RESUMO
We report findings in five patients who presented with venous thrombosis and thrombocytopenia 7 to 10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against coronavirus disease 2019 (Covid-19). The patients were health care workers who were 32 to 54 years of age. All the patients had high levels of antibodies to platelet factor 4-polyanion complexes; however, they had had no previous exposure to heparin. Because the five cases occurred in a population of more than 130,000 vaccinated persons, we propose that they represent a rare vaccine-related variant of spontaneous heparin-induced thrombocytopenia that we refer to as vaccine-induced immune thrombotic thrombocytopenia.
Assuntos
Autoanticorpos/sangue , Vacinas contra COVID-19/efeitos adversos , Fator Plaquetário 4/imunologia , Trombocitopenia/etiologia , Trombose/etiologia , Adulto , Doenças Autoimunes/etiologia , Análise Química do Sangue , ChAdOx1 nCoV-19 , Ensaio de Imunoadsorção Enzimática , Evolução Fatal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária , Contagem de PlaquetasRESUMO
BACKGROUND: In acromegaly, the primary tumor is usually found during magnetic resonance imaging (MRI) of the pituitary gland. A remnant tumor after surgery is, however, harder to depict. When a tumor is missed, the remaining option is usually lifelong pharmacological treatment. PURPOSE: To identify tumors by reassessment of all available MRI scans in pharmacologically treated patients, operated or not, and to compare our results with the routine MRI reports. MATERIAL AND METHODS: Adult patients diagnosed with acromegaly and managed at a tertiary care center between 2005 and 2021 and currently on pharmacological treatment were included. MRI scans were evaluated in a standardized manner and classified independently by a radiologist and an endocrinologist into "certain," "suspected," or "no tumor." In case of disagreement, consensus was achieved with a senior neuroradiologist. The results were compared using the clinical radiologists' routine MRI reports. RESULTS: We identified certain and suspected tumors in 29/74 and 36/74 patients, respectively. No tumor was identified in nine patients. In five of these, no MRI contrast agent was given. Discrepancy between our results and the routine MRI reports was found in 31/74 patients (P = 0.01). In 22 patients, the routine reports described no tumor while we identified certain tumors in 2/22 patients and suspected tumors in 13/22 patients. CONCLUSION: In most patients with pharmacologically treated acromegaly, we identified a certain or suspected pituitary tumor. These findings were more frequent compared to the routine MRI reports. Based on our results, patients will be considered for a change in long-term treatment modality.
Assuntos
Acromegalia , Imageamento por Ressonância Magnética , Neoplasias Hipofisárias , Humanos , Acromegalia/diagnóstico por imagem , Acromegalia/tratamento farmacológico , Imageamento por Ressonância Magnética/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/diagnóstico por imagem , Adulto , Idoso , Hipófise/diagnóstico por imagem , Hipófise/patologia , Estudos RetrospectivosRESUMO
BACKGROUND: Clinical observations indicated that vaccine-induced immune thrombosis with thrombocytopenia (VITT)-associated cerebral venous sinus thrombosis (CVST) often has a space-occupying effect and thus necessitates decompressive surgery (DS). While comparing with non-VITT CVST, this study explored whether VITT-associated CVST exhibits a more fulminant clinical course, different perioperative and intensive care unit management, and worse long-term outcome. METHODS: This multicenter, retrospective cohort study collected patient data from 12 tertiary centers to address priorly formulated hypotheses concerning the clinical course, the perioperative management with related complications, extracerebral complications, and the functional outcome (modified Rankin Scale) in patients with VITT-associated and non-VITT CVST, both with DS. RESULTS: Both groups, each with 16 patients, were balanced regarding demographics, kind of clinical symptoms, and radiological findings at hospital admission. Severity of neurological symptoms, assessed with the National Institute of Health Stroke Scale, was similar between groups at admission and before surgery, whereas more patients with VITT-associated CVST showed a relevant midline shift (≥ 4 mm) before surgery (100% vs. 68.8%, p = 0.043). Patients with VITT-associated CVST tended to undergo DS early, i.e., ≤ 24 h after hospital admission (p = 0.077). Patients with VITT-associated CVST more frequently received platelet transfusion, tranexamic acid, and fibrinogen perioperatively. The postoperative management was comparable, and complications were evenly distributed. More patients with VITT-associated CVST achieved a favorable outcome (modified Rankin Scale ≤ 3) at 3 months (p = 0.043). CONCLUSIONS: Although the prediction of individual courses remains challenging, DS should be considered early in VITT-associated CVST because an overall favorable outcome appears achievable in these patients.
