Orthopedic surgery increases atherosclerotic lesions and necrotic core area in ApoE-/- mice

Background and aims Observational studies show a peak incidence of cardiovascular events after major surgery. For example, the risk of myocardial infarction increases 25-fold early after hip replacement. The acuteness of this increased risk suggests abrupt enhancement in plaque vulnerability, which may be related to intra-plaque inflammation, thinner fibrous cap and/or necrotic core expansion. We hypothesized that acute systemic inflammation following major orthopedic surgery induces such changes. Methods ApoE−/− mice were fed a western diet for 10 weeks. Thereafter, half the mice underwent mid-shaft femur osteotomy followed by realignment with an intramedullary K-wire, to mimic major orthopedic surgery. Mice were sacrificed 5 or 15 days post-surgery (n = 22) or post-saline injection (n = 13). Serum amyloid A (SAA) was measured as a marker of systemic inflammation. Paraffin embedded slides of the aortic root were stained to measure total plaque area and to quantify fibrosis, calcification, necrotic core, and inflammatory cells. Results Surgery mice showed a pronounced elevation of serum amyloid A (SAA) and developed increased plaque and necrotic core area already at 5 days, which reached significance at 15 days (p = 0.019; p = 0.004 for plaque and necrotic core, respectively). Macrophage and lymphocyte density significantly decreased in the surgery group compared to the control group at 15 days (p = 0.037; p = 0.024, respectively). The density of neutrophils and mast cells remained unchanged. Conclusions Major orthopedic surgery in ApoE−/− mice triggers a systemic inflammatory response. Atherosclerotic plaque area is enlarged after surgery mainly due to an increase of the necrotic core. The role of intra-plaque inflammation in this response to surgical injury remains to be fully elucidated. © 2016 Elsevier Ireland Lt

Mutations in <i>N</i>-acetylglucosamine (<i>O</i>-GlcNAc) transferase in patients with X-linked intellectual disability

Contains fulltext : 177227.pdf (publisher's version ) (Open Access)N-Acetylglucosamine (O-GlcNAc) transferase (OGT) regulates protein O-GlcNAcylation, an essential and dynamic post-translational modification. The O-GlcNAc modification is present on numerous nuclear and cytosolic proteins and has been implicated in essential cellular functions such as signaling and gene expression. Accordingly, altered levels of protein O-GlcNAcylation have been associated with developmental defects and neurodegeneration. However, mutations in the OGT gene have not yet been functionally confirmed in humans. Here, we report on two hemizygous mutations in OGT in individuals with X-linked intellectual disability (XLID) and dysmorphic features: one missense mutation (p.Arg284Pro) and one mutation leading to a splicing defect (c.463-6T>G). Both mutations reside in the tetratricopeptide repeats of OGT that are essential for substrate recognition. We observed slightly reduced levels of OGT protein and reduced levels of its opposing enzyme O-GlcNAcase in both patient-derived fibroblasts, but global O-GlcNAc levels appeared to be unaffected. Our data suggest that mutant cells attempt to maintain global O-GlcNAcylation by down-regulating O-GlcNAcase expression. We also found that the c.463-6T>G mutation leads to aberrant mRNA splicing, but no stable truncated protein was detected in the corresponding patient-derived fibroblasts. Recombinant OGT bearing the p.Arg284Pro mutation was prone to unfolding and exhibited reduced glycosylation activity against a complex array of glycosylation substrates and proteolytic processing of the transcription factor host cell factor 1, which is also encoded by an XLID-associated gene. We conclude that defects in O-GlcNAc homeostasis and host cell factor 1 proteolysis may play roles in mediation of XLID in individuals with OGT mutations

Risk stratification to improve Pediatric Early Warning Systems: it is all about the context

Contains fulltext : 208059.pdf (publisher's version ) (Open Access

Postmortem diagnostics in sudden unexpected death in infants and children:use and utility

Sudden unexpected death in infants (SUDI) and children (SUDC) requires thorough investigation to identify causes and prevention strategies. In the Netherlands, these deaths are investigated using the standardized postmortem evaluation of sudden unexpected death in infants and children (PESUDIC) procedure. This study examines the use of various diagnostic tests within PESUDIC and their effectiveness in determining causes of death. This observational study included infants and children who died suddenly and underwent the PESUDIC procedure from 2016 to 2022. Standardized data on medical history, postmortem examinations, and diagnostic outcomes were collected. Findings were classified by consensus of two experts as “contributory” if they supported the cause of death and “decisive” if they were leading for determination. A total of 275 cases were included. Median age was 13 months (IQR 3.5–73.3). Fifty-nine percent were boys. Over 95% of cases had a medical history, postmortem physical examination, biochemical, and microbiological testing available. Total body postmortem CT and/or MRI was done in 93% (n = 255) and autopsy in 62% (n = 171). The cause of death was determined in 193 (70%). History, imaging, and autopsy provided contributory results in 50% (n = 137/275), 40% (n = 103/255), and 67% (n = 115/171) of applicable cases, respectively. More than two different tests showed contributory findings in 52% of diagnosed cases. Autopsy and microbiological testing had decisive findings most often: in 83/171 and 44/265 cases respectively. Conclusion: A routinely performed wide array of postmortem investigations has additional value to an autopsy for identifying the cause of death in SUDI and SUDC. A thorough SUDY investigation should therefore minimally include an autopsy, microbiological testing, and whole-body imaging. (Table presented.)</p

