Original Dynamometric and Tomographic evidence of site-specific muscle effects on bone structure. Towards a wider scope on the bone Mechanostat concept

Para analizar el impacto directo de la musculatura sobre la estructura ósea se determinaronel área (CtA), la densidad mineral ósea volumétrica (vDMOc) y los momentos de inerciacorticales para flexión anteroposterior y lateral(MIap, MIlat) ajustados a CtA, y las relacionesentre MI y vDMOc (de ʻdistribución/calidadʼ, d/c,que describen la eficiencia de la optimizaciónbiomecánica del diseño cortical por el mecanostato) en 18 cortes seriados a lo largo detodo el peroné del lado hábil (pQCT), y lafuerza de salto y de rotación externa del pie(dinamometría computarizada) de 22 hombressanos de 18 a 33 años entrenados en fútbolcompetitivo por más de 4 años, y de 9 controlesetarios no entrenados. Los entrenados tuvieronvalores más altos de MI en función de la fuerzade rotación del pie (no de salto), con un ajustehomogéneo para MIap pero variable (más pobredistalmente y más alto proximalmente, en laregión de inserción de los peroneos) para MIlat,coincidiendo este último con pobres ajustes delas relaciones d/c (efecto arquitectónico independiente de la rigidez del tejido). Esto evidencia la influencia directa de la tracción de lamusculatura peronea sobre la estructura cortical proximal subyacente del hueso y tambiénsugiere que el mecanostato procedería, en estecaso, fuera de su conocida concepción comomecanismo regulatorio de la resistencia ósea.To analyze the direct impact of muscle contractions on the structure of bones, we determined the cortical cross-sectional area (CtA), volumetric mineral density (vBMDc) and the CtA-adjusted moments of inertia for anterior-posterior and lateral bending (MIap, MIlat), and the ‘distribution/quality’ (d/c) relationships between MIs and vBMDc (which describe the efficiency of the biomechanical optimization of cortical design by bone mechanostat) in 18 serial scans taken throughout the fibula of the dominant side (pQCT), and the jump and the foot-lateral-rotation forces (computed dynamometry) of 22 healthy men aged 18-33 years, who had been trained in competitive soccer for more than 4 years, and of 9 untrained, age-matched controls. Trained individuals showed higher MI values as a function of the rotative force of the foot (not the jumping force). The adjustment of these relationships was homogeneous for MIap throughout the bone, but variable (poorer distally and higher proximally, at the insertion area of peroneus muscles) for MIlat, this latter being paralleled by poor adjustments of the corresponding, d/c relation-ships (architectural effect independent of tissue stiffness). These findings,1. Show the direct influence of the traction force of peroneal muscles on proximal fibula structure close to the insertion area, and 2. Suggest that, in the studied conditions, the bone mechanostat would proceed beyond its known conception as a regulatory mechanism of structural bone strength.Fil: Nocciolino, Laura Marcela. Universidad Gran Rosario. Centro Universitario de Asistencia, Docencia e Investigación. Unidad de Estudios Biomecánicos Osteo-Musculares ; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Luscher, Sergio Hugo. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; ArgentinaFil: Pilot, Nicolás. Universidad Gran Rosario. Centro Universitario de Asistencia, Docencia e Investigación. Unidad de Estudios Biomecánicos Osteo-Musculares ; ArgentinaFil: Pisani, Leandro Matias. Universidad Gran Rosario. Centro Universitario de Asistencia, Docencia e Investigación. Unidad de Estudios Biomecánicos Osteo-Musculares ; ArgentinaFil: Mackler, Leandro. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; ArgentinaFil: Cointry, Gustavo Roberto. Manchester Metropolitan University; Reino Unido. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ireland, Alex. Institute of Aerospace Medicine. Division of Space Physiology; AlemaniaFil: Rittweger, Jörn. Institute of Aerospace Medicine. Division of Space Physiology; AlemaniaFil: Ferretti, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; Argentina. Universidad Gran Rosario. Centro Universitario de Asistencia, Docencia e Investigación. Unidad de Estudios Biomecánicos Osteo-Musculares ; ArgentinaFil: Capozza, Ricardo Francisco. Universidad Gran Rosario. Centro Universitario de Asistencia, Docencia e Investigación. Unidad de Estudios Biomecánicos Osteo-Musculares ; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; Argentin

