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BACKGROUND AND PURPOSE: An increasing number of cases of iatrogenic cerebral amyloid angiopathy (CAA) have now been reported worldwide. Proposed diagnostic criteria require a history of medical intervention with potential for amyloid-ß transmission, for example those using cadaveric dura mater or requiring instrumentation of the brain or spinal cord. Clinical presentation occurs after an appropriate latency (usually three or four decades); to date, most patients with iatrogenic CAA have had 'early-onset' disease (compared to sporadic, age-related, CAA), as a consequence of childhood procedures. RESULTS: We describe five cases of possible iatrogenic CAA in adults presenting in later life (aged 65 years and older); all had prior neurosurgical interventions and presented after a latency suggestive of iatrogenic disease (range 30-39 years). Use of cadaveric dura mater was confirmed in one case, and highly likely in the remainder. CONCLUSION: The presentation of iatrogenic CAA in older adults widens the known potential spectrum of this disease and highlights the difficulties of making the diagnosis in this age group, and particularly in differentiating iatrogenic from sporadic CAA. Increased vigilance for cases presenting at an older age is essential for furthering our understanding of the clinical phenotype and broader implications of iatrogenic CAA.
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Angiopatía Amiloide Cerebral , Enfermedad Iatrogénica , Humanos , Angiopatía Amiloide Cerebral/complicaciones , Anciano , Femenino , Masculino , Anciano de 80 o más AñosRESUMEN
OBJECTIVES: The ischaemic core and penumbra volumes derived from CTP aid the selection of patients with an arterial occlusion for mechanical thrombectomy. Different post-processing software packages may give different CTP outputs, potentially causing variable patient selection for mechanical thrombectomy. The study aims were, firstly, to assess the correlation in CTP outputs from software packages provided by Brainomix and RapidAI. Secondly, the correlation between automated ASPECTS and neuroradiologist-derived ASPECTS and accuracy in detecting large vessel occlusion was assessed. MATERIALS AND METHODS: This retrospective study included patients undergoing CTP for suspected anterior circulation large vessel occlusion. Pearson's correlation coefficient was used for testing the correlation in CTP outputs, ASPECTS/automated ASPECTS, and-in those with complete or near complete occlusion-final infarct volume. Diagnostic statistics were calculated for large vessel occlusion detection. RESULTS: Correlation was high for ischaemic core and penumbra volumes (0.862 and 0.832, respectively) but lower for the mismatch ratio (0.477). Agreement in mechanical thrombectomy eligibility was achieved in 85% of cases (46/54). Correlation between ischaemic core and final infarct volume was higher for Brainomix (0.757) than for RapidAI (0.595). The correlation between ASPECTS and automated ASPECTS (0.738 and 0.659) and the accuracy of detecting large vessel occlusion (77% and 71%) was higher for Brainomix than for RapidAI. CONCLUSION: There was high correlation between the CTP output from Brainomix and RapidAI. However, there was a difference in MT eligibility in 15% of cases, which highlights that the decision regarding MT should not be based on imaging parameters alone.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Isquemia Encefálica/diagnóstico por imagen , Isquemia Encefálica/terapia , Circulación Cerebrovascular , Infarto , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Accidente Cerebrovascular Isquémico/terapia , Imagen de Perfusión/métodos , Estudios Retrospectivos , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/terapia , Trombectomía/métodos , Tomografía Computarizada por Rayos X/métodosRESUMEN
In transplantation, development of humoral alloimmunity against donor HLA is a major cause of organ transplant failure, but our ability to assess the immunological risk associated with a potential donor-recipient HLA combination is limited. We hypothesized that the capacity of donor HLA to induce a specific alloantibody response depends on their structural and physicochemical dissimilarity compared with recipient HLA. To test this hypothesis, we first developed a novel computational scoring system that enables quantitative assessment of surface electrostatic potential differences between donor and recipient HLA molecules at the tertiary structure level [three-dimensional electrostatic mismatch score (EMS-3D)]. We then examined humoral alloimmune responses in healthy females subjected to a standardized injection of donor lymphocytes from their male partner. This analysis showed a strong association between the EMS-3D of donor HLA and donor-specific alloantibody development; this relationship was strongest for HLA-DQ alloantigens. In the clinical transplantation setting, the immunogenic potential of HLA-DRB1 and -DQ mismatches expressed on donor kidneys, as assessed by their EMS-3D, was an independent predictor of development of donor-specific alloantibody after graft failure. Collectively, these findings demonstrate the translational potential of our approach to improve immunological risk assessment and to decrease the burden of humoral alloimmunity in organ transplantation.
