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Amyloid aggregates of the protein α-synuclein (αS) called Lewy Bodies (LB) and Lewy Neurites (LN) are the pathological hallmark of Parkinson’s disease (PD) and other synucleinopathies. We have previously shown that high extracellular αS concentrations can be toxic to cells and that neurons take up αS. Here we aimed to get more insight into the toxicity mechanism associated with high extracellular αS concentrations (50–100 μM). High extracellular αS concentrations resulted in a reduction of the firing rate of the neuronal network by disrupting synaptic transmission, while the neuronal ability to fire action potentials was still intact. Furthermore, many cells developed αS deposits larger than 500 nm within five days, but otherwise appeared healthy. Synaptic dysfunction clearly occurred before the establishment of large intracellular deposits and neuronal death, suggesting that an excessive extracellular αS concentration caused synaptic failure and which later possibly contributed to neuronal death. [ABSTRACT FROM AUTHOR]

Introduction: To evaluate the diagnostic efficacy of the office blood pressure (OBP) and ambulatory blood pressure monitoring (ABPM) in the assessment of hypertension (HTN) in children with diabetes mellitus type 1 (T1DM). Methods: We analyzed OBP and ABPM measurements in 84 diabetic children (43 boys) obtained at a median age of 14.9 yr and 6.3 ± 3.5 yr after diagnosis of T1DM. OBP and ABPM results were converted into standard deviation scores (SDS). In addition, we analyzed blood pressure loads and nighttime dipping. The comparison between OBP and ABPM was performed using kappa coefficient and receiver operator curve (ROC). Results: HTN was diagnosed in 43/84 (51%) patients using OBP (>95th percentile), and in 24/84 (29%) patients using ABPM ( >=95th percentile during 24 h, day or night). Both methods were in agreement in 33 ABPM normotensive and 16 ABPM hypertensive patients (most had nighttime HTN); 32% patients had white-coat HTN and 9.5% patients had masked HTN. The kappa coefficient was 0.175 (95% CI from -0.034 to 0.384) suggesting poor agreement between OBP and ABPM. Diastolic OBP was a better predictor of ABPM HTN (ROC area under the curve (AUC) = 0.71 ± 0.06) than systolic OBP (AUC = 0.58 ± 0.07). The percentage of non-dippers ranged from 7 to 23% in ABPM normotensive patients, and 21-42% in ABPM hypertensive patients who also had significantly higher BP loads (p < 0.0001). Conclusion: Children with T1DM often suffer from nocturnal, white coat- and masked HTN, which can not be assessed and predicted by the OBP. [ABSTRACT FROM AUTHOR]

Gupta M, Diaz-Mitoma F, Feber J, Shaw L, Forget C, Filler G. Tissue HHV6 and 7 determination in pediatric solid organ recipients – a pilot study. Pediatr Transplantation 2003: 7: 458–463. © 2003 Blackwell Munksgaard Herpes virus infections remain a major challenge in solid organ transplantation. HHV6 and 7 blood viral load was associated with pathology after renal transplantation. Little is known about the significance of tissue HHV6 and 7 infections. A total of 18 tissue biopsies (13 kidney, three GI and two BAL) from nine pediatric transplant patients (five kidney, two liver, one combined liver and kidney and one bone marrow transplant) were subjected to blood HHV6 IgG and IgM testing. In addition, tissue HHV6 and 7 semi-quantitative PCR analysis with subsequent detection by ELISA and quantitative methods were applied to the same samples. We also studied four native kidney biopsies of children with other kidney disease. The results of the biopsies were correlated with clinical data. Of the transplant patients, 78% were HHV6 IgG positive. Six of nine had a positive IgM on at least one occasion, however, only two of nine transplant patients were symptomatic with a mixed CMV/EBV septic picture of multi-organ failure. Only these two patients had a significant tissue viral load for HHV6. Additionally, a very significant tissue viral load for HHV6 was detected in an immunocompromised patient 3 wk after a roseola-like febrile illness. The HHV6 copies were 31, 88 and 206 per 10 μL of DNA, respectively. In the patient who also had the fourth positive ELISA for HHV6 PCR product, the Multiplex PCR and restriction enzyme assay on its PCR product revealed a significant contribution by HHV7, while the HHV6-B signal was rather weak. Significant tissue HHV6 loads can be found in tissue biopsies from organ recipients with significant illness and also in native kidneys after primary infection. This may explain the high prevalence of HHV6 in transplanted kidneys. Further studies on HHV6 and 7 using molecular techniques should be supported. [ABSTRACT FROM AUTHOR]

Acute renal failure (ARF) is a rare but potentially fatal complication of diabetic ketoacidosis (DKA). Early recognition and aggressive treatment of ARF during DKA may im-prove the prognosis of these patients. We present a case report of a 12 year old female admitted to the hospital with severe DKA as the 1s t manifestation of her diabetes mellitus. She presented with severe metabolic acidosis, hypophosphatemia, and oliguric ARF. In addition, rhabdomyolysis was noted during the course of DKA which probably contributed to the ARF. Management of DKA and renal replacement therapy resulted in quick recovery of renal function. We suggest that early initiation of renal replacement therapy for patients with DKA developing ARF may improve the potentially poor outcome of patients with ARF associated with DKA.

