RESUMEN
BACKGROUND: Autosomal recessive renal tubular dysgenesis is a rare, usually fatal inherited disorder of the renin-angiotensis system (RAS). Herein, we report an adolescent individual experiencing an unknown chronic kidney disease and aim to provide novel insights into disease mechanisms. METHODS: Exome sequencing for a gene panel associated with renal disease was performed. The RAS was assessed by comprehensive biochemical analysis in blood. Renin expression was determined in primary tubular cells by quantitative polymerase chain reaction and in situ hybridization on kidney biopsy samples. Allele frequencies of heterozygous and biallelic deleterious variants were determined by analysis of the Genomics England 100,000 Genomes Project. RESULTS: The patient was delivered prematurely after oligohydramnios was detected during pregnancy. Postnatally, he recovered from third-degree acute kidney injury but developed chronic kidney disease stage G3b over time. Exome sequencing revealed a previously reported pathogenic homozygous missense variant, p.(Arg375Gln), in the AGT (angiotensinogen) gene. Blood AGT concentrations were low, but plasma renin concentration and gene expression in kidney biopsy, vascular, and tubular cells revealed strong upregulation of renin. Angiotensin II and aldosterone in blood were not abnormally elevated. CONCLUSIONS: Renal tubular dysgenesis may present as chronic kidney disease with a variable phenotype, necessitating broad genetic analysis for diagnosis. Functional analysis of the RAS in a patient with AGT mutation revealed novel insights regarding compensatory upregulation of renin in vascular and tubular cells of the kidney and in plasma in response to depletion of AGT substrate as a source of Ang II (similarly observed with hepatic AGT silencing for the treatment of hypertension).
Asunto(s)
Angiotensinógeno , Humanos , Angiotensinógeno/genética , Masculino , Adolescente , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiología , Progresión de la Enfermedad , Renina/genética , Renina/sangre , Renina/metabolismo , Mutación Missense/genética , Secuenciación del Exoma/métodos , Femenino , Túbulos Renales Proximales/anomalías , Anomalías UrogenitalesRESUMEN
OBJECTIVE: Recent work on ischemic cerebellar stroke has suggested that the resection of infarcted tissue may lead to improved functional outcomes compared with decompressive surgery alone. Nonetheless, no studies have assessed the extent to which necrotic tissue should be resected or if there are any volumetric thresholds capable of predicting functional outcomes in this patient population. In this study, the authors aimed to determine potential thresholds for volume reduction in ischemic cerebellar stroke in an effort to optimize the management of ischemic cerebellar stroke and, in so doing, improve functional outcomes. METHODS: This study is a multicentric retrospective study of patients who underwent surgery for the management of ischemic cerebellar stroke. Volumetric analyses of infarcted tissue present on CT scans were performed before and after surgical intervention(s). The final infarct volume (FIV) was computed as a percentage of the initial infarct volume (postoperative infarct volume/preoperative infarct volume × 100). The primary endpoint was functional outcome at 3 months, as determined by the modified Rankin Scale (mRS) score; mRS scores 0-2 were considered as favorable and mRS scores 3-6 as unfavorable. Receiver operating characteristic curves were used to explore the relationship between postoperative infarct volumes and FIV versus mRS score, and Youden's index was used to estimate potential volumetric thresholds. RESULTS: A total of 91 patients were included in the study. The mean pre- and postoperative infarct volumes were 45.25 (SD 18.32) cm3 and 29.56 (SD 26.61) cm3, respectively. Patients undergoing necrosectomy, regardless of whether via craniotomy or craniectomy, were more likely to have a favorable outcome at discharge (OR 16.62, 95% CI 2.12-130.33; p = 0.008) and at 3 months (OR 24.12, 95% CI 3.03-192.18; p = 0.003) postoperatively. Postoperative infarct volumes ≤ 17 cm3 yielded a sensitivity of 77% and a specificity of 68% with regard to the prediction of favorable outcome at 3 months. The resection ≥ 50% of infarcted tissue was also predictive of favorable outcomes at 3 months (OR 7.7, 95% CI 2.7-21.8; p < 0.001). CONCLUSIONS: The reduction of necrotic tissue volumes by at least 50% and/or the reduction of the infarct volume by ≤ 17 cm3 appear to be associated with favorable outcomes in patients with surgically managed ischemic cerebellar strokes.
RESUMEN
BACKGROUND AND PURPOSE: Swallowing is a complex task, moderated by a sophisticated bilateral network including multiple supratentorial regions, the brainstem and the cerebellum. To date, conflicting data exist about whether focal lesions to the cerebellum are associated with dysphagia. Therefore, the aim of the study was to evaluate dysphagia prevalence, recovery and dysphagia pattern in patients with ischaemic cerebellar stroke. METHODS: A retrospective analysis of patients consecutively admitted to an academic stroke centre with ischaemic stroke found only in the cerebellum was performed. The presence of dysphagia was the primary end-point and was assessed by a speech-language pathologist, according to defined criteria. Dysphagia pattern was evaluated by analysing the videos of the flexible endoscopic evaluation of swallowing. Brain imaging was used to identify lesion size and location associated with dysphagia. RESULTS: Between January 2016 and December 2021, 102 patients (35.3% female) with a mean age of 52.8 ± 17.3 years were included. Thirteen (12.7%) patients presented with dysphagia. The most frequently observed flexible endoscopic evaluation of swallowing phenotype was premature spillage (n = 7; 58.3%), whilst significant residues or aspiration did not occur. One patient died (7.7%); the other patients showed improvement of dysphagia and one patient (7.7%) was discharged with dietary restrictions. CONCLUSIONS: Although the involvement of the cerebellum in deglutition has become increasingly evident, isolated lesions to the cerebellum are less likely to cause clinically relevant and persisting dysphagia compared to other brain regions. The observed dysphagia pattern shows a lack of coordination and control, resulting in premature spillage or fragmented bolus transfer in some patients.