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Rechazo de Injerto/inmunología , Antígenos HLA-DQ/química , Cadenas HLA-DRB1/química , Inmunidad Humoral , Isoanticuerpos/biosíntesis , Isoantígenos/química , Trasplante de Riñón , Femenino , Rechazo de Injerto/diagnóstico , Antígenos HLA-DQ/inmunología , Cadenas HLA-DRB1/inmunología , Histocompatibilidad , Prueba de Histocompatibilidad , Humanos , Isoantígenos/inmunología , Masculino , Electricidad Estática , Donantes de Tejidos , Receptores de TrasplantesRESUMEN
A large increase in the use of kidneys from donation after circulatory death (DCD) donors prompted us to examine the impact of donor type on the incidence of ureteric complications (UCs; ureteric stenosis, urinary leak) after kidney transplantation. We studied 1072 consecutive kidney transplants (DCD n=494, live donor [LD] n=273, donation after brain death [DBD] n=305) performed during 2008-2014. Overall, there was a low incidence of UCs after kidney transplantation (3.5%). Despite a trend toward higher incidence of UCs in DCD (n=22, 4.5%) compared to LD (n=10, 3.7%) and DBD (n=5, 1.6%) kidney transplants, donor type was not a significant risk factor for UCs in multivariate analysis (DCD vs DBD HR: 2.33, 95% CI: 0.77-7.03, P=.13). There was no association between the incidence of UCs and donor, recipient, or transplant-related characteristics. Management involved surgical reconstruction in the majority of cases, with restenosis in 2.7% requiring re-operation. No grafts were lost secondary to UCs. Despite a significant increase in the number of kidney transplants from DCD donors, the incidence of UCs remains low. When ureteric complications do occur, they can be treated successfully with surgical reconstruction with no adverse effect on graft or patient survival.
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Muerte Encefálica , Trasplante de Riñón/efectos adversos , Complicaciones Posoperatorias , Donantes de Tejidos , Obtención de Tejidos y Órganos/métodos , Uréter/patología , Enfermedades Urológicas/etiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Constricción Patológica , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Humanos , Incidencia , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Reino Unido/epidemiología , Enfermedades Urológicas/patología , Adulto JovenRESUMEN
PURPOSE OF REVIEW: The immunogenic capacity of donor human leukocyte antigen (HLA) to induce humoral immune responses is not an intrinsic property of the mismatched alloantigen but depends on the HLA phenotype of the recipient. In recent years, advances in molecular sequence technology and information from X-ray crystallography have enabled structural comparison of donor and recipient HLA type providing an opportunity for a more rational approach for determining HLA compatibility. In this article, we review studies investigating the molecular basis of antibody-antigen interactions and present computational approaches to determine the complex physiochemical and structural properties of B-cell epitopes. RECENT FINDINGS: The relative immunogenicity of individual HLA mismatches may be predicted from analysis of polymorphic amino acids at continuous and discontinuous HLA sequence positions. The use of alloantigen sequence information alone, however, provides limited insight into key determinants of B-cell epitope immunogenicity, such as the orientation, accessibility and physiochemical properties of amino acid side chains. Advances in computational molecular modelling techniques now enable assessment of HLA-alloantibody interactions at the atomic level. Recent evidence supports a strong link between HLA B-cell epitope surface electrostatic potential and their immunogenicity. SUMMARY: Assessment of the surface electrostatic properties of HLA alloantigens and computational analyses of HLA-alloantibody interactions represent a promising area for future research into the molecular basis of HLA immunogenicity and antigenicity.