Background: Effective treatments to improve brain recovery after cardiac arrest are needed. Ghrelin showed efficacy in experimental models and was associated with lower neuron specific enolase levels in the clinical Ghrelin in Coma (GRECO) trial. Here we present cognitive and psychosocial outcomes at one-year follow-up., Methods: GRECO was a phase 2 multicenter, double-blind, randomized, placebo-controlled trial in comatose patients after cardiac arrest. The intervention was intravenous acyl-ghrelin 600 μg twice daily or placebo for one week, starting within 12 hours after the arrest. Patients were assessed after one year using cognitive tests and questionnaires measuring participation, health-related quality of life, mood, and caregiver strain. Composite z-scores of the cognitive tests were computed by comparing the scores to those of a norm-population and averaging the tests for memory, attention and executive functioning separately. Groups were compared based on composite z-scores and cutoff scores for psychosocial outcomes., Results: Of the 160 participants originally included, 66 of the 85 participants who survived to one year after OHCA completed the psychosocial and cognitive follow-up. The intervention group scored numerically higher across all cognitive domains compared to the control group, but the differences were not statistically significant (memory median = -.850 vs. -1.385, U = 424.5, p = .587; attention median = -.733 vs. -.717, U = 420.5, p = .548; executive functioning median = -.311 vs. -.369, U = 408.5, p = .323). There were significantly fewer signs of depression in the intervention group, U = 322.5, p = .014., Conclusions: This predefined secondary analysis found that ghrelin treatment was associated with non-significantly but consistently better cognitive outcomes and significantly fewer signs of depression. This is in line with the primary outcomes., Trial Registration: Clinicaltrialsregister.eu: EUCTR2018-000005-23-NL., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: There is increasing evidence that plaque instability in the extracranial carotid artery may lead to an increased stroke risk independently of the degree of stenosis. We aimed to determine diagnostic accuracy of vulnerable and stable plaque using noninvasive imaging modalities when compared to histology in patients with symptomatic and asymptomatic carotid atherosclerosis., Methods and Results: Medline Ovid, Embase, Cochrane Library, and Web of Science were searched for diagnostic accuracy of noninvasive imaging modalities (CT, MRI, US) in the detection of 1) vulnerable/stable plaque, and 2) vulnerable/stable plaque characteristics, compared to histology. The quality of included studies was assessed by QUADAS-2 and univariate and bivariate random-effect meta-analyses were performed. We included 36 vulnerable and 5 stable plaque studies in the meta-analysis, and out of 211 plaque characteristics from remaining studies, we classified 169 as vulnerable and 42 as stable characteristics (28 CT, 120 MRI, 104 US characteristics). We found that MRI had high accuracy [90% (95% CI: 82-95%)] in the detection of vulnerable plaque, similar to CT [86% (95% CI: 76-92%); P > 0.05], whereas US showed less accuracy [80% (95% CI: 75-84%); P = 0.013]. CT showed high diagnostic accuracy in visualizing characteristics of vulnerable or stable plaques (89% and 90%) similar to MRI (86% and 89%; P > 0.05); however, US had lower accuracy (77%, P < 0.001 and 82%, P > 0.05)., Conclusion: CT and MRI have a similar, high performance in detecting vulnerable carotid plaques, whereas US showed significantly less diagnostic accuracy. Moreover, MRI visualized all vulnerable plaque characteristics allowing for a better stroke risk assessment., Registration: PROSPERO ID CRD42022329690., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Pediatric blood pressure (BP) assessment and