Asunto(s)
Trastornos de Deglución , Accidente Cerebrovascular Isquémico , Fenotipo , Humanos , Femenino , Trastornos de Deglución/etiología , Trastornos de Deglución/fisiopatología , Trastornos de Deglución/epidemiología , Masculino , Persona de Mediana Edad , Anciano , Accidente Cerebrovascular Isquémico/complicaciones , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Accidente Cerebrovascular Isquémico/epidemiología , Estudios Retrospectivos , Prevalencia , Adulto , Recuperación de la Función/fisiología , Cerebelo/diagnóstico por imagen , Cerebelo/patología , Enfermedades Cerebelosas/complicaciones , Enfermedades Cerebelosas/epidemiología , Enfermedades Cerebelosas/diagnóstico por imagenRESUMEN
Background: The clinical course of ischemic and hemorrhagic strokes can be influenced by the coagulation status of individual patients. The prior use of antiplatelet therapy (APT) such as acetylsalicylic acid (ASA) or P2Y12-antagonists has been inconsistently described as possibly increasing the risk of hemorrhagic transformation or expansion. Since clinical studies describing prior use of antiplatelet medication are overwhelmingly lacking specific functional tests, we aimed to implement testing in routine stroke care. Methods: We used fluorescence-activated cell sorting (FACS) with antibodies against CD61 for thrombocyte identification and CD62p or platelet activation complex-1 (PAC-1) to determine platelet activation. Aggregometry and automated platelet functioning analyzer (PFA-200) were employed to test thrombocyte reactivity. FACS and aggregometry samples were stimulated in vitro with arachidonic acid (AA) and adenosine diphosphate (ADP) to measure increase in CD62p-/PAC-1-expression or aggregation, respectively. Results: Between February and July 2023, 20 blood samples (n = 11 ischemic strokes; n = 7 hemorrhagic strokes; n = 2 controls) were acquired and analyzed within 24 h of symptom onset. N = 11 patients had taken ASA, n = 8 patients no APT and n = 1 ASA+clopidogrel. ASA intake compared to no APT was associated with lower CD62p expression after stimulation with AA on FACS analysis (median 15.8% [interquartile range {IQR} 12.6-37.2%] vs. 40.1% [IQR 20.3-56.3%]; p = 0.020), lower platelet aggregation (9.0% [IQR 7.0-12.0%] vs. 88.5% [IQR 11.8-92.0%]; p = 0.015) and longer time to plug formation with PFA-200 (248.0 s [IQR 157.0-297] vs. 121.5 s [IQR 99.8-174.3]; p = 0.027). Significant correlations were noted between AA-induced CD62p expression and aggregometry analysis (n = 18; ρ = 0.714; p < 0.001) as well as a negative correlation between CD62p increase and PFA clot formation time (n = 18; ρ = -0.613; p = 0.007). Sensitivity for ASA intake was highest for PFA (81.8% for values ≥155.5 s). The combination of ASA + clopidogrel also affected ADP-induced CD62p and PAC-1 expression. Conclusion: In the clinical setting it is feasible to use differentiated platelet analytics to determine alterations caused by antiplatelet therapy. Among the tests under investigation, PFA-200 showed the highest sensitivity for the intake of ASA in stroke patients. FACS analysis on the other hand might be able to provide a more nuanced approach to altered platelet reactivity.