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Epítopos de Linfocito B/inmunología , Antígenos HLA/inmunología , Formación de Anticuerpos/inmunología , Antígenos HLA/química , Antígenos HLA/genética , Humanos , Inmunidad Innata , Isoantígenos/inmunología , Electricidad EstáticaRESUMEN
BACKGROUND: Cerebral small vessel disease (CSVD) causes between 25% and 30% of all ischaemic strokes. In acute lacunar ischaemic stroke, despite often mild initial symptoms, early neurological deterioration (END) occurs in approximately 15-20% of patients and is associated with poor functional outcome, yet its mechanisms are not well understood. AIMS: In this review we systematically evaluated data on: (1) definitions and incidence of END; (2) mechanisms of small vessel occlusion; (3) predictors and mechanisms of END; and (4) prospects for the prevention or treatment of patients with END. SUMMARY OF REVIEW: We identified 67 reports (including 13407 participants) describing the incidence of END in acute lacunar ischaemic stroke. The specified timescale for END varied from <24h to 3 weeks. The rate of END ranged between 2.3% and 47.5 with a pooled incidence of 23.54% (95% CI 21.02-26.05%) but heterogeneity was high (I2=90.29%). The rates of END defined by NIHSS decreases of ≥1, ≥2, ≥3, and 4 points were: 24.17 (21.19-27.16)%; 22.98 (20.48-25.30)%; 23.33 (16.23-30.42)%; and 10.79 (2.09-23.13)%, respectively, with lowest heterogeneity and greatest precision for a cut-off of ≥2 points. Of the 20/67 studies (30%) reporting associations of END with clinical outcome, 19/20 (95%) reported worse outcomes (usually measured using the modified Rankin score at 90 days or at hospital discharge) in patients with END. In a meta-regression analysis female sex, hypertension, diabetes, and smoking, were associated with END. CONCLUSIONS: Early neurological deterioration occurs in over 20% of patients with acute lacunar ischaemic stroke and might provide a novel target for clinical trials. A definition of an NIHSS ≥2 decrease is most used and provides the best between-study homogeneity. END is consistently associated with poor functional outcome. Further research is needed to better identify patients at risk of END, to understand the underlying mechanisms and to carry out new trials to test potential interventions.
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BACKGROUND AND OBJECTIVES: To test the performance of the 2023 myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) criteria in adults and children with inflammatory demyelinating conditions who were tested for MOG antibodies (Abs). METHODS: This was a retrospective study of patients tested for MOG-Abs from 2018 to 2022 in 2 specialist hospitals. The inclusion criteria comprised ≥1 attendance in an adult or pediatric demyelinating disease clinic and complete clinical and MRI records. The final clinical diagnosis of MOGAD, made by the treating neurologist, was taken as the benchmark against which the new criteria were tested. The international MOGAD diagnostic criteria were applied retrospectively; they stipulate at least 1 clinical or MRI supporting feature for MOGAD diagnosis in positive fixed MOG cell-based assay without a titer. The performance MOG-Ab testing alone for MOGAD diagnosis was also assessed and compared with that of MOGAD criteria using the McNemar test. RESULTS: Of the 1,879 patients tested for MOG-Abs, 539 (135 pediatric and 404 adults) met the inclusion criteria. A clinical diagnosis of MOGAD was made in 86/539 (16%) patients (37 adults, 49 children), with a median follow-up of 3.6 years. The MOGAD diagnostic criteria had sensitivity of 96.5% (adults 91.9%, children 100%), specificity of 98.9% (adults 98.8%, children 98.9%), positive predictive value of 94.3% (adults 89.4%, children 98%), negative predictive value of 99.3% (adults 99.2%, children 100%), and accuracy of 98.5% (adults 98.3%, children 99.2%). When compared with MOG-Ab testing alone, a difference was seen only in adults: a significantly higher specificity (98.9% vs 95.6%, p = 0.0005) and nonstatistically significant lower sensitivity (91.9% vs 100%, p = 0.08). DISCUSSION: The international MOGAD diagnostic criteria exhibit high performance in selected patients with inflammatory demyelinating diseases (who had a high pretest probability of having MOGAD) compared with best clinical judgment; their performance was better in children than in adults. In adults, the MOGAD criteria led to an improvement in specificity and positive predictive value when compared with MOG-Ab testing alone, suggesting that the requirement of at least 1 clinical or MRI supporting feature is important. Future work should address the generalizability of the diagnostic criteria to cohorts of greater clinical diversity seen within neurologic settings.