Assuntos
Trombose dos Seios Intracranianos , Trombocitopenia , Trombose , Humanos , Estudos Retrospectivos , Trombose dos Seios Intracranianos/etiologia , Trombose dos Seios Intracranianos/cirurgia , Trombose/complicações , Trombocitopenia/induzido quimicamente , Progressão da DoençaRESUMO
OBJECTIVE: Cerebral venous thrombosis (CVT) caused by vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse effect of adenovirus-based severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines. In March 2021, after autoimmune pathogenesis of VITT was discovered, treatment recommendations were developed. These comprised immunomodulation, non-heparin anticoagulants, and avoidance of platelet transfusion. The aim of this study was to evaluate adherence to these recommendations and its association with mortality. METHODS: We used data from an international prospective registry of patients with CVT after the adenovirus-based SARS-CoV-2 vaccination. We analyzed possible, probable, or definite VITT-CVT cases included until January 18, 2022. Immunomodulation entailed administration of intravenous immunoglobulins and/or plasmapheresis. RESULTS: Ninety-nine patients with VITT-CVT from 71 hospitals in 17 countries were analyzed. Five of 38 (13%), 11 of 24 (46%), and 28 of 37 (76%) of the patients diagnosed in March, April, and from May onward, respectively, were treated in-line with VITT recommendations (p < 0.001). Overall, treatment according to recommendations had no statistically significant influence on mortality (14/44 [32%] vs 29/55 [52%], adjusted odds ratio [OR] = 0.43, 95% confidence interval [CI] = 0.16-1.19). However, patients who received immunomodulation had lower mortality (19/65 [29%] vs 24/34 [70%], adjusted OR = 0.19, 95% CI = 0.06-0.58). Treatment with non-heparin anticoagulants instead of heparins was not associated with lower mortality (17/51 [33%] vs 13/35 [37%], adjusted OR = 0.70, 95% CI = 0.24-2.04). Mortality was also not significantly influenced by platelet transfusion (17/27 [63%] vs 26/72 [36%], adjusted OR = 2.19, 95% CI = 0.74-6.54). CONCLUSIONS: In patients with VITT-CVT, adherence to VITT treatment recommendations improved over time. Immunomodulation seems crucial for reducing mortality of VITT-CVT. ANN NEUROL 2022;92:562-573.
Assuntos
COVID-19 , Trombose Intracraniana , Trombose Venosa , Adenoviridae , Anticoagulantes/uso terapêutico , Vacinas contra COVID-19/efeitos adversos , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , SARS-CoV-2 , Vacinação/efeitos adversos , Trombose Venosa/complicaçõesRESUMO
Increased levels of neutrophil extracellular traps (NETs) have been detected in individuals with vaccine complications after the ChAdOx1 nCov vaccine with a correlation between the severity of vaccine side effects and the level of NETosis. DNases may disrupt NETs by degrading their content of DNA, and a balance has been reported between NETs and DNases. Because of this and since the inflammatory marker NETs may be used as a confirmatory test in diagnosing VITT, it is of interest to monitor levels of DNase in patients with increased NETs levels. The current novel rapid DNase ELISA was tested in blood samples of patients with known increased levels of NETs with or without VITT after ChAdOx1 nCoV-19 vaccination. DNase levels in VITT patients were significantly increased compared with normal unvaccinated blood donors and compared with patients with post-vaccination symptoms but not VITT. However, since EDTA was found to inhibit DNase, serum and not EDTA-plasma samples should be applied for DNase testing. The novel DNase assay may serve as a supplementary test to the NETs test when analysing samples from patients with suspected increased NETs levels.
