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Inflammation including immunothrombosis by neutrophil extracellular traps (NETs) has important implications in acute ischemic stroke and can affect reperfusion status, susceptibility to stroke associated infections (SAI) as well as functional clinical outcome. NETs were shown to be prevalent in stroke thrombi and NET associated markers were found in stroke patients' blood. However, little is known whether blood derived NET markers reflect the amount of NETs in thrombi. Conclusions from blood derived markers to thrombus composition might open avenues for novel strategies in diagnostic and therapeutic approaches. We prospectively recruited 166 patients with acute ischemic stroke undergoing mechanical thrombectomy between March 2018 and May 2021. Available thrombi (n = 106) were stained for NET markers DNA-histone-1 complexes and myeloperoxidase (MPO). Cell free DNA (cfDNA), deoxyribonuclease (DNase) activity, MPO-histone complexes and a cytokine-panel were measured before thrombectomy and after seven days. Clinical data, including stroke etiology, reperfusion status, SAI and functional outcome after rehabilitation, were collected of all patients. NET markers were present in all thrombi. At onset the median concentration of cfDNA in blood was 0.19 µg/ml increasing to 0.30 µg/ml at 7 days. Median DNase activity at onset was 4.33 pmol/min/ml increasing to 4.96 pmol/min/ml at 7 days. Within thrombi DNA-histone-1 complexes and MPO correlated with each other (ρ = 0.792; p < 0.001). Moreover, our study provides evidence for an association between the amount of NETs and endogenous DNase activity in blood with amounts of NETs in cerebral thrombi. However, these associations need to be confirmed in larger cohorts, to investigate the potential clinical implications for individualized therapeutic and diagnostic approaches in acute ischemic stroke.
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Biomarcadores , Armadilhas Extracelulares , AVC Isquêmico , Humanos , Armadilhas Extracelulares/metabolismo , Biomarcadores/sangue , Masculino , Feminino , Idoso , AVC Isquêmico/sangue , AVC Isquêmico/diagnóstico , Pessoa de Meia-Idade , Estudos Prospectivos , Peroxidase/sangue , Idoso de 80 Anos ou mais , Ácidos Nucleicos Livres/sangue , Trombectomia , Trombose/sangue , Trombose/diagnóstico , Neutrófilos/metabolismoRESUMO
BACKGROUND: Many ischemic strokes are diagnosed as embolic strokes of undetermined source (ESUS). Recent evidence suggests that nonstenotic carotid plaque (nsCP) may be a substantial contributor to the risk for ESUS. We aimed to investigate the risk factor profile associated with nsCP in ESUS and defined stroke etiologies. METHODS: In this retrospective case-control study, we investigated consecutive patients with acute ischemic stroke due to ESUS, small-vessel disease, or cardioembolism proven by magnetic resonance imaging. The association of vascular risk factors age, arterial hypertension, diabetes, dyslipoproteinemia, body mass index, alcohol consumption, tobacco use, kidney failure, and history of stroke with the presence of nsCP was investigated using binary logistic regression analysis and further stratified by stroke etiology and sex. RESULTS: In total, 609 patients (median age, 76 years; 46% women) who were treated from 2018 to 2020 were considered. In patients with ESUS, sex played a more important role for the prevalence of nsCP than in defined etiologies. Female patients with ESUS had lower odds of exhibiting nsCP compared with male patients with ESUS (adjusted odds ratio, 0.36 [95% CI, 0.15-0.86]). In male patients with ESUS, we observed that age (adjusted odds ratio per 10-year increase, 2.55 [95% CI, 1.26-5.17]) and hypertension (adjusted odds ratio, 2.49 [95% CI, 0.56-11.1]) were the main risk factors for nsCP, whereas in female patients with ESUS also tobacco use was particularly relevant (adjusted odds ratio, 3.71 [95% CI, 0.61-22.5]). These results were in line with a sensitivity analysis in nsCP located ipsilateral to the infarct. CONCLUSIONS: Sex differences play an important role in nsCP prevalence in patients with ESUS. These findings may have important implications for the management in targeted secondary prevention following ESUS.
