Bone Marrow Osteoblast Damage by Chemotherapeutic Agents

Hematopoietic reconstitution, following bone marrow or stem cell transplantation, requires a microenvironment niche capable of supporting both immature progenitors and stem cells with the capacity to differentiate and expand. Osteoblasts comprise one important component of this niche. We determined that treatment of human primary osteoblasts (HOB) with melphalan or VP-16 resulted in increased phospho-Smad2, consistent with increased TGF-β1 activity. This increase was coincident with reduced HOB capacity to support immature B lineage cell chemotaxis and adherence. The supportive deficit was not limited to committed progenitor cells, as human embryonic stem cells (hESC) or human CD34+ bone marrow cells co-cultured with HOB pre-exposed to melphalan, VP-16 or rTGF-β1 had profiles distinct from the same populations co-cultured with untreated HOB. Functional support deficits were downstream of changes in HOB gene expression profiles following chemotherapy exposure. Melphalan and VP-16 induced damage of HOB suggests vulnerability of this critical niche to therapeutic agents frequently utilized in pre-transplant regimens and suggests that dose escalated chemotherapy may contribute to post-transplantation hematopoietic deficits by damaging structural components of this supportive niche

TOTAL HIP ARTHROPLASTY IN PATIENTS SUFFERING FROM RHEUMATOID ARTHRITIS – A REPORT ON TWO CASES

Rheumatoid arthritis is traditionally considered a chronic, inflammatory autoimmune disorder of unknown etiology.It is a disabling and painful inflammatory condition, which can lead to substantial loss of mobility due to pain and joint destruction. Clinical characteristics of the rheumatoid hip are pain, limited range of motion, and rapid onset of cartilage destruction resulting in secondary changes in other lower limb joints and the spine. Radiography showed intensive osteoporosis and later protrusion of acetabulum. Treatment of rheumatoid coxitis is specific, which depends on the stage of disease, subjective and objective complications, and can be medicamentous, functional and operative.The study presents the treatment of two patients with rheumatoid arthritis with total hip arthroplasty at the Clinic of Orthopaedics and Traumatology Clinical Center Nis. In a fifty-five-old patient with the diagnosis of rheumatoid arthritis, the rheumatoid hip joint underwent a cementless total hip arthroplasty. In a sixty-eight-year old patient, the rheumatoid hip joint underwent total hip arthroplasty with cement. In both patients we obtained good functional results.Total hip arthroplasty in patients with rheumatoid coxitis relieves pain and prevents invalidity conditioned by destruction of the hip joint

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field