[Oral cavity as a target and a marker of environmental exposures: developmental dental defects]. / La sphère orale, cible et marqueur de l'exposition environnementale - I. Défauts du développement dentaire.

The oral cavity is one of the main route for environmental contaminations associated to many chronic diseases (cancers, fertility and behavior disorders for example) via alimentation, medications and respiration. These environmental factors including, among others, endocrine disruptors and excessive fluoride can disrupt dental development and thus generate irreversible enamel defects. These defects are then treated with materials that may release molecules capable of generating these defects, leading to a vicious circle, particularly in pregnant women and young children. The present paper aims to review the state of knowledge, questions and controversies on common environmental factors in contact with the oral cavity. It also reviews their mechanisms of action and the mediators involved in enamel pathologies associated with environmental conditions. Dental tissues can not only be targeted by environmental factors but can also serve as early and easily accessible markers of exposure to these agents. Understanding and characterizing the environmental impact in the oral cavity will help to prevent multiple diseases, oral and distant, whose link with oral homeostasis is just being explored.

TITLE: La sphère orale, cible et marqueur de l'exposition environnementale - I. Défauts du développement dentaire. ABSTRACT: La cavité buccale est l'une des voies majeures des contaminations environnementales connues pour être impliquées dans de nombreuses pathologies chroniques (cancers, troubles de la fertilité et du comportement) via l'alimentation, les médications ou même la respiration. Ces facteurs environnementaux incluant, entre autres, des perturbateurs endocriniens et le fluor en excès, peuvent perturber le développement dentaire et ainsi générer des défauts irréversibles de l'émail. Ces défauts sont alors traités avec des matériaux dont certains libèrent des molécules capables à leur tour de générer ces défauts, conduisant à un cercle vicieux, notamment chez la femme enceinte et le jeune enfant. Cette synthèse fait le point sur l'état des connaissances, les questions et controverses sur les facteurs environnementaux courants susceptibles d'entrer en contact avec la sphère orale, leurs mécanismes d'actions et les médiateurs impliqués dans les pathologies de l'émail associées aux conditions environnementales.

Subchondral bone dysplasia mediates susceptibility to osteoarthritis in female adult offspring rats induced by prenatal caffeine exposure.

Our previous studies confirmed that prenatal caffeine exposure (PCE) could induce susceptibility to osteoarthritis in adult offspring rats due to poor chondrocyte differentiation, but its mechanism remains to be further investigated. This study aimed to explore whether subchondral bone dysplasia mediates susceptibility to osteoarthritis in adult offspring rats induced by PCE. Pregnant Wistar rats were treated with caffeine (120 mg/kg.d) or saline from gestational day (GD) 9 to 20. The female offspring were euthanized to collect femurs at GD20, postnatal week (PW) 6, and PW28 (non-ovariectomy and ovariectomy groups) to detect osteoarthritis-like phenotype, subchondral bone mass, ossification center development, and other evidence. The results showed that PCE increased the Mankin score of pathological articular cartilage, but decreased articular cartilage thickness and subchondral bone mass, which were more obvious after ovariectomy. Meanwhile, the correlation analysis results demonstrated that the Mankin score of articular cartilage was significantly negatively correlated with subchondral bone mass, and the thickness of articular cartilage was significantly positively correlated with subchondral bone mass. Further, the length and area of the primary and secondary ossification centers, the number of osteoblasts, and the related genes' expression of osteogenic differentiation (e.g., Runx2, BSP, ALP, and OCN) were all significantly decreased in the PCE group before and after birth. Taken together, PCE induced susceptibility to osteoarthritis in adult female offspring, which was likely related to the subchondral bone dysplasia and reduction of subchondral bone mass production due to developmental disorder of primary and secondary ossification centers caused by osteoblast differentiation disability before and after birth.

Defining a critical period in calvarial development for Hedgehog pathway antagonist-induced frontal bone dysplasia in mice.

