Metamorphosis of human lumbar vertebrae induced by VEPTR growth modulation and stress shielding

INTRODUCTION Distraction-based spinal growth modulation by growing rods or vertical expandable prosthetic titanium ribs (VEPTRs) is the mainstay of instrumented operative strategies to correct early onset spinal deformities. In order to objectify the benefits, it has become common sense to measure the gain in spine height by assessing T1-S1 distance on anteroposterior (AP) radiographs. However, by ignoring growth changes on vertebral levels and by limiting measurement to one plane, valuable data is missed regarding the three-dimensional (3D) effects of growth modulation. This information might be interesting when it comes to final fusion or, even more so, when the protective growing implants are removed and the spine re-exposed to physiologic forces at the end of growth. METHODS The goal of this retrospective radiographic study was to assess the growth modulating impact of year-long, distraction-based VEPTR treatment on the morphology of single vertebral bodies. We digitally measured lumbar vertebral body height (VBH) and upper endplate depth (VBD) at the time of the index procedure and at follow-up in nine patients with rib-to-ileum constructs (G1) spanning an anatomically normal lumbar spine. Nine patients with congenital thoracic scoliosis and VEPTR rib-to-rib constructs, but uninstrumented lumbar spines, served as controls (G2). All had undergone more than eight half-yearly VEPTR expansions. A Wilcoxon signed-rank test was used for statistical comparison of initial and follow-up VBH, VBD and height/depth (H/D) ratio (significance level 0.05). RESULTS The average age was 7.1 years (G1) and 5.2 year (G2, p > 0.05) at initial surgery; the average overall follow-up time was 5.5 years (p = 1). In both groups, VBH increased significantly without a significant intergroup difference. Group 1 did not show significant growth in depth, whereas VBD increased significantly in the control group. As a consequence, the H/D ratio increased significantly in group 1 whereas it remained unchanged in group 2. The growth rate for height in mm/year was 1.4 (group 1) and 1.1 (group 2, p = 0.45), and for depth, it was -0.3 and 1.1 (p < 0.05), respectively. CONCLUSIONS VEPTR growth modulating treatment alters the geometry of vertebral bodies by increasing the H/D ratio. We hypothesize that the implant-related deprivation from axial loads (stress-shielding) impairs anteroposterior growth. The biomechanical consequence of such slender vertebrae when exposed to unprotected loads in case of definitive VEPTR removal at the end of growth is uncertain.

Platelet-rich concentrates differentially release growth factors and induce cell migration in vitro

BACKGROUND Platelet-rich concentrates are used as a source of growth factors to improve the healing process. The diverse preparation protocols and the gaps in knowledge of their biological properties complicate the interpretation of clinical results. QUESTIONS/PURPOSES In this study we aimed to (1) analyze the concentration and kinetics of growth factors released from leukocyte- and platelet-rich fibrin (L-PRF), leukocyte- and platelet-rich plasma (L-PRP), and natural blood clot during in vitro culture; (2) investigate the migration of mesenchymal stem cells (MSCs) and human umbilical vein endothelial cells (HUVECs) as a functional response to the factors released; and (3) uncover correlations between individual growth factors with the initial platelet/leukocyte counts or the induced cell migration. METHODS L-PRF, L-PRP, and natural blood clot prepared from 11 donors were cultured in vitro for 28 days and media supernatants collected after 8 hours and 1, 3, 7, 14, and 28 days. Released transforming growth factor β1 (TGF-β1), vascular endothelial growth factor (VEGF), insulin growth factor (IGF-1), platelet-derived growth factor AB (PDGF-AB), and interleukin-1β (IL-1β) were measured in the supernatants with enzyme-linked immunosorbent assay. Migration of MSC and HUVEC induced by the supernatants was evaluated in Boyden chambers. RESULTS More TGF-ß1 was released (mean ± SD in pg/mL of blood) from L-PRF (37,796 ± 5492) compared with L-PRP (23,738 ± 6848; p < 0.001) and blood clot (3739 ± 4690; p < 0.001), whereas more VEGF and IL-1ß were released from blood clot (1933 ± 704 and 2053 ± 908, respectively) compared with both L-PRP (642 ± 208; p < 0.001 and 273 ± 386; p < 0.001, respectively) and L-PRF (852 ± 376; p < 0.001 and 65 ± 56, p < 0.001, respectively). No differences were observed in IGF-1 and PDGF-AB released from any of the concentrates. TGF-β1 release peaked at Day 7 in L-PRF and at 8 hours and Day 7 in L-PRP and 8 hours and Day 14 in blood clot. In all concentrates, main release of VEGF occurred between 3 and 7 days and of IL-1β between Days 1 and 7. IGF-1 and PDGF-AB were released until Day 1 in L-PRP and blood clot, in contrast to sustained release over the first 3 days in L-PRF. The strongest migration of MSC occurred in response to L-PRF, and more HUVEC migration was seen in L-PRF and blood clot compared with L-PRP. TGF-β1 correlated with initial platelet counts in L-PRF (Pearson r = 0.66, p = 0.0273) and initial leukocyte counts in L-PRP (Pearson r = 0.83, p = 0.0016). A positive correlation of IL-1β on migration of MSC and HUVEC was revealed (Pearson r = 0.16, p = 0.0208; Pearson r = 0.31, p < 0.001). CONCLUSIONS In comparison to L-PRP, L-PRF had higher amounts of released TGF-β1, a long-term release of growth factors, and stronger induction of cell migration. Future preclinical studies should confirm these data in a defined injury model. CLINICAL RELEVANCE By characterizing the biologic properties of different platelet concentrates in vitro, we may gain a better understanding of their clinical effects and develop guidelines for specific future applications.

