Effect of GH/IGF-1 on Bone Metabolism and Osteoporsosis

Background. Growth hormone (GH) and insulin-like growth factor (IGF-1) are fundamental in skeletal growth during puberty and bone health throughout life. GH increases tissue formation by acting directly and indirectly on target cells; IGF-1 is a critical mediator of bone growth. Clinical studies reporting the use of GH and IGF-1 in osteoporosis and fracture healing are outlined. Methods. A Pubmed search revealed 39 clinical studies reporting the effects of GH and IGF-1 administration on bone metabolism in osteopenic and osteoporotic human subjects and on bone healing in operated patients with normal GH secretion. Eighteen clinical studies considered the effect with GH treatment, fourteen studies reported the clinical effects with IGF-1 administration, and seven related to the GH/IGF-1 effect on bone healing. Results. Both GH and IGF-1 administration significantly increased bone resorption and bone formation in the most studies. GH/IGF-1 administration in patients with hip or tibial fractures resulted in increased bone healing, rapid clinical improvements. Some conflicting results were evidenced. Conclusions. GH and IGF-1 therapy has a significant anabolic effect. GH administration for the treatment of osteoporosis and bone fractures may greatly improve clinical outcome. GH interacts with sex steroids in the anabolic process. GH resistance process is considered

Optical filter based on two coupled PhC GaAs-membranes.

We demonstrate an ultracompact optical filter based on two coupled high-index contrast GaAs photonic crystal (PhC) membranes. The PhC membranes consist of a square lattice of air holes and behave as a Fabry-Perot cavity whose reflectivity and transmissivity depend on the air gap between the two membranes. The normal-incidence reflectance measurements and the numerical simulation of reflection spectra show a high sensitivity to the geometrical parameters, such as the distance between the slabs, whose control would make the device suitable for a new class of tunable optical filters

Optical filter based on a coupled bilayer photonic crystal

We report on the fabrication of an ultra-compact optical filter based on photonic crystal free-standing membranes in bi-layer configuration. The basic heterostructure consists of two 376nm-thick GaAs-membranes sandwiched between air on a GaAs substrate. The air gap between the two membranes is 520nm thick. The normal-incidence reflectance measurements and the numerical simulation of reflection spectra show a high sensitivity to the holes diameter

STIM Proteins and Orai Ca2+ Channels Are Involved in the Intracellular Pathways Activated by TLQP-21 in RAW264.7 Macrophages

TLQP-21 is a neuropeptide which has been implicated in regulation of nociception and other relevant physiologic functions. Although recent studies identified C3a and gC1q receptors as targets for TLQP-21, its intracellular molecular mechanisms of action remain largely unidentified. Our aim was (i) to explore the intracellular signaling pathway(s) activated by JMV5656, a novel derivative of TLQP-21, in RAW264.7 macrophages, and (ii) to assess linkages of these pathways with its purported receptors. JMV5656 stimulated, in a dose-dependent fashion, a rapid and transient increase in intracellular Ca2+ concentrations in RAW264.7 cells; repeated exposure to the peptide resulted in a lower response, suggesting a possible desensitization mechanism of the receptor. In particular, JMV5656 increased cytoplasmic Ca2+ levels by a PLC-dependent release of Ca2+ from the endoplasmic reticulum. STIM proteins and Orai Ca2+ channels were activated and played a crucial role. In fact, treatment of the cells with U73122 and thapsigargin modulated the increase of intracellular Ca2+ levels stimulated by JMV5656. Moreover, in RAW264.7 cells intracellular Ca2+ increases did not occur through the binding of JMV5656 to the C3a receptor, since the increase of intracellular Ca2+ levels induced by JMV5656 was not affected by specific siRNA against C3aR. In summary, our study provides new indications for the downstream effects of JMV5656 in macrophages, suggesting that it could activate receptors different from the C3aR

Congenital amegakaryocytic thrombocytopenia: clinical and biological consequences of five novel mutations

