In vivo rAAV-mediated human TGF-ß overexpression reduces perifocal osteoarthritis and improves osteochondral repair in a large animal model at one year.

OBJECTIVE: Osteoarthritis (OA) is a serious consequence of focal osteochondral defects. Gene transfer of human transforming growth factor beta (hTGF-ß) with recombinant adeno-associated virus (rAAV) vectors offers a strategy to improve osteochondral repair. However, the long-term in vivo effects of such rAAV-mediated TGF-ß overexpression including its potential benefits on OA development remain unknown. METHOD: Focal osteochondral defects in minipig knees received rAAV-lacZ (control) or rAAV-hTGF-ß in vivo. After one year, osteochondral repair and perifocal OA were visualized using validated macroscopic scoring, ultra-high-field MRI at 9.4 T, and micro-CT. A quantitative estimation of the cellular densities and a validated semi-quantitative scoring of histological and immunohistological parameters completed the analysis of microarchitectural parameters. RESULTS: Direct rAAV-hTGF-ß application induced and maintained significantly improved defect filling and safranin O staining intensity and overall cartilage repair at one year in vivo. In addition, rAAV-hTGF-ß led to significantly higher chondrocyte densities within the cartilaginous repair tissue without affecting chondrocyte hypertrophy and minimized subarticular trabecular separation. Of note, rAAV-hTGF-ß significantly improved the adjacent cartilage structure and chondrocyte density and reduced overall perifocal OA development after one year in vivo. CONCLUSIONS: rAAV-hTGF-ß treatment improves long-term osteochondral repair and delays the progression of perifocal OA in a translational model. These findings have considerable potential for targeted molecular approaches to treat focal osteochondral defects.

Postnatal circulation in patients with aortic stenosis undergoing fetal aortic valvuloplasty: systematic review and meta-analysis.

OBJECTIVES: Fetal aortic valvuloplasty (FAV) has become a treatment option for critical fetal aortic stenosis (AS) with the goal of preserving biventricular circulation (BVC); however, to date, it is unclear how many patients undergoing FAV achieve BVC. The aim of this systematic review and meta-analysis was to investigate the type of postnatal circulation achieved following FAV. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. MEDLINE, EMBASE, Web of Science and the Cochrane Library were searched systematically for studies investigating postnatal circulation in patients with AS following FAV. Eligible for inclusion were original papers in the English language, published from 2000 to 2020, with at least 12 months of follow-up after birth. Review papers, abstracts, expert opinions, books, editorials and case reports were excluded. The titles and abstracts of all retrieved literature were screened, duplicates were excluded and the full texts of potentially eligible articles were obtained and assessed. The primary endpoint was type of postnatal circulation. Additional assessed outcomes included fetal death, live birth, neonatal death (NND), termination of pregnancy (TOP) and technical success of the FAV procedure. The quality of articles was assessed using the Critical Appraisal Skills Programme (CASP) tool. To estimate the overall proportion of each endpoint, meta-analysis of proportions was employed using a random-effects model. RESULTS: The electronic search identified 579 studies, of which seven were considered eligible for inclusion in the systematic review and meta-analysis. A total of 266 fetuses underwent FAV with median follow-up per study from 12 months to 13.2 years. There were no maternal deaths and only one case of FAV-related maternal complication was reported. Hydrops was present in 29 (11%) patients. The pooled prevalence of BVC and univentricular circulation (UVC) among liveborn patients was 45.8% (95% CI, 39.2-52.4%) and 43.6% (95% CI, 33.9-53.8%), respectively. The pooled prevalence of technically successful FAV procedure was 82.1% (95% CI, 74.3-87.9%), of fetal death it was 16.0% (95% CI, 11.2-22.4%), of TOP 5.7% (95% CI, 2.0-15.5%), of live birth 78.8% (95% CI, 66.5-87.4%), of NND 8.7% (95% CI, 4.7-15.5%), of palliative care 4.0% (95% CI, 1.9-8.4%) and of infant death 10.3% (95% CI, 3.6-26.1%). The pooled prevalence of BVC and UVC among liveborn patients who had technically successful FAV was 51.9% (95% CI, 44.7-59.1%) and 39.8% (95% CI, 29.7-50.9%), respectively. CONCLUSIONS: This study showed a BVC rate of 46% among liveborn patients with AS undergoing FAV, which improved to 52% when subjects underwent technically successful FAV. Given the lack of randomized clinical trials, results should be interpreted with caution. Currently, data do not suggest a true benefit of FAV for achieving BVC. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Predictors of perioperative complications in paediatric cranial vault reconstruction surgery: a multicentre observational study from the Pediatric Craniofacial Collaborative Group.

