered from postural headaches after chiropractic manipulation of her neck was reported. Brain and spinal magnetic resonance (MR) imaging showed brain sagging, a C7-T1 dural defect, and overt CSF leakage. Heavy T2-weighted MR myelography revealed paravertebral fluid collections, communicating with pleural effusions through bilateral SPFs. The postural headaches were relieved by 3 courses of epidural blood patches. DISCUSSIONS: From the patient's history, her severe SPFs were attributed to rupture of the spinal leptomeninges during vigorous chiropractic manipulation of her neck. Heavy T2-weighted MR myelography could delineate the route of SPFs and CSF leakages.
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Pérdida de Líquido Cefalorraquídeo/complicaciones , Fístula/complicaciones , Cefalea/etiología , Postura/fisiología , Adulto , Pérdida de Líquido Cefalorraquídeo/diagnóstico por imagen , Femenino , Fístula/diagnóstico por imagen , Cefalea/diagnóstico por imagen , Humanos , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: Molecular signaling of angiogenesis begins within hours after initiation of a stroke and the following regulation of endothelial integrity mediated by growth factor receptors and vascular growth factors. Recent studies further provided insights into the coordinated patterns of post-stroke gene expressions and the relationships between neurodegenerative diseases and neural function recovery processes after a stroke. RESULTS: Differential protein-protein interaction networks (PPINs) were constructed at 3 post-stroke time points, and proteins with a significant stroke relevance value (SRV) were discovered. Genes, including UBC, CUL3, APP, NEDD8, JUP, and SIRT7, showed high associations with time after a stroke, and Ingenuity Pathway Analysis results showed that these post-stroke time series-associated genes were related to molecular and cellular functions of cell death, cell survival, the cell cycle, cellular development, cellular movement, and cell-to-cell signaling and interactions. These biomarkers may be helpful for the early detection, diagnosis, and prognosis of ischemic stroke. CONCLUSIONS: This is our first attempt to use our theory of a systems biology framework on strokes. We focused on 3 key post-stroke time points. We identified the network and corresponding network biomarkers for the 3 time points, further studies are needed to experimentally confirm the findings and compare them with the causes of ischemic stroke. Our findings showed that stroke-associated biomarker genes at different time points were significantly involved in cell cycle processing, including G2-M, G1-S and meiosis, which contributes to the current understanding of the etiology of stroke. We hope this work helps scientists reveal more hidden cellular mechanisms of stroke etiology and repair processes.
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Miocardio/metabolismo , Mapas de Interacción de Proteínas , Accidente Cerebrovascular/metabolismo , Biología de Sistemas/métodos , Biomarcadores/metabolismo , Humanos , Miocardio/patología , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/patología , Factores de TiempoRESUMEN
Denbinobin, a phenanthraquinone derivative, was shown to exert antitumor activities in several types of cancer cell lines. However, the precise mechanism underlying denbinobin-induced cell death remains unclear. In this study, we investigated the apoptotic signaling cascade elicited by denbinobin in human glioblastoma multiforme (GBM) cells. Denbinobin concentration-dependently caused a decrease in the cell viability of GBM cells. A flow cytometric analysis of propidium iodide (PI)-stained cells demonstrated that denbinobin induced GBM cell apoptosis. Denbinobin evoked caspase-3 activation and degradation of poly (ADP-ribose) polymerase (PARP) and N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk), a broad-spectrum caspase inhibitor that prevented denbinobin-induced cell death. In addition, denbinobin-induced cell death was diminished by the transfection of wild-type (WT) Akt or IκB kinase (IKK) into GBM cells. Denbinobin reduced IKK phosphorylation in a time-dependent manner, and denbinobin-dephosphorylated IKK was accompanied by a decrease in Akt phosphorylation. The phosphorylation status of forkhead in rhabdomyosarcoma (FKHR), a downstream signal molecule of Akt, was also diminished by the presence of denbinobin. Furthermore, transfection of GBM cells with WT IKKα markedly suppressed the decreases in Akt and FKHR phosphorylation caused by denbinobin. In contrast, transfection with WT IKKß only slightly affected denbinobin's action against IKK, Akt, and FKHR. These results suggest that IKKα inactivation, followed by Akt and FKHR dephosphorylation and caspase-3 activation, contributes to denbinobin-induced GBM cell apoptosis.