Clinical biological and genetic heterogeneity of the inborn errors of pulmonary surfactant metabolism

Pulmonary surfactant is a multimolecular complex located at the air-water interface within the alveolus to which a range of physical (surface-active properties) and immune functions has been assigned. This complex consists of a surface-active lipid layer (consisting mainly of phospholipids), and of an aqueous subphase. From discrete surfactant sub-fractions one can isolate strongly hydrophobic surf acta nt proteins B (SP-B) and C (SP-C) as well as collectins SP-A and SP-D, which were shown to have specific structural, metabolic, or immune properties. Inborn or acquired abnormalities of the surfactant, qualitative or quantitative in nature, account for a number of human diseases. Beside hyaline membrane disease of the preterm neonate, a cluster of hereditary or acquired lung diseases has been characterized by periodic acid-Schiff-positive material filling the alveoli. From this heterogeneous nosologic group, at least two discrete entities presently emerge. The first is the SP-B deficiency, in which an essentially proteinaceous material is stored within the alveoli, and which represents an autosomal recessive Mendelian entity linked to the SFTPB gene (MIM 1786640). The disease usually generally entails neonatal respiratory distress with rapid fatal outcome, although partial or transient deficiencies have also been observed. The second is alveolar proteinosis, characterized by the storage of a mixed protein and lipid material, which constitutes a relatively heterogeneous clinical and biological syndrome, especially with regard to age at onset (from the neonate through to adulthood) as well as the severity of associated signs. Murine models, with a targeted mutation of the gene encoding granulocyte macrophage colony-stimulating factor (GM-CSF) (Csfgm) or the beta subunit of its receptor (II3rb1) support the hypothesis of an abnormality of surfactant turnover in which the alveolar macrophage is a key player. Apart from SP-B deficiency, in which a near-consensus diagnostic chart can be designed, the ascertainment of other abnormalities of surfactant metabolism is not straightforward. The disentanglement of this disease cluster is however essential to propose specific therapeutic procedures: repeated broncho-alveolar ravages, GM-CSF replacement, bone marrow grafting or lung transplantation

To what question is ‘bone’ the answer?: A matter of structural directionality and biological organization (Bone and bones, from the Big Bang to osteoporosis)