The Hedgehog (Hh) signalling pathway is essential for cellular proliferation and differentiation during embryonic development. Gain and loss of function of Hh signalling are known to result in an array of craniofacial malformations. To determine the critical period for Hh pathway antagonist-induced frontal bone hypoplasia, we examined patterns of dysmorphology caused by Hh signalling inhibition. Pregnant mice received a single oral administration of Hh signalling inhibitor GDC-0449 at 100 mg•kg-1 or 150 mg•kg-1 body weight at preselected time points between embryonic days (E)8.5 and 12.5. The optimal teratogenic concentration of GDC-0449 was determined to be 150 mg•kg-1. Exposure between E9.5 and E10.5 induced frontal bone dysplasia, micrognathia and limb defects, with administration at E10.5 producing the most pronounced effects. This model showed decreased ossification of the frontal bone with downregulation of Hh signalling. The osteoid thickness of the frontal bone was significantly reduced. The amount of neural crest-derived frontal bone primordium was reduced after GDC-0449 exposure owing to a decreased rate of cell proliferation and increased cell death.

[Side effects of methylphenidate in children and the young]. / Efectos secundarios del metilfenidato en poblacion infantil y juvenil.

INTRODUCTION: The use of psychostimulants has been present in common medical practice since the 20th century and has undergone an exponential growth in terms of the number of prescriptions. AIM: To review the current state of knowledge about the side effects of psychostimulants in the child and teen populations. DEVELOPMENT: A review was performed by searching in different databases and included clinical analyses, observational prospective studies and systematic reviews. A minimum increase in blood pressure and heart rate are observed, but some studies highlight an underestimation of the long-term risk. As regards appetite and growth, almost all the current literature points to a slowing of the rate of growth, which is regained on interrupting treatment. One important factor, as is the parallel evolution of bone age, has not been evaluated in most of the studies carried out to date. No significant worsening of sleep was noted in patients treated with psychostimulants with respect to those who are not being treated. With regard to the central nervous system, there does not seem to be any evidence of an increased risk of the appearance or exacerbation of tics following introduction of the treatment. Affect and emotion are areas that have been barely explored. CONCLUSIONS: It is important to have more evidence on the safety of these drugs. It is therefore essential to have access to studies that cover a period of time consistent with the duration of these treatments.

TITLE: Efectos secundarios del metilfenidato en poblacion infantil y juvenil.Introduccion. El uso de farmacos psicoestimulantes esta presente en la practica medica habitual desde principios del siglo XX y ha experimentado un incremento exponencial en cuanto a prescripciones. Objetivo. Revisar el estado de conocimiento actual sobre los efectos secundarios de los psicoestimulantes en poblacion infantil y juvenil. Desarrollo. Se realiza una revision tras consultar diferentes bases de datos, incluyendo en esta revision analisis clinicos, metaanalisis, estudios prospectivos observacionales y revisiones sistematicas. Se observa un incremento minimo en la tension arterial y la frecuencia cardiaca, pero algunos estudios recientes apuntan a una infraestimacion del riesgo a largo plazo. En lo que se refiere al apetito y el crecimiento, casi toda la bibliografia actual apunta a una ralentizacion del ritmo de crecimiento, que se recupera al interrumpir el tratamiento. Un factor importante, como es la evolucion en paralelo de la edad osea, no se ha valorado en la mayoria de los estudios realizados. En el sueño no habria empeoramiento significativo en los pacientes tratados con psicoestimulantes respecto a los no tratados. En relacion con el sistema nervioso central, no parece haber evidencia de un incremento del riesgo de aparicion o empeoramiento de tics tras introducir el tratamiento. El afecto y la emocion son areas poco exploradas. Conclusiones. Es importante tener una mayor evidencia de la seguridad de estos farmacos. Para ello es imprescindible poder disponer de estudios de una extension en el tiempo consecuente con la duracion de estos tratamientos.