RESUMEN
Importance: According to the current American Heart Association/American Stroke Association guidelines, decompressive surgery is indicated in patients with cerebellar infarcts that demonstrate severe cerebellar swelling. However, there is no universal definition of swelling and/or infarct volume(s) available to support a decision for surgery. Objective: To evaluate functional outcomes in surgically compared with conservatively managed patients with cerebellar infarcts. Design, Setting, and Participants: In this retrospective multicenter cohort study, patients with cerebellar infarcts treated at 5 tertiary referral hospitals or stroke centers within Germany between 2008 and 2021 were included. Data were analyzed from November 2020 to November 2023. Exposures: Surgical treatment (ie, posterior fossa decompression plus standard of care) vs conservative management (ie, medical standard of care). Main Outcomes and Measures: The primary outcome examined was functional status evaluated by the modified Rankin Scale (mRS) at discharge and 1-year follow-up. Secondary outcomes included the predicted probabilities for favorable outcome (mRS score of 0 to 3) stratified by infarct volumes or Glasgow Coma Scale score at admission and treatment modality. Analyses included propensity score matching, with adjustments for age, sex, Glasgow Coma Scale score at admission, brainstem involvement, and infarct volume. Results: Of 531 included patients with cerebellar infarcts, 301 (57%) were male, and the mean (SD) age was 68 (14.4) years. After propensity score matching, a total of 71 patients received surgical treatment and 71 patients conservative treatment. There was no significant difference in favorable outcomes (ie, mRS score of 0 to 3) at discharge for those treated surgically vs conservatively (47 [66%] vs 45 [65%]; odds ratio, 1.1; 95% CI, 0.5-2.2; P > .99) or at follow-up (35 [73%] vs 33 [61%]; odds ratio, 1.8; 95% CI, 0.7-4.2; P > .99). In patients with cerebellar infarct volumes of 35 mL or greater, surgical treatment was associated with a significant improvement in favorable outcomes at 1-year follow-up (38 [61%] vs 3 [25%]; odds ratio, 4.8; 95% CI, 1.2-19.3; P = .03), while conservative treatment was associated with favorable outcomes at 1-year follow-up in patients with infarct volumes of less than 25 mL (2 [34%] vs 218 [74%]; odds ratio, 0.2; 95% CI, 0-1.0; P = .047). Conclusions and Relevance: Overall, surgery was not associated with improved outcomes compared with conservative management in patients with cerebellar infarcts. However, when stratifying based on infarct volume, surgical treatment appeared to be beneficial in patients with larger infarct volumes, while conservative management appeared favorable in patients with smaller infarct volumes.
RESUMEN
BACKGROUND AND OBJECTIVES: Space-occupying cerebellar stroke (SOCS) when coupled with neurological deterioration represents a neurosurgical emergency. Although current evidence supports surgical intervention in such patients with SOCS and rapid neurological deterioration, the optimal surgical methods/techniques to be applied remain a matter of debate. METHODS: We conducted a retrospective, multicenter study of patients undergoing surgery for SOCS. Patients were stratified according to the type of surgery as (1) suboccipital decompressive craniectomy (SDC) or (2) suboccipital craniotomy with concurrent necrosectomy. The primary end point examined was functional outcome using the modified Rankin Scale (mRS) at discharge and at 3 months (mRS 0-3 defined as favorable and mRS 4-6 as unfavorable outcome). Secondary end points included the analysis of in-house postoperative complications, mortality, and length of hospitalization. RESULTS: Ninety-two patients were included in the final analysis: 49 underwent necrosectomy and 43 underwent SDC. Those with necrosectomy displayed significantly higher rate of favorable outcome at discharge as compared with those who underwent SDC alone: 65.3% vs 27.9%, respectively ( P < .001, odds ratios 4.9, 95% CI 2.0-11.8). This difference was also observed at 3 months: 65.3% vs 41.7% ( P = .030, odds ratios 2.7, 95% CI 1.1-6.7). No significant differences were observed in mortality and/or postoperative complications, such as hemorrhagic transformation, infection, and/or the development of cerebrospinal fluid leaks/fistulas. CONCLUSION: In the setting of SOCS, patients treated with necrosectomy displayed better functional outcomes than those patients who underwent SDC alone. Ultimately, prospective, randomized studies will be needed to confirm this finding.
Asunto(s)
Isquemia Encefálica , Enfermedades Cerebelosas , Craniectomía Descompresiva , Humanos , Estudios Retrospectivos , Craniectomía Descompresiva/métodos , Estudios Prospectivos , Isquemia Encefálica/cirugía , Enfermedades Cerebelosas/cirugía , Complicaciones Posoperatorias/cirugía , Infarto/cirugía , Resultado del TratamientoRESUMEN
Despite the enormous health burden of lacunar stroke, data from low- and middle-income countries on lacunar stroke characteristics and its comparison with that of high-income countries are scarce. Thus, we aimed to investigate and compare the variable characteristics and vascular status in patients from Egypt and Germany suffering lacunar stroke. Two cohorts of lacunar stroke patients from Ain Shams University Hospital, Egypt and Goethe University Hospital Frankfurt, Germany were retrospectively collected between January 2019 and December 2020 and analyzed for demographics, risk factors, mode of presentation, neuroimaging features, treatment protocols and outcomes. MRI showed a different distribution pattern of lacunar strokes between cohorts, detecting posterior circulation lacunar infarctions preponderantly in patients from Egypt and anterior circulation lacunar infarctions preponderantly in patients from Germany. Complementary MR/CT angiography revealed a significantly higher proportion of intracranial and combined intracranial and extracranial arterial stenosis in patients from Egypt than in patients from Germany, suggesting differences in pathological processes. Younger age, higher NIHSS on admission, and posterior circulation lacunar infarction were predictors of Egyptian origin, whereas hypertension was a predictor of German origin. Our results support the idea of clinical and neuroimaging phenotype variations in lacunar stroke, including different sources of lacunar stroke in patients of different populations and geographical regions. This implies that guidelines for management of lacunar stroke might be tailored to these differences accordingly.