BACKGROUND: The current incidence of major complications in paediatric craniofacial surgery in North America has not been accurately defined. In this report, the Pediatric Craniofacial Collaborative Group evaluates the incidence and determines the independent predictors of major perioperative complications using a multicentre database. METHODS: The Pediatric Craniofacial Surgery Perioperative Registry was queried for subjects undergoing complex cranial vault reconstruction surgery over a 5-year period. Major perioperative complications were identified through a structured a priori consensus process. Logistic regression was applied to identify predictors of a major perioperative complication with bootstrapping to evaluate discrimination accuracy and provide internal validity of the multivariable model. RESULTS: A total of 1814 patients from 33 institutions in the US and Canada were analysed; 15% were reported to have a major perioperative complication. Multivariable predictors included ASA physical status 3 or 4 (P=0.005), craniofacial syndrome (P=0.008), antifibrinolytic administered (P=0.003), blood product transfusion >50 ml kg-1 (P<0.001), and surgery duration over 5 h (P<0.001). Bootstrapping indicated that the predictive algorithm had good internal validity and excellent discrimination and model performance. A perioperative complication was estimated to increase the hospital length of stay by an average of 3 days (P<0.001). CONCLUSIONS: The predictive algorithm can be used as a prognostic tool to risk stratify patients and thereby potentially reduce morbidity and mortality. Craniofacial teams can utilise these predictors of complications to identify high-risk patients. Based on this information, further prospective quality improvement initiatives may decrease complications, and reduce morbidity and mortality.

Causal somatic mutations in urine DNA from persons with the CLOVES subgroup of the PIK3CA-related overgrowth spectrum.

Congenital lipomatous overgrowth with vascular, epidermal, and skeletal (CLOVES) anomalies and Klippel-Trenaunay (KTS) syndromes are caused by somatic gain-of-function mutations in PIK3CA, encoding a catalytic subunit of phosphoinositide 3-kinase. Affected tissue is needed to find mutations, as mutant alleles are not detectable in blood. Because some patients with CLOVES develop Wilms tumor, we tested urine as a source of DNA for mutation detection. We extracted DNA from the urine of 17 and 24 individuals with CLOVES and KTS, respectively, and screened 5 common PIK3CA mutation hotspots using droplet digital polymerase chain reaction. Six of 17 CLOVES participants (35%) had mutant PIK3CA alleles in urine. Among 8 individuals in whom a mutation had been previously identified in affected tissue, 4 had the same mutant allele in the urine. One study participant with CLOVES had been treated for Wilms tumor. We detected the same PIK3CA mutation in her affected tissue, urine, and tumor, indicating Wilms tumors probably arise from PIK3CA mutant cells in patients with CLOVES. No urine sample from a participant with KTS had detectable PIK3CA mutations. We suggest that urine, which has the advantage of being collected non-invasively, is useful when searching for mutations in individuals with CLOVES syndrome.

The efficacy of GlideScope® videolaryngoscopy compared with direct laryngoscopy in children who are difficult to intubate: an analysis from the paediatric difficult intubation registry.

BACKGROUND: We analysed data from the Paediatric Difficult Intubation Registry examining the use of direct laryngoscopy and GlideScope® videolaryngoscopy. METHODS: Data collected by a multicentre, paediatric difficult intubation registry from 1295 patients were analysed. Rates of success and complications between direct laryngoscopy and GlideScope videolaryngoscopy were analysed. RESULTS: Initial (464/877 = 53% vs 33/828 = 4%, Z-test = 22.2, P < 0.001) and eventual (720/877 = 82% vs. 174/828 = 21%, Z-test = 25.2, P < 0.001) success rates for GlideScope were significantly higher than direct laryngoscopy. Children weighing <10 kg had lower success rates with the GlideScope than the group as a whole. There were no differences in complication rates per attempt between direct laryngoscopy and GlideScope. The direct laryngoscopy group had more complications associated with the greater number of attempts needed to intubate. There were no increased risks of hypoxia or trauma with GlideScope use. Each additional attempt at intubation with either device resulted in a two-fold increase in complications (odds ratio: 2.0, 95% confidence interval: 1.5-2.5, P < 0.001). CONCLUSIONS: During difficult tracheal intubation in children, direct laryngoscopy is an overly used technique with a low chance of success. GlideScope use was associated with a higher chance of success with no increased risk of complications. GlideScope use in children with difficult tracheal intubation has a lower success rate than in adults with difficult tracheal intubation. Children weighing less than 10 kilograms had lower success rates with either device. Attempts should be minimized with either device to decrease complications.

