An Ovariectomy-Induced Rabbit Osteoporotic Model: A New Perspective

Study DesignExperimental Animal Model.PurposeThe aim of our study was to validate a pure bilateral ovariectomy (OVX) female New Zealand white rabbit model of postmenopausal osteoporosis utilizing animal-sparing in vivo techniques for evaluating bone mineral density (BMD). We also sought to demonstrate that bilateral OVX in female New Zealand white rabbits can produce diminished BMD in the spinal column and simulate osteoporosis, without the need for adjuvant chemotherapeutic agents (i.e., no additional glucocorticosteroids or other drugs were used for stimulating accelerated BMD loss), which can be assessed by in vivo BMD testing.Overview of LiteratureMultiple animal models of postmenopausal osteoporosis have been described. Rat ovariectomy models have been successful, but are limited by rats' inability to achieve true skeletal maturity and a slight morphology that limits surgical instrumentation. Rabbit models have been described which do not have these limitations, but previous models have relied on adjunctive steroid therapy to achieve osteoporosis and have required animal sacrifice for bone mineral density assessment.MethodsThirty-six skeletally mature female rabbits underwent bilateral OVX. BMD was measured using dual-energy X-ray absorptiometry on the metaphysis of the proximal tibia and distal femur, at baseline and 17 weeks postoperatively.ResultsMean BMD values were significantly reduced by 21.9% (p<0.05) in the proximal tibia and 11.9% (p<0.001) in the distal femur at 17 weeks.ConclusionsThis study is the first to demonstrate a significant bone loss within four months of pure OVX in rabbits using animal-sparing validation techniques. We believe that this OVX model is safe, reproducible, and can be employed to longitudinally evaluate the effect of anti-osteoporosis therapeutics and surgical interventions

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe

Hypercholestérolémie (alternatives phytothérapeutiques et conseil officinal)

Le cholestérol, bien qu indispensable à l organisme peut entraîner de graves conséquences lorsqu il est présent en excès. L hypercholestérolémie est en effet un des facteurs de risques majeur des maladies cardiovasculaires, première cause de mortalité mondiale selon l Organisation Mondiale de la Santé. La prise en charge médicamenteuse, essentiellement par statines, est souvent mal tolérée par les patients ou bien délaissée au profit de méthodes plus naturelles pour se soigner. En effet, de nombreuses alternatives naturelles revendiquent un effet bénéfique sur la lipémie. Cette thèse se consacre à l étude de ces alternatives et de leur efficacité. De plus, que ce soit seul, en complément d un traitement médicamenteux ou de plantes, le suivi de conseils hygiéno-diététiques adaptés est primordial pour lutter contre cet excès et limiter le risque de maladies cardiovasculaires. Le pharmacien se doit de connaitre et dispenser ces conseils aux patients afin de les aider au mieux dans la prise en charge d une pathologie dont ils ne ressentent pas les symptômes. Ce manuscrit présente dans une première partie un bref rappel sur le métabolisme du cholestérol et sa régulation. La seconde partie est consacrée à un exposé des différentes alternatives naturelles disponibles et à une étude de leur efficacité. Enfin la dernière partie s intéresse au rôle du conseil pharmaceutique pour la prise en charge des patients atteints d hypercholestérolémie.TOURS-BU Sciences Pharmacie (372612104) / SudocSudocFranceF

Etude comparative de deux techniques de lambeaux pour reconstruction commissurale dans la libération de syndactylies congénitales (à propos de 59 cas)