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AVC Embólico , Hipertensão , Embolia Intracraniana , AVC Isquêmico , Placa Aterosclerótica , Acidente Vascular Cerebral , Humanos , Feminino , Masculino , Idoso , AVC Embólico/complicações , Estudos de Casos e Controles , Estudos Retrospectivos , AVC Isquêmico/complicações , Placa Aterosclerótica/complicações , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/epidemiologia , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Fatores de Risco , Hipertensão/complicações , Hipertensão/epidemiologia , Embolia Intracraniana/epidemiologiaRESUMO
Ischemic stroke is one of the leading causes of death worldwide and the most frequent cause of permanent disability in adulthood. The acute treatment of stroke is time-critical and, according to the time is brain principle, it is important to determine as soon as possible whether recanalization treatment that can save the penumbra is possible. Intravenous thrombolysis (IVT) and, if a large vessel occlusion is identified, endovascular treatment (EVT) possibly in combination with IVT, are recommended. Further treatment in a stroke unit is another important component of acute stroke treatment. The best secondary preventive treatment must already be initiated in the acute phase. The cause of stroke guides making decisions on the ideal secondary preventive strategy. The most important etiologies of stroke are cardiac embolism, atherosclerotic macroangiopathy and cerebral microangiopathy (small vessel disease). Less frequent causes are dissections of arteries supplying the brain or vasculitis. In up to 20-30% of all cases, however, no clear etiology can be determined despite intensive investigation of the cause. This means corresponding uncertainty in the optimal secondary prevention that consists in particular of an anticoagulant medication adapted to the etiology, treatment of cardiovascular risk factors and if necessary surgical or interventional desobliterative procedures. This article describes the diagnostic procedure and the evidence-based treatment of ischemic stroke.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Fibrinolíticos/uso terapêutico , AVC Isquêmico/complicações , Terapia Trombolítica/efeitos adversos , Isquemia Encefálica/complicações , Acidente Vascular Cerebral/diagnósticoRESUMO
In patients with left ventricular assist device (LVAD), infections and thrombotic events represent severe complications. We investigated device-specific local and systemic inflammation and its impact on cerebrovascular events (CVE) and mortality. In 118 LVAD patients referred for 18F-FDG-PET/CT, metabolic activity of LVAD components, thoracic aortic wall, lymphoid and hematopoietic organs, was quantified and correlated with clinical characteristics, laboratory findings, and outcome. Driveline infection was detected in 92/118 (78%) patients by 18F-FDG-PET/CT. Activity at the driveline entry site was associated with increased signals in aortic wall (r = 0.32, p < 0.001), spleen (r = 0.20, p = 0.03) and bone marrow (r = 0.20, p = 0.03), indicating systemic interactions. Multivariable analysis revealed independent associations of aortic wall activity with activity of spleen (ß = 0.43, 95% CI 0.18-0.68, p < 0.001) and driveline entry site (ß = 0.04, 95% CI 0.01-0.06, p = 0.001). Twenty-two (19%) patients suffered CVE after PET/CT. In a binary logistic regression analysis metabolic activity at the driveline entry site missed the level of significance as an influencing factor for CVE after adjusting for anticoagulation (OR = 1.16, 95% CI 1-1.33, p = 0.05). Metabolic activity of the subcutaneous driveline (OR = 1.13, 95% CI 1.02-1.24, p = 0.016) emerged as independent risk factor for mortality. Molecular imaging revealed systemic inflammatory interplay between thoracic aorta, hematopoietic organs, and infected device components in LVAD patients, the latter predicting CVE and mortality.
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Insuficiência Cardíaca , Coração Auxiliar , Infecções Relacionadas à Prótese , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fluordesoxiglucose F18 , Coração Auxiliar/efeitos adversos , Infecções Relacionadas à Prótese/etiologia , Inflamação/etiologia , Insuficiência Cardíaca/complicações , Estudos RetrospectivosRESUMO
Background A substantial proportion of ischemic strokes remain cryptogenic, which has important implications for secondary prevention. Identifying genetic variants related to mechanisms of stroke causes may provide a chance to clarify the actual causes of cryptogenic strokes. Methods and Results In a 2-step process, 2 investigators independently and systematically screened studies that reported genetic variants in regard to stroke causes that were published between January 1991 and April 2021. Studies on monogenetic disorders, investigation of vascular risk factors as the primary end point, reviews, meta-analyses, and studies not written in English were excluded. We extracted information on study types, ancestries, corresponding single nucleotide polymorphisms, and sample and effect sizes. There were 937 studies screened, and 233 were eligible. We identified 35 single nucleotide polymorphisms and allele variants that were associated with an overlap between cryptogenic strokes and another defined cause. Conclusions Associations of single variants with an overlap between cryptogenic stroke and another defined cause were limited to a few polymorphisms. A limitation of all studies is a low granularity of clinical data, which is of major importance in a complex disease such as stroke. Deep phenotyping is in supposed contradiction with large sample sizes but needed for genome-wide analyses. Future studies should attempt to address this restriction to advance the promising approach of elucidating the cause of stroke at the genetic level. Especially in a highly heterogenous disease such as ischemic stroke, genetics are promising to establish a personalized approach in diagnostics and treatment in the sense of precision medicine.