Optimal Timing of Pulmonary Banding for Newborns with Single Ventricle Physiology and Unrestricted Pulmonary Blood Flow.

The aim of this study was to determine the optimal timing of pulmonary artery band (PAB) placement in neonates with single ventricle physiology, unrestricted pulmonary blood flow, and no systemic outflow tract obstruction. Retrospective chart review of all patients who underwent isolated PAB for single ventricle physiology between January 2005 and December 2014 was carried out. The influence of age at the time of PAB on operative mortality, the need for reoperation to adjust the PAB, the preparedness of the pulmonary vascular bed prior to the second-stage bidirectional cavopulmonary shunt (BCPS), and the outcomes following BCPS were studied. The study cohort included 54 subjects (34 males). The median age at the time of PAB was 18 days. The overall mortality following PAB was 4 % (2/54). Reoperation for PAB adjustment was 7 % (4/54). Younger age at the time of PAB was not associated with mortality or increased risk of reoperation. There was a mild positive correlation between the age at PAB and the mean pulmonary artery pressure prior to BCPS. There was also a weak positive correlation between the age at PAB and the duration of ventilation following BCPS. Age at the time of PAB did not influence pulmonary vascular resistance (PVR) prior to BCPS or the mortality and hospital stay following BCPS. PAB can be done safely and effectively soon after birth in neonates with single ventricle physiology, increased pulmonary blood flow, and no potential or actual systemic outflow tract obstruction. It may not be necessary to wait for a few weeks after birth for the neonatal PVR to fall before placing a PAB.

Splitting blood and blood product packaging reduces donor exposure for patients undergoing cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass for congenital heart surgery requires packed red cells (PRBC) and fresh frozen plasma (FFP) to be available, both for priming of the circuit as well as to replace blood loss. This study examines the hypothesis that splitting one unit of packed red blood cells and one unit of fresh frozen plasma into two half units reduces blood product exposure and wastage in the Operating Room. METHODS: Beginning August 2013, the blood bank at Children's National Medical Center began splitting one unit of packed red blood cells (PRBC) and one unit of fresh frozen plasma (FFP) for patients undergoing cardiopulmonary bypass (CPB). The 283 patients who utilized CPB during calendar year 2013 were divided into 2 study groups: before the split and after the split. The principal endpoints were blood product usage and donor exposure intra-operatively and within 72 hours post-operatively. RESULTS: There was a significant decrease in median total donor exposures for FFP and cryoprecipitate from 5 to 4 per case (p = 0.007, Mann-Whitney U-test). However, there was no difference in the volume of blood and blood products used; in fact, there was a significant increase in the amount of FFP that was wasted with the switch to splitting the unit of FFP. CONCLUSIONS: We found that modification of blood product packaging can decrease donor exposure. Future investigation is needed as to how to modify packaging to minimize wastage.

Urinary TIMP-1 and MMP-2 levels detect the presence of pancreatic malignancies.