Assuntos
Desoxirribonucleases , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , ChAdOx1 nCoV-19 , Doadores de Sangue , Vacinação/efeitos adversosRESUMO
BACKGROUND AND PURPOSE: Cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) is an adverse drug reaction occurring after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. CVST-VITT patients often present with large intracerebral haemorrhages and a high proportion undergoes decompressive surgery. Clinical characteristics, therapeutic management and outcomes of CVST-VITT patients who underwent decompressive surgery are described and predictors of in-hospital mortality in these patients are explored. METHODS: Data from an ongoing international registry of patients who developed CVST within 28 days of SARS-CoV-2 vaccination, reported between 29 March 2021 and 10 May 2022, were used. Definite, probable and possible VITT cases, as defined by Pavord et al. (N Engl J Med 2021; 385: 1680-1689), were included. RESULTS: Decompressive surgery was performed in 34/128 (27%) patients with CVST-VITT. In-hospital mortality was 22/34 (65%) in the surgical and 27/94 (29%) in the non-surgical group (p < 0.001). In all surgical cases, the cause of death was brain herniation. The highest mortality rates were found amongst patients with preoperative coma (17/18, 94% vs. 4/14, 29% in the non-comatose; p < 0.001) and bilaterally absent pupillary reflexes (7/7, 100% vs. 6/9, 67% with unilaterally reactive pupil, and 4/11, 36% with bilaterally reactive pupils; p = 0.023). Postoperative imaging revealed worsening of index haemorrhagic lesion in 19 (70%) patients and new haemorrhagic lesions in 16 (59%) patients. At a median follow-up of 6 months, 8/10 of surgical CVST-VITT who survived admission were functionally independent. CONCLUSIONS: Almost two-thirds of surgical CVST-VITT patients died during hospital admission. Preoperative coma and bilateral absence of pupillary responses were associated with higher mortality rates. Survivors often achieved functional independence.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Púrpura Trombocitopênica Idiopática , Trombose dos Seios Intracranianos , Trombocitopenia , Humanos , Coma , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Trombose dos Seios Intracranianos/induzido quimicamente , Trombose dos Seios Intracranianos/cirurgia , Trombocitopenia/induzido quimicamente , Trombocitopenia/cirurgia , Púrpura Trombocitopênica Idiopática/induzido quimicamente , Púrpura Trombocitopênica Idiopática/cirurgiaRESUMO
PURPOSE: Sustained cure of acromegaly can only be achieved by surgery. Most growth hormone (GH) secreting pituitary adenomas are macroadenomas (≥ 10 mm) at diagnosis, with reported surgical cure rates of approximately 50%. Long-term data on disease control rates after surgery are limited. Our aim was to estimate short- and long-term rates of biochemical control after pituitary surgery in acromegaly and identify predictive factors. METHODS: Patients operated for GH-secreting pituitary adenomas between 2005-2020 were included from the local pituitary registry (n = 178). Disease activity and treatment data were recorded at one-year (short-term) and five-year (long-term) postoperative follow-up. Biochemical control was defined as insulin-like growth factor 1 (IGF-1) ≤ 1.2 × upper limit of normal value. Multivariate regression models were used to identify factors potentially predicting biochemical control. RESULTS: A total of 178 patients with acromegaly (median age at diagnosis 49 (IQR: 38-59) years, 46% women) were operated for a pituitary adenoma. Biochemical control was achieved by surgery in 53% at short-term and 41% at long-term follow-up, without additional treatment for acromegaly. Biochemical control rates by surgery were of same magnitude in paired samples (45% vs. 41%, p = 0.213) for short- and long-term follow-up, respectively. At short-term, 62% of patients with microadenomas and 51% with macroadenomas, achieved biochemical control. At long-term, the biochemical control rate was 58% for microadenomas and 37% for macroadenomas (p = 0.058). With adjunctive treatment, 82% achieved biochemical control at long-term. Baseline IGF-1 levels significantly predicted biochemical control by surgery at short-term (OR: 0.98 (95% CI: 0.96-0.99), p = 0.011), but not at long-term (OR: 0.76 (95% CI: 0.57-1.00), p = 0.053). CONCLUSION: In unselected patients with acromegaly, the long-term biochemical control rate remains modest. Our findings indicate a need to identify patients at an earlier stage and improve therapeutic methods and surgical outcomes.