Preliminary study on the biocompatibility and osteoconductive properties of a new bovine bone graft / Estudio preliminar sobre las propiedades de biocompatibilidad y osteoconductividad de un nuevo injerto de hueso bovino

To prevent post-extraction resorption and preserve the integrity of the alveolar ridges, the placement of bone grafts at the time of extraction is recommended. Bovine bone grafts are biocompatibile and osteoconductive, allowing new bone apposition by osteoprogenitor cells. Although there are trademarks recognized internationally regarding bovine bone grafts, they are expensive and even difficult to acquire. Therefore, domestic industry development of high quality biomaterials will reduce the public health high costs in the dental field. Here, we evaluated and compared the effects of an Argentinean manufactured bovine bone graft (Synergy Bone Matrix) with a bovine bone graft recognized for its osteoconductive effects (Bio-Oss), on bone healing in an experimental model in rats. We created critical sized bone defects in rat tibiae and filled them with either one of the bovine bone grafts or control. Clinical responses, X-ray findings, bone mineral density, and histological parameters were evaluated. No abscess, encapsulation, suppuration or inflammation of lymphatic nodes were observed. Radiographically, all implants were amalgamated to the surrounding bony margins, suggesting proper healing. On the other hand, control tibiae exhibited no signs of recovery and remained either unfilled or showed fibrous tissue formation. No statistical differences were observed in BMC and BMD between tibiae filled with Synergy Bone Matrix or Bio-Oss. Histological analysis revealed particles of both bone grafts surrounded by laminar bone tissue indicating osteoconductivity, without any inflammatory sign. This preliminary study suggests that Synergy Bone Matrix, as well as Bio-Oss, present similar properties of biocompatibility and osteoconductivity. (AU)

Para prevenir la resorción post-exodoncia y preservar la integridad de los rebordes alveolares, se recomienda la colocación de injertos óseos en el momento de la extracción. Los injertos de hueso bovino son biocompatibles y osteoconductivos, permitiendo nueva aposición ósea por células osteoprogenitoras. Existen marcas internacionales de injertos de hueso bovino, pero resultan caros e incluso difíciles de adquirir. Por ello, la elaboración de biomateriales de alta calidad, nacionales, reduciría los altos costos de salud pública en odontología. En este estudio, se evaluaron y compararon los efectos de un injerto de hueso bovino fabricado en Argentina (Synergy Bone Matrix) versus un injerto de hueso bovino reconocido por sus efectos osteoconductivos (Bio-Oss), en el proceso de cicatrización ósea en un modelo experimental en ratas. Para ello, creamos un defecto óseo crítico en tibia de rata el cual se rellenó con uno de los injertos de hueso bovino o control. Se evaluó: respuesta clínica y radiográfica, densidad mineral ósea e histología. No se observaron abscesos, encapsulación, supuración o inflamación de los ganglios linfáticos. Radiográficamente, todos los implantes se integraron a los márgenes óseos circundantes, sugiriendo una cicatrización adecuada. Por el contrario, las tibias control no mostraron signos de recuperación con formación de tejido fibroso. No se observaron diferencias estadísticas en las BMC y BMD entre las tibias Synergy Bone Matrix o Bio-Oss. La histología reveló partículas de ambos injertos óseos rodeadas por tejido óseo laminar indicando osteoconductividad sin signos inflamatorios. Este estudio preliminar sugiere que Synergy Bone Matrix presenta propiedades similares de biocompatibilidad y osteoconductividad que Bio-Oss. (AU)

Embryotoxicity Caused by DON-Induced Oxidative Stress Mediated by Nrf2/HO-1 Pathway.