La “razón de ser” de nuestros huesos y esqueletos constituye un dilema centralizado en los conceptos biológicos de “estructura” y “organización”, cuya solución necesitamos comprender para interpretar, diagnosticar, tratar y monitorear correctamente las osteopatías fragilizantes. Últimamente se ha reunido conocimiento suficiente para proponer aproximaciones razonables a ese objetivo. La que exponemos aquí requiere la aplicación de nomenos de 6 criterios congruentes: 1) Un criterio cosmológico, que propone un origen común para todas las cosas; 2) Un criterio biológico, que explica el origen común de todos los huesos; 3) Un enfoque epistemológico, que desafía nuestra capacidad de comprensión del concepto concreto de estructura y del concepto abstracto de organización, focalizada en la noción rectora de direccionalidad espacial; 4) Una visión ecológica, que destaca la importancia del entorno mecánico de cada organismo para la adecuación de la calidad mecánica de sus huesos a las “funciones de sostén” que les adjudicamos; 5) Una correlación entre todo ese conocimiento y el necesario para optimizar nuestra aptitud para resolver los problemas clínicos implicados y 6) Una jerarquización del papel celular en el manejo de las interacciones genético-ambientales necesario para asimilar todo el problema a una simple cuestión de organización direccional de la estructura de cada hueso. Solo aplicando estos 6 criterios estaríamos en condiciones de responder a la incógnita planteada por el título. La conclusión de esta interpretación de la conducta y función de los huesos debería afectar el fundamento de la mayoría de las indicaciones farmacológicas destinadas al tratamiento de la fragilidad ósea.The nature of the general behavior of our bones as weight-bearing structures is a matter of two biological concepts, namely, structure and organization, which are relevant to properly interpret, diagnose, treat, and monitor all boneweakening diseases. Different approaches can be proposed to trace the corresponding relationships. The one we present here involves six congruent criteria, namely, 1) a cosmological proposal of a common origin for everything; 2) a biological acknowledgement of a common origin for all bones; 3) the epistemological questioning of our understanding of the concrete concept of structure and the abstract notion of organization, focused on the lead idea of directionality; 4) the ecological insight that emphasizes the relevance of the en forma direccional, es decir, privilegiando una determinada orientación espacial.3 Ese conocimiento se podría impartir y asimilar más o menos fácilmente, si no fuera por la cantidad de conceptos confusos que se han difundido últimamente entre los osteólogos respecto de las relaciones entre la estructura ósea y sus entornos mecánico y metabólico. Que tengamos dificultad para entenderlo no significa que no sea sencillo. Quizá lo que hace falta es cambiar el modo de pensar. Por tal razón, nos parece que el mejor método para revisar esta cuestión debería comenzar por razonar ‘en limpio’, como si se ignorase mechanical environment of every organism to the naturally-selected adjustment of the mechanical properties of their mobile bones to act as struts or levers; 5) The clinical aspects of all the alluded associations; 6) The central role of bone cells to control the genetics/ environment interactions of any individual as needed to optimize the directionality of the structure of each of his/her bones to keep their mechanical ability within physiological limits. From our point of view, we could only solve the riddle posed by the title by addressing all of these six criteria. The striking conclusion of our analysis suggests that the structure (not the mass) of every bone would be controlled not only to take care of its mechanical ability, but also to cope with other properties which show a higher priority concerning natural selection. The matter would be that this interpretation of bone behavior and ‘function’ should affect the rationales for most pharmacological indications currently made to take care of bone fragility.Fil: Ferretti, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; ArgentinaFil: Pilot, Nicolas Carlos. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; ArgentinaFil: Pisani, Leandro Matias. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; Argentina. Instituto Universidad del Gran Rosario; ArgentinaFil: Luscher, Sergio Hugo. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; ArgentinaFil: Mackler, Leandro. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; ArgentinaFil: Cointry, Gustavo Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; ArgentinaFil: Capozza, Ricardo Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; Argentin

Original demonstration of the interference of the expansive cortical modeling effects of one training on those of another further training (Modeling ‘sets limits’ for remodeling)