Assuntos
Acromegalia , Adenoma , Adenoma Hipofisário Secretor de Hormônio do Crescimento , Hormônio do Crescimento Humano , Neoplasias Hipofisárias , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Masculino , Acromegalia/cirurgia , Fator de Crescimento Insulin-Like I/metabolismo , Hipófise/cirurgia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/cirurgia , Neoplasias Hipofisárias/cirurgia , Adenoma/cirurgia , Resultado do Tratamento , Estudos Retrospectivos , Hormônio do Crescimento Humano/metabolismoRESUMO
OBJECTIVES: Fatal complications have occurred after vaccination with ChAdOx1 nCoV-19, a vaccine against Covid-19. Vaccine-induced immune thrombotic thrombocytopenia (VITT) with severe outcome is characterized by venous thrombosis, predominantly in cerebral veins, thrombocytopenia and anti-PF4/polyanion antibodies. Prolonged headaches and cutaneous hemorrhages, frequently observed after the ChAdOx1 nCoV-19 vaccine, have therefore caused anxiety among vaccinees. We investigated whether these symptoms represent a mild form of VITT, with a potential for aggravation, e.g. in case of a second vaccination dose, or a different entity of vaccine complications MATERIALS AND METHODS: We included previously healthy individuals who had a combination of headache and spontaneous severe cutaneous hemorrhages emerging after the 1st dose of the ChAdOx1 nCoV-19 vaccine. Twelve individuals were found to meet the inclusion criteria, and a phone interview, cerebral MRI, assessment of platelet counts, anti PF4/polyanion antibodies and other laboratory tests were performed. RESULTS: None of the symptomatic vaccinees had cerebral vein thrombosis, hemorrhage or other pathology on MRI. Platelet counts were within normal range and no anti-PF4/polyanion platelet activating antibodies were found. Moreover, vasculitis markers, platelet activation markers and thrombin generation were normal. Furthermore, almost all symptoms resolved, and none had recurrence of symptoms after further vaccination with mRNA vaccines against Covid-19. CONCLUSIONS: The combination of headaches and subcutaneous hemorrhage did not represent VITT and no other specific coagulation disorder or intracranial pathology was found. However, symptoms initially mimicking VITT demand vigilance and low threshold for a clinical evaluation combined with platelet counts and D-dimer.
Assuntos
COVID-19 , Púrpura Trombocitopênica Idiopática , Trombocitopenia , Vacinas , Humanos , ChAdOx1 nCoV-19 , Estudos de Coortes , Vacinas contra COVID-19/efeitos adversos , COVID-19/prevenção & controle , AnticorposRESUMO
Tumours in the pituitary fossa region can be resected by endoscopic transnasal surgery using a four-hands technique. The technique, which is atraumatic, safe and minimally invasive, should be the first-line treatment for pituitary tumours and certain skull-base tumours.
Assuntos
Neoplasias Hipofisárias , Humanos , EndoscopiaRESUMO
BACKGROUND: Primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves comprise a heterogenous group of pathology, dominantly represented by meningioma, nerve sheath tumours (NST) and glioma. Body height and body mass index (BMI) are risk factors for certain brain tumour subgroups, but no other study has specifically assessed height and BMI in relation to primary tumours of the spine and peripheral nerves in women and men. METHODS: In this prospective population-based cohort study height and weight were measured in 1.7 million adult Norwegian women and men at baseline. Incident cases of primary tumours arising from the spinal cord, spinal meninges, spinal and peripheral nerves during follow-up were identified by linkage to the National Cancer Registry. Tumour risk was assessed by Cox regression analyses in relation to height and BMI. RESULTS: During 49 million person-years of follow-up, 857 primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves were identified. Overweight and obesity were not associated with risk for all tumours or any tumour subgroup. Height was positively associated with risk for all tumours (HR per 10 cm increase: 1.30, 95% CI 1.16-1.46). The association between height and tumour risk varied between tumour subgroups: while height was not significantly associated with NST, height increased the risk for meningioma (HR 1.42, 95% CI 1.13-1.78) and glioma (HR 1.56, 95% CI 1.06-2.28). The strongest association between height and tumour risk was found for the glioma subgroup of ependymoma in women (HR 3.38, 95% CI 1.64-6.94). CONCLUSION: This study could not identify overweight and obesity as risk factors for primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves in women or men. Increasing body height was associated with increased tumour risk overall, but not universal for all tumour subgroups.Importance of the studyPrimary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves have received little focus in epidemiologic studies, although the incidence and histo-pathological tumour subgroups differ significantly from primary brain tumours. Risk factors for these tumours have hardly been assessed in previous studies. Height, overweight and obesity are known risk factors for several cancers, including certain brain tumour subgroups, such as meningioma.This is the first study to report the association between height, overweight and obesity and primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves. This includes tumour subgroups of meningioma, nerve sheath tumour, glioma and the most common spinal glioma subgroup of ependymoma. While overweight and obesity were not associated with either of the tumour subgroups, an association between increasing body height and risk for spinal meningioma and glioma, including ependymoma, was found. Nerve sheath tumour risk was not associated with increasing body height.