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AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Estudo de Associação Genômica Ampla , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/genética , AVC Isquêmico/complicações , Fatores de Risco , CausalidadeRESUMO
BACKGROUND: In the general population, carotid intima-media thickness (CIMT) is associated with atherosclerosis as well as atrial fibrillation (AF). However, the extent to which CIMT might be of diagnostic value in clarifying stroke etiology is currently unclear. METHODS: In this retrospective cohort study, we included 800 consecutive patients with acute ischemic stroke. We compared CIMT-values between stroke etiologies. The association between CIMT and cardioembolic stroke was investigated via logistic regression analysis adjusting for vascular risk factors. Receiver operating characteristic analyses were conducted to investigate the diagnostic value of CIMT in comparison to vascular risk factors and clinical AF risk scores (CHA2DS2VASc, HAVOC, and AS5F). RESULTS: CIMT-values were highest in patients with cardioembolic or atherosclerotic stroke origin. CIMT was associated with newly diagnosed AF compared against cryptogenic strokes (crude odds ratio (OR) per 0.1 mm-increase of CIMT: 1.26 (95% confidence interval (CI): 1.13-1.41)). After adjustment for vascular risk factors, the effect of CIMT on AF-diagnosis, however, was weakened (adjusted OR: 1.10 (95% CI: 0.97-1.25)). The diagnostic value of CIMT for detection of AF (AUC: 0.60, 95% CI: 0.54-0.65) was outperformed by AF risk scores. Among the scores investigated, the AS5F-score yielded best accuracy and calibration to predict newly diagnosed AF (AUC: 0.71, 95% CI: 0.65-0.78). CONCLUSIONS: CIMT may help in the diagnosis of stroke etiology. However, compared with vascular risk factors or clinical AF risk scores, CIMT does not provide substantial additional information on the risk of newly detected AF. Thus, stratification of AF risk based on scores, such as the AS5F, is advisable.
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Aterosclerose , Fibrilação Atrial , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Espessura Intima-Media Carotídea , AVC Isquêmico/complicações , Estudos Retrospectivos , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Aterosclerose/complicações , Fibrilação Atrial/diagnósticoRESUMO
BACKGROUND: In patients with left ventricular assist devices (LVADs), ischemic and hemorrhagic stroke are dreaded complications. Predictive markers for these events are lacking. This study aimed to investigate the prevalence and predictive value of microembolic signals (MES) for stroke, detected by Transcranial Doppler sonography (TCD) in patients with HeartMate 3 (HM 3) or HeartWare (HW). METHODS: A thirty-minute bilateral TCD monitoring of the middle cerebral artery (MCA) was performed in 62 outpatients with LVAD (HM 3 N = 31, HW N = 31) and 31 healthy controls. Prevalence and quantity of MES were investigated regarding clinical and laboratory parameters. Cerebrovascular events (CVE) were recorded on follow-up at 90 and 180 days. RESULTS: MES were detected in six patients with HM 3, three patients with HW, and three controls. Within the LVAD groups, patients on monotherapy with vitamin-K-antagonist (VKA) without antiplatelet therapy were at risk for a higher count of MES (negative binomial regression: VKA: 1; VKA + ASA: Exp(B) = 0.005, 95%CI 0.001-0.044; VKA + clopidogrel: Exp(B) = 0.012, 95%CI 0.002-0.056). There was no association between the presence of MES and CVE or death on follow-up (p > 0.05). CONCLUSION: For the first time, the prevalence of MES was prospectively investigated in a notable outpatient cohort of patients with HM 3 and HW. Despite optimized properties of the latest LVAD, MES remain detectable depending on antithrombotic therapy. No association between MES and CVE could be detected.