BACKGROUND: A majority of patients with pancreatic malignancies, including both pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumours (pNETs), present with advanced disease due to a lack of specific symptoms and current diagnostic limitations, making this disease extremely difficult to detect. Our goal was to determine whether urinary matrix metalloproteases (uMMPs) and/or their endogenous inhibitors, urinary tissue inhibitor of metalloproteases (uTIMPs), could be detected in the urine of patients with pancreatic malignancies and whether they may serve as independent predictors of disease status. METHODS: Retrospective analyses of urine samples (n=139) from PDAC and pNET patients as well as age- and sex-matched controls were conducted. Urinary MMP-2 and uTIMP-1 levels were determined using ELISA and zymography. Biomarker expression in tumour and normal pancreatic tissues was analysed via immunohistochemistry (IHC). RESULTS: Multivariable logistic regression analyses indicated that, when controlling for age and sex, uMMP-2 (P<0.0001) and uTIMP-1 (P<0.0001) but not uMMP-9, were significant independent predictors for distinguishing between PDAC patients and healthy controls. Our data also indicated that uMMP-2 was an independent predictor of the presence of pNET. In addition, uTIMP-1 levels could differentiate the two cancer groups, PDAC and pNET, respectively. Immunohistochemistry analysis confirmed that MMP-2 and TIMP-1 protein expression is significantly upregulated in PDAC tissue compared with the normal pancreas. CONCLUSIONS: Taken together, our results suggest that the detection of uMMP-2 and uTIMP-1 may have diagnostic value in the detection of pancreatic malignancies and that uTIMP-1 may be useful in distinguishing between pancreatic adenocarcinoma and neuroendocrine tumours.

2D and 3D MOCART scoring systems assessed by 9.4 T high-field MRI correlate with elementary and complex histological scoring systems in a translational model of osteochondral repair.

OBJECTIVE: To compare the 2D and 3D MOCART system obtained with 9.4 T high-field magnetic resonance imaging (MRI) for the ex vivo analysis of osteochondral repair in a translational model and to correlate the data with semiquantitative histological analysis. METHODS: Osteochondral samples representing all levels of repair (sheep medial femoral condyles; n = 38) were scanned in a 9.4 T high-field MRI. The 2D and adapted 3D MOCART systems were used for grading after point allocation to each category. Each score was correlated with corresponding reconstructions between both MOCART systems. Data were next correlated with corresponding categories of an elementary (Wakitani) and a complex (Sellers) histological scoring system as gold standards. RESULTS: Correlations between most 2D and 3D MOCART score categories were high, while mean total point values of 3D MOCART scores tended to be 15.8-16.1 points higher compared to the 2D MOCART scores based on a Bland-Altman analysis. "Defect fill" and "total points" of both MOCART scores correlated with corresponding categories of Wakitani and Sellers scores (all P ≤ 0.05). "Subchondral bone plate" also correlated between 3D MOCART and Sellers scores (P < 0.001). CONCLUSIONS: Most categories of the 2D and 3D MOCART systems correlate, while total scores were generally higher using the 3D MOCART system. Structural categories "total points" and "defect fill" can reliably be assessed by 9.4 T MRI evaluation using either system, "subchondral bone plate" using the 3D MOCART score. High-field MRI is valuable to objectively evaluate osteochondral repair in translational settings.

Negative pressure wound therapy for sternal wound infections following congenital heart surgery.

OBJECTIVE: This study examines the efficacy of a comprehensive, multidisciplinary wound management team and negative pressure wound therapy (NPWT) for the treatment of sternal wound infections in congenital heart surgery patients. METHOD: A single-institution retrospective review of all congenital heart surgery patients with post-operative sternal wound infections who were treated with NPWT was performed. Patients were evaluated based on (a) whether NPWT occurred before or after the establishment of a multidisciplinary wound management team, and (b) whether NPWT was initiated early (within 2 days) or late (greater than 2 days) after diagnosis of a sternal wound infection. RESULTS: The median duration of NPWT was 12 days (range 2-50 days). NPWT was successfully initiated in patients as young as 15 days of age. There was a trend toward shorter duration of both NPWT and antibiotic use following (a) the implementation of the multidisciplinary wound management team, and (b) in patients with early use of NPWT; however, these results did not achieve statistical significance. CONCLUSION: NPWT can be successfully utilised in congenital heart surgery patients, including young neonates, for the treatment of sternal wound infections. The trends observed in the reduction of wound therapy duration and antibiotic duration with early implementation of negative pressure therapy and multidisciplinary wound management require further investigation to verify their clinical efficacy in patient care.

Parathyroid hormone [1-34] improves articular cartilage surface architecture and integration and subchondral bone reconstitution in osteochondral defects in vivo.