Assuntos
Glioma , Neoplasias Meníngeas , Neoplasias da Medula Espinal , Adulto , Estatura , Índice de Massa Corporal , Estudos de Coortes , Feminino , Humanos , Masculino , Neoplasias Meníngeas/epidemiologia , Meninges , Nervos Periféricos , Estudos Prospectivos , Fatores de Risco , Neoplasias da Medula Espinal/epidemiologiaRESUMO
Moyamoya is a rare condition that affects the blood vessels of the brain in children and young adults. It can cause both ischaemic stroke and cerebral haemorrhage. Although established diagnostic criteria and examinations exist, limited knowledge of the condition often leads to a mistaken or delayed diagnosis. Treatment consists of antiplatelet drugs and surgical revascularisation. Prognosis after successful surgery is good, but the disease requires a dedicated medical team.
Assuntos
Isquemia Encefálica , Doença de Moyamoya , Acidente Vascular Cerebral , Encéfalo , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/etiologia , Criança , Humanos , Doença de Moyamoya/diagnóstico , Doença de Moyamoya/cirurgia , Inibidores da Agregação Plaquetária , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/terapia , Adulto JovemRESUMO
BACKGROUND: Tuberculum sellae meningiomas (TSMs) adherent to neurovascular structures are particularly challenging lesions requiring delicate and precise microneurosurgery. There is an ongoing debate about the optimal surgical approach. METHOD: We describe technical nuances and challenges in TSM resection using the endoscopic endonasal approach (EEA) in two cases of fibrous tumors with adherence to neurovascular structures. The cases are illustrated with a video (case 1) and figures (cases 1 and 2). CONCLUSION: A dedicated team approach and precise microsurgical technique facilitate safe resection of complex TSMs through the EEA.
Assuntos
Neoplasias Meníngeas , Meningioma , Neuroendoscopia , Neoplasias da Base do Crânio , Humanos , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/cirurgia , Meningioma/diagnóstico por imagem , Meningioma/cirurgia , Sela Túrcica/cirurgia , Neoplasias da Base do Crânio/diagnóstico por imagem , Neoplasias da Base do Crânio/cirurgia , Resultado do TratamentoRESUMO
Careful brain monitoring saves lives and is beneficial to patients' health. Nevertheless, Norway lacks guidelines for brain monitoring in hospitals.
Assuntos
Encéfalo , Hospitais , Encéfalo/diagnóstico por imagem , Humanos , NoruegaRESUMO
In the postprandial stomach, processes such as secretion, digestion, and gastric emptying all occur simultaneously. Therefore, the system is highly heterogeneous and dynamically changing, for instance, in terms of various physicochemical parameters such as pH value or viscosity. Thus, the administration of a drug together with food can result in highly variable drug plasma concentrations, which may affect the efficacy and safety of the pharmacotherapy. In this work, the pharmacokinetic (PK) data obtained from two fed-state bioequivalence studies with the immediate release (IR) drug products Viagra (sildenafil) and Adenuric (febuxostat) have been analyzed. This evaluation revealed that basically three characteristic types of onset behaviors of drug plasma concentration can be distinguished. It was hypothesized that the different types of onset behaviors were mainly caused by the interplay between gastric drug dissolution and gastric emptying. To study this interplay in vitro, a biopredictive dissolution tool-GastroDuo-was developed and used for both drug products. Therefore, three different test programs have been applied to simulate certain aspects of the postprandial human stomach, which included dynamic pH changes, gastric peristalsis, and the kinetics of gastric emptying. Specifically, the behavior of noncaloric fluids by the so-called "Magenstrasse" was taken into deeper consideration. The experiments revealed that the dissolution and emptying behavior of the two drug products were affected in different ways by the three test programs. The in vitro data nicely explained the tendencies of the drug products for certain types of onset behaviors observed in the PK data. While Viagra was strongly affected by simulated peristalsis, Adenuric was more sensitive to the simulated emptying kinetics. This work clearly demonstrated the important role of gastric fluid emptying for the onset of drug plasma concentration after oral administration of IR formulations in the fed state. Moreover, this was the first study in which GastroDuo was applied as a biopredictive in vitro model which is able to simulate crucial parameters of the human stomach (e.g., pH profiles and gastric emptying) in a realistic manner.