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Coração Auxiliar , Acidente Vascular Cerebral , Humanos , Fibrinolíticos/efeitos adversos , Acidente Vascular Cerebral/etiologia , Anticoagulantes/uso terapêutico , Clopidogrel , Coração Auxiliar/efeitos adversos , Ultrassonografia Doppler TranscranianaRESUMO
Background: In acute ischemic stroke, timely treatment is of utmost relevance. Identification of delaying factors and knowledge about challenges concerning hospital structures are crucial for continuous improvement of process times in stroke care. Objective: In this study, we report on our experience in optimizing the door-to-needle time (DNT) at our tertiary care center by continuous quality improvement. Methods: Five hundred forty patients with acute ischemic stroke receiving intravenous thrombolysis (IVT) at Hannover Medical School were consecutively analyzed in two phases. In study phase I, including 292 patients, process times and delaying factors were collected prospectively from May 2015 until September 2017. In study phase II, process times of 248 patients were obtained from January 2019 until February 2021. In each study phase, a new clinical standard operation procedure (SOP) was implemented, considering previously identified delaying factors. Pre- and post-SOP treatment times and delaying factors were analyzed to evaluate the new protocols. Results: In study phase I, SOP I reduced the median DNT by 15 min. The probability to receive treatment within 30 min after admission increased by factor 5.35 [95% confidence interval (CI): 2.46-11.66]. Further development of the SOP with implementation of a mobile thrombolysis kit led to a further decrease of DNT by 5 min in median in study phase II. The median DNT was 29 (25th-75th percentiles: 18-44) min, and the probability to undergo IVT within 15 min after admission increased by factor 4.2 (95% CI: 1.63-10.83) compared with study phase I. Conclusion: Continuous process analysis and subsequent development of targeted workflow adjustments led to a substantial improvement of DNT. These results illustrate that with appropriate vigilance, there is constantly an opportunity for improvement in stroke care.
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Acute stroke care is a time-critical process. Improving communication and documentation process may support a positive effect on medical outcome. To achieve this goal, a new system using a mobile application has been integrated into existing infrastructure at Hannover Medical School (MHH). Within a pilot project, this system has been brought into clinical daily routine in February 2022. Insights generated may support further applications in clinical use-cases.
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Aplicativos Móveis , Acidente Vascular Cerebral , Telemedicina , Documentação , Humanos , Projetos Piloto , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/terapiaRESUMO
During the COVID-19 pandemic, vaccination is the most important countermeasure. Pharmacovigilance concerns however emerged with very rare, but potentially disastrous thrombotic complications following vaccination with ChAdOx1. Platelet factor-4 antibody mediated vaccine-induced immune thrombotic thrombocytopenia (VITT) was described as an underlying mechanism of these thrombotic events. Recent work moreover suggests that mechanisms of immunothrombosis including neutrophil extracellular trap (NET) formation might be critical for thrombogenesis during VITT. In this study, we investigated blood and thrombus specimens of a female patient who suffered severe stroke due to VITT after vaccination with ChAdOx1 in comparison to 13 control stroke patients with similar clinical characteristics. We analyzed cerebral thrombi using histological examination, staining of complement factors, NET-markers, DNase and LL-37. In blood samples at the hyper-acute phase of stroke and 7 days later, we determined cell-free DNA, myeloperoxidase-histone complexes, DNase activity, myeloperoxidase activity, LL-37 and inflammatory cytokines. NET markers were identified in thrombi of all patients. Interestingly, the thrombus of the VITT-patient exclusively revealed complement factors and high amounts of DNase and LL-37. High DNase activity was also measured in blood, implying a disturbed NET-regulation. Furthermore, serum of the VITT-patient inhibited reactive oxygen species-dependent NET-release by phorbol-myristate-acetate to a lesser degree compared to controls, indicating either less efficient NET-inhibition or enhanced NET-induction in the blood of the VITT-patient. Additionally, the changes in specific cytokines over time were emphasized in the VITT-patient as well. In conclusion, insufficient resolution of NETs, e.g. by endogenous DNases or protection of NETs against degradation by embedded factors like the antimicrobial peptide LL-37 might thus be an important factor in the pathology of VITT besides increased NET-formation. On the basis of these findings, we discuss the potential implications of the mechanisms of disturbed NETs-degradation for diagnostic and therapeutic approaches in VITT-related thrombogenesis, other auto-immune disorders and beyond.