A Systematic Approach to Evaluate Sudden Unexplained Death in Children

Objective: To evaluate in the Netherlands the national outcomes in providing cause of and insights into sudden and unexplained child deaths among children via the Postmortem Evaluation of Sudden Unexplained Death in Youth (PESUDY) procedure. Study design: Children aged 0-18 years in the Netherlands who died suddenly were included in the PESUDY procedure if their death was unexplained and their parents gave consent. The PESUDY procedure consists of pediatric and forensic examination, biochemical, and microbiological tests; radiologic imaging; autopsy; and multidisciplinary discussion. Data on history, modifiable factors, previous symptoms, performed diagnostics, and cause of death were collected between October 2016 and December 2021. Results: In total, 212 cases (median age 11 months, 56% boys, 33% comorbidity) were included. Microbiological, toxicological, and metabolic testing was performed in 93%, 34%, and 32% of cases. In 95% a computed tomography scan or magnetic resonance imaging was done and in 62% an autopsy was performed. The cause of death was explained in 58% of cases and a plausible cause was identified in an additional 13%. Most children died from infectious diseases. Noninfectious cardiac causes were the second leading cause of death found. Modifiable factors were identified in 24% of non-sudden infant death syndrome/unclassified sudden infant death cases and mostly involved overlooked alarming symptoms. Conclusions: The PESUDY procedure is valuable and effective for determining the cause of death in children with sudden unexplained deaths and for providing answers to grieving parents and involved health care professionals.</p

Effective low-dose sirolimus regimen for kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon in young infants

Aims Management of kaposiform haemangioendotheliomas (KHE) with Kasabach-Merritt phenomenon is challenging in young infants who are subjected to developmental pharmacokinetic changes. Sirolimus, sometimes combined with corticosteroids, can be used as an effective treatment of KHE. Simultaneously, toxicities such as interstitial pneumonitis related to the use of sirolimus may be fatal. As infants have a very low CYP3-enzyme expression at birth, which rises during ageing, we hypothesize that a reduced metabolization of sirolimus might lead to high sirolimus serum levels and low dose may be sufficient without the side effects. Methods A case series of 5 infants with kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon was analysed retrospectively. All infants were treated with sirolimus 0.2 mg/m(2) every 24 or 48 hours according to their age. Prednisone was added to the therapy for additional effect in 4 patients. Results In all patients, low dose of sirolimus led to therapeutic sirolimus levels (4-6 ng/mL). All infants (aged 4 days-7 months) had a complete haematological response, without serious adverse events. In all patients, the Kasabach-Merritt phenomenon resolved, the coagulation profile normalized and tumour size reduction was seen. Conclusion Low-dose sirolimus treatment is safe for infants with kaposiform haemangioendothelioma and Kasabach-Merritt phenomenon. It is essential to realize that during the first months of life, metabolism is still developing and enzymes necessary to metabolise drugs like sirolimus still have to mature. To avoid toxic levels, the sirolimus dosage should be based on age and the associated pharmacological developments

Screening over 100 000 patients in 39 general practices in the Netherlands for anticoagulation underprescription in atrial fibrillation: a descriptive, cross-sectional study

Objectives To investigate the underprescription of oral anticoagulation (OAC) in individual atrial fibrillation (AF) patients in primary care. Setting Screening of patient records in 39 participating general practitioners (GPs) across the Netherlands. Participants We screened 101 207 patient records identifying 2375 non-valvular AF patients. Methods Using electronic patient files, we were able to screen the entire GP population for AF, CHA 2 DS 2 -VASc stroke risk scores, and the use of guidelines recommended OAC prescription. In case of a deviation from guidelines recommended OAC prescription, we checked the electronic patient file for any documented reason. Additionally, 6 weeks following the screening, we asked all GPs to provide information on any actions taken for the underprescribed patients. Results We found a mean CHA 2 DS 2 -VASc score of 3.2. OAC prescription consisted of direct OAC in 1342/1984 (68%) and vitamin K-antagonists in the remainder of patients. OAC underprescription was present in 93/944 (9.9%) females and 101/1374 (9.7%) in males, respectively. In 111/146 (76.0%) of the underprescribed AF patients, no reason to withhold OAC was reported. Reported reasons to withhold OAC were patient refusal (n=10), cardiologist advice (n=7) and high risk of bleeding (n=7). Data regarding actions following the identification of OAC underprescription were available for 92/194 (47%) of the OAC underprescribed cases. After consultation OAC was initiated in 9/92 (10%) only. Conclusions In this large Dutch study among GPs, we observed 9.8% underprescription of OAC in AF patients. In 76% of the AF patients lacking a prescription for OAC, no documentation for deviating from the guidelines was found. Only in a minority of cases detection of OAC underprescription lead to OAC initiation