Asunto(s)
Hipertensión , Accidente Vascular Cerebral Lacunar , Accidente Cerebrovascular , Humanos , Accidente Vascular Cerebral Lacunar/diagnóstico por imagen , Accidente Vascular Cerebral Lacunar/epidemiología , Egipto/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/epidemiologíaRESUMEN
BACKGROUND: Several individual predictors for outcomes in patients with cerebellar stroke (CS) have been previously identified. There is, however, no established clinical score for CS. Therefore, the aim of this study was to develop simple and accurate grading scales for patients with CS in an effort to better estimate mortality and outcomes. METHODS: This multicentric retrospective study included 531 patients with ischemic CS presenting to 5 different academic neurosurgical and neurological departments throughout Germany between 2008 and 2021. Logistic regression analysis was performed to determine independent predictors related to 30-day mortality and unfavorable outcome (modified Rankin Scale score of 4-6). By weighing each parameter via calculation of regression coefficients, an ischemic CS-score and CS-grading scale (CS-GS) were developed and internally validated. RESULTS: Independent predictors for 30-day mortality were aged ≥70 years (odds ratio, 5.2), Glasgow Coma Scale score 3 to 4 at admission (odds ratio, 2.6), stroke volume ≥25 cm3 (odds ratio, 2.7), and involvement of the brain stem (odds ratio, 3.9). When integrating each parameter into the CS-score, age≥70 years and brain stem stroke were assigned 2 points, Glasgow Coma Scale score 3 to 4, and stroke volume≥25 cm3 1 point resulting in a score ranging from 0 to 6. CS-score of 0, 1, 2, 3, 4, 5, and 6 points resulted in 30-day mortality of 1%, 6%, 6%, 17%, 21%, 55%, and 67%, respectively. Independent predictors for 30-day unfavorable outcomes consisted of all components of the CS-score with an additional variable focused on comorbidities (CS-GS). Except for Glasgow Coma Scale score 3 to 4 at admission, which was assigned 3 points, all other parameters were assigned 1 point resulting in an overall score ranging from 0 to 7. CS-GS of 0, 1, 2, 3, 4, 5, 6, and 7 points resulted in 30-day unfavorable outcome of 1%, 17%, 33%, 40%, 50%, 80%, 77%, and 100%, respectively. Both 30-day mortality and unfavorable outcomes increased with increasing CS-score and CS-GS (P<0.001). CONCLUSIONS: The CS-score and CS-GS are simple and accurate grading scales for the prediction of 30-day mortality and unfavorable outcome in patients with CS. While the score systems proposed here may not directly impact treatment decisions, it may help discuss mortality and outcome with patients and caregivers.
Asunto(s)
Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/terapia , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/terapia , Resultado del Tratamiento , AncianoRESUMEN
Objectives: The survival of pediatric patients with short bowel syndrome has improved in recent years. Enteric hyperoxaluria as a pathophysiological consequence has been hardly addressed so far. It can be associated with nephrolithiasis, nephrocalcinosis or even renal insufficiency. We assessed the prevalence of hyperoxaluria and its pathogenic consequences in a retrospective single centre study over the last 12 years. Methods: We conducted an internal database search for all pediatric patients suffering from short bowel syndrome treated from 2010 to 2022 in the department of pediatric gastroenterology as well as the pediatric nephrology and dialysis unit. Out of 56 patients identified, 26 patients were analysed for etiology of short bowel syndrome, renal excretion of oxalate (24/26), remaining short bowel and large intestinal length as well as further clinical parameters such as eGFR, nephrocalcinosis/urinary stone formation or stool frequency. Results: Hyperoxaluria was detected in 14/26 patients (54%). Nephrocalcinosis was present in four patients. Out of these four patients, hyperoxaluria could be proven (21% of all hyperoxaluric patients) in three cases, one hyperoxaluric patient had nephrolithiasis (7%). In one patient hyperoxaluria lead to end stage renal disease. We found that 80% of patients with volvulus developed enteric hyperoxaluria. None of the investigated factors had an effect on oxalate excretion. Conclusion: Enteric hyperoxaluria is a relevant pathophysiological finding in patients with short bowel syndrome occurring in about 50% of our cohort with multiple pathogenic complications. Regular screening for hyperoxaluria may be implemented in medical care for patients with short bowel syndrome. If necessary, prophylaxis, e.g., dietary advice or metaphylaxis should be initiated.
RESUMEN
BACKGROUND: The presence of contrast enhancement (CE) on magnetic resonance imaging (MRI) is one of the principal criteria for diagnosis and disease activity of multiple sclerosis (MS). Therefore, MS patients are frequently exposed to contrast agents, which may cause deposition in the brain, restricting its use in repeat examinations. Thus, serum biomarkers may be valuable as surrogate parameters to evaluate MS activity. METHODS: REDUCE-GAD was a prospective, multicentric, biobanking study to determine whether established serum markers (neurofilament light chain [NfL], glial fibrillary acidic protein [GFAP], tau protein, ubiquitin-carboxyl-terminal-hydrolase (UCH-L1), S100B and matrix-metalloproteinase 9 [MMP9]) are predictive of CE-positive MRI lesions. Blood samples were obtained from patients undergoing MRI 5 days before or after collection. RESULTS: Patients (N = 102) from four different centers with confirmed MS or related disorders were included; n = 57 (55.9%) showed CE on MRI versus n = 45 (44.1%) without CE. Only higher NfL values indicated CE (odds ratio [OR] 1.05; 95% CI 1.0-1.09) and were correlated with number (ρ = 0.47; p < 0.001) and diameter of CE lesions (ρ = 0.58; p < 0.001). Nfl Z-scores improved diagnostic accuracy (OR 1.52; 95% CI 1.06-2.18). Receiver operator characteristic analysis revealed a reasonable cut-off value for NfL at 14.1 pg/mL (sensitivity 49.1%; specificity 82.2%; positive predictive value 77.8%; negative predictive value 56.0%). NfL ≥59.2 pg/mL was exclusively observed in patients with CE. CONCLUSIONS: Evaluation of several possible serum biomarkers for CE in MS patients provided the most robust results for NfL, particularly as Z-scores. Following further evaluation, biomarkers may help stratify the application of contrast agents for brain imaging in MS patients.