Assuntos
Esvaziamento Gástrico/fisiologia , Período Pós-Prandial/fisiologia , Estômago/fisiologia , Administração Oral , Adolescente , Adulto , Idoso , Disponibilidade Biológica , Liberação Controlada de Fármacos/fisiologia , Febuxostat/metabolismo , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Citrato de Sildenafila/metabolismo , Solubilidade , Adulto JovemRESUMO
Vascular targeting with pro-thrombotic antibody-conjugates is a promising biological treatment for brain arteriovenous malformations (bAVMs). However, targeted drug delivery relies on the identification of unique or overexpressed markers on the surface of a target cell. In the absence of inherent biological markers, stereotactic radiosurgery may be used to prime induction of site-specific and targetable molecular changes on the endothelial surface. To investigate lumen-accessible, endothelial targets induced by radiation, we combined Gamma knife surgery in an AVM animal model with in vivo biotin-labeling and comparative proteomics. Two proteins, αB-crystallin (CRYAB)-a small heat shock protein that normally acts as an intracellular chaperone to misfolded proteins-and activated leukocyte cell adhesion molecule CD166, were further validated for endothelial surface expression after irradiation. Immunostaining of endothelial cells in vitro and rat AVM tissue ex vivo confirmed de novo induction of CRYAB following irradiation (20 Gy). Western analysis demonstrated that CRYAB accumulated intracellularly as a 20 kDa monomer, but, at the cell surface, a novel 65 kDa protein was observed, suggesting radiation stimulates translocation of an atypical CRYAB isoform. In contrast, CD166 had relatively high expression in non-irradiated cells, localized predominantly to the lateral surfaces. Radiation increased CD166 surface exposure by inducing translocation from intercellular junctions to the apical surface without significantly altering total protein levels. These findings reinforce the dynamic molecular changes induced by radiation exposure, particularly at the cell surface, and support further investigation of radiation as a priming mechanism and these molecules as putative targets for focused drug delivery in irradiated tissue.
Assuntos
Cristalinas/metabolismo , Células Endoteliais/efeitos da radiação , Malformações Arteriovenosas Intracranianas/radioterapia , Proteínas Associadas aos Microtúbulos/metabolismo , Radiocirurgia/efeitos adversos , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Animais , Membrana Celular/metabolismo , Células Cultivadas , Células Endoteliais/metabolismo , Raios gama/efeitos adversos , Malformações Arteriovenosas Intracranianas/metabolismo , Camundongos , Transporte Proteico , Ratos , Ratos Sprague-DawleyRESUMO
The drug plasma profile after oral administration of immediate release dosage forms can be affected by the human gastrointestinal physiology, the formulation, and the drug itself. In this work, we investigated the in vivo and in vitro performance of two formulations (granules vs. tablet) containing the highly soluble drug N-Acetylcysteine (BCS class I). Thereby, special attention was paid to the effect of the dosage form and the coadministration of water on drug release. Interestingly, the in vivo results from a pharmacokinetic study with 11 healthy volunteers indicated that the drug plasma concentrations were comparable for the tablet given with water as well as for the granules given with and without water. In order to mechanistically understand this outcome, we used a biorelevant dissolution test device, the dynamic open flow-through test apparatus. With the aid of this test apparatus, we were able to simulate biorelevant parameters, such as gastric emptying, hydrodynamic flow as well as physical stress. By this, it was possible to mimic the intake conditions of the clinical trial (i.e., drug intake with and without water). Whereas the experiments in the USP paddle apparatus revealed differences between the two formulations, we could not observe significant differences in the release profiles of the two formulations by using the dynamic open flow-through test apparatus. Even by considering the different intake conditions, drug release was slow and amounted to around 30% until simulated gastric emptying. These results suggest that dissolution was irrespective of coadministered water and the formulation. Despite the high aqueous solubility of N-Acetylcysteine, the limiting factor for drug release was the slow dissolution rate in relation to the gastric emptying rate under simulated gastric conditions. Thus, in case of administration together with water, large amounts of the drug are still present in the stomach even after complete gastric emptying of the water. Consequently, the absorption of the drug is largely controlled by the nature of gastric emptying of the remaining drug. The data of this study indicated that the water emptying kinetics are only determining drug absorption if drug release is rapid enough. If this is not the case, physiological mechanisms, such as the migrating motor complex, play an important role for oral drug delivery.