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Autoanticuerpos , Glicoproteína Mielina-Oligodendrócito , Humanos , Glicoproteína Mielina-Oligodendrócito/inmunología , Niño , Adulto , Masculino , Femenino , Estudios Retrospectivos , Adolescente , Autoanticuerpos/sangre , Preescolar , Adulto Joven , Persona de Mediana Edad , Imagen por Resonancia Magnética , Lactante , Anciano , Estudios de Cohortes , Sensibilidad y EspecificidadRESUMEN
BACKGROUND AND PURPOSE: Brainomix e-Stroke is an artificial intelligence-based decision support tool that aids the interpretation of CT imaging in the context of acute stroke. While e-Stroke has the potential to improve the speed and accuracy of diagnosis, real-world validation is essential. The aim of this study was to prospectively evaluate the performance of Brainomix e-Stroke in an unselected cohort of patients with suspected acute ischaemic stroke. METHODS: The study cohort included all patients admitted to the University College London Hospital Hyperacute Stroke Unit between October 2021 and April 2022. For e-ASPECTS and e-CTA, the ground truth was determined by a neuroradiologist with access to all clinical and imaging data. For e-CTP, the values of the core infarct and ischaemic penumbra were compared with those derived from syngo.via, an alternate software used at our institution. RESULTS: 1163 studies were performed in 551 patients admitted during the study period. Of these, 1130 (97.2%) were successfully processed by e-Stroke in an average of 4 min. For identifying acute middle cerebral artery territory ischaemia, e-ASPECTS had an accuracy of 77.0% and was more specific (83.5%) than sensitive (58.6%). The accuracy for identifying hyperdense thrombus was lower (69.1%), which was mainly due to many false positives (positive predictive value of 22.9%). Identification of acute haemorrhage was highly accurate (97.8%) with a sensitivity of 100% and a specificity of 97.6%; false positives were typically caused by areas of calcification. The accuracy of e-CTA for large vessel occlusions was 91.5%. The core infarct and ischaemic penumbra volumes provided by e-CTP strongly correlated with those provided by syngo.via (ρ=0.804-0.979). CONCLUSION: Brainomix e-Stroke software provides rapid and reliable analysis of CT imaging in the acute stroke setting although, in line with the manufacturer's guidance, it should be used as an adjunct to expert interpretation rather than a standalone decision-making tool.
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BACKGROUND: Idiopathic Normal Pressure Hydrocephalus (iNPH) can be effectively treated through shunt insertion. However, most shunted patients experience little or no clinical benefit, which suggests suboptimal patient selection. While contentious, multiple studies have reported poorer shunt outcomes associated with concomitant Alzheimer's disease. Prompted by this observation, multiple studies have assessed the role of amyloid PET, a specific test for Alzheimer's disease, in patient selection for shunting. METHODS: A comprehensive literature search was performed to identify studies that assessed the association between amyloid PET result and the clinical response to shunting in patients with suspected iNPH. Pooled diagnostic statistics were calculated. RESULTS: Across three relevant studies, a total of 38 patients with suspected iNPH underwent amyloid PET imaging and shunt insertion. Twenty-three patients had a positive clinical response to shunting. 18/28 (64.3%) of patients with a negative amyloid PET and 5/10 (50%) with a positive amyloid PET had a positive response to shunting. The pooled sensitivity, specificity and accuracy was 33.3%, 76.2% and 58.3%. None of these statistics reached statistical significance. CONCLUSION: The results of this pooled analysis do not support the selection of patients with suspected iNPH for shunting on the basis of amyloid PET alone. However, due to small cohort sizes and weakness in study design, further high-quality studies are required to properly determine the role of amyloid PET in assessing this complex patient group.