Asunto(s)
Esclerosis Múltiple , Humanos , Esclerosis Múltiple/diagnóstico por imagen , Gadolinio , Estudios Prospectivos , Bancos de Muestras Biológicas , Medios de Contraste , Biomarcadores , Proteína Ácida Fibrilar de la Glía , Proteínas de NeurofilamentosRESUMEN
Necroptosis is a lytic and inflammatory form of cell death that is highly constrained to mitigate detrimental collateral tissue damage and impaired immunity. These constraints make it difficult to define the relevance of necroptosis in diseases such as chronic and persistent viral infections and within individual organ systems. The role of necroptotic signalling is further complicated because proteins essential to this pathway, such as receptor interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL), have been implicated in roles outside of necroptotic signalling. We sought to address this issue by individually defining the role of RIPK3 and MLKL in chronic lymphocytic choriomeningitis virus (LCMV) infection. We investigated if necroptosis contributes to the death of LCMV-specific CD8+ T cells or virally infected target cells during infection. We provide evidence showing that necroptosis was redundant in the pathogenesis of acute forms of LCMV (Armstrong strain) and the early stages of chronic (Docile strain) LCMV infection in vivo. The number of immune cells, their specificity and reactivity towards viral antigens and viral loads are not altered in the absence of either MLKL or RIPK3 during acute and during the early stages of chronic LCMV infection. However, we identified that RIPK3 promotes immune dysfunction and prevents control of infection at later stages of chronic LCMV disease. This was not phenocopied by the loss of MLKL indicating that the phenotype was driven by a necroptosis-independent function of RIPK3. We provide evidence that RIPK3 signaling evoked a dysregulated type 1 interferone response which we linked to an impaired antiviral immune response and abrogated clearance of chronic LCMV infection.
Asunto(s)
Virus de la Coriomeningitis Linfocítica , Proteínas Quinasas , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Virus de la Coriomeningitis Linfocítica/metabolismo , Necroptosis , Linfocitos T CD8-positivos/metabolismo , Muerte Celular , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismoRESUMEN
Background: Measurement of D-dimer in cerebrospinal fluid (CSF) allows insight into coagulation system activation in the central nervous system and can be utilized to monitor intracranial hemorrhage as well as acute phase processes beyond hemostasis in inflammatory and neoplastic diseases. So far, the measurability of D-dimer in low and very low concentrations in CSF was limited in conventional immunoassays. Novel high-sensitivity chemiluminescent immunoassays such as the luminescent oxygen channeling immunoassay (LOCI®) are getting increasingly available but have not been validated in CSF. The aim of this study was to investigate the accuracy and linearity of the LOCI® in assessing D-dimer in CSF. Methods: INNOVANCE LOCI hs D-dimer reagent cartridge was used for the measurement of D-dimer in CSF of patients with different neurological diseases. For the evaluation of linearity, dilution series were performed in a pooled CSF sample with the determination of intra-assay precision (CV, coefficient of variation) in 3 individual samples with 20 replicates. Furthermore, D-dimer concentrations measured by LOCI® were compared with the respective results of a routinely available clinical latex-enhanced immunoassay (HemosiIL D-Dimer HS 500). Results: Linear regression analysis of the LOCI® method revealed a r 2 of 1.00 (p < 0.001) with a regression coefficient B of 1.012 ± 0.003 (CI: 1.005-1.019, p < 0.001) and an intercept of -1.475 ± 1.309 (CI: -4.493 to 1.543); the median intra-assay CV was 0.69% (range: 0.68-0.75). In total, 185 CSF samples were measured by LOCI® technology, showing a mean concentration of 204.84 ± 2,214.93 ng/ml. D-dimer concentration between LOCI and latex-enhanced immunoassay differed by a factor of 10.6 ± 13.6 on average with a maximum deviation by a factor of 61.3; the maximum deviation was found at low concentrations. Conclusion: D-dimer in CSF of patients with neurological disease can be reliably measured by the LOCI® method with high linearity and accuracy at low concentrations.
RESUMEN
Intracellular infections rely on host cell survival for replication and have evolved several mechanisms to prevent infected cells from dying. Drugs that promote apoptosis, a noninflammatory form of cell death, can dysregulate these survival mechanisms to kill infected cells via a mechanism that resists the evolution of drug resistance. Two such drug classes, known as SMAC mimetics and BH3 mimetics, have shown preclinical efficacy at mediating clearance of liver-stage malaria and chronic infections such as hepatitis-B virus and Mycobacterium tuberculosis. Emerging toxicity and efficacy data have reinforced the broad applicability of these drugs and form the foundations for preclinical and clinical studies into their various usage cases.