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COVID-19 , Armadilhas Extracelulares , Púrpura Trombocitopênica Idiopática , Acidente Vascular Cerebral , Trombocitopenia , Trombose , Vacinas , Desoxirribonuclease I/metabolismo , Desoxirribonucleases , Feminino , Humanos , Neutrófilos , Pandemias , Peroxidase/metabolismo , Fator Plaquetário 4/metabolismo , Púrpura Trombocitopênica Idiopática/metabolismo , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Trombocitopenia/induzido quimicamente , Trombocitopenia/metabolismo , Trombose/etiologia , Trombose/metabolismo , Vacinas/metabolismoRESUMO
BACKGROUND: Cell-free DNA (cfDNA) and endogenous deoxyribonuclease activity are opposing mediators and might influence the inflammatory response following acute ischemic stroke. In this cohort study, we investigated the relation between these markers, circulating inflammatory mediators and clinical course including occurrence of stroke-associated infections (SAI) in patients with acute stroke. METHODS: Ninety-two patients with stroke due to large vessel occlusion undergoing mechanical thrombectomy were prospectively recruited at Hannover Medical School from March 2018 to August 2019. Deoxyribonuclease activity, cfDNA, damage-associated molecular patterns, and circulating cytokines were measured in venous blood collected immediately before mechanical thrombectomy and 7 days later. Reperfusion status was categorized (sufficient/insufficient). Clinical outcome was evaluated using the modified Rankin Scale after 90 days, where a score of 3 to 6 was considered unfavorable. To validate findings regarding SAI, another stroke cohort (n=92) was considered with blood taken within 24 hours after stroke onset. RESULTS: Patients with unfavorable clinical outcome had higher cfDNA concentrations. After adjustment for confounders (Essen Stroke Risk Score, National Institutes of Health Stroke Scale, and sex), 7-day cfDNA was independently associated with clinical outcome and especially mortality (adjusted odds ratio: 3.485 [95% CI, 1.001-12.134] and adjusted odds ratio: 9.585 [95% CI, 2.006-45.790]). No association was found between reperfusion status and cfDNA or deoxyribonuclease activity. While cfDNA concentrations correlated positively, deoxyribonuclease activity inversely correlated with distinct biomarkers. Baseline deoxyribonuclease activity was lower in patients who developed SAI compared with patients without SAI. This association was confirmed after adjustment for confounding factors (adjusted odds ratio: 0.447 [95% CI, 0.237-0.844]). In cohort 2, differences of deoxyribonuclease activity between patients with and without SAI tended to be higher with higher stroke severity. CONCLUSIONS: The interplay of endogenous deoxyribonuclease activity and cfDNA in acute stroke entails interesting novel diagnostic and potential therapeutic approaches. We confirm an independent association of cfDNA with a detrimental clinical course after stroke due to large vessel occlusion. This study provides first evidence for lower endogenous deoxyribonuclease activity as risk factor for SAI after severe stroke.
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Isquemia Encefálica , Ácidos Nucleicos Livres , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/terapia , Estudos de Coortes , Desoxirribonucleases , Humanos , Estudos Retrospectivos , Acidente Vascular Cerebral/terapia , Trombectomia/efeitos adversos , Resultado do TratamentoRESUMO
Background: The identification of the underlying mechanism in ischemic stroke has important implications for secondary prevention. A disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS-13) has antithrombotic properties and was repeatedly implicated in the pathophysiology of stroke. In this study, we, therefore, aimed to investigate whether ADAMTS-13 is associated with stroke etiology and the burden of vascular risk factors. Methods: We determined ADAMTS-13 activity in two prospectively recruited stroke cohorts in the long-term course after the event. Cohort 1 (n = 88) consisted of patients who suffered a stroke due to embolic stroke of undetermined source (ESUS), cardioembolic stroke due to atrial fibrillation (AF), large-artery atherosclerosis, or small vessel disease. In cohort 2, patients with cryptogenic stroke and patent foramen ovale (PFO) scheduled for PFO closure (n = 38) were enrolled. As measures of vascular risk factor burden, the CHA2DS2VASC score, the Essen Stroke Risk Score (ESRS), and the Risk of Paradoxical Embolism (RoPE) score were calculated, as appropriate. Results: ADAMTS-13 activity was lower in patients with AF-related stroke compared to patients with ESUS (p = 0.0227), which was, however, due to confounding by vascular risk factors. ADAMTS-13 activity inversely correlated with the ESRS (r = -0.452, p < 0.001) and CHA2DS2VASC (r = -0.375, p < 0.001) in cohort 1. In accordance with these findings, we found a positive correlation between ADAMTS-13 activity and the RoPE score in cohort 2 (r = 0.413, p = 0.010). Conclusion: ADAMTS-13 activity is inversely correlated with the number of vascular risk factors across different stroke etiologies. Further study is warranted to establish ADAMTS-13 as a mediator of cerebrovascular risk.