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Amiloide , Derivaciones del Líquido Cefalorraquídeo/métodos , Hidrocéfalo Normotenso/diagnóstico por imagen , Hidrocéfalo Normotenso/cirugía , Tomografía de Emisión de Positrones/métodos , Anciano , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultados Negativos , Selección de Paciente , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Resultado del TratamientoRESUMEN
Sickle cell disease is the most common hereditary hemoglobinopathy, which results in abnormally shaped and rigid red blood cells. These sickle-shaped red blood cells cause vaso-occlusion and ischemic phenomena that can affect any organ in the body. As a common cause of disability, the neurological manifestations of sickle cell disease are particularly important. Neuroimaging has a crucial role in the diagnosis, management, and prevention of the complications of sickle cell disease. These complications can affect the brain parenchyma, vasculature, and skull and can be ascribed directly or indirectly to a vasculopathy of small and large vessels. Vaso-occlusion can cause ischemic stroke. Ischemic damage in the absence of an acute neurological deficit, and therefore only apparent on neuroimaging, is termed silent cerebral ischemia. Weakening of the arterial walls can cause aneurysms. In its most severe form, a vasculopathy of the terminal internal carotid arteries can progress to moyamoya syndrome, characterized by steno-occlusive disease and the formation of friable collateral arteries. Rupture of aneurysms or friable collateral arteries is a potential cause of intracranial hemorrhage. The skull and vertebrae may be affected by extra-medullary hematopoiesis, due to severe anemia, or iron deposition, due to chronic red blood cell transfusion. Impaired blood supply to bone is associated with osteomyelitis and osteonecrosis. Fat embolization syndrome is a rare complication of osteonecrosis, which may cause devastating neurological impairment. Awareness and early recognition of the diverse manifestations of sickle cell disease on neuroimaging is crucial to ensure optimal treatment in a complex patient cohort.
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Anemia de Células Falciformes/diagnóstico por imagen , Isquemia Encefálica/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Enfermedad de Moyamoya/diagnóstico por imagen , Neuroimagen/métodos , Accidente Cerebrovascular/diagnóstico por imagen , Anemia de Células Falciformes/complicaciones , Isquemia Encefálica/etiología , Humanos , Imagen por Resonancia Magnética , Enfermedad de Moyamoya/etiología , Accidente Cerebrovascular/etiologíaRESUMEN
BACKGROUND: Evidence supporting uterine artery embolisation (UAE) for giant fibroids (≥ 10 cm and/or uterine volume ≥ 700 CC) remains sparse. We performed a systemic review and meta-analysis of UAE outcomes for symptomatic giant versus non-giant fibroids. METHODS: The literature was systematically reviewed. Research studies of UAE as an adjunct to surgery, and those not using peri-operative MRI were excluded. Primary outcomes were fibroid size and uterine volume reduction, procedure time, length of hospital stay, reinterventions, patient symptom improvement/satisfaction and complications. RESULTS: We identified four observational studies (839 patients; giant = 163, non-giant = 676). Both groups demonstrated reduction in fibroid size and uterine volume after UAE, with equivocal difference in uterine volume reduction (Mean difference (MD) - 0.3 95% confidence interval (CI) - 3.8 to 3.1, p = 0.86) and greater reduction in non-giant dominant fibroid size (MD - 5.9 95% CI - 10.3 to - 1.5, p < 0.01). Giant fibroids were associated with 5.6 min longer mean operative time (MD 5.6 min 95% CI 2.6-8.6, p < 0.01) and 4.8 h longer mean hospital stay (MD 4.8 h 95% CI 1.1-8.6, p = 0.01). Patient symptoms/satisfaction outcomes were summarised, but too heterogeneous for meta-analysis. Major complication and reintervention rates were low, with a statistically higher rate of major complications (Odds ratio (OR) 4.7 95% CI 1.5-14.6, p < 0.01) and reinterventions (OR 3.6 95% CI 1.7-7.5, p < 0.01) in giant fibroids. CONCLUSIONS: Current evidence shows UAE is a safe and effective option to treat giant fibroids. However, the limited available data indicate a relatively higher risk of complications and reinterventions when compared with non-giant fibroids. Patients should be selected, counselled and managed accordingly. LEVEL OF EVIDENCE: Level III, Systematic review of retrospective cohort studies.
