The use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in orthopaedic applications

Preclinical proof-of-concept, feasibility and efficacy studies in lower animals resulted in the accumulation of data that served as a backbone for clinical trials with the recombinant, osteogenic bone morphogenetic protein-2 (BMP-2). Among the important observations was the dependence of dose and carrier on the outcome for osseous union in relation to the animal model used. Clinical outcome data for spinal applications indicate better overall results compared with traditional controls that utilised autogenous iliac crest bone graft for fusion. Parameters include less blood loss, less operating room time and costs, better fusion outcomes and increased patient satisfaction. At this juncture, the long journey from the identification of BMP-2 in demineralised bone fraction to FDA approval for use in a singular orthopaedic application has been completed. It has been demonstrated to be safe, efficacious and cost-effective, leading to increased patient satisfaction and improved clinical outcome.     

Plasma 15-F2t-isoprostane in idiopathic pulmonary arterial hypertension

Background

15-F_2t-isoprostane (15-F_2t-IsoP), a prostaglandin F₂-like compound, is widely recognized as a biomarker of chronic heart failure. This study investigated the potential role and prognostic significance of plasma 15-F_2t-IsoP in patients with idiopathic pulmonary arterial hypertension (IPAH).

Methods

Plasma 15-F_2t-IsoP concentrations were determined in 80 consecutive IPAH patients at the time of their first right heart catheterization, and monitored for 30 ± 12 months. The expression of 15-F_2t-IsoP protein in autopsy lung samples was determined by immunohistochemical staining.

Results

Plasma 15-F_2t-IsoP concentrations were significantly increased in patients with IPAH compared with healthy controls (91 pg/ml vs. 30 pg/ml, respectively; P < 0.001). Patients with baseline 15-F_2t-IsoP concentrations ≥ 97 pg/ml had a significantly lower survival rate than those with lower baseline concentrations (P < 0.001). During follow-up, 15-F_2t-IsoP concentrations in survivors decreased, whereas concentrations in non-surviving patients increased further (P < 0.05). Elevated concentrations of 15-F_2t-IsoP were correlated with a severity of WHO functional class, lower 6-minute walking distance and mixed venous oxygen saturation, higher mean right atrial pressure and brain natriuretic peptide. Multivariate analysis revealed that the plasma 15-F_2t-IsoP concentration was an independent factor associated with mortality. Histological studies showed that the expression of 15-F_2t-IsoP was up-regulated in remodeled pulmonary vessels.

Conclusions

An elevated plasma 15-F_2t-IsoP concentration and a further increase during follow-up may be a risk factor for higher mortality in patients with IPAH.     

The SARS-CoV-2 B.1.618 variant slightly alters the spike RBD–ACE2 binding affinity and is an antibody escaping variant: a computational structural perspective

Continuing reports of new SARS-CoV-2 variants have caused worldwide concern and created a challenging situation for clinicians. The recently reported variant B.1.618, which possesses the E484K mutation specific to the receptor-binding domain (RBD), as well as two deletions of Tyr145 and His146 at the N-terminal binding domain (NTD) of the spike protein, must be studied in depth to devise new therapeutic options. Structural variants reported in the RBD and NTD may play essential roles in the increased pathogenicity of this SARS-CoV-2 new variant. We explored the binding differences and structural-dynamic features of the B.1.618 variant using structural and biomolecular simulation approaches. Our results revealed that the E484K mutation in the RBD slightly altered the binding affinity through affecting the hydrogen bonding network. We also observed that the flexibility of three important loops in the RBD required for binding was increased, which may improve the conformational optimization and consequently binding of the new variant. Furthermore, we found that deletions of Tyr145 and His146 at the NTD reduced the binding affinity of the monoclonal antibody (mAb) 4A8, and that the hydrogen bonding network was significantly affected consequently. This data show that the new B.1.618 variant is an antibody-escaping variant with slightly altered ACE2–RBD affinity. Moreover, we provide insights into the binding and structural-dynamics changes resulting from novel mutations in the RBD and NTD. Our results suggest the need for further in vitro and in vivo studies that will facilitate the development of possible therapies for new variants such as B.1.618.