Deoxynivalenol (DON) belongs to the type B group of trichothecenes family, which is composed of sesquiterpenoid metabolites produced by Fusarium and other fungi in grain. DON may cause various toxicities, such as cytotoxicity, immunotoxicity, genotoxicity as well as teratogenicity and carcinogenicity. In the present study, we focus on a hypothesis that DON alters the expressions of Nrf2/HO-1 pathway by inducing embryotoxicity in C57BL/6 mouse (5.0, 2.5, 1.0, and 0 mg/kg/day) and BeWo cell lines (0 and 50 nM; 3 h, 12 h and 24 h). Our results indicate that DON treatment in mice during pregnancy leads to ROS accumulation in the placenta, which results in embryotoxicity. At the same time Nrf2/HO-1 pathway is up-regulated by ROS to protect placenta cells from oxidative damage. In DON-treated BeWo cells, the level of ROS has time-effect and dose-effect relationships with HO-1 expression. Moderate increase in HO-1 protects the cell from oxidative damage, while excessive increase in HO-1 aggravates the oxidative damage, which is called in some studies the "threshold effect". Therefore, oxidative stress may be the critical molecular mechanism for DON-induced embryotoxicity. Besides, Nrf2/HO-1 pathway accompanied by the "threshold effect" also plays an important role against DON-induced oxidative damage in this process.

miR-21 is involved in skeletal deficiencies of zebrafish embryos exposed to polychlorinated biphenyls.

Polychlorinated biphenyl (PCB) exposure increases the incidence and severity of skeletal diseases, but little is known about the mechanisms that mediate this relationship. We exposed zebrafish embryos to PCB1254 and assessed the changes in bone morphology protein receptor II (BMPRII), which is involved in bone formation and embryonic development, miRNA-21, for which BMPRII is a known target, and calcium metabolism. PCB1254 upregulated the expression of miR-21 and suppressed BMPRII expression. The inhibition of miR-21 reversed the downregulation of BMPRII and alleviated the PCB1254-induced loss of calcium. These findings suggest new biomarkers of developmental defects of the skeleton caused by PCBs.

Genetic risk factors for decreased bone mineral accretion in children with asthma receiving multiple oral corticosteroid bursts.

BACKGROUND: Long-term intermittent oral corticosteroid (OCS) use in children with asthma leads to significant decreases in bone mineral accretion (BMA). OBJECTIVE: We aimed to identify genetic factors influencing OCS dose effects on BMA in children with asthma. METHODS: We first performed a gene-by-OCS interaction genome-wide association study (GWAS) of BMA in 489 white participants in the Childhood Asthma Management Program trial who took short-term oral prednisone bursts when they experienced acute asthma exacerbations. We selected the top-ranked 2000 single nucleotide polymorphisms (SNPs) in the GWAS and determined whether these SNPs also had cis-regulatory effects on dexamethasone-induced gene expression in osteoblasts. RESULTS: We identified 2 SNPs (rs9896933 and rs2074439) associated with decreased BMA and related to the tubulin γ pathway. The rs9896933 variant met the criteria for genome-wide significance (P = 3.15 × 10(-8) in the GWAS) and is located on the intron of tubulin folding cofactor D (TBCD) gene. The rs2074439 variant (P = 2.74 × 10(-4) in the GWAS) showed strong cis-regulatory effects on dexamethasone-induced tubulin γ gene expression in osteoblasts (P = 8.64 × 10(-4)). Interestingly, we found that BMA worsened with increasing prednisone dose as the number of mutant alleles of the 2 SNPs increased. CONCLUSIONS: We have identified 2 novel tubulin γ pathway SNPs, rs9896933 and rs2074439, showing independent interactive effects with cumulative corticosteroid dose on BMA in children with asthma receiving multiple OCS bursts.

Sub-NOAEL amounts of vinclozolin and xenoestrogens target rat chondrogenesis in vivo.