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Leiomioma/terapia , Embolización de la Arteria Uterina/métodos , Neoplasias Uterinas/terapia , Adulto , Femenino , Humanos , Tempo Operativo , Satisfacción del Paciente/estadística & datos numéricos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Diffusion-weighted imaging (DWI) has a central role in the assessment of the brain parenchyma, particularly in the context of acute stroke. However, the applications of DWI extend far beyond the brain parenchyma and include the assessment of the extra-axial structures of the head and neck that are included in routine brain imaging. In this pictorial review, the added-value of DWI over other conventional sequences is illustrated through discussion of a broad range of disorders affecting the vasculature, skull, orbits, nasal cavity and salivary glands. This article highlights the requirement for all structures, both intra- and extra-axial, to be carefully reviewed on DWI.
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Imagen de Difusión por Resonancia Magnética , Accidente Cerebrovascular , Encéfalo/diagnóstico por imagen , Cabeza , Humanos , Neuroimagen , Accidente Cerebrovascular/diagnóstico por imagenRESUMEN
BACKGROUND: Cerebral microhaemorrhages are increasingly being recognised as a complication of COVID-19. This observational retrospective study aims to further investigate the potential pathophysiology through assessing the pattern of microhaemorrhage and clinical characteristics of patients with COVID-19 and microhaemorrhage. By comparing with similar patterns of microhaemorrhage in other non-COVID-19 disease, this study aims to propose possible common pathogenic mechanisms. METHODS: A retrospective observational case series was performed identifying all patients with COVID-19 complicated by cerebral microhaemorrhage on MRI. The distribution and number of microhaemorrhages were recorded using the microbleed anatomical scale, and patients' baseline characteristics and salient test results were also recorded. RESULTS: Cerebral microhaemorrhages were noted to have a predilection for the corpus callosum, the juxtacortical white matter and brainstem. All patients had a preceding period of critical illness with respiratory failure and severe hypoxia necessitating intubation and mechanical ventilation. DISCUSSION: This study demonstrates a pattern of cerebral microhaemorrhage that is similar to the pattern reported in patients with non-COVID-19 related critical illness and other causes of severe hypoxia. This raises questions regarding whether microhaemorrhage occurs from endothelial dysfunction due the direct effect of SARS-CoV-2 infection or from the secondary effects of critical illness and hypoxia.
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COVID-19/complicaciones , Hemorragia Cerebral/etiología , Anciano , Tronco Encefálico/diagnóstico por imagen , COVID-19/diagnóstico por imagen , Hemorragia Cerebral/diagnóstico por imagen , Cuerpo Calloso/diagnóstico por imagen , Enfermedad Crítica , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Respiración Artificial , Insuficiencia Respiratoria/etiología , Estudios Retrospectivos , Resultado del Tratamiento , Sustancia Blanca/diagnóstico por imagenRESUMEN
OBJECTIVE: To describe a novel case of coronavirus disease 2019 (COVID-19)-associated acute necrotizing encephalopathy (ANE) in a patient with aplastic anemia where there was early brain stem-predominant involvement. METHODS: Evaluation of cause, clinical symptoms, and treatment response. RESULTS: A 59-year-old woman with a background of transfusion-dependent aplastic anemia presented with seizures and reduced level of consciousness 10 days after the onset of subjective fever, cough, and headache. Nasopharyngeal swab testing for severe acute respiratory syndrome coronavirus (SARS-CoV-2) was positive, and CT during admission demonstrated diffuse swelling of the brain stem. She required intubation and mechanical ventilation for airway protection, given her reduced level of consciousness. The patient's condition deteriorated, and MRI on day 6 demonstrated worsening brain stem swelling with symmetrical hemorrhagic lesions in the brain stem, amygdalae, putamina, and thalamic nuclei. Appearances were consistent with hemorrhagic ANE with early brain stem involvement. The patient showed no response to steroid therapy and died on the eighth day of admission. CONCLUSIONS: COVID-19 may be associated with an acute severe encephalopathy and, in this case, was considered most likely to represent an immune-mediated phenomenon. As the pandemic continues, we anticipate that the spectrum of neurologic presentation will broaden. It will be important to delineate the full clinical range of emergent COVID-19-related neurologic disease.