management is increasingly important. Uncontrolled systolic and combined hypertension leads to hypertension-mediated organ damage. The impact of isolated diastolic hypertension is less clearly understood., Methods: We analyzed the prevalence of ambulatory isolated diastolic hypertension (IDH) in primary (PH) and secondary (SH) hypertension, and associations with BMI Z-score (BMIz) and left ventricular mass index adjusted to the 95th percentile (aLVMI) in a large, multicenter cohort of hypertensive children. Hypertensive children were divided and analyzed in three ambulatory hypertension subgroups: 24-h, daytime, and nighttime. Specifically, we sought to determine the prevalence of ambulatory 24-h, daytime, or nighttime IDH., Results: Prevalence of IDH varied based on ambulatory phenotypes, ranging from 6 to 12%, and was highest in children with SH. Children with IDH tended to be more likely female and, in some cases, were leaner than those with isolated systolic hypertension (ISH). Despite previous pediatric studies suggesting no strong association between diastolic blood pressure and left ventricular hypertrophy (LVH), we observed that children with IDH were equally likely to have LVH and had comparable aLVMI to those with ISH and combined systolic-diastolic hypertension., Conclusions: In summary, ambulatory IDH appears to be a unique phenotype with a female sex, and younger age predilection, but equal risk for LVH in children with either PH or SH., (© 2024. The Author(s).)

Carotid plaque composition represents one of the main risk factors of future ischemic stroke. MRI provides excellent soft tissue contrast that can distinguish plaque characteristics. Our objective was to analyze the diagnostic accuracy of MRI imaging in the detection of carotid plaque characteristics compared to histology in patients with symptomatic and asymptomatic carotid atherosclerosis through a systematic review. After prospective registration in PROSPERO (ID CRD42022329690), Medline Ovid, Embase.com, Cochrane Library, and Web of Science Core were searched without any search limitation up to May 27, 2022 to identify eligible articles. Of the 8168 studies, 53 (37 × 1.5 T MRI, 17 × 3 T MRI) evaluated MRI accuracy in the detection of 13 specific carotid plaque characteristics in 169 comparisons. MRI demonstrated high diagnostic accuracy for detection of calcification (3 T MRI: mean sensitivity 92%/mean specificity 90%; 1.5 T MRI: mean sensitivity 81%/mean specificity 91%), fibrous cap (1.5 T: 89%/87%), unstable plaque (1.5 T: 89%/87%), intraplaque hemorrhage (1.5 T: 86%/88%), and lipid-rich necrotic core (1.5 T: 89%/79%). MRI also proved to have a high level of tissue discrimination for the carotid plaque characteristics investigated, allowing potentially for a better risk assessment and follow-up of patients who may benefit from more aggressive treatments. These results emphasize the role of MRI as the first-line imaging modality for comprehensive assessment of carotid plaque morphology, particularly for unstable plaque. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2., (© 2024 The Author(s). Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background and Objecitves: The currently available kidney volume normative values in children are restricted to small populations from single-centre studies not assessing kidney function and including none or only a small number of adolescents. This study aimed to obtain ultrasound-based kidney volume normative values derived from a large European White/Caucasian paediatric population with normal kidney function., Methods: After recruitment of 1427 children aged 0-19 years, 1396 individuals with no history of kidney disease and normal estimated glomerular filtration rate were selected for the sonographic evaluation of kidney volume. Kidney volume was correlated with age, height, weight, body surface area and body mass