Assuntos
Acetilcisteína/farmacocinética , Liberação Controlada de Fármacos , Esvaziamento Gástrico/fisiologia , Técnicas In Vitro/instrumentação , Água/fisiologia , Absorção Fisiológica/fisiologia , Acetilcisteína/administração & dosagem , Administração Oral , Adulto , Biofarmácia/instrumentação , Biofarmácia/métodos , Química Farmacêutica , Estudos Cross-Over , Sistemas de Liberação de Medicamentos , Feminino , Interações Alimento-Droga/fisiologia , Voluntários Saudáveis , Humanos , Técnicas In Vitro/métodos , Masculino , Pessoa de Meia-Idade , Solubilidade , Comprimidos , Adulto JovemRESUMO
BACKGROUND: In 2016, the International Agency for Research on Cancer (IARC) has announced that avoiding body fatness (i.e. overweight and obesity) contributes to prevent meningioma occurrence, but considered the available evidence for glioma inadequate. The association of body fatness with other CNS tumor subgroups is largely unknown. OBJECTIVES: To assess whether body fatness or body height are associated with risk for meningioma, glioma, pituitary adenoma (PA) or nerve sheath tumor (NST) in a large population-based Norwegian cohort. METHODS: In this prospective cohort study of 1.8 million Norwegian residents, weight and height were measured at baseline and incident intracranial tumors were subsequently identified by linkage to the Cancer Registry of Norway. Cox regression analyses were performed to estimate risk for each tumor subgroup in relation to anthropometric measures, stratified by sex and in different age groups. RESULTS: During 54 million person-years of follow-up 3335 meningiomas, 4382 gliomas, 1071 PAs and 759 NSTs were diagnosed. Obesity (BMI ≥30 kg/m2) was not associated with risk for meningioma or glioma, but was significantly associated with risk for PA (HR 1.43; 95% CI 1.09-1.88) compared with the reference group (BMI 20-24.9 kg/m2). For intracranial NSTs, obesity was associated with reduced tumor risk (HR 0.68; 95% CI 0.46-0.99). Body height was associated with increased risk for all four tumor subgroups. CONCLUSIONS: This study does not confirm overweight or obesity as risk factors for meningioma. Additionally, overweight and obesity can be quite confidently excluded as risk factors for glioma. However, this study indicates that body fatness increases the risk for PA, while it reduces the risk for NST.