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Anemia Aplásica/complicaciones , Infecciones por Coronavirus/complicaciones , Leucoencefalitis Hemorrágica Aguda/etiología , Neumonía Viral/complicaciones , Amígdala del Cerebelo/diagnóstico por imagen , Anemia Aplásica/terapia , Edema Encefálico/diagnóstico por imagen , Edema Encefálico/etiología , Edema Encefálico/fisiopatología , Edema Encefálico/terapia , Tronco Encefálico/diagnóstico por imagen , COVID-19 , Infecciones por Coronavirus/terapia , Dexametasona/uso terapéutico , Imagen de Difusión por Resonancia Magnética , Resultado Fatal , Femenino , Glucocorticoides/uso terapéutico , Humanos , Hemorragias Intracraneales/diagnóstico por imagen , Hemorragias Intracraneales/etiología , Hemorragias Intracraneales/fisiopatología , Leucoencefalitis Hemorrágica Aguda/diagnóstico por imagen , Leucoencefalitis Hemorrágica Aguda/fisiopatología , Leucoencefalitis Hemorrágica Aguda/terapia , Imagen por Resonancia Magnética , Persona de Mediana Edad , Pandemias , Transfusión de Plaquetas , Neumonía Viral/terapia , Hemorragia Putaminal/diagnóstico por imagen , Hemorragia Putaminal/etiología , Hemorragia Putaminal/fisiopatología , Respiración Artificial , Convulsiones/etiología , Núcleos Talámicos/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
This case report describes a 17-year-old boy with reduced consciousness and T2-weighted hyperintensity, focal diffusion restriction, and microhemorrhages within the deep gray nuclei and surrounding white matter.
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Linfadenitis Necrotizante Histiocítica , Humanos , Linfadenitis Necrotizante Histiocítica/diagnóstico , Linfadenitis Necrotizante Histiocítica/complicaciones , Masculino , Femenino , Adulto , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: Solid-phase assays to distinguish complement binding from noncomplement binding HLA-specific antibodies have been introduced, but technical limitations may compromise their interpretation. We have examined the extent to which C1q-binding to HLA-class I single-antigen beads (SAB) is influenced by denatured HLA on SAB, antibody titre, and complement interference that causes a misleading low assessment of HLA-specific antibody levels. METHODS: Sera from 25 highly sensitized patients were tested using Luminex IgG-SAB and C1q-SAB assays. Sera were tested undiluted, at 1:20 dilution to detect high-level IgG, and after ethylene diamine tetraacetic acid treatment to obviate complement interference. Conformational HLA and denatured HLA protein levels on SAB were determined using W6/32 and HC-10 monoclonal antibodies, respectively. Denatured HLA was expressed as HC-10 binding to untreated SAB as a percentage of maximal binding to acid-treated SAB. RESULTS: For undiluted sera, Luminex mean fluorescence intensity (MFI) values for IgG-SAB and C1q-SAB correlated poorly (r = 0.42). ethylene diamine tetraacetic acid and serum dilution improved the correlation (r = 0.57 and 0.77, respectively). Increasing levels of denatured HLA interfered with the detection of C1q binding. Consequently, the correlation between IgG-SAB MFI and C1q-SAB MFI was lowest using undiluted sera and SAB with greater than 30% denatured HLA (r = 0.40) and highest using diluted sera and SAB with 30% or less denatured HLA (r = 0.86). CONCLUSIONS: Antibody level, complement interference, and denatured HLA class I on SAB may all affect the clinical interpretation of the C1q-SAB assay. The C1q-SAB assay represents a substantial additional cost for routine clinical use, and we question its justification given the potential uncertainty about its interpretation.