La expansión modeladora de la geometría cortical de un hueso inducida por su entorno mecánico podría ser difícil de modificar por estímulos ulteriores con diferente direccionalidad. Este estudio, que por primera vez combina datos tomográficos del peroné (pQCT) y dinamométricos de la musculatura peronea lateral, intenta demostrar que, en individuos jóvenes no entrenados, el entrenamiento en fútbol produce cambios geométricos peroneos expansivos, similares a los del rugby, que podrían interferir en los efectos de un entrenamiento ulterior direccionalmente diferente (carrera larga). Confirmando la hipótesis, los resultados indican, con evidencias originales, 1) la relevancia creciente del uso del pie (rotación externa y eversión provocadas por los peroneos laterales) para la determinación de la geometría peronea (incremento del desarrollo de los indicadores de masa y de diseño óseos), evidenciada por la secuencia creciente de efectos: carrera < fútbol < rugby; 2) la predominancia de esos efectos sobre el desarrollo centro-proximal del peroné para resistir a la flexión lateral, y en la región distal para resistir el buckling (principal sitio y causa de fractura del hueso) y 3.) la relevancia de la anticipación de esos efectos para interferir en la manifestación de los cambios producidos por un entrenamiento ulterior (carrera), cuando los del primero (fútbol) afectan la modelación cortical de modo expansivo. Esta última deducción demuestra, en forma inédita, que un cambio modelatorio expansivo tempranamente inducido sobre la estructura cortical ósea ‘delimitaría el terreno’ para la manifestación de cualquier otro efecto ulterior por estímulos de distinta direccionalidad.The modeling-dependent, geometrical expansion of cortical bone induced by the mechanical environment could be hard to modify by subsequent stimulations with a different directionality. The current study aimed to demonstrate that in young, untrained individuals, training in soccer or rugby enhances the geometric properties of the fibula cortical shell in such a way that the geometrical changes could interfere on the effects of a second training in which the loads are induced in a different direction, e.g. long-distance running. The original findings reported herein confirm our hypothesis and support 1) The relevance of the use of the foot (external rotation and eversion produced by peroneus muscles) to determine fibula geometry (improved development of indicators of bone mass and design) as evidenced by the increasing nature of the effects induced by running < soccer < rugby trainings; 2) The predominance of those effects on the ability of the fibula to resist lateral bending in the centralproximal region (insertion of peroneus muscles), and to resist buckling in the distal region (the main cause and site of the most frequent bone fractures), and 3) The interaction of the effects of a previous training with those of a subsequent training with a different orientation of the loads when the former induced a modeling-dependent expansion of the cortex. Our results support the proposed hypothesis with original arguments by showing that a first, expansive effect induced on cortical bone modeling would set the stage the manifestation of any subsequent effect derived from mechanical stimuli.Fil: Pisani, Leandro Matias. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; Argentina. Instituto Universidad del Gran Rosario; ArgentinaFil: Pilot, Nicolas Carlos. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; Argentina. Instituto Universidad del Gran Rosario; ArgentinaFil: Luscher, Sergio Hugo. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; ArgentinaFil: Mackler, Leandro. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; ArgentinaFil: Nocciolino, Laura Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; ArgentinaFil: Ferretti, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; ArgentinaFil: Cointry, Gustavo Roberto. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; ArgentinaFil: Capozza, Ricardo Francisco. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; Argentin

Safety and Efficacy of Ombitasvir, Paritaprevir With Ritonavir ± Dasabuvir With or Without Ribavirin in Patients With Human Immunodeficiency Virus-1 and Hepatitis C Virus Genotype 1 or Genotype 4 Coinfection: TURQUOISE-I Part 2.

BACKGROUND: Ombitasvir, paritaprevir with ritonavir, and dasabuvir (OBV/PTV/r ± DSV) ±ribavirin (RBV) are approved to treat hepatitis C virus (HCV) genotype 1 and 4 infection. Here, we investigate the safety and efficacy of OBV/PTV/r + DSV ±RBV for HCV genotype 1, and OBV/PTV/r + RBV for HCV genotype 4, in human immunodeficiency virus (HIV)-1 coinfected patients with or without compensated cirrhosis. METHODS: TURQUOISE-I, Part 2 is a phase 3 multicenter study. Patients with or without cirrhosis were HCV treatment-naive or -experienced, on an HIV-1 antiretroviral regimen containing atazanavir, raltegravir, dolutegravir, or darunavir (for genotype 4 only), and had plasma HIV-1 ribonucleic acid <40 copies/mL at screening. Patients received OBV/PTV/r ± DSV ±RBV for 12 or 24 weeks. RESULTS: In total, 228 patients were treated according to guidelines. Sustained virologic response at posttreatment week 12 (SVR12) was achieved by 194 of 200 (97%) and 27 of 28 (96%) patients with HCV genotype 1 and genotype 4 infection, respectively. There were 2 virologic failures: 1 breakthrough and 1 relapse in a cirrhotic and a noncirrhotic patient with genotype 1b and 1a infection, respectively. One reinfection occurred at posttreatment week 12 in a genotype 1a-infected patient. Excluding nonvirologic failures, the SVR12 rates were 98% (genotype 1) and 100% (genotype 4). Adverse events were mostly mild in severity and did not lead to discontinuation. Laboratory abnormalities were rare. CONCLUSIONS: The OBV/PTV/r ±DSV was well tolerated and yielded high SVR12 rates in patients with HCV genotype 1 or genotype 4/HIV-1 coinfection. The OBV/PTV/r ± DSV ±RBV is a potent HCV treatment option for patients with HIV-1 coinfection, regardless of treatment experience