Several endocrine disrupting compounds (EDC) elicit skeletal dysgenesis at pharmacological doses. We have investigated the impact of doses below the "No Observed Adverse Effect" (NOAEL) for vinclozolin (V), an anti-androgenic fungicide, alone or associated with xenoestrogens (Genistein, G and bisphenol-A, BPA). V, G, BPA and their combinations were administered orally to female Wistar rats during gestation and lactation. F1 and F2 offspring were investigated for skeletal anomalies at post-natal days 30, 110 (d30, d110). Skeletal development was monitored by measuring caudal vertebrae and long bones dimensions by X-ray micro-CT-scan. A significant increase in Inter Transverse Apophysis (ITA) distance at the upper head of caudal vertebrae, associated with a reduction in vertebral body height was observed in treated F1 females, but not males. Histometrical analysis of vertebral body growth plate cartilage was performed on serial sections of caudal vertebrae. F1 females but not males showed a diminution in growth plate thickness, with greater impact on the hypertrophic zone. All effects were maximal at d30. Effects on ITA width persisted until d110 while effects on growth plate disappeared. These effects were essentially vinclozolin or BPA-dependent. F2 animals were not affected. Our data suggest that vinclozolin and xenoestrogens act as cartilage developmental disruptors. We suggest that present NOAEL values for these compounds, and EDC at large, might be reconsidered using gestational exposure models. Finally, micro CT-scan appears a valuable non-invasive technique to detect EDC effects on live fauna.

The impact of the use of antiepileptic drugs on the growth of children.

BACKGROUND: This study investigated whether long-term treatment with antiepileptic drugs (AEDs) had negative effects on statural growth and serum calcium levels in children with epilepsy in Taiwan. METHODS: Children with epilepsy treated with one prescription of AEDs (monotherapy) for at least 1 year were selected. The AEDs included valproic acid (VPA; Deparkin) in 27 children (11 boys and 16 girls) aged 4-18 years, oxcarbazepine (Trileptal) in 30 children (15 boys and 15 girls) aged 5-18 years, topiramate (Topamax) in 19 children (10 boys and 9 girls) aged 6-18 years, and lamotrigine (Lamicta) in eight children (5 boys and 3 girls) aged 5-13 years. Patients with a history of febrile convulsions were selected as the controls. RESULTS: One year of VPA treatment significantly impaired the statural growth of pediatric patients with epilepsy (p < 0.005) compared with the control group. The underlying mechanism may have been due to the direct effect of VPA on the proliferation of growth plate chondrocytes rather than alterations of serum calcium. CONCLUSIONS: These results raise serious concerns about the growth of pediatric epilepsy patients who use AEDs, and potentially the need to closely monitor growth in children with epilepsy and adolescents under AED treatment, especially VPA.

Deferoxamine-induced dysplasia-like skeletal abnormalities at radiography and MRI.

BACKGROUND: Current thalassemia major treatment includes blood transfusion and iron chelation, which is associated with growth disturbances and radiographic changes in the long bone metaphyses. OBJECTIVE: To explore and discuss the spectrum of deferoxamine-induced bone-dysplasia-like changes in children with thalassemia major in Egypt. MATERIALS AND METHODS: We studied 59 Egyptian children with thalassemia major and generalized arthralgia. All started deferoxamine treatment at 3 years of age. We conducted skeletal survey and MRI of both knees in radiographically positive children. Each child's age, serum ferritin, age of onset and duration of therapy were compared with the radiologic findings. RESULTS: Twenty-two (37.3%) children had variable degrees of skeletal dysplasia-like changes similar to those described with deferoxamine intake, mostly around the knees. Mild dysplasia-like changes were seen in 4 (18%) children; moderate changes were seen in 11 (50%) children and severe changes were seen in 7 (31.8%) children. No statistically significant relationships were detected between bone changes and the children's age, age of starting deferoxamine, duration of therapy, or serum ferritin level. CONCLUSION: A wider spectrum of deferoxamine-induced bone-dysplasia-like changes was recognized despite delayed onset and small doses of therapy. These changes should be considered as a possible cause of arthropathy in children with thalassemia major, especially symptomatic children.

Perinatal exposure to environmental contaminants detected in Canadian Arctic human populations changes bone geometry and biomechanical properties in rat offspring.