A novel mutation in BCS1L associated with deafness, tubulopathy, growth retardation and microcephaly

We report a novel homozygous missense mutation in the ubiquinol-cytochrome c reductase synthesis-like (BCS1L) gene in two consanguineous Turkish families associated with deafness, Fanconi syndrome (tubulopathy), microcephaly, mental and growth retardation. All three patients presented with transitory metabolic acidosis in the neonatal period and development of persistent renal de Toni-Debré-Fanconi-type tubulopathy, with subsequent rachitis, short stature, microcephaly, sensorineural hearing impairment, mild mental retardation and liver dysfunction. The novel missense mutation c.142A>G (p.M48V) in BCS1L is located at a highly conserved region associated with sorting to the mitochondria. Biochemical analysis revealed an isolated complex III deficiency in skeletal muscle not detected in fibroblasts. Native polyacrylamide gel electrophoresis (PAGE) revealed normal super complex formation, but a shift in mobility of complex III most likely caused by the absence of the BCS1L-mediated insertion of Rieske Fe/S protein into complex III. These findings expand the phenotypic spectrum of BCS1L mutations, highlight the importance of biochemical analysis of different primary affected tissue and underline that neonatal lactic acidosis with multi-organ involvement may resolve after the newborn period with a relatively spared neurological outcome and survival into adulthood. CONCLUSION Mutation screening for BCS1L should be considered in the differential diagnosis of severe (proximal) tubulopathy in the newborn period. What is Known: • Mutations in BCS1L cause mitochondrial complex III deficiencies. • Phenotypic presentations of defective BCS1L range from Bjornstad to neonatal GRACILE syndrome. What is New: • Description of a novel homozygous mutation in BCS1L with transient neonatal acidosis and persistent de Toni-Debré-Fanconi-type tubulopathy. • The long survival of patients with phenotypic presentation of severe complex III deficiency is uncommon.

Concepts of Bitemporal Database Theory and the Evolution of Web-Documents

A vast amount of temporal information is provided on the Web. Even though many facts expressed in documents are time-related, the temporal properties of Web presentations have not received much attention. In database research, temporal databases have become a mainstream topic in recent years. In Web documents, temporal data may exist as meta data in the header and as user-directed data in the body of a document. Whereas temporal data can easily be identified in the semi-structured meta data, it is more difficult to determine temporal data and its role in the body. We propose procedures for maintaining temporal integrity of Web pages and outline different approaches of applying bitemporal data concepts for Web documents. In particular, we regard desirable functionalities of Web repositories and other Web-related tools that may support the Webmasters in managing the temporal data of their Web documents. Some properties of a prototype environment are described.

Early growth characteristics and the risk of reduced lung function and asthma: A meta-analysis of 25,000 children

BACKGROUND Children born preterm or with a small size for gestational age are at increased risk for childhood asthma. OBJECTIVE We sought to assess the hypothesis that these associations are explained by reduced airway patency. METHODS We used individual participant data of 24,938 children from 24 birth cohorts to examine and meta-analyze the associations of gestational age, size for gestational age, and infant weight gain with childhood lung function and asthma (age range, 3.9-19.1 years). Second, we explored whether these lung function outcomes mediated the associations of early growth characteristics with childhood asthma. RESULTS Children born with a younger gestational age had a lower FEV1, FEV1/forced vital capacity (FVC) ratio, and forced expiratory volume after exhaling 75% of vital capacity (FEF75), whereas those born with a smaller size for gestational age at birth had a lower FEV1 but higher FEV1/FVC ratio (P < .05). Greater infant weight gain was associated with higher FEV1 but lower FEV1/FVC ratio and FEF75 in childhood (P < .05). All associations were present across the full range and independent of other early-life growth characteristics. Preterm birth, low birth weight, and greater infant weight gain were associated with an increased risk of childhood asthma (pooled odds ratio, 1.34 [95% CI, 1.15-1.57], 1.32 [95% CI, 1.07-1.62], and 1.27 [95% CI, 1.21-1.34], respectively). Mediation analyses suggested that FEV1, FEV1/FVC ratio, and FEF75 might explain 7% (95% CI, 2% to 10%) to 45% (95% CI, 15% to 81%) of the associations between early growth characteristics and asthma. CONCLUSIONS Younger gestational age, smaller size for gestational age, and greater infant weight gain were across the full ranges associated with childhood lung function. These associations explain the risk of childhood asthma to a substantial extent.