BACKGROUND AND OBJECTIVES: Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, autosomal recessive disorder induced by mutations of the gene coding for thrombopoietin (TPO) receptor (c-MPL). Patients initially present with isolated thrombocytopenia that subsequently progresses into pancytopenia. Although the mechanisms leading to aplasia are unknown, the age of onset has been reported to depend on the severity of the c-MPL functional defect. To improve our knowledge in this field, we studied clinical and biological features of five new patients. DESIGN AND METHODS: We diagnosed five CAMT patients, identified c-MPL mutations, including five novel alterations and investigated relationships between mutations and their clinical-biological consequences. RESULTS: In all cases, platelet c-MPL and bone marrow colonies were reduced, while serum TPO levels were elevated. We also documented that the percentage of bone marrow cells expressing tumor necrosis factor-a and interferon-g was increased during pancytopenia as compared to in controls, suggesting that, as in other bone marrow failure diseases, these inhibitory cytokines contributed to the pancytopenia. Contrary to previously published data, we found no evidence of correlations between different types of mutations and the clinical course. INTERPRETATION AND CONCLUSIONS: These results suggest that therapies, such as hematopoietic stem cell transplantation, which are potentially curative although associated with a risk of treatment-related mortality, should not be postponed even in those CAMT patients whose c-MPL mutations might predict residual activity of the TPO receptor

Quantitative Anatomic Comparison of Endoscopic Transnasal and Microsurgical Transcranial Approaches to the Anterior Cranial Fossa

BACKGROUND: Several microsurgical transcranial approaches (MTAs) and endoscopic transnasal approaches (EEAs) to the anterior cranial fossa (ACF) have been described. OBJECTIVE: To provide a preclinical, quantitative, anatomic, comparative analysis of surgical approaches to the ACF. METHODS: Five alcohol-fixed specimens underwent high-resolution computed tomography. The following approaches were performed on each specimen: EEAs (transcribriform, transtuberculum, and transplanum), anterior MTAs (transfrontal sinus interhemispheric, frontobasal interhemispheric, and subfrontal with unilateral and bilateral frontal craniotomy), and anterolateral MTAs (supraorbital, minipterional, pterional, and frontotemporal orbitozygomatic approach). An optic neuronavigation system and dedicated software (ApproachViewer, part of GTx-Eyes II-UHN) were used to quantify the working volume of each approach and extrapolate the exposure of different ACF regions. Mixed linear models with random intercepts were used for statistical analyses. RESULTS: EEAs offer a large and direct route to the midline region of ACF, whose most anterior structures (ie, crista galli, cribriform plate, and ethmoidal roof) are also well exposed by anterior MTAs, whereas deeper ones (ie, planum sphenoidale and tuberculum sellae) are also well exposed by anterolateral MTAs. The orbital roof region is exposed by both anterolateral and lateral MTAs. The posterolateral region (ie, sphenoid wing and optic canal) is well exposed by anterolateral MTAs. CONCLUSION: Anterior and anterolateral MTAs play a pivotal role in the exposure of most anterior and posterolateral ACF regions, respectively, whereas midline regions are well exposed by EEAs. Furthermore, certain anterolateral approaches may be most useful when involvement of the optic canal and nerves involvement are suspected

miRNA-218 targets lipin-1 and glucose transporter type 4 genes in 3T3-L1 cells treated with lopinavir/ritonavir