Asunto(s)
Proteínas Reguladoras de la Apoptosis , Apoptosis , Humanos , Muerte CelularRESUMEN
Background The incidence of ischemic stroke was previously expected to rise among countries with an aging population. Lately, several studies from developed countries have reported a decline in certain cohorts. Whether this applies to all sexes, however, is uncertain, with limited data on the temporal development in incidence, treatment, and recovery. Methods and Results We analyzed a prospective stroke inpatient quality-assurance registry of the federal state of Hesse, Germany. Recruitment of all patients with a final diagnosis of ischemic stroke at hospital discharge (International Classification of Diseases, Tenth Revision [ICD-10]: I63) is mandatory by law. Incidence rates were calculated based on census data of all inhabitants and stratified according to age. Between 2010 and 2019, there were 141 277 patients included, 73 770 (52.2%) male patients and 67 507 (47.8%) female patients. Overall, the incidence of ischemic stroke was 228 per 100 000 in 2010 and 226 per 100 000 in 2019 (-0.8%; odds ratio [OR], 0.99 [95% CI, 0.96-1.02]; P=0.50). For male patients, the incidence increased continuously from 236 per 100 000 to 245 per 100 000 (+3.8%); in female patients it decreased from 220 per 100 000 to 208 per 100 000 (-5.6%). After adjusting for age, the OR for ischemic stroke between male and female patients was 1.40 in 2010 (95% CI, 1.35-1.44; P<0.001) and 1.48 in 2019 (95% CI, 1.43-1.53; P<0.001). This development was most pronounced in male patients aged 45 to 59 years with an increase from 151 per 100 000 to 176 per 100 000. In this age group, male patients showed increasing rates of prior strokes and atrial fibrillation, surpassing the prevalence in female patients over time. After multivariable regression analysis, male patients had a lower modified Rankin Scale at discharge compared with female patients, but this difference has decreased since 2015 (common OR in 2010, 0.83 [95% CI, 0.78-0.88]; common OR in 2019, 0.90 [95% CI, 0.84-0.95]), which coincided with rising rates of endovascular treatment. Conclusions Over the past decade in the federal state of Hesse, the overall incidence of ischemic stroke has declined predominantly in the female population. In contrast, for male patients, the incidence has risen by about 4%, with a steeper increase of 16% in male patients aged 45 to 59 years, which might be related to increasing rates of recurrent strokes and atrial fibrillation in this cohort. This finding provides a cautionary tale for effective secondary prevention. Female patients were generally less likely to achieve a favorable outcome, but since the introduction of endovascular treatment, the outcome gap is decreasing.
Asunto(s)
Fibrilación Atrial , Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Masculino , Femenino , Anciano , Fibrilación Atrial/epidemiología , Accidente Cerebrovascular Isquémico/diagnóstico , Accidente Cerebrovascular Isquémico/epidemiología , Accidente Cerebrovascular Isquémico/terapia , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Alemania/epidemiología , Sistema de Registros , Incidencia , Factores de Riesgo , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiología , Isquemia Encefálica/terapiaRESUMEN
Understanding the collective behavior of ions at charged surfaces is of paramount importance for geological and electrochemical processes. Ions screen the surface charge, and interfacial fields break the centro-symmetry near the surface, which can be probed using second-order nonlinear spectroscopies. The effect of electrolyte concentration on the nonlinear optical response has been semi-quantitatively explained by mean-field models based on the Poisson-Boltzmann equation. Yet, to explain previously reported ion-specific effects on the spectroscopic response, drastic ion-specific changes in the interfacial properties, including surface acidities and dielectric permittivities, or strong ion adsorption/desorption had to be invoked. Here, we use sum-frequency generation (SFG) spectroscopy to probe the symmetry-breaking of water molecules at a charged silica surface in contact with alkaline metal chloride solutions (LiCl, NaCl, KCl, and CsCl) at various concentrations. We find that the water response varies with the cation: the SFG response is markedly enhanced for LiCl compared to CsCl. We show that within mean-field models, neither specific ion-surface interactions nor a reduced dielectric constant of water near the interface can account for the variation of spectral intensities with cation nature. Molecular dynamics simulations confirm that the decay of the electrochemical potential only weakly depends on the salt type. Instead, the effect of different salts on the optical response is indirect, through the reorganization of the interfacial water: the salt-type-dependent alignment of water directly at the interface can explain the observations.