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Mechanical thrombectomy (MT) is a highly efficient treatment in patients with acute ischemic stroke due to large vessel occlusion (LVO). However, in a relevant proportion of LVO, no sufficient recanalization can be achieved. The composition of cerebral thrombi is highly heterogeneous and may constitute a relevant factor for insufficient reperfusion. We hypothesized that circulating cytokines and growth factors involved in thromboinflammation and platelet activation may be associated with reperfusion status and thrombus composition in patients undergoing MT. An according biomarker panel was measured in plasma specimens taken prior to MT and at a 7-day follow-up. The reperfusion status was categorized into sufficient or insufficient. The composition of retrieved thrombi was histologically analyzed. Differences of baseline biomarker concentrations between insufficient and sufficient reperfusions were highest for interferon (IFN)-γ, epidermal growth factor, platelet-derived growth factor (PDGF)-AB/BB, and IFN-γ-induced protein 10 (IP-10/CXCL10). After applying correction for multiple comparisons and logistic regression analysis adjusting for stroke etiology, intravenous thrombolysis, and vascular risk factors, PDGF-AB/BB was identified as an independent predictor of reperfusion status (odds ratio: 0.403; 95% confidence interval: 0.199-0.819). Histological analysis revealed that the majority of thrombi had a mixed composition. In conclusion, this study provides the first evidence that cytokines and growth factors are potential effectors in patients undergoing MT for the treatment of acute ischemic stroke.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Trombose , Isquemia Encefálica/terapia , Citocinas , Humanos , Inflamação/etiologia , Acidente Vascular Cerebral/complicações , Trombectomia/efeitos adversos , Trombose/etiologia , Resultado do TratamentoRESUMO
Gonadotropin releasing hormone (GnRH)-secretion is not only regulated by neuronal factors but also by astroglia cells via growth factors and ErbB receptors of the epidermal growth factor family. Studies in transgenic mice carrying mutations in the ErbB receptor system experience impaired reproductive capacity. In addition, some of these animals show a typical skin phenotype with wavy hair and curly whiskers. The rat strain SPRD-CU3 (CU3), examined in this study, displays a similar skin phenotype and a significant impairment of the timing of puberty onset and reproductive performance, suggesting a disruption in the astrocytic to GnRH neuronal communication. To address this issue, we analyzed astrocytic prostaglandin E2 (PGE2 ) release from primary hypothalamic astrocytic cell cultures after stimulation with transforming growth factor α (TGFα), ligand for ErbB1/ErbB2, or Neuregulin 1 beta 2 (NRG1ß2 ), ligand for ErbB4/ErbB2 signaling pathway. Compared to cultures from wild type animals, astrocytic cultures from CU3 rats were unable to respond to NRG stimulation, suggesting a disruption of the ErbB4/ErbB2 signaling pathway. This is confirmed by mutational analysis of ErbB4 that revealed a single point mutation at 3125 bp resulting in an amino acid change from proline to glutamine located at the carboxy-terminal region. As a consequence, substantial conformational changes occur in the transmembrane and intracellular domain of the protein, affecting the ability to form a receptor dimer with a partner and the ability to function as a transcriptional regulator. Thus, astroglia to GnRH neuronal signaling via ErbB4 is essential of timely onset of puberty and reproductive function.