Molecular modeling of hair keratin/peptide complex : using MM-PBSA calculations to describe experimental binding results

Molecular dynamics simulations of a keratin/peptide complex have been conducted to predict the binding affinity of four different peptides toward human hair. Free energy calculations on the peptides' interaction with the keratin model demonstrated that electrostatic interactions are believed to be the main driving force stabilizing the complex. The molecular mechanics–Poisson-Boltzmann surface area methodology used for the free energy calculations demonstrated that the dielectric constant in the protein's interior plays a major role in the free energy calculations, and the only way to obtain accordance between the free energy calculations and the experimental binding results was to use the average dielectric constant.Grant sponsor: Contract Research Program "Compromisso com a Ciencia''; Grant number: C2008-UMINHO-CQ-03; Grant sponsor: FCT "Fundacao para a Ciencia e Tecnologia'' (PhD); Grant number: SFRH/BD/38363/200

Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin

BACKGROUND The interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r) and the NS5A inhibitor ombitasvir (also known as ABT-267) plus the nonnucleoside polymerase inhibitor dasabuvir (also known as ABT-333) and ribavirin has shown efficacy against the hepatitis C virus (HCV) in patients with HCV genotype 1 infection. In this phase 3 trial, we evaluated this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis

Glecaprevir-Pibrentasvir for 8 or 12 Weeks in HCV Genotype 1 or 3 Infection

The trials (NCT02604017, NCT02640157) were funded by AbbVie Inc

An interferon-free antiviral regimen for HCV after liver transplantation.

Background Hepatitis C virus (HCV) infection is the leading indication for liver transplantation worldwide, and interferon-containing regimens are associated with low response rates owing to treatment-limiting toxic effects in immunosuppressed liver-transplant recipients. We evaluated the interferon-free regimen of the NS5A inhibitor ombitasvir coformulated with the ritonavir-boosted protease inhibitor ABT-450 (ABT-450/r), the nonnucleoside NS5B polymerase inhibitor dasabuvir, and ribavirin in liver-transplant recipients with recurrent HCV genotype 1 infection. Methods We enrolled 34 liver-transplant recipients with no fibrosis or mild fibrosis, who received ombitasvir-ABT-450/r (at a once-daily dose of 25 mg of ombitasvir, 150 mg of ABT-450, and 100 mg of ritonavir), dasabuvir (250 mg twice daily), and ribavirin for 24 weeks. Selection of the initial ribavirin dose and subsequent dose modifications for anemia were at the investigator's discretion. The primary efficacy end point was a sustained virologic response 12 weeks after the end of treatment. Results Of the 34 study participants, 33 had a sustained virologic response at post-treatment weeks 12 and 24, for a rate of 97% (95% confidence interval, 85 to 100). The most common adverse events were fatigue, headache, and cough. Five patients (15%) required erythropoietin; no patient required blood transfusion. One patient discontinued the study drugs owing to adverse events after week 18 but had a sustained virologic response. Blood levels of calcineurin inhibitors were monitored, and dosages were modified to maintain therapeutic levels; no episode of graft rejection was observed during the study. Conclusions Treatment with the multitargeted regimen of ombitasvir-ABT-450/r and dasabuvir with ribavirin was associated with a low rate of serious adverse events and a high rate of sustained virologic response among liver-transplant recipients with recurrent HCV genotype 1 infection, a historically difficult-to-treat populatio