Yaroslavna Nosikova

Very low-birth-weight infants with congenital cardiac lesions: Is there merit in delaying intervention to permit growth and maturation?

BACKGROUND Low birth weight and prematurity and are known risks for mortality in congenital heart lesions. It is not known whether risks of delayed intervention are offset by benefits of growth and maturation. We explored this question. METHODS All 1618 infants admitted to our institution within 30 days after birth for a congenital heart defect since 2000 were analyzed. Birth details and admission progress notes were detailed on all. For infants requiring cardiac interventions, clinical conference records and progress notes enabled their management to be classified as either USUAL (normal timing and mode of intervention) or DELAYED (intentional delay for growth/maturation). The survival implications of birth weight and prematurity were examined via parametric multiphase methodology with bootstrap resampling. Subsequently, the impact of DELAYED management was sought in propensity-adjusted and multivariable time-related models. RESULTS Low birth weight is a strong, robust and independent predictor of death within the first year of life (P < .0001; 99.6% bootstrap resamples). The relationship is nonlinear with an inflection point at approximately 2.0 kg, below which decrements in survival are increasingly pronounced. Prematurity is also associated with poor outcome but less reliably so (P < .0001; 53% resamples); its variance appears partially mitigated by colinearity with multiple factors including diagnosis and chromosomal aneuploidy. Of the 149 infants with birth weight less than 2.0 kg (highest risk and most likely to receive delayed care in this cohort), care was USUAL in 34 and DELAYED in 46. The remaining children received comfort care only (27), were not considered for intervention owing to severe noncardiac problems (12) or were routinely observed for nonurgent lesions (30). Survival between the children weighing less than 2.0 kg and receiving USUAL or DELAYED care was identical (78% ± 2% at 1 year; P = .88), even when adjusted via propensity score (P = 0.65) or multivariable analysis (P = 0.55). Major determinants of death in this very low-birth-weight population were antenatal diagnosis (P = .01), presence of congenital gastrointestinal defects (P = .07), or lesion type (all higher risk: anomalous pulmonary venous drainage, P = .03; pulmonary atresia and intact septum, P = .05; and truncus, P = .01). CONCLUSIONS For very low-birth-weight neonates (<2.0 kg) with congenital heart defects, imposed delays in intervention neither compromise nor improve survival. Other factors instead appear to account for survival differences, including lesion type, associated noncardiac congenital defects, and antenatal diagnosis.

Characterization of the annulus fibrosus-vertebral body interface: identification of new structural features.

Current surgical treatments for degenerative intervertebral disc disease do not restore full normal spinal movement. Tissue engineering a functional disc replacement may be one way to circumvent this limitation, but will require an integration of the different tissues making up the disc for this approach to be successful. Hence, an in‐depth characterization of the native tissue interfaces, including annulus insertion into bone is necessary, as knowledge of this interface is limited. The objective of this study was to characterize the annulus fibrosus–vertebral bone (AF–VB) interface in immature (6–9 months old) and mature (18–24 months old) bovine discs, as well as to define these structures for normal adult human (22 and 45 years old) discs. Histological assessment showed that collagen fibers in the inner annulus, which are predominantly type II collagen, all appear to insert into the mineralized endplate zone. In contrast, some of the collagen fibers of the outer annulus, predominantly type I collagen, insert into this endplate, while other fibers curve laterally, at an ∼ 90 ° angle, to the outer aspect of the bone, and merge with the periosteum. This is seen in both human and bovine discs. Where the AF inserts into the calcified zone of the AF–VB interface, it passes through a chondroid region, rich in type II collagen and proteoglycans. Annulus cells (elongated cells that are not surrounded by proteoglycans) are present at this interface. This cartilage zone is evident in both human and bovine discs. Type X collagen and alkaline phosphatase are localized to the interface region. Age‐associated differences in bovine spines are observed when examining the interface thickness and the matrix composition of the cartilaginous endplate, as well as the thickness of the mineralized endplate. These findings will assist with the design of the AF–VB interface in the tissue engineered disc.