A Systematic Approach to Evaluate Sudden Unexplained Death in Children

Objective: To evaluate in the Netherlands the national outcomes in providing cause of and insights into sudden and unexplained child deaths among children via the Postmortem Evaluation of Sudden Unexplained Death in Youth (PESUDY) procedure. Study design: Children aged 0-18 years in the Netherlands who died suddenly were included in the PESUDY procedure if their death was unexplained and their parents gave consent. The PESUDY procedure consists of pediatric and forensic examination, biochemical, and microbiological tests; radiologic imaging; autopsy; and multidisciplinary discussion. Data on history, modifiable factors, previous symptoms, performed diagnostics, and cause of death were collected between October 2016 and December 2021. Results: In total, 212 cases (median age 11 months, 56% boys, 33% comorbidity) were included. Microbiological, toxicological, and metabolic testing was performed in 93%, 34%, and 32% of cases. In 95% a computed tomography scan or magnetic resonance imaging was done and in 62% an autopsy was performed. The cause of death was explained in 58% of cases and a plausible cause was identified in an additional 13%. Most children died from infectious diseases. Noninfectious cardiac causes were the second leading cause of death found. Modifiable factors were identified in 24% of non-sudden infant death syndrome/unclassified sudden infant death cases and mostly involved overlooked alarming symptoms. Conclusions: The PESUDY procedure is valuable and effective for determining the cause of death in children with sudden unexplained deaths and for providing answers to grieving parents and involved health care professionals

Postmortem diagnostics in sudden unexpected death in infants and children: use and utility

Sudden unexpected death in infants (SUDI) and children (SUDC) requires thorough investigation to identify causes and prevention strategies. In the Netherlands, these deaths are investigated using the standardized postmortem evaluation of sudden unexpected death in infants and children (PESUDIC) procedure. This study examines the use of various diagnostic tests within PESUDIC and their effectiveness in determining causes of death. This observational study included infants and children who died suddenly and underwent the PESUDIC procedure from 2016 to 2022. Standardized data on medical history, postmortem examinations, and diagnostic outcomes were collected. Findings were classified by consensus of two experts as “contributory” if they supported the cause of death and “decisive” if they were leading for determination. A total of 275 cases were included. Median age was 13 months (IQR 3.5–73.3). Fifty-nine percent were boys. Over 95% of cases had a medical history, postmortem physical examination, biochemical, and microbiological testing available. Total body postmortem CT and/or MRI was done in 93% (n = 255) and autopsy in 62% (n = 171). The cause of death was determined in 193 (70%). History, imaging, and autopsy provided contributory results in 50% (n = 137/275), 40% (n = 103/255), and 67% (n = 115/171) of applicable cases, respectively. More than two different tests showed contributory findings in 52% of diagnosed cases. Autopsy and microbiological testing had decisive findings most often: in 83/171 and 44/265 cases respectively. Conclusion: A routinely performed wide array of postmortem investigations has additional value to an autopsy for identifying the cause of death in SUDI and SUDC. A thorough SUDY investigation should therefore minimally include an autopsy, microbiological testing, and whole-body imaging. (Table presented.

Optical imaging in vivo with a focus on paediatric disease: technical progress, current preclinical and clinical applications and future perspectives

To obtain information on the occurrence and location of molecular events as well as to track target-specific probes such as antibodies or peptides, drugs or even cells non-invasively over time, optical imaging (OI) technologies are increasingly applied. Although OI strongly contributes to the advances made in preclinical research, it is so far, with the exception of optical coherence tomography (OCT), only very sparingly applied in clinical settings. Nevertheless, as OI technologies evolve and improve continuously and represent relatively inexpensive and harmful methods, their implementation as clinical tools for the assessment of children disease is increasing. This review focuses on the current preclinical and clinical applications as well as on the future potential of OI in the clinical routine. Herein, we summarize the development of different fluorescence and bioluminescence imaging techniques for microscopic and macroscopic visualization of microstructures and biological processes. In addition, we discuss advantages and limitations of optical probes with distinct mechanisms of target-detection as well as of different bioluminescent reporter systems. Particular attention has been given to the use of near-infrared (NIR) fluorescent probes enabling observation of molecular events in deeper tissue