Asunto(s)
Dióxido de Silicio , Agua , Cationes , Cloruros , Cloruro de SodioRESUMEN
Background In patients with covert cerebrovascular disease or proximal source of embolism, embolic silent brain infarction may precede major stroke events. Therefore, characterization of particularly cortical silent brain infarction is essential for identifying affected patients and commencing adequate secondary prevention. This study aimed to investigate differences in the distribution pattern of cortical ischemic stroke lesions to assess potential predilection sites of cortical silent brain infarction. Methods and Results We prospectively included all consecutive patients with stroke presenting from January 1 to December 31, 2018. Diffusion-weighted imaging lesions were used to generate voxel-based lesion maps and assigned to atlas-based cortical regions of interest in middle cerebral artery territories. Each region-of-interest lesion frequency was related to the respective region-of-interest volume to identify frequently affected and underrepresented cerebral cortex areas. Diffusion-weighted imaging data for voxel-based lesion maps were available in 334 out of 633 patients. Primary analysis revealed that small- (<0.24 cc) and medium-sized (0.24-2640 cc) lesions distributed predominantly along regions associated with sensorimotor or language function. Detailed analysis within middle cerebral artery territories showed an approximated frequency of missed cortical stroke lesions of up to 67% in the right and 69% in the left hemisphere. In particular, the frontal, temporal, and occipital cortices were underrepresented. Larger lesion size and areas associated with higher cortical function led to hospital admission. Conclusions Cortical brain infarcts in hospitalized patients are not dispersed equally but are predominantly located in brain structures associated with motor control and sensory and language function. Matching underrepresented cerebral cortex regions to symptoms not yet associated with stroke warrants further exploration.
Asunto(s)
Accidente Cerebrovascular Embólico , Embolia , Accidente Cerebrovascular , Infarto Encefálico , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Imagen de Difusión por Resonancia Magnética , Embolia/complicaciones , Humanos , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/etiologíaRESUMEN
Background: Endovascular therapy (EVT) in acute ischemic stroke has been widely established. Globally, stroke patients are transferred either directly to a thrombectomy center (DC) or a peripheral stroke unit with a "drip-and-ship" (DS) model. We aimed to determine differences between the DS and DC paradigms after EVT of acute stroke patients with large-vessel-occlusion (LVO) in the database of the German Stroke Registry (GSR). Methods: We performed a retrospective analysis of GSR patients between June 2015 and December 2019 in 23 German centers. Primary outcome was an ordinal shift analysis of modified Rankin Scale (mRS) 90 days after index event. Secondary endpoints included time from symptom onset to recanalization and complications. Tertiary endpoint was the association of imaging strategies in DS admissions with outcome. Results: 2,813 patients were included in the DS and 3,819 in the DC group. After propensity score matching mRS after 90 days was higher in DS than DC admissions (OR 1.26; 95%-CI 1.13-1.40). Time from symptom-onset to flow-restoration was shorter in DC than DS (median 199.0 vs. 298.0 min; p < 0.001). DS patients undergoing magnetic resonance imaging (MRI; n=183) before EVT had a lower 90-day mRS than without (n = 944) (OR 0.63; 95%-CI 0.45-0.88). ASPECTS assessed on MRI correlated with 90-day mRS (ρ = -0.326; p < 0.001). Conclusions: Clinical outcome was worse for EVT-eligible patients in the DS setting, even though patients were in a better state of health prior to stroke. A potentially mutable factor was the time delay of 99 min from symptom-onset to successful recanalization. Performing MRI before thrombectomy was associated with good outcome and MRI-ASPECTS was negatively correlated with mRS after 90 days.
RESUMEN
BACKGROUND & AIMS: Necroptosis is a highly inflammatory mode of cell death that has been implicated in causing hepatic injury including steatohepatitis/ nonalcoholic steatohepatitis (NASH); however, the evidence supporting these claims has been controversial. A comprehensive, fundamental understanding of cell death pathways involved in liver disease critically underpins rational strategies for therapeutic intervention. We sought to define the role and relevance of necroptosis in liver pathology. METHODS: Several animal models of human liver pathology, including diet-induced steatohepatitis in male mice and diverse infections in both male and female mice, were used to dissect the relevance of necroptosis in liver pathobiology. We applied necroptotic stimuli to primary mouse and human hepatocytes to measure their susceptibility to necroptosis. Paired liver biospecimens from patients with NASH, before and after intervention, were analyzed. DNA methylation sequencing was also performed to investigate the epigenetic regulation of RIPK3 expression in primary human and mouse hepatocytes. RESULTS: Identical infection kinetics and pathologic outcomes were observed in mice deficient in an essential necroptotic effector protein, MLKL, compared with control animals. Mice lacking MLKL were indistinguishable from wild-type mice when fed a high-fat diet to induce NASH. Under all conditions tested, we were unable to induce necroptosis in hepatocytes. We confirmed that a critical activator of necroptosis, RIPK3, was epigenetically silenced in mouse and human primary hepatocytes and rendered them unable to undergo necroptosis. CONCLUSIONS: We have provided compelling evidence that necroptosis is disabled in hepatocytes during homeostasis and in the pathologic conditions tested in this study.