Assuntos
Adenoma/etiologia , Estatura , Glioma/etiologia , Meningioma/etiologia , Neoplasias de Bainha Neural/etiologia , Obesidade/complicações , Sobrepeso/complicações , Neoplasias Hipofisárias/etiologia , Estudos de Coortes , Humanos , Estudos Prospectivos , Fatores de RiscoAssuntos
Neoplasias Meníngeas/complicações , Meningioma/complicações , Doenças do Nervo Óptico/etiologia , Idoso , Feminino , Angiofluoresceinografia , Humanos , Imageamento por Ressonância Magnética , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/cirurgia , Meningioma/diagnóstico por imagem , Meningioma/cirurgia , Doenças do Nervo Óptico/diagnóstico por imagem , Papiledema/diagnóstico por imagem , Papiledema/etiologiaRESUMO
Intraoperative aneurysm rupture (IAR) is a feared complication and an unnerving experience for any neurosurgeon. If not managed properly, the consequences may be devastating. Although overall patient outcomes in IAR have been shown to improve with a neurosurgeon's experience, the likelihood of rupture does not necessarily decrease, and the key to success lies in appropriate management. Microsurgical dexterity, remaining calm and acting sensible are important skills that all neurosurgeons need to master early on in order to achieve good patient outcomes. The landscape of cerebrovascular disease management has evolved significantly, with a growing preference for endovascular approaches. Consequently, the case-load of microsurgical procedures available for trainees have been diminished. As microsurgical cases decline and the remaining cases become more complex, the need for a systematic approach to IAR management becomes critical, to ensure a swift and efficient response and to compensate for reduced experience. This video article aims to empower the next generation of neurosurgeons by emphasizing essential skills and a systematic algorithmic approach required to navigate IAR situations successfully. In this video, we present the unedited sequence of IAR management in a posterior communicating artery (PCoA) aneurysm, from rupture to clipping. A 43-year-old female patient presented with headache and diplopia caused by a left oculomotor nerve palsy. Computed tomography (CT) did not show subarachnoid hemorrhage, but CT angiogram revealed a 7-mm left PCoA aneurysm affecting the oculomotor nerve. Patient consent was obtained for surgical management. The predissection phase was uneventful, however during dissection of the aneurysm neck, IAR occurred from the aneurysm dome. One contributing factor to rupture may have been the traction exerted on the aneurysm with the dissector, possibly due to adhesion of the aneurysm dome to the tentorial edge. Additionally, performing intradural drilling of the anterior clinoid process during the approach could have provided better access to proximal control of the internal carotid artery, making clip application easier. By remaining calm and proceeding with the steps illustrated in the decision algorithm (Fig. 1), the right actions were made, and the aneurysm was successfully clipped. In this article, we provide early career vascular neurosurgeons with a systematic strategy for managing IAR, offering guidance that may facilitate the 'right move' during these high-stress situations.
Assuntos
Aneurisma Roto , Aneurisma Intracraniano , Hemorragia Subaracnóidea , Adulto , Feminino , Humanos , Aneurisma Roto/diagnóstico por imagem , Aneurisma Roto/cirurgia , Aneurisma Roto/complicações , Aneurisma Intracraniano/diagnóstico por imagem , Aneurisma Intracraniano/cirurgia , Aneurisma Intracraniano/complicações , Neurocirurgiões , Poder Psicológico , Hemorragia Subaracnóidea/cirurgia , Hemorragia Subaracnóidea/complicaçõesRESUMO
Introduction: Moyamoya disease (MMD) is a chronic cerebrovascular steno-occlusive disease of largely unknown etiology. Variants in the RNF213 gene are strongly associated with MMD in East-Asia. In MMD patients of Northern-European origin, no predominant susceptibility variants have been identified so far. Research question: Are there specific candidate genes associated with MMD of Northern-European origin, including the known RNF213 gene? Can we establish a hypothesis for MMD phenotype and associated genetic variants identified for further research? Material and methods: Adult patients of Northern-European origin, treated surgically for MMD at Oslo University Hospital between October 2018 to January 2019 were asked to participate. WES was performed, with subsequent bioinformatic analysis and variant filtering. The selected candidate genes were either previously reported in MMD or known to be involved in angiogenesis. The variant filtering was based on variant type, location, population frequency, and predicted impact on protein function. Results: Analysis of WES data revealed nine variants of interest in eight genes. Five of those encode proteins involved in nitric oxide (NO) metabolism: NOS3, NR4A3, ITGAV, GRB7 and AGXT2. In the AGXT2 gene, a de novo variant was detected, not previously described in MMD. None harboured the p.R4810K missense variant in the RNF213 gene known to be associated with MMD in East-Asian patients. Discussion and conclusion: Our findings suggest a role for NO regulation pathways in Northern-European MMD and introduce AGXT2 as a new susceptibility gene. This pilot study warrants replication in larger patient cohorts and further functional investigations.