OBJECTIVE: The 1-34 amino acid segment of the parathyroid hormone (PTH [1-34]) mediates anabolic effects in chondrocytes and osteocytes. The aim of this study was to investigate whether systemic application of PTH [1-34] improves the repair of non-osteoarthritic, focal osteochondral defects in vivo. DESIGN: Standardized cylindrical osteochondral defects were bilaterally created in the femoral trochlea of rabbits (n = 8). Daily subcutaneous injections of 10 µg PTH [1-34]/kg were given to the treatment group (n = 4) for 6 weeks, controls (n = 4) received saline. Articular cartilage repair was evaluated by macroscopic, biochemical, histological and immunohistochemical analyses. Reconstitution of the subchondral bone was assessed by micro-computed tomography. Effects of PTH [1-34] on synovial membrane, apoptosis, and expression of the PTH receptor (PTH1R) were determined. RESULTS: Systemic PTH [1-34] increased PTH1R expression on both, chondrocytes and osteocytes within the repair tissue. PTH [1-34] ameliorated the macro- and microscopic aspect of the cartilaginous repair tissue. It also enhanced the thickness of the subchondral bone plate and the microarchitecture of the subarticular spongiosa within the defects. No significant correlations were established between these coexistent processes. Apoptotic levels, synovial membrane, biochemical composition of the repair tissue, and type-I/II collagen immunoreactivity remained unaffected. CONCLUSIONS: PTH [1-34] emerges as a promising agent in the treatment of focal osteochondral defects as its systemic administration simultaneously stimulates articular cartilage and subchondral bone repair. Importantly, both time-dependent mechanisms of repair did not correlate significantly at this early time point and need to be followed over prolonged observation periods.

Cartilage constructs engineered from chondrocytes overexpressing IGF-I improve the repair of osteochondral defects in a rabbit model.

Tissue engineering combined with gene therapy is a promising approach for promoting articular cartilage repair. Here, we tested the hypothesis that engineered cartilage with chondrocytes overexpressing a human insulin-like growth factor I (IGF-I) gene can enhance the repair of osteochondral defects, in a manner dependent on the duration of cultivation. Genetically modified chondrocytes were cultured on biodegradable polyglycolic acid scaffolds in dynamic flow rotating bioreactors for either 10 or 28 d. The resulting cartilaginous constructs were implanted into osteochondral defects in rabbit knee joints. After 28 weeks of in vivo implantation, immunoreactivity to ß-gal was detectable in the repair tissue of defects that received lacZ constructs. Engineered cartilaginous constructs based on IGF-I-overexpressing chondrocytes markedly improved osteochondral repair compared with control (lacZ) constructs. Moreover, IGF-I constructs cultivated for 28 d in vitro significantly promoted osteochondral repair vis-à-vis similar constructs cultivated for 10 d, leading to significantly decreased osteoarthritic changes in the cartilage adjacent to the defects. Hence, the combination of spatially defined overexpression of human IGF-I within a tissue-engineered construct and prolonged bioreactor cultivation resulted in most enhanced articular cartilage repair and reduction of osteoarthritic changes in the cartilage adjacent to the defect. Such genetically enhanced tissue engineering provides a versatile tool to evaluate potential therapeutic genes in vivo and to improve our comprehension of the development of the repair tissue within articular cartilage defects. Insights gained with additional exploration using this model may lead to more effective treatment options for acute cartilage defects.

Experimental scoring systems for macroscopic articular cartilage repair correlate with the MOCART score assessed by a high-field MRI at 9.4 T--comparative evaluation of five macroscopic scoring systems in a large animal cartilage defect model.

OBJECTIVE: To develop a new macroscopic scoring system which allows for an overall judgment of experimental articular cartilage repair and compare it with four existing scoring systems and high-field magnetic resonance imaging (MRI). METHODS: A new macroscopic scoring system was developed to assess the repair of cartilage defects. Cartilage repair was graded by three observers with different experience in cartilage research at 2-3 time points and compared with the protocol A of the international cartilage repair society (ICRS) cartilage repair assessment score, the Oswestry arthroscopy score, and macroscopic grading systems designed by Jung and O'Driscoll. Parameters were correlated with the two-dimensional (2D) magnetic resonance observation of cartilage repair tissue (MOCART) score based on a 9.4 T MRI as an external reference standard. RESULTS: All macroscopic scores exhibited high intra- and interobserver reliability and high internal correlation. The newly developed macroscopic scoring system had the highest intraobserver [0.866 ≤ intraclass correlation (ICC) ≤ 0.895] and the highest interobserver reliability (ICC = 0.905) for "total points". Here, Cronbach's alpha indicated good homogeneity and functioning of the items (mean = 0.782). "Total points" of the 2D MOCART score correlated with all macroscopic scores (all P < 0.0001). The newly developed macroscopic scoring system yielded the highest correlation for the MRI parameter "defect fill" (rho = 0.765; all P < 0.0001). CONCLUSIONS: "Total points" and "defect fill", two clinically relevant indicators of cartilage repair, can be reliably and directly assessed by macroscopic evaluation, using either system. These data support the use of macroscopic assessment to precisely judge cartilage repair in preclinical large animal models.