index. Kidney volume curves and tables related to anthropometric parameters were generated using the LMS method. Kidney volume predictors were evaluated using multivariate regression analysis with collinearity checks., Results: No clinically significant differences in kidney volume in relation to height were found between males and females, between supine and prone position and between left and right kidneys. Males had, however, larger age-related kidney volumes than females in most age categories. For the prediction of kidney volume, the highest coefficient correlation was observed for body surface area (r = 0.94), followed by weight (r = 0.92), height (r = 0.91), age (r = 0.91), and body mass index (r = 0.67; p < 0.001 for all)., Conclusions: This study presents LMS-percentile curves and tables for kidney volume which can be used as reference values for children aged 0-19 years., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Importance: Out-of-hospital cardiac arrest survival rates have markedly risen in the last decades, but neurological outcome only improved marginally. Despite research on more than 20 neuroprotective strategies involving patients in comas after cardiac arrest, none have demonstrated unequivocal evidence of efficacy; however, treatment with acyl-ghrelin has shown improved functional and histological brain recovery in experimental models of cardiac arrest and was safe in a wide variety of human study populations., Objective: To determine safety and potential efficacy of intravenous acyl-ghrelin to improve neurological outcome in patients in a coma after cardiac arrest., Design, Setting, and Participants: A phase 2, double-blind, placebo-controlled, multicenter, randomized clinical trial, Ghrelin Treatment of Comatose Patients After Cardiac Arrest: A Clinical Trial to Promote Cerebral Recovery (GRECO), was conducted between January 18, 2019, and October 17, 2022. Adult patients 18 years or older who were in a comatose state after cardiac arrest were assessed for eligibility; patients were from 3 intensive care units in the Netherlands. Expected death within 48 hours or unfeasibility of treatment initiation within 12 hours were exclusion criteria., Interventions: Patients were randomized to receive intravenous acyl-ghrelin, 600 μg (intervention group), or placebo (control group) within 12 hours after cardiac arrest, continued for 7 days, twice daily, in addition to standard care., Main Outcomes and Measures: Primary outcome was the score on the Cerebral Performance Categories (CPC) scale at 6 months. Safety outcomes included any serious adverse events. Secondary outcomes were mortality and neuron-specific enolase (NSE) levels on days 1 and 3., Results: A total of 783 adult patients in a coma after cardiac arrest were assessed for eligibility, and 160 patients (median [IQR] age, 68 [57-75] years; 120 male [75%]) were enrolled. A total of 81 patients (51%) were assigned to the intervention group, and 79 (49%) were assigned to the control group. The common odds ratio (OR) for any CPC improvement in the intervention group was 1.78 (95% CI, 0.98-3.22; P = .06). This was consistent over all CPC categories. Mean (SD) NSE levels on day 1 after cardiac arrest were significantly lower in the intervention group (34 [6] μg/L vs 56 [13] μg/L; P = .04) and on day 3 (28 [6] μg/L vs 52 [14] μg/L; P = .08). Serious adverse events were comparable in incidence and type between the groups. Mortality was 37% (30 of 81) in the intervention group vs 51% (40 of 79) in the control group (absolute risk reduction, 14%; 95% CI, -2% to 29%; P = .08)., Conclusions and Relevance: In patients in a coma after cardiac arrest, intravenous treatment with acyl-ghrelin was safe and potentially effective to improve neurological outcome. Phase 3 trials are needed for conclusive evidence., Trial Registration: Clinicaltrialsregister.eu: EUCTR2018-000005-23-NL.