Background: Metabolic complications represent a common and serious problem associated with HIV infection and combined Antiretroviral Therapy (cART). Alterations in body fat distribution are associated with significantly increased risks of (i) metabolic derangements, (ii) cardiovascular pathologies, and (iii) insulin resistance. A case control study showed that in subcutaneous adipose tissue from HIV-infected patients on cART presenting lipodystrophy (LS), the levels of miRNA-218 were upregulated and those of lipin-1, a putative target gene of miRNA-218, were downregulated compared with HIVnegative subjects. Lipin-1 is one of the most important factors linked to development of LS. Lipin-1, by controlling PPARg2, regulates the expression of specific genes, such as that of glucose transporter type 4 (GLUT-4), required for maturation and maintenance of adipocytes. Objectives: To determine whether lopinavir/ritonavir (LPV/RTV) can modulate lipogenesis in adipocytes affecting miRNA-218 and lipin-1 mRNA expression, and to investigate the functional link between miRNA-218 and GLUT-4 mRNA expression. Methods: Differentiated 3T3-L1 cells were treated with various combinations of LPV/RTV, followed by measurements of cell viability, lipid accumulation, lipin-1 and GLUT-4 mRNA and miRNA-218 levels. Transfection of anti-miR-218 or a miRNA-218 mimic were used to investigate the role of miRNA-218 in lipogenesis. Results: LPV/RTV treatment of 3T3-L1 cells did not affect the viability of differentiated 3T3-L1 cells, but caused (i) a significant decrease of lipid accumulation, (ii) an overexpression of miRNA-218, and (iii) a reduction of lipin-1 and GLUT-4 mRNA levels. The anti-miR-218 transfection of 3T3-L1 cells significantly ameliorated the adipogenic dysfunction and restored mRNA levels of lipin-1 and GLUT-4 consequent to LPV/RTV treatment. By contrast, 3T3-L1 cells transfected with a specific miRNA-218 mimic showed (i) an overexpression of miRNA-218, (ii) a reduced cellular lipid fraction, and (iii) decreased levels of mRNA for lipin-1 and GLUT-4. Conclusion: 3T3-L1 cells, treated with LPV/RTV, show altered lipid content due to increased miRNA-218 levels, which affects lipin-1 mRNA. Moreover, increased miRNA- 218 levels were inversely correlated with changes in GLUT-4 expression, which suggests a role for miRNA-218 in mediating the insulin resistance consequent to cART

Road traffic pollution and childhood leukemia: a nationwide case-control study in Italy

Background The association of childhood leukemia with traffic pollution was considered in a number of studies from 1989 onwards, with results not entirely consistent and little information regarding subtypes. Aim of the study We used the data of the Italian SETIL case-control on childhood leukemia to explore the risk by leukemia subtypes associated to exposure to vehicular traffic. Methods We included in the analyses 648 cases of childhood leukemia (565 Acute lymphoblastic–ALL and 80 Acute non lymphoblastic-AnLL) and 980 controls. Information on traffic exposure was collected from questionnaire interviews and from the geocoding of house addresses, for all periods of life of the children. Results We observed an increase in risk for AnLL, and at a lower extent for ALL, with indicators of exposure to traffic pollutants. In particular, the risk was associated to the report of closeness of the house to traffic lights and to the passage of trucks (OR: 1.76; 95% CI 1.03–3.01 for ALL and 6.35; 95% CI 2.59–15.6 for AnLL). The association was shown also in the analyses limited to AML and in the stratified analyses and in respect to the house in different period of life. Conclusions Results from the SETIL study provide some support to the association of traffic related exposure and risk for AnLL, but at a lesser extent for ALL. Our conclusion highlights the need for leukemia type specific analyses in future studies. Results support the need of controlling exposure from traffic pollution, even if knowledge is not complete

Effects of ACL Reconstructive Surgery on Temporal Variations of Cytokine Levels in Synovial Fluid

Anterior cruciate ligament (ACL) reconstruction restores knee stability but does not reduce the incidence of posttraumatic osteoarthritis induced by inflammatory cytokines. The aim of this research was to longitudinally measure IL-1β, IL-6, IL-8, IL-10, and TNF-α levels in patients subjected to ACL reconstruction using bone-patellar tendon-bone graft. Synovial fluid was collected within 24-72 hours of ACL rupture (acute), 1 month after injury immediately prior to surgery (presurgery), and 1 month thereafter (postsurgery). For comparison, a "control" group consisted of individuals presenting chronic ACL tears. Our results indicate that levels of IL-6, IL-8, and IL-10 vary significantly over time in reconstruction patients. In the acute phase, the levels of these cytokines in reconstruction patients were significantly greater than those in controls. In the presurgery phase, cytokine levels in reconstruction patients were reduced and comparable with those in controls. Finally, cytokine levels increased again with respect to control group in the postsurgery phase. The levels of IL-1β and TNF-α showed no temporal variation. Our data show that the history of an ACL injury, including trauma and reconstruction, has a significant impact on levels of IL-6, IL-8, and IL-10 in synovial fluid but does not affect levels of TNF-α and IL-1β