Asunto(s)
Necroptosis , Enfermedad del Hígado Graso no Alcohólico , Humanos , Femenino , Masculino , Ratones , Animales , Epigénesis Genética , Enfermedad del Hígado Graso no Alcohólico/genética , Hepatocitos , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteínas Quinasas/genéticaRESUMEN
BACKGROUND: The interaction of central nervous system inflammation and coagulation system activation in multiple sclerosis (MS) receives increasing attention for its diagnostic and therapeutic potential. During blood-brain barrier (BBB) disruption, fibrinogen migrates into the CNS and contributes to inflammation. In the coagulation cascade, fibrinogen is converted into fibrin by thrombin, which itself is cleaved from prothrombin by activated factor XII. We hypothesized that the conversion of prothrombin to thrombin can be quantified by prothrombin fragment 1+2 (PF1.2) in cerebrospinal fluid (CSF). Primary endpoint was the correlation between PF1.2, D-dimer and fibrinogen in CSF of patients with neuroinflammatory diseases. Secondary endpoints were PF1.2 levels depending on presence of contrast enhancement (CE) on MRI, and correlation between PF1.2 with serum-CSF albumin quotient (Qalb). Additionally, an exploratory analysis of CSF PF1.2 levels to distinguish between MS-patients and controls without neurological disease was performed. METHODS: Patients admitted for a suspected inflammatory CNS disease were prospectively recruited from October 2017 to December 2020. Citrated CSF samples were obtained and analyzed for PF1.2, fibrinogen and D-dimer using a highly sensitive luminescent oxygen channeling immunoassay. Patient clinical data and final diagnoses were retrospectively collected and analyzed. RESULTS: 187 patients were included, of whom 116 received diagnoses of relapsing-remitting (RRMS), primary-progressive MS, clinically or radiologically isolated syndrome, or anti-aquaporin-4-/anti-myelin-oligodendrocyte-glycoprotein-antibody-related diseases. CSF analysis of those 116 patients revealed a correlation between PF1.2 and CSF fibrinogen (ρ=.315; p<.001) as well as between PF1.2 and CSF D-dimer (ρ=.531; p<.001). Among all 187 patients, CSF PF1.2 was increased in patients with CE on MRI (n=71; 147.38 pmol/l; IQR 83.68-215.36) compared to patients without CE (n=86; 100.03 pmol/l; IQR 33.87-162.80; p=.008). CSF PF1.2 correlated significantly with Qalb (ρ=.445; p<.001). No differences of CSF PF1.2 levels were observed between RRMS (131.48 pmol/l, IQR 42.75-204.10) and disease controls (102.28 pmol/l; IQR 55.60-159.94; p=.606). CONCLUSION: In patients with autoimmune inflammatory CNS diseases PF1.2 correlated strongly with fibrinogen and D-dimer in CSF, indicating coagulation system activation. The findings suggest that thrombin generation might require acute BBB dysfunction to exert autoimmune effects in the CNS.
Asunto(s)
Enfermedades del Sistema Nervioso Central , Esclerosis Múltiple , Enfermedades del Sistema Nervioso Central/diagnóstico por imagen , Fibrinógeno , Humanos , Inflamación , Esclerosis Múltiple/diagnóstico por imagen , Fragmentos de Péptidos , Precursores de Proteínas , Protrombina , Estudios Retrospectivos , TrombinaRESUMEN
BACKGROUND AND OBJECTIVES: Proteins of the coagulation system contribute to autoimmune inflammation in patients with multiple sclerosis (MS). On blood-brain barrier (BBB) disruption, fibrinogen enters the CNS and is rapidly converted to fibrin, unfolding pleiotropic autoimmune mechanisms. Fibrin accumulation leads to subsequent proteolytic degradation that results in D-dimer generation. The primary objective of this study was to determine intrathecal levels of D-dimer in CSF as a measure of intrathecal coagulation cascade activation and to evaluate its diagnostic utility in patients with MS in contrast to healthy subjects. Key secondary objectives included analysis of CSF D-dimer in differential diagnoses of MS and its relation to routine clinical markers of disease activity. METHODS: Patients admitted for the assessment of suspected MS were prospectively recruited from October 2017 to December 2020. Blood plasma and citrated CSF samples were analyzed using a highly sensitive luminescent oxygen channeling immunoassay. Intrathecal generation of D-dimer was analyzed by adjusting for CSF/serum albumin (Qalb) and CSF/plasma D-dimer quotients (QD-dimer), and corresponding CSF fibrinogen levels were determined. Final diagnoses after full evaluation and clinical data were recorded. RESULTS: Of 187 patients, 113 patients received a diagnosis of MS or clinically/radiologically isolated syndrome. We found increased intrathecal CSF D-dimer generation levels (QD-dimer/Qalb-index) for patients with relapsing-remitting MS (RRMS; n = 71, median 4.7, interquartile range [IQR] 2.5-8.0) when compared with those for disease controls (n = 22, median 2.6, IQR 2.1-4.8, p = 0.031). Absolute CSF D-dimer values correlated with CSF fibrinogen levels (r = 0.463; p < 0 .001) and CSF leukocytes (r = 0.273; p = 0.003) and were elevated in MS patients with contrast enhancement (CE) compared with MS patients without CE on MRI (n = 48, median 6 ng/mL, and IQR 3-15.25 vs n = 41, median 4 ng/mL, and IQR 2-7; p = 0.026). Exploratory subgroup analyses indicated a correlation of intrathecal inflammatory activity and CSF D-dimer levels. DISCUSSION: D-dimer in CSF can be reliably determined and correlates with markers of CNS inflammation and CSF fibrinogen levels. Adjusted for BBB dysfunction, CSF D-dimer may allow the identification of intrathecal coagulation cascade activation in patients with MS. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that CSF D-dimer levels are elevated in patients with RRMS.