This study explored the binding patterns of the wild type and B.1.618 variant using which revealed that the B.1.618 variant possess a stronger binding affinity for the host ACE2 and escape the neutralizing antibodies.     

Gene therapy for spinal applications

Gene therapy is a promising drug delivery mechanism for the treatment of spinal disorders. Currently, the technique has been most useful in enhancing growth factor therapy for spinal fusion, intervertebral disc regeneration, and spinal cord injury healing. Gene therapy allows for the high-level local production of growth factors, obviating the need for slow release carriers or continuous infusion pumps that are otherwise necessary because of the short half-lives of most peptide growth factors. Although continuous expression is desirable, growth factor therapy is usually intended to be transient. The typical expression profile of Ad vectors--at a high level over 2 weeks or so--has been ideal, leading to its widespread use in these applications. Despite the ability of Ad to deliver genes directly in vivo, however, the cell-based ex vivo approach has been used widely in spinal applications. In spinal cord injury, cells such as peripheral nerve or Schwann cells may provide a permissive substrate for axonal growth [51]. For spinal fusion and IVD regeneration, ex vivo manipulation of cells facilitates gene transfer, because bone and IVD tissue are too dense to be penetrated by injection of Ad or other vectors. The use of cells may be advantageous in these applications in which new tissue formation is the goal. Finally, the use of genetically modified cells may decrease the inflammatory reaction induced by Ad vectors. Although gene therapy for spinal disorders has been centered around Ad-mediated transfer of single growth factor genes, the options for candidate genes and vectors are growing rapidly. Ad vectors are being improved by decreasing their immunogenicity and altering their tropism [2]. Vectors based on other viruses (such as herpes, adeno-associated virus, and lentivirus) are being developed, also with lower immunogenicity and with longer durations of expression [26,67]. Regulated expression, such as with the tetracycline regulated promoter, is being developed so that genes can be turned on or off as needed. Such regulation may be sensitive even to physiologic cues in the future [68,69]. Finally, the high throughput technologies, such as the gene chip, are elucidating thousands of genes that may be good candidates for the enhancement of bone healing and IVD and spinal cord regeneration. Genes whose products not only support bone, fibrocartilage, or axon growth but also neutralize natural inhibitors or promote tissue remodeling and maturation may be good future candidates. In the future, a series of vectors with multiple genes that are regulated by physiologic cues might be used to enhance spinal fusion, restore IVD tissue, or support spinal cord healing.     

An Introduction to Health Disparities for the Practicing Radiologist

A substantial and growing body of literature explores health disparities in radiology and imaging. The term “health disparities” refers to health differences related to disadvantages experienced by vulnerable populations, often caused by underlying social determinants of health. As such, health disparities are often closely tied to issues of social justice. Radiologists can work to reduce health disparities in different ways, including through supporting education, diversity and inclusion efforts, disparities research, and advocacy.     

Blastomycosis in solid organ transplant recipients

BACKGROUND: Blastomyces dermatitidis, the etiologic agent of blastomycosis, causes severe disease and substantial mortality in those immunocompromised by acquired immunodeficiency syndrome or malignancy. In solid organ transplant recipients, the epidemiology, clinical features, and outcomes have not been fully described. METHODS: We conducted a retrospective case-series at the University of Wisconsin Hospital and Clinics. Case patients were solid organ transplant recipients with blastomycosis. RESULTS: From 1986 to 2004, we identified 11 cases of post-transplant blastomycosis with 64% occurring between 2000 and 2004. Onset of infection occurred a median of 26 months post transplantation with near equal distribution before and after the first year of transplantation. Rejection did not precede any case of post-transplant blastomycosis. Opportunistic co-infections were common, occurring in 36% of patients. Pneumonia was the most common clinical presentation and was frequently complicated by acute respiratory distress syndrome (ARDS). Extrapulmonary disease predominantly involved the skin and spared the central nervous system. The overall mortality rate was 36%; however, this increased to 67% in those with ARDS. None of the surviving patients relapsed or received routine secondary antifungal prophylaxis. CONCLUSION: Blastomycosis is an uncommon infection following solid organ transplantation that is frequently complicated by ARDS, dissemination, and opportunistic co-infection. After cure, post-transplant blastomycosis may not require lifelong antifungal suppression.