Combinatorial Inhibition of Myostatin and Activin A Improves Femoral Bone Properties in the G610C Mouse Model of Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a collagen-related bone disorder characterized by fragile osteopenic bone and muscle weakness. We have previously shown that the soluble activin receptor type IIB decoy (sActRIIB) molecule increases muscle mass and improves bone strength in the mild to moderate G610C mouse model of OI. The sActRIIB molecule binds multiple transforming growth factor-β (TGF-β) ligands, including myostatin and activin A. Here, we investigate the musculoskeletal effects of inhibiting activin A alone, myostatin alone, or both myostatin and activin A in wild-type (Wt) and heterozygous G610C (+/G610C) mice using specific monoclonal antibodies. Male and female Wt and +/G610C mice were treated twice weekly with intraperitoneal injections of monoclonal control antibody (Ctrl-Ab, Regn1945), anti-activin A antibody (ActA-Ab, Regn2476), anti-myostatin antibody (Mstn-Ab, Regn647), or both ActA-Ab and Mstn-Ab (Combo, Regn2476, and Regn647) from 5 to 16 weeks of age. Prior to euthanasia, whole body composition, metabolism and muscle force generation assessments were performed. Post euthanasia, hindlimb muscles were evaluated for mass, and femurs were evaluated for changes in microarchitecture and biomechanical strength using micro–computed tomography (μCT) and three-point bend analyses. ActA-Ab treatment minimally impacted the +/G610C musculoskeleton, and was detrimental to bone strength in male +/G610C mice. Mstn-Ab treatment, as previously reported, resulted in substantial increases in hindlimb muscle weights and overall body weights in Wt and male +/G610C mice, but had minimal skeletal impact in +/G610C mice. Conversely, the Combo treatment outperformed ActA-Ab alone or Mstn-Ab alone, consistently increasing hindlimb muscle and body weights regardless of sex or genotype and improving bone microarchitecture and strength in both male and female +/G610C and Wt mice. Combinatorial inhibition of activin A and myostatin more potently increased muscle mass and bone microarchitecture and strength than either antibody alone, recapturing most of the observed benefits of sActRIIB treatment in +/G610C mice. © 2022 American Society for Bone and Mineral Research (ASBMR).     

Penetrating Bile Duct Injury Successful Treatment by Endobiliary Stenting

Background:   

Cases of extrahepatic biliary tree trauma are not as common as other intraabdominal injuries and may pose a diagnostic and therapeutic challenge.     

3D reconstruction of the cardiovascular and central nervous system of a human embryo Carnegie-stage 15--case report.

A human embryo at Carnegie stage 15 was serially sectioned and 3D computer aided reconstructions were made to demonstrate the cardiovascular system and cranial structures and to study developmental variations at this stage. The development of the heart and pharyngeal arteries was according to the existing literature. Differences were found in the development of the arterial circle of Willis and the central nervous system. The cranial venous system seemed to show great variability. Whereas the telencephalon was not developed according to the stage, the development of the hypophysis had occurred prior to stage 15. From the results we conclude that there are remarkable individual differences in embryological differentiation of structures which have to be taken into account during staging of human embryos.     

The Role of Donor Bone Marrow Infusions in Withdrawal of Immunosuppression in Adult Liver Allotransplantation

We investigated the role of donor bone marrow cell (DBMC) infusions in immunosuppression withdrawal in adult liver transplantation. Patients enrolled were at least 3 years post-transplantation, with stable graft function. Forty-five (study group: G1) received DBMC, and 59 (control group: G2) did not. Immunosuppression was reduced by one third upon enrollment, by another third the second year of the study and was completely withdrawn the third year. Patient and graft survival were similar between the two groups. Although rejection episodes were significantly less in G1 the first 2 years of the study (35% vs. 57%, p = 0.016), there was no significant difference overall (74% vs. 81%, p = 0.14). Until February 2004, 20 patients, 10 in each group, were immunosuppression free for 1-3 years. Approximately 20% of long-term survivors of liver transplantation can successfully discontinue their immunosuppression. DBMC infusions, do not increase this likelihood.     

New developments in a consolidating health care industry.

The current health care industry has recently seen a great deal of consolidation in the form of mergers and acquisitions. These mergers and acquisitions invariably result in a loss of jobs. This paper focuses on two strategies that health care companies use to reduce workforce under these circumstances. Specifically, the paper will focus on the mergers between SmithKline Beckman and Beecham plc in the late 1980s, FHP Health Care and TakeCare Health Plans, and PacifiCare's recent acquisition of FHP Health-care. It will compare and contrast theory, strategy and practices of these six companies as they endeavoured to merge or acquire each other.     

Effect of the external donors on the polymerization of 4-methyl-1-pentene with high activity MgCl2/TiCl4 catalytic system

In order to find out correlations between the structure of an external donor and the obtained polymer, the effects of different external donors on the activity and stereospecificity of the MgCl₂/TiCl₄ catalytic system in the bulk polymerization of 4-methyl-1-pentene (4MP) were carefully studied. Different silane compounds of the structure R_nSi(OR')_4-n (where: n = 1–3, R = alkyl/phenyl, R = alkyl) and Al(i-Bu)₃ (TIBA) were used as external donors and cocatalyst, respectively. The effect of the donor/TIBA mole ratio on the activity and stereospecificity of the catalytic system was studied. Some major effects were observed for the three different external donors, namely, Me₃Si(OMe), Me₂Si(OMe)₂, and Me₃Si(OBu)₃, in the 4MP polymerization process. It was observed that the effect of the external silane donor on the polymerization strongly depends upon the size of the alkoxy and hydrocarbon (alkyl/phenyl) groups which are attached to the silicon atom. A selective deactivation of the non-stereospecific centers, as well as a transformation of the non-stereospecific into isospecific centers, is assumed to occur. On the basis of the obtained results and literature data available for the propene polymerization, the concept of structural conformity between the ligand-surrounded active center and the monomer molecule was carried forward.     

The chondrogenesis of rib perichondrial grafts for repair of full thickness articular cartilage defects in a rabbit model: a one year postoperative assessment

The purpose of this study was to investigate the results or rib perichondrial grafting after the creation of a full thickness articular cartilage defect. In a rabbit model, rib perichondrium was used to repair defects created in the femoral condyle. The formation of repair tissue (neocartilage) and its chondrogenesis into a tissue resembling articular cartilage was found over time. The gross, histological and biochemical characteristics of the neocartilage were evaluated at intervals of 6, 12, 18, 26 and 52 weeks post transplant, and compared to normal articular cartilage. The neocartilage was characterized by the early formation of relatively large amounts of glycosaminoglycans. A steady increase in the proportion of type II collagen over the time periods was also observed. Improved attachment of the neocartilage to host tissues was seen over the period of 6 to 52 weeks. Successful grafts were seen to proliferate to fill the articular defect and to undergo a chondrogenesis over a post transplant time period of one year.