De nombreuses techniques de reconstruction commissurale pour libération de syndactylies ont été décrites. Notre étude est la première à comparer les résultats à long terme de deux types de lambeaux. Il s agit d une série rétrospective de 39 patients, soit 59 commissures opérées entre 1991 et 2008 (36 lambeaux en T et 23 en Oméga). Une greffe de peau totale a toujours été réalisée. Les principaux facteurs évalués à long terme sont la survenue de rétraction commissurale et de déformations digitales en flessum et clinodactylie. Les patients ont été revus avec un recul moyen de 5 ans et 8 mois (de 3 à 180 mois). Les syndactylies complexes sont plus fréquemment responsables de déformation et raideur digitales, et entraînent 96 % des clinodactylies. Il n existe pas de différence entre les deux types de lambeaux sur la survenue de déformations à long terme. Cependant 17 % des lambeaux en T ont présenté une rétraction commissurale contre 5 % des lambeaux en Oméga. La technique de séparation des syndactylies utilisant le lambeau en T ou en Oméga est fiable et permet la reconstruction d une commissure de forme naturelle. Le type de lambeau n influence pas directement les résultats à long terme en matière de mobilité ou désaxation. Néanmoins, la technique du lambeau Oméga, prenant en compte la réalisation de deux lambeaux palmaires latéro-digitaux, évite les greffes sur les faces latérales de la commissure et limite la survenue de rétraction. Le principal facteur pronostique est le type de syndactylie avec des résultats aléatoires et un taux plus important de complications pour les syndactylies complexes compliquées.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Unusually severe cases of Kingella kingae osteoarticular infections in children

With the development of molecular biology and specific polymerase chain reaction, Kingella kingae has become the primary diagnosis of osteoarticular infections in young children. Clinical features of these osteoarticular infections are typically mild, and outcome is almost always favorable. We report a series of unusually severe cases of K. kingae osteoarticular infections

Acute monoarthritis in young children: comparing the characteristics of patients with juvenile idiopathic arthritis versus septic and undifferentiated arthritis

International audienceAcute arthritis is a common cause of consultation in pediatric emergency wards. Arthritis can be caused by juvenile idiopathic arthritis (JIA), septic (SA) or remain undetermined (UA). In young children, SA is mainly caused by Kingella kingae (KK), a hard to grow bacteria leading generally to a mild clinical and biological form of SA. An early accurate diagnosis between KK-SA and early-onset JIA is essential to provide appropriate treatment and follow-up. The aim of this work was to compare clinical and biological characteristics, length of hospital stays, duration of intravenous (IV) antibiotics exposure and use of invasive surgical management of patients under 6 years of age hospitalized for acute monoarthritis with a final diagnosis of JIA, SA or UA. We retrospectively analyzed data from < 6-year-old children, hospitalized at a French tertiary center for acute mono-arthritis, who underwent a joint aspiration. Non-parametric tests were performed to compare children with JIA, SA or UA. Bonferroni correction for multiple comparisons was applied with threshold for significance at 0.025. Among the 196 included patients, 110 (56.1%) had SA, 20 (10.2%) had JIA and 66 (33.7%) had UA. Patients with JIA were older when compared to SA (2.7 years [1.8-3.6] versus 1.4 [1.1-2.1], p < 0.001). Presence of fever was not different between JIA and SA or UA. White blood cells in serum were lower in JIA (11.2 × 109/L [10-13.6]) when compared to SA (13.2 × 109/L [11-16.6]), p = 0.01. In synovial fluid leucocytes were higher in SA 105.5 × 103 cells/mm3 [46-211] compared to JIA and UA (42 × 103 cells/mm3 [6.4-59.2] and 7.29 × 103 cells/mm3 [2.1-72] respectively), p < 0.001. Intravenous antibiotics were administered to 95% of children with JIA, 100% of patients with SA, and 95.4% of UA. Arthrotomy-lavage was performed in 66.7% of patients with JIA, 79.6% of patients with SA, and 71.1% of patients with UA. In children less than 6 years of age with acute mono-arthritis, the clinical and biological parameters currently used do not reliably differentiate between JIA, AS and UA. JIA subgroups that present a diagnostic problem at the onset of monoarthritis before the age of 6 years, are oligoarticular JIA and systemic JIA with hip arthritis. The development of new biomarkers will be required to distinguish JIA and AS caused by Kingella kingae in these patients