Surgical scar remodelling after photodynamic therapy using aminolaevulinic acid or its methylester: a retrospective, blinded study of patients with field cancerization.

BACKGROUND: Photodynamic therapy (PDT) is a nonsurgical alternative to conventional tumour excision for nonmelanoma skin cancers (NMSCs). OBJECTIVES: We evaluated whether patients with field cancerization (multiple NMSCs) treated with aminolaevulinic acid (ALA) or its methylester (MAL) for that indication had PDT-induced changes in surgical scars in the treatment field. METHODS: Six adult patients with multiple NMSCs and a total of 21 scars from previous excisions were studied in a retrospective blinded evaluation from clinical photographs of scar response to ALA/MAL-PDT. After a 3-h application of topical 20% ALA or 16·8% MAL under occlusion, each field was irradiated with 635-nm light-emitting diode light at the fluence of 200Jcm(-2) . Patients underwent one to three PDT sessions per field at ∼1month intervals, to fields that included scars on the back, thigh, arms and neck. Pre- and post-treatment digital photographs of scars were combined into 92 pairs that were independently and blindly evaluated by three board-certified dermatologists. This study was performed at our academic practice at the Massachusetts General Hospital. RESULTS: PDT produced a statistically significant improvement in scar appearance. The degree of improvement correlated with the number of treatment sessions (two or three treatments; P<0·05). Improvement after a single treatment was not statistically different from baseline ratings (P=0·99). CONCLUSIONS: Surgical scar remodelling and clinical improvement may be accomplished via ALA/MAL-PDT, but may require repeated treatment sessions. Larger, prospective studies are necessary to confirm the effectiveness of PDT for this indication.

Postoperative complications following the Fontan procedure: the role of aprotinin.

OBJECTIVE: To determine how the anti-inflammatory properties of aprotinin impact on postoperative complications in children undergoing the Fontan procedure. METHODS: We included all patients between 14 months and 18 years (n=56) undergoing a Fontan operation at our institution between January 2005 and June 2009. The study group (n=29) included patients from January 2005 through December 2007 all of whom received aprotinin. The control group (n=27) included all patients from January 2008 through June 2009 who did not receive aprotinin. We reviewed all medical records and collected preoperative, intraoperative and postoperative data. Duration and volume of chest tube drainage were the primary outcome measures. RESULTS: Of the 20% of patients who had postoperative arrhythmias, multivariate logistic regression analysis demonstrated only aprotinin was associated with significantly decreased postoperative arrhythmias (P=0.01). Renal function and fenestration or Fontan thrombosis did not differ significantly; there was no statistically significant difference in volume or duration of chest tube drainage. Median duration of chest tube drainage was 7 days in the aprotinin group and 8 days for patients who did not receive aprotinin (P=0.36). CONCLUSION: The anti-inflammatory properties of aprotinin may be protective against postoperative arrhythmias. Aprotinin does not confer increased risks of prolonged chest tube drainage, renal dysfunction or thrombosis in patients undergoing the Fontan procedure.

Neutral endopeptidase modulation of septic shock.

Neutral endopeptidase (NEP; EC. 3.4.24.11) is a type 2 cell surface metalloprotease known by a variety of eponyms, including enkephalinase, common acute lymphoblastic leukemia antigen, and CD10. Identified substrates are largely neural or humoral oligopeptide agonists, and the enzyme functions to terminate signaling by degrading the ligand, analogously to acetylcholine/acetylcholinesterase. Targeted disruption of the NEP locus in mice results in enhanced lethality to endotoxin shock with a pronounced gene dosage effect. The site(s) of action appears downstream from release of tumor necrosis factor and interleukin-1 since NEP-deficient animals demonstrate increased sensitivity to these mediators as well. This unexpected finding indicates an important protective role for NEP in septic shock.