Arctic inhabitants consume large proportions of fish and marine mammals, and are therefore continuously exposed to levels of environmental toxicants, which may produce adverse health effects. Fetuses and newborns are the most vulnerable groups. The aim of this study was to evaluate changes in bone geometry, mineral density, and biomechanical properties during development following perinatal exposure to a mixture of environmental contaminants corresponding to maternal blood levels in Canadian Arctic human populations. Sprague-Dawley rat dams were dosed with a Northern Contaminant Mixture (NCM) from gestational day 1 to postnatal day (PND) 23. NCM contains 27 contaminants comprising polychlorinated biphenyls, organochlorine pesticides, and methylmercury. Femurs were collected on PND 35, 77 and 350, and diaphysis was analyzed by peripheral quantitative computed tomography and three-point bending test, while femoral neck was assessed in an axial loading experiment. Dose-response modeling was performed to establish the benchmark dose (BMD) for the analyzed bone parameters. Exposure to the high dose of NMC resulted in short and thin femur with reduced mechanical strength in offspring at PND35. BMD of femur length, cortical area, and stiffness were 3.2, 1.6, and 0.8 mg/kg bw/d, respectively. At PND77 femur was still thin, but at PND350 no treatment-related bone differences were detected. This study provides new insights on environmental contaminants present in the maternal blood of Canadian Arctic populations, showing that perinatal exposure induces bone alterations in the young offspring. These findings could be significant from a health risk assessment point of view.

Thrombophilic-type placental pathologies and skeletal growth delay following maternal administration of angiostatin4.5 in mice.

During placentation, the concentration of fibrinous deposits on the surfaces of maternal vasculature plays a role in villous development and has been strongly implicated in the pathophysiology of human fetal growth restriction (FGR). Fibrinous deposits are conspicuous sites of platelet aggregation where there is local activation of the hemostatic cascade. During activation of the hemostatic cascade, a number of pro- and antiangiogenic agents may be generated at the cell surface, and an imbalance in these factors may contribute to the placental pathology characteristic of FGR. We tested the hypothesis that angiostatin(4.5) (AS(4.5)), a cleavage fragment of plasminogen liberated at the cell surface, is capable of causing FGR in mice. Increased maternal levels of AS(4.5) in vivo result in reproducible placental pathology, including an altered vascular compartment (both in decidual and labyrinthine layers) and increased apoptosis throughout the placenta. In addition, there is significant skeletal growth delay and conspicuous edema in fetuses from mothers that received AS(4.5). Maternally generated AS(4.5), therefore, can access maternal placental vasculature and have a severe effect on placental architecture and inhibit fetal development in vivo. These findings strongly support the hypothesis that maternal AS(4.5) levels can influence placental development, possibly by directly influencing trophoblast turnover in the placenta, and contribute to fetal growth delay in mice.

Micro-computed tomography and alizarin red evaluations of boric acid-induced fetal skeletal changes in Sprague-Dawley rats.

BACKGROUND: Assessment of developmental toxicity has historically included assessment of fetal skeletal morphology after alizarin red staining. X-ray micro-computed tomography (micro-CT) produces high-resolution images of skeletal structures and was investigated as an alternative method. METHODS: Groups of 5 mated Crl:CD (SD) female rats each were administered vehicle or boric acid (40 to 500 mg/kg/day) from GD 6 through 11. On GD 21, all live fetuses were weighed, euthanized, and viscera removed. Each litter was placed into a custom-made polystyrene holder and scanned in the micro-CT imaging system. Raw projection data were acquired in approximately 15 sec ( approximately 20 litters per hour) and reconstructed images at 100-micron cubic voxel dimension could be viewed as early as 20 min later. Fetuses were subsequently stained with alizarin red, and findings recorded separately for each method without knowledge of treatment group. RESULTS: Micro-CT evaluation of fetal rat skeletons detected essentially the same skeletal malformations, variations, and incomplete ossifications as seen by the staining method. The specific skeletal abnormalities that did not match exactly involved the smallest skeletal elements with minimal degrees of ossification (i.e., cervical ribs, hypoplastic 13(th) ribs, supernumerary ribs, the 5(th) sternebra, and numbers of caudal vertebrae), but the differences did not impact the overall conclusions. Additional measures such as femur length were easily measured by micro-CT. CONCLUSIONS: These results indicate that micro-CT imaging can effectively assess rat fetal skeletal structures, and for those laboratories with this resource, it may be used to significantly reduce time prior to skeletal evaluation and hazardous wastes associated with staining.