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Astrócitos/efeitos dos fármacos , Dinoprostona/metabolismo , Transtornos do Desenvolvimento Sexual/patologia , Hormônio Liberador de Gonadotropina/metabolismo , Neurregulinas/farmacologia , Neurônios/metabolismo , Receptor ErbB-4/genética , Animais , Astrócitos/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Transtornos do Desenvolvimento Sexual/tratamento farmacológico , Transtornos do Desenvolvimento Sexual/genética , Transtornos do Desenvolvimento Sexual/metabolismo , Feminino , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/efeitos da radiação , Hipotálamo/citologia , Modelos Moleculares , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Mutação Puntual/genética , Ratos , Ratos Transgênicos , Receptor ErbB-4/metabolismo , Fator de Crescimento Transformador alfa/metabolismoRESUMO
Background: Informal urban settlements, known as slums, are the home for a large proportion of the world population. Healthcare in these environments is extremely complex, driven by poverty, environmental challenges, and poor access to formal health infrastructures. This study investigated healthcare challenges faced and choices made by slum dwellers in Mumbai, India. Methods: Structured interviews with 549 slum dwellers from 13 slum areas in Mumbai, India, were conducted in order to obtain a population profile of health-related socio-economic and lifestyle factors, disease history and healthcare access. Statistical tools such as multinomial logistic regression were used to examine the association between such factors and health choices. Results: Private providers (or a mixture of public and private) were seen to be preferred by the study population for most health conditions (62% - 90% health consultations), apart from pregnancy (43% health consultations). Community-based services were also preferred to more remote options. Stark differences in healthcare access were observed between well-known conditions, such as minor injuries, pulmonary conditions, and pregnancy and emerging challenges, such as hypertension and diabetes. A number of socio-economic and lifestyle factors were found to be associated with health-related decisions, including choice of provider and expenditure. Conclusions: Better planning and coordination of health services, across public and private providers, is required to address mortality and morbidity in slum communities in India. This study provides insights into the complex landscape of diseases and health providers that slum dwellers navigate when accessing healthcare. Findings suggest that integrated services and public-private partnerships could help address demand for affordable community-based care and progress towards the target of universal health coverage.
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AIMS: Previous generations of home monitoring systems have had limited usability. We aimed to develop and evaluate a user-centred and adaptive system for health monitoring and self-management support in patients with heart failure. METHODS AND RESULTS: Patients with heart failure were recruited from three UK centres and provided with Internet-enabled tablet computers that were wirelessly linked with sensor devices for blood pressure, heart rate, and weight monitoring. Patient observations, interviews, and concurrent analyses of the automatically collected data from their monitoring devices were used to increase the usability of the system. Of the 52 participants (median age 77 years, median follow-up 6 months [interquartile range, IQR, 3.6-9.2]), 24 (46%) had no, or very limited prior, experience with digital technologies. It took participants about 1.5 min to complete the daily monitoring tasks, and the rate of failed attempts in completing tasks was <5%. After 45 weeks of observation, participants still used the system on 4.5 days per week (confidence interval 3.2-5.7 days). Of the 46 patients who could complete the final survey, 93% considered the monitoring system as easy to use and 38% asked to keep the system for self-management support after the study was completed. CONCLUSION: We developed a user-centred home monitoring system that enabled a wide range of heart failure patients, with differing degrees of IT literacy, to monitor their health status regularly. Despite no active medical intervention, patients felt that they benefited from the reassurance and sense of connectivity that the monitoring system provided.
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BACKGROUND: Children of patients with cancer are at increased risk for developing emotional and behavioral problems. This study explored the prevalence and predictors of emotional and behavioral problems in Children of cancer patients in a multisite research project. METHODS: A cross-sectional sample of N = 235 families was recruited simultaneously in 5 university medical centers. The participants, including parents (N = 402) and children (N = 324; ages 11-21 years) completed standardized questionnaires. Emotional and behavioral problems in children were measured by the Strengths and Difficulties Questionnaire (SDQ). On the basis of previous research and using a mixed-model approach, child-, parent-, family- and cancer-related variables were examined in addition to socioeconomic status as potential predictors. Descriptive statistics and a multiple random coefficient model were used in the analyses. RESULTS: Compared to norms, Children of cancer patients show increased mean levels of emotional and behavioral symptoms. The best predictor of emotional and behavioral problems from the perspectives of the child, the healthy parent, and the ill parent was general family dysfunction. Although family dysfunction was identified as the main predictor, the analysis revealed that the main part of variance was related to the individual child's level. CONCLUSIONS: The results indicate that screening for child mental health problems and family dysfunction in oncological and psychosocial treatment units can identify the families most in need of psychosocial support. Psychological services need to be both family-oriented and child-centered and focus on family dysfunction to prevent mental health problems in children.