Purpose: In this 6-year study we identified factors associated with spontaneous vertebral body reshaping in glucocorticoid (GC)-treated children with leukemia, rheumatic disorders, and nephrotic syndrome., Methods: Subjects were 79 children (mean age 7.4 years) who had vertebral fracture (VF) evaluation on lateral spine radiographs at least 1 year after VF detection. VF were graded using the modified Genant semiquantitative method and fracture burden for individuals was quantified using the spinal deformity index (SDI; sum of grades from T4 to L4)., Results: Sixty-five children (82.3%) underwent complete vertebral body reshaping (median time from VF detection to complete reshaping 1.3 years by Cox proportional hazard modeling). Of 237 VF, the majority (83.1%) ultimately reshaped, with 87.2% reshaping in the thoracic region vs 70.7% in the lumbar region (P = .004). Cox models showed that (1) every g/m2 increase in GC exposure in the first year after VF detection was associated with a 19% decline in the probability of reshaping; (2) each unit increase in the SDI at the time of VF detection was associated with a 19% decline in the probability of reshaping [hazard ratio (HR) = 0.81; 95% confidence interval (CI) = 0.71, 0.92; P = .001]; (3) each additional VF present at the time of VF detection reduced reshaping by 25% (HR = 0.75; 95% CI = 0.62, 0.90; P = .002); and (4) each higher grade of VF severity decreased reshaping by 65% (HR = 0.35; 95% CI = 0.21, 0.57; P < .001)., Conclusion: After experiencing a VF, children with higher GC exposure, higher SDI, more severe fractures, or lumbar VF were at increased risk for persistent vertebral deformity., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To inform updated recommendations by the Canadian Task Force on Preventive Health Care on screening in a primary care setting for hypertension in adults aged 18 years and older. This protocol outlines the scope and methods for a series of systematic reviews and one overview of reviews., Methods: To evaluate the benefits and harms of screening for hypertension, the Task Force will rely on the relevant key questions from the 2021 United States Preventive Services Task Force systematic review. In addition, a series of reviews will be conducted to identify, appraise, and synthesize the evidence on (1) the association of blood pressure measurement methods and future cardiovascular (CVD)-related outcomes, (2) thresholds for discussions of treatment initiation, and (3) patient acceptability of hypertension screening methods. For the review of blood pressure measurement methods and future CVD-related outcomes, we will perform a de novo review and search MEDLINE, Embase, CENTRAL, and APA PsycInfo for randomized controlled trials, prospective or retrospective cohort studies, nested case-control studies, and within-arm analyses of intervention studies. For the thresholds for discussions of treatment initiation review, we will perform an overview of reviews and update results from a relevant 2019 UK NICE review. We will search MEDLINE, Embase, APA PsycInfo, and Epistemonikos for systematic reviews. For the acceptability review, we will perform a de novo systematic review and search MEDLINE, Embase, and APA PsycInfo for randomized controlled trials, controlled clinical trials, and observational studies with comparison groups. Websites of relevant organizations, gray literature sources, and the reference lists of included studies and reviews will be hand-searched. Title and abstract screening will be completed by two independent reviewers. Full-text screening, data extraction, risk-of-bias assessment, and GRADE (Grading of Recommendations Assessment, Development and Evaluation) will be completed independently by two reviewers. Results from included studies will be synthesized narratively and pooled via meta-analysis when appropriate. The GRADE approach will be used to assess the certainty of evidence for outcomes., Discussion: The results of the evidence reviews will be used to inform Canadian recommendations on screening for hypertension in adults aged 18 years and older., Systematic Review Registration: This protocol is registered on PROSPERO and is available on the Open Science Framework (osf.io/8w4tz)., (© 2023. The Author(s).)

Arterial hypertension (HTN) in children after kidney transplantation is an important risk factor not only for graft loss but also for cardiovascular morbidity and mortality. The prevalence of posttransplant HTN ranges between 60% and 90%. The etiology of posttransplant HTN is multifactorial and includes residual chronic native kidney disease, immunosuppressive therapy, and chronic allograft dysfunction among other causes. Clinic blood pressure (BP) should be measured at each outpatient visit. However, ambulatory blood pressure monitoring (ABPM) is the gold standard method for BP evaluation in children after kidney transplantation, as it often reveals masked and nocturnal HTN; given this, it should be regularly performed in each transplanted child. All classes of antihypertensive drugs are used in the treatment of posttransplant HTN because it has never been proven that one class is better than another. However, in several retrospective studies, the use of calcium channel blockers is associated with better graft function. The optimal target BP for transplanted children is still a matter of debate; it is recommended to target the same BP as for healthy children, that is, <95th percentile. Control of HTN in transplanted children remains poor - only 20%-50% of treated children have normal BP. There is a great potential for improvement of antihypertensive treatment that could potentially result in improvement of both graft and patient survival in children after kidney transplantation., (© 2023 The Authors. Pediatric Transplantation published by Wiley Periodicals LLC.)