Annulus fibrosus cells can induce mineralization: an in vitro study

BACKGROUND CONTEXT There is still no consensus as to whether the calcification observed in degenerate intervertebral discs (IVDs) is a cause or a consequence of disc degeneration. PURPOSE To investigate the mineralization potential of healthy (independent of other associated changes) annulus fibrosus (AF) cells under controlled in vitro conditions. STUDY DESIGN/SETTING In vitro study to investigate the mineralization potential of the AF cells. METHODS Annulus fibrosus cells, isolated from bovine IVDs, were grown in monolayer. The effect of cell density, culture time, age of cell source, and passage on the percentage of AF cells with alkaline phosphatase activity (ALPa) was evaluated. Gene expression of mineralization-associated markers was determined. Cells were immunostained for Type I, II, and X collagens. To study mineralization potential, AF cells and AF cells that were sorted into two populations, high (top 5% ± 1%) or low (bottom 5% ± 1%) ALPa expressors, were grown in the presence of β-glycerophosphate for 2 weeks. RESULTS The percentage of AF cells that express ALPa changes with time in culture and seeding density for primary immature and mature cell sources but not for passaged cells. Gene expression of ALP, matrix metallopeptidase-13 (MMP-13), osteopontin, and runt-related transcription factor 2 was upregulated by Day 7. Under mineralization-inducing conditions, high ALPa expressors and unsorted AF cells formed von Kossa-positive nodules, composed of hydroxyapatite as determined by electron diffraction analysis. Low ALPa expressors had significantly fewer von Kossa-positive nodules (p<.01) compared with high ALPa expressors. Cells showed colocalization of Type I collagen and ALPa. No Type II collagen was detected suggesting that these were AF cells and not chondrocytes. CONCLUSIONS Annulus fibrosus cells have mineralizing capability and form hydroxyapatite crystalline deposits when cultured under appropriate conditions. This system could be used to investigate mineralization mechanisms in the AF during pathological calcification and at the AF-bone interface in disc degeneration.

AVIATION “THREAT AND ERROR MODEL” IN CONGENITAL CARDIOVASCULAR SURGERY: INEFFECTIVE INTRA-OPERATIVE ERROR RESCUE LEADS TO DANGEROUS ERROR CYCLES

tion with response to heparin. METHODS: Pediatric patients had a comprehensive coagulation panel performed prior to cardiac surgery (antithrombin, protein C/S, coagulation factors II (FII), FVII, FVIII, FIX, FX, FXI, FXIII, fibrinogen, prothrombin time/international normalized ratio (PT/INR) and activated partial thromboplastin time). Previously published, age-appropriate values obtained from normal children were used as reference values across age groups. We also examined the effect of preoperative oxygen saturation and C-reactive protein on blood levels of coagulation factors. The Hemostatic Management System (Medtronic) was used to measure response to the initial heparin dose. RESULTS: Of the 157 enrolled patients, 8%were 10 years old; 31% had a cyanotic condition and 11% had recent heparin exposure. Patients had lower coagulation circulating level activity than expected for age, ranging from 61% to 92% of age-appropriate values (p<0.001 for all) with the exception of PT/INR (106% of age-normal, p1⁄40.002) and circulating FVIII (114% of age-normal, p<0.001). Abnormalities were mostly consistent across age groups. Lower oxygen saturation was associated with lower coagulation system activity (FIX:2.6(1.4)% per -10% oxygen saturation, p1⁄40.06; FVII:3.3(1.3)%, p1⁄40.01; protein C:-3.4(1.6)%, p1⁄40.04). Increasing C-reactive protein was associated with increased FX (+4.0(1.8)% per pmol/L C-reactive protein, p1⁄40.03) and fibrinogen levels (+1.5(0.7)g/L per pmol/L C-reactive protein, p1⁄40.03). Response to initial heparin dose (prior to bypass) was impaired in patients with lower activity of the coagulation system, particularly antithrombin, factors II, IX, X, XI and fibrinogen reuslting in greater thrombin generation during cardiac surgery. CONCLUSION: Children about to undergo cardiac surgery have multiple abnormalities within their coagulation system that affect response to heparin; this in turn affects heparin management and monitoring during surgery and predisposes to both thrombosis and bleeding. Future research identifying determinants of heparin sensitivity and developing potential corrective strategies are warranted. CIHR