Iron Metabolism Disturbance in a French Cohort of ALS Patients

Objective. The aim of this study was to assess iron status in a cohort of amyotrophic lateral sclerosis (ALS) patients compared to controls in order to evaluate these parameters as a risk factor or a modifying factor of ALS. Methods. We collected serum iron, ferritin, transferrin, total iron-binding capacity, and transferrin saturation coefficient (TSC) from 104 ALS patients at the time of diagnosis and from 145 controls. We reported phenotypic characteristics and evolution parameters such as ALSFRS-R and forced vital capacity at diagnosis and after one year of follow-up. In a first step we compared iron status between ALS patients and controls, and then we evaluated the relation between iron status and disease evolution of ALS patients using univariate and multivariate analysis. Results. We observed increased concentrations of serum iron (P=0.002) and ferritin (P<0.0001) and increased TSC (P=0.017) in ALS patients. We also showed an association between markers of iron status and high body weight loss in ALS patients. The multivariate analysis of survival highlighted a significant relation between ferritin level and disease duration (P=0.038). Conclusion. This is the first study showing a higher concentration of serum iron in ALS patients, strengthening the involvement of a deregulation of iron metabolism in ALS

Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model

Achondroplasia (ACH) is the most frequent form of dwarfism and is caused by gain-of-function mutations in the fibroblast growth factor receptor 3-encoding (FGFR3-encoding) gene. Although potential therapeutic strategies for ACH, which aim to reduce excessive FGFR3 activation, have emerged over many years, the use of tyrosine kinase inhibitor (TKI) to counteract FGFR3 hyperactivity has yet to be evaluated. Here, we have reported that the pan-FGFR TKI, NVP-BGJ398, reduces FGFR3 phosphorylation and corrects the abnormal femoral growth plate and calvaria in organ cultures from embryos of the Fgfr3Y367C/+ mouse model of ACH. Moreover, we demonstrated that a low dose of NVP-BGJ398, injected subcutaneously, was able to penetrate into the growth plate of Fgfr3Y367C/+ mice and modify its organization. Improvements to the axial and appendicular skeletons were noticeable after 10 days of treatment and were more extensive after 15 days of treatment that started from postnatal day 1. Low-dose NVP-BGJ398 treatment reduced intervertebral disc defects of lumbar vertebrae, loss of synchondroses, and foramen-magnum shape anomalies. NVP-BGJ398 inhibited FGFR3 downstream signaling pathways, including MAPK, SOX9, STAT1, and PLCγ, in the growth plates of Fgfr3Y367C/+ mice and in cultured chondrocyte models of ACH. Together, our data demonstrate that NVP-BGJ398 corrects pathological hallmarks of ACH and support TKIs as a potential therapeutic approach for ACH

Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model

Achondroplasia (ACH) is the most frequent form of dwarfism and is caused by gain-of-function mutations in the fibroblast growth factor receptor 3–encoding (FGFR3-encoding) gene. Although potential therapeutic strategies for ACH, which aim to reduce excessive FGFR3 activation, have emerged over many years, the use of tyrosine kinase inhibitor (TKI) to counteract FGFR3 hyperactivity has yet to be evaluated. Here, we have reported that the pan-FGFR TKI, NVP-BGJ398, reduces FGFR3 phosphorylation and corrects the abnormal femoral growth plate and calvaria in organ cultures from embryos of the Fgfr3(Y367C/+) mouse model of ACH. Moreover, we demonstrated that a low dose of NVP-BGJ398, injected subcutaneously, was able to penetrate into the growth plate of Fgfr3(Y367C/+) mice and modify its organization. Improvements to the axial and appendicular skeletons were noticeable after 10 days of treatment and were more extensive after 15 days of treatment that started from postnatal day 1. Low-dose NVP-BGJ398 treatment reduced intervertebral disc defects of lumbar vertebrae, loss of synchondroses, and foramen-magnum shape anomalies. NVP-BGJ398 inhibited FGFR3 downstream signaling pathways, including MAPK, SOX9, STAT1, and PLCγ, in the growth plates of Fgfr3(Y367C/+) mice and in cultured chondrocyte models of ACH. Together, our data demonstrate that NVP-BGJ398 corrects pathological hallmarks of ACH and support TKIs as a potential therapeutic approach for ACH