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Transtornos do Comportamento Infantil/etiologia , Filho de Pais com Deficiência/psicologia , Transtornos Mentais/etiologia , Neoplasias/psicologia , Pais/psicologia , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Prevalência , Fatores de Risco , Inquéritos e Questionários , Adulto JovemRESUMO
The purpose of this study was the analysis of psychological distress and health-related quality of life (HRQoL) of parents with minor children during curative resp. palliative treatment.Cross-sectional design with a sample of N=89 parent dyads. Dyadic analysis of demographic, illness and family variables via mixed linear models.Patients and healthy partners indicated psychological distress on different subscales. Intradyadic correlations were small-moderate. Most important predictors of psychological distress and HRQoL were treatment stadium, gender, family functioning, and employment status.Dependent on demographic variables, psychooncological support was evident mainly for parents in palliative care and for families with dysfunctional functioning.
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Família , Neoplasias/psicologia , Pais/psicologia , Qualidade de Vida , Estresse Psicológico/psicologia , Adulto , Criança , Pré-Escolar , Estudos Transversais , Emprego , Feminino , Humanos , Lactente , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Testes Neuropsicológicos , Cuidados Paliativos , Escalas de Graduação Psiquiátrica , Estresse Psicológico/etiologiaRESUMO
BACKGROUND: Cancer patients and their minor children have been shown to experience psychological distress. The objectives of the current study were to 1) describe the need for and use of psychosocial support and 2) determine predictors of family-centered support use in patients with minor children. METHODS: A population-based sample of 1809 patients was recruited via 2 cancer registries. The eligibility criteria were age 25 years to 55 years, an initial diagnosis received no longer than 6 years before this survey, and having at least 1 minor child. Medical characteristics and self-report measures were used. RESULTS: Overall, approximately 38% cases were identified as being borderline or probable anxiety cases and 16% were identified as being borderline or probable depression cases. Since diagnosis, 44% of the patients had used psychosocial support and 9% had received family-focused and child-focused support. These patients perceived a lower quality of life and poorer family functioning. Approximately 73% of patients with children wanted information concerning or psychosocial services to support their children or parenting. Use of family-centered support was not found to be predicted by disease-related factors (eg, cancer staging) but rather by subjective needs (eg, mental health and having a distressed child in the family). CONCLUSIONS: The results of the current study emphasize the importance of child and parenting concerns in psychosocial care in oncology. Screenings for children and appropriate training programs for health care may increase awareness of this issue.
Assuntos
Neoplasias/psicologia , Apoio Social , Adulto , Transtornos de Ansiedade/psicologia , Criança , Transtorno Depressivo/psicologia , Família/psicologia , Feminino , Alemanha , Necessidades e Demandas de Serviços de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Poder Familiar/psicologia , Sistema de Registros , Fatores SocioeconômicosRESUMO
BACKGROUND: Parental palliative disease is a family affair, however adolescent's well-being and coping are still rarely considered. The objectives of this paper were a) to identify differences in psychosocial adjustment and health-related quality of life (HRQoL) among adolescents and young adults with parents suffering from palliative cancer or cancers in other disease stages, b) to relate psychosocial adjustment and health-related quality of life to adolescent coping, and c) to explore significant mediator and predictor variables. METHODS: Cross-sectional data were derived from a multi-site research study of families before child-centered counselling. N=86 adolescents and young adults were included, their mean age 13.78 years (sd 2.45), 56% being female. Performed analyses included ANCOVA, multiple linear regression, and mediation analysis. RESULTS: Adolescents with parents suffering from palliative cancers reported significantly less total psychosocial problems, and better overall HRQoL. There were no significant group differences regarding coping frequency and efficacy. Our set of coping items significantly mediated the effect of parental disease stage on psychosocial problems and HRQoL. Further, parental disease status and general family functioning predicted psychosocial problems (R2adj =.390) and HRQoL (R2adj =.239) best. CONCLUSION: The study indicates distress among adolescents throughout the entire parental disease process. Our analysis suggests that counselling services could offer supportive interventions which focus particularly on adolescent coping as well as family functioning.