Evaluation of hydroxyurea-induced fetal skeletal changes in Dutch belted rabbits by micro-computed tomography and alizarin red staining.

BACKGROUND: This laboratory has been investigating the utility of X-ray micro-computed tomography (micro-CT) to produce high-resolution, 3D images of skeletal structures in common laboratory species. The present investigation uses micro-CT evaluation of skeletons from rabbit fetuses exposed to the known teratogen, hydroxyurea. METHODS: Groups of 4-6 mated Dutch Belted female rabbits each were administered vehicle or hydroxyurea (62.5 to 500 mg/kg) once on GD 12. On GD 28, all live fetuses were weighed, euthanized, and viscera removed. Up to 7 fetuses per litter were placed into a custom-made polystyrene holder and scanned in the micro-CT imaging system. Raw projection data were acquired in approximately 15 seconds, and reconstructed images at 100-micron cubic voxel dimension could be viewed as early as 20 minutes later. Fetuses were subsequently stained with alizarin red, and findings recorded separately for each method without knowledge of treatment group. RESULTS: Except for a few isolated cases, micro-CT evaluation detected the same skeletal malformations, variations, and incomplete ossifications as seen by the staining method. Skeletal elements that are very small (e.g., caudal-most vertebrae, metacarpal no. 1) or those with a minimal degree of ossification were occasionally not observed with micro-CT. However, this difference did not impact the overall study conclusions. Femur length was easily measured by micro-CT. CONCLUSIONS: These results indicate that micro-CT imaging can effectively assess rabbit fetal skeletal structures, and for those laboratories with this resource, may be used to significantly reduce time prior to skeletal evaluation and hazardous wastes associated with staining.

Association of Harris lines and shorter stature with ethanol consumption during growth.

Ethanol consumption may impair bone growth. Transverse radiopaque lines (Harris lines) have been interpreted as manifestations of bone growth arrest due to nutritional stress. It is possible that ethanol consumption during growth leads to Harris lines formation and to a shorter stature. Plain X-ray film of the right tibia was performed to 175 individuals, who were inquired about ethanol consumption, periods of perceived hunger, and protracted illness during growth period (from birth to 18 years of age). Stature was also recorded. Men who drank during growth showed a shorter stature than those who did not (t=3.65, P<.001). Differences were not statistically significant among women (t=0.95). Neither periods of perceived hunger nor illness were associated to differences in stature. Ethanol consumption during growth showed a significant association with the presence of Harris lines (chi(2)=15, P<.001, Odds Ratio [OR]=3.39, confidence interval [CI]=1.81-6.33), an association which was more marked between having two or more Harris lines and drinking during growth (chi(2)=23.19, P<.001, OR=6.04, CI=2.79-13.11) or having three or more lines and drinking during growth (chi(2)=15.93, P<.001, OR=7.41, CI=2.47-22.21). Periods of perceived hunger during growth were also related to the presence of two or more Harris lines (chi(2)=4.66, P=.031, OR=2.055, CI=1.065-3.965), but no association was observed between illness and Harris lines, two or more Harris lines, and three or more Harris lines. Multivariate analysis showed that only ethanol consumption during growth period was associated with Harris lines.

Inhibition of ALK5 signaling induces physeal dysplasia in rats.