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Antraquinonas/farmacología , Apoptosis/efectos de los fármacos , Factores de Transcripción Forkhead/metabolismo , Glioblastoma/patología , Quinasa I-kappa B/metabolismo , Fenantrenos/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Antineoplásicos/farmacología , Caspasa 3/metabolismo , Línea Celular Tumoral , Activación Enzimática/efectos de los fármacos , Proteína Forkhead Box O1 , Humanos , Fosforilación/efectos de los fármacos , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteolisis/efectos de los fármacosRESUMEN
BACKGROUND: Zerumbone, a sesquiterpene compound isolated from subtropical ginger, Zingiber zerumbet Smith, has been documented to exert antitumoral and anti- inflammatory activities. In this study, we demonstrate that zerumbone induces apoptosis in human glioblastoma multiforme (GBM8401) cells and investigate the apoptotic mechanism. METHODS: We added a caspase inhibitor and transfected wild-type (WT) IKK and Akt into GBM 8401 cells, and measured cell viability and apoptosis by MTT assay and flow cytometry. By western blotting, we evaluated activation of caspase-3, dephosphorylation of IKK, Akt, FOXO1 with time, and change of IKK, Akt, and FOXO1 phosphorylation after transfection of WT IKK and Akt. RESULTS: Zerumbone (10~50 µM) induced death of GBM8401 cells in a dose-dependent manner. Flow cytometry studies showed that zerumbone increased the percentage of apoptotic GBM cells. Zerumbone also caused caspase-3 activation and poly (ADP-ribose) polymerase (PARP) production. N-benzyloxycarbonyl -Val-Ala-Asp- fluoromethylketone (zVAD-fmk), a broad-spectrum caspase inhibitor, hindered zerumbone-induced cell death. Transfection of GBM 8401 cells with WT IKKα inhibited zerumbone-induced apoptosis, and zerumbone significantly decreased IKKα phosphorylation levels in a time-dependent manner. Similarly, transfection of GBM8401 cells with Akt suppressed zerumbone-induced apoptosis, and zerumbone also diminished Akt phosphorylation levels remarkably and time-dependently. Moreover, transfection of GBM8401 cells with WT IKKα reduced the zerumbone-induced decrease in Akt and FOXO1 phosphorylation. However, transfection with WT Akt decreased FOXO1, but not IKKα, phosphorylation. CONCLUSION: The results suggest that inactivation of IKKα, followed by Akt and FOXO1 phosphorylation and caspase-3 activation, contributes to zerumbone-induced GBM cell apoptosis.
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Apoptosis , Factores de Transcripción Forkhead , Quinasa I-kappa B , Proteína Oncogénica v-akt , Sesquiterpenos , Apoptosis/efectos de los fármacos , Apoptosis/genética , Caspasa 3/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Zingiber officinale/química , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Quinasa I-kappa B/genética , Quinasa I-kappa B/metabolismo , Proteína Oncogénica v-akt/genética , Proteína Oncogénica v-akt/metabolismo , Fosforilación , Sesquiterpenos/química , Sesquiterpenos/farmacología , Transducción de SeñalRESUMEN
BACKGROUND: Adopting thrombolytic therapy with tissue plasminogen activator (tPA) in clinical practice presents many challenges. One major factor is the restrictive time window of 0-3 hours after symptom onset, for the commencement of treatment. OBJECTIVE: To test the efficacy of a newly developed plasminogen activator (human tissue urokinase type plasminogen activator [HTUPA]) for the treatment of acute ischaemic stroke within 5 hours of symptom onset. DESIGN: An open-label, dose escalation trial. The initial dose was 0.3 mg/kg and could be increased or decreased depending on tolerability. SETTING: Three teaching hospitals in Taiwan. PARTICIPANTS: Thirty-three patients who presented with National Institute of Health Stroke Scale (NIHSS) scores of between 9 and 20, who had evidence of ischaemic stroke confirmed by CT. MAIN OUTCOMES MEASURES: Efficacy was assessed by the NIHSS, the Modified Rankin Scale (MRS), the Barthel Index and the Glasgow Outcome Scale. Preliminary efficacy endpoints included major neurological improvement at 24 hours and favourable outcome at 90 days after administration of HTUPA. RESULTS: Of the 33 patients who received HTUPA, 29 received 0.3 mg/kg, 3 received 0.35 mg/kg and 1 received 0.4 mg/kg. Major neurological improvement, defined as improvement of > or =4 points on the NIHSS 24 hours after treatment, was observed in 45% of all patients treated (15/33) and in 48% (14/29) of those treated with 0.3 mg/kg. Ninety days after symptom onset, in those who received HTUPA 0.3 mg/kg, the proportion of patients with a favourable outcome was 34% on the NIHSS (< or =1), 45% on the MRS (0 or 1), 41% on the Barthel Index (> or =95) and 45% on the Glasgow Outcome Scale (1). Eighty six percent of the patients treated with 0.3 mg/kg within 0-3 hours of symptom onset reached scores of 0-1 on both the NIHSS and the MRS. CONCLUSIONS: Approximately 50% of patients treated with HTUPA 0.3 mg/kg within a 5-hour window after symptom onset experienced major neurological improvement within 24 hours of drug administration. Thrombolytic agents, in this case HTUPA, may be suitable for Taiwanese or Asian patients with acute ischaemic stroke who meet the inclusion criteria.