Fetal and Neonatal MRI Predictors of Aggressive Early Clinical Course in Vein of Galen Malformation.

BACKGROUND AND PURPOSE: Neonates with vein of Galen malformations are split into 2 cohorts: one needing urgent neonatal embolization, with relatively high mortality and morbidity even with expert care, and a cohort in which embolization can be deferred until infancy, with far better prognosis. We aimed to identify brain MR imaging characteristics obtained from fetal and early neonatal scans that can predict the clinical presentation. MATERIALS AND METHODS: Patients with vein of Galen malformations were stratified into a neonatal at-risk cohort if the patient needed urgent neonatal intervention or if neonatal death occurred; or an infantile treatment cohort if they were stable enough not to require treatment until >1 month of age. Twelve vascular MR imaging parameters, measured by 2 independent observers, were systematically correlated with the need for early neonatal intervention and/or neonatal mortality. RESULTS: A total of 32 neonatal patients (21 patients in the neonatal at-risk cohort, 11 in the infantile treatment cohort) were identified. Maximal mediolateral diameter (area under the curve = 0.866, P < .001) and cross-sectional area (area under the curve = 0.836, P = .002) at the narrowest point of the straight or falcine sinus were most predictive of clinical evolution into the neonatal at-risk cohort. There were 15 patients who had fetal MRIs (10 in the neonatal at-risk cohort and 5 in the infantile treatment cohort). Here too, maximal mediolateral diameter (area under the curve = 0.980, P = .003) and cross-sectional area (area under the curve = 0.941, P = .007) at the narrowest point of the straight or falcine sinus were highly predictive of the neonatal at-risk cohort. CONCLUSIONS: Early neonatal and fetal MR imaging can be readily used for accurate early risk stratification, assisting in directing resources, timing treatment decisions, and identifying appropriate cohorts for novel interventions.

Biological and behavioral markers of pain following nerve injury in humans.

The evolution of peripheral and central changes following a peripheral nerve injury imply the onset of afferent signals that affect the brain. Changes to inflammatory processes may contribute to peripheral and central alterations such as altered psychological state and are not well characterized in humans. We focused on four elements that change peripheral and central nervous systems following ankle injury in 24 adolescent patients and 12 age-sex matched controls. Findings include (a) Changes in tibial, fibular, and sciatic nerve divisions consistent with neurodegeneration; (b) Changes within the primary motor and somatosensory areas as well as higher order brain regions implicated in pain processing; (c) Increased expression of fear of pain and pain reporting; and (d) Significant changes in cytokine profiles relating to neuroinflammatory signaling pathways. Findings address how changes resulting from peripheral nerve injury may develop into chronic neuropathic pain through changes in the peripheral and central nervous system.

Individualized developmental care for a large sample of very preterm infants: health, neurobehaviour and neurophysiology.

AIM: To assess medical and neurodevelopmental effects of Newborn Individualized Developmental Care and Assessment Program (NIDCAP) for a large sample of very early-born infants. METHODS: One hundred and seven singleton inborn preterm infants, <29 weeks gestational age (GA), <1250 g birth weight, enrolled in three consecutive phases, were randomized within phase to NIDCAP (treatment, E) or standard care (C). Treatment extended from admission to the Newborn Intensive Care Unit to 2 weeks corrected age (wCA). Outcome included medical, neurobehavioural and neurophysiological status at 2 wCA, and growth and neurobehavioural status at 9 months (m) CA. RESULTS: The C- and E-group within each of the three consecutive phases and across the three phases were comparable in terms of all background measures; they therefore were treated as one sample. The results indicated for the E-group significant reduction in major medical morbidities of prematurity as well as significantly improved neurodevelopmental (behaviour and electrophysiology) functioning at 2 wCA; significantly better neurobehavioural functioning was also found at 9 mCA. CONCLUSION: The NIDCAP is an effective treatment for very early-born infants. It reduces health morbidities and enhances neurodevelopment, functional competence and life quality for preterm infants at 2 w and 9 mCA.