TGF-beta, and its type 1 (ALK5) receptor, are critical to the pathogenesis of fibrosis. In toxicologic studies of 4 or more days in 10-week-old Sprague-Dawley rats, using an ALK5 inhibitor (GW788388), expansion of hypertrophic and proliferation zones of femoral physes were noted. Subphyseal hyperostosis, chondrocyte hypertrophy/hyperplasia, and increased matrix were present. Physeal zones were laser microdissected from ALK5 inhibitor-treated and control rats sacrificed after 3 days of treatment. Transcripts for TGF-beta1, TGF-beta2, ALK5, IHH, VEGF, BMP-7, IGF-1, bFGF, and PTHrP were amplified by real-time PCR. IGF and IHH increased in all physis zones with treatment, but were most prominent in prehypertrophic zones. TGF-beta2, bFGF and BMP7 expression increased in proliferative, pre-and hypertrophic zones. PTHrP expression was elevated in proliferative zones but decreased in hypertrophic zones. VEGF expression was increased after treatment in pre- and hypertrophic zones. ALK5 expression was elevated in prehypertrophic zones. Zymography demonstrated gelatinolytic activity was reduced after treatment. Apoptotic markers (TUNEL and caspase-3) were decreased in hypertrophic zones. Proliferation assessed by Topoisomerase II and Ki67 was increased in multiple zones. Movat stains demonstrated that proteoglycan deposition was altered. Physeal changes occurred at doses well above those resulting in fibrosis. Interactions of factors is important in producing the physeal dysplasia phenotype.

Disseminated thrombosis-induced growth plate necrosis in rat: a unique model for growth plate arrest.

Exposure of rats to 2-butoxyethanol (BE) produces early hemolytic anemia and disseminated thrombosis. This leads to infarctions in multiple organs, including bones and cartilage. BE, administered for different durations of exposure in two separate experiments, produced metaphyseal vascular thrombosis, growth plate infarction, and partial or complete physeal growth arrest. This reproducible model may serve as a useful tool in the study of some conditions that manifest growth plate damage. The suitability of this model for investigating the pathogenesis of growth plate necrosis and as a model for potential therapy for various human growth plate disorders are discussed.

Patterns of bone diseases in transfusion-dependent homozygous thalassaemia major: predominance of osteoporosis and desferrioxamine-induced bone dysplasia.

OBJECTIVE: To study the radiographic skeletal changes in transfusion-dependent homozygous beta-thalassaemia. MATERIALS AND METHODS: This was a retrospective review of radiographs of 41 homozygous beta-thalassaemic patients over 3 years. These included 55 left hand radiographs for bone age, 37 chest radiographs, 7 scanograms of lower limbs, 8 knee radiographs and 3 skull radiographs. The radiographs were evaluated for the skeletal changes owing to medullary expansion, as well as for the skeletal dysplasia related to desferrioxamine therapy. The combined cortical width of the mid shaft of the second metacarpal was measured on left hand radiographs to assess osteoporosis. RESULTS: Sixteen patients had radiographic evidence of desferrioxamine-induced bone dysplasia. These included metaphyseal sclerosis in long bone ( n=16), irregular sclerosis at the costochondral junction ( n=3) and platyspondyly ( n= 1). Two patients had radiographic evidence of medullary expansion with widening of medulla and marked thinning of cortex in the tubular bones. Osteoporosis, as indicated by thinning of metacarpal cortex, was noted in 17 patients (8 with and 9 without desferrioxamine-induced bone dysplasia). CONCLUSIONS: With provision of the modern regime of regular transfusion and desferrioxamine chelation, desferrioxamine-induced bone dysplasia was a much more frequently detected radiographic abnormality in beta-thalassaemia major than radiographic features owing to medullary expansion. Osteoporosis, as indicated by thinned metacarpal cortices, remained a frequent feature irrespective of the status of the skeletal dysplasia.