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Activación de Complemento , Complemento C1q/inmunología , Antígenos HLA/inmunología , Prueba de Histocompatibilidad/métodos , Histocompatibilidad , Inmunoglobulina G/inmunología , Isoanticuerpos/inmunología , Adulto , Especificidad de Anticuerpos , Femenino , Rechazo de Injerto/sangre , Rechazo de Injerto/inmunología , Supervivencia de Injerto , Antígenos HLA/química , Humanos , Inmunoglobulina G/sangre , Isoanticuerpos/sangre , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Unión Proteica , Desnaturalización Proteica , Pliegue de Proteína , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
BACKGROUND: We have previously shown that qualitative assessment of surface electrostatic potential of HLA class I molecules helps explain serological patterns of alloantibody binding. We have now used a novel computational approach to quantitate differences in surface electrostatic potential of HLA B-cell epitopes and applied this to explain HLA Bw4 and Bw6 antigenicity. METHODS: Protein structure models of HLA class I alleles expressing either the Bw4 or Bw6 epitope (defined by sequence motifs at positions 77 to 83) were generated using comparative structure prediction. The electrostatic potential in 3-dimensional space encompassing the Bw4/Bw6 epitope was computed by solving the Poisson-Boltzmann equation and quantitatively compared in a pairwise, all-versus-all fashion to produce distance matrices that cluster epitopes with similar electrostatics properties. RESULTS: Quantitative comparison of surface electrostatic potential at the carboxyl terminal of the α1-helix of HLA class I alleles, corresponding to amino acid sequence motif 77 to 83, produced clustering of HLA molecules in 3 principal groups according to Bw4 or Bw6 epitope expression. Remarkably, quantitative differences in electrostatic potential reflected known patterns of serological reactivity better than Bw4/Bw6 amino acid sequence motifs. Quantitative assessment of epitope electrostatic potential allowed the impact of known amino acid substitutions (HLA-B*07:02 R79G, R82L, G83R) that are critical for antibody binding to be predicted. CONCLUSIONS: We describe a novel approach for quantitating differences in HLA B-cell epitope electrostatic potential. Proof of principle is provided that this approach enables better assessment of HLA epitope antigenicity than amino acid sequence data alone, and it may allow prediction of HLA immunogenicity.
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Mapeo Epitopo/métodos , Epítopos , Antígenos HLA-B/química , Antígenos HLA-B/inmunología , Isoanticuerpos/inmunología , Simulación de Dinámica Molecular , Secuencias de Aminoácidos , Sitios de Unión de Anticuerpos , Antígenos HLA-B/metabolismo , Histocompatibilidad , Humanos , Isoanticuerpos/metabolismo , Dominios y Motivos de Interacción de Proteínas , Estructura Secundaria de Proteína , Electricidad Estática , Relación Estructura-Actividad , Propiedades de SuperficieRESUMEN
Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.
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Mapeo Cromosómico/métodos , Cadenas HLA-DRB1/genética , Enfermedades Inflamatorias del Intestino/genética , Complejo Mayor de Histocompatibilidad/genética , Polimorfismo de Nucleótido Simple , Alelos , Colitis Ulcerosa/genética , Enfermedad de Crohn/genética , Ligamiento Genético , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Técnicas de Genotipaje , Heterocigoto , Humanos , FenotipoRESUMEN
BACKGROUND: Delayed graft function (DGF) after renal transplantation can be diagnosed according to several different definitions, complicating comparison between studies that use DGF as an endpoint. This is a particular problem after transplantation with kidneys from donation after circulatory death (DCD) kidneys, because DGF is common, and its relationship to early graft failure may differ depending on the definition of DGF. METHODS: The presence of DGF in 213 donation after brain death (DBD) and 312 DCD kidney transplants from October 2005 to August 2011 was determined according to 10 different, but widely used, definitions (based on dialysis requirements, creatinine changes, or both). The relationship of DGF to graft function and graft survival was determined. RESULTS: The incidence of DGF varied widely depending on the definition used (DBD; 24%-70%: DCD; 41%-91%). For kidneys from DCD donors, development of DGF was only associated with poorer 1-year estimated glomerular filtration rate for 1 of 10 definitions of DGF, and no definition of DGF was associated with impaired graft survival. Conversely, for DBD kidneys, DGF, as defined in 9 of 10 different ways, was associated with poorer 1-year estimated glomerular filtration rate and inferior graft survival. Importantly, the predictive power for poorer transplant outcome was comparable for all definitions of DGF. CONCLUSION: No definition of DGF is superior. We suggest that the most widely used and most easily calculated definition--the use of dialysis in the first postoperative week--should be universally adopted as the definition of DGF clinically and as a study endpoint.