Nicholas E. Dietz

Recent strategies in cartilage repair: A systemic review of the scaffold development and tissue engineering

Osteoarthritis results in irreparable loss of articular cartilage. Due to its avascular nature and low mitotic activity, cartilage has little intrinsic capacity for repair. Cartilage loss leads to pain, physical disability, movement restriction, and morbidity. Various treatment strategies have been proposed for cartilage regeneration, but the optimum treatment is yet to be defined. Tissue engineering with engineered constructs aimed towards developing a suitable substrate may help in cartilage regeneration by providing the mechanical, biological and chemical support to the cells. The use of scaffold as a substrate to support the progenitor cells or autologous chondrocytes has given promising results. Leakage of cells, poor cell survival, poor cell differentiation, inadequate integration into the host tissue, incorrect distribution of cells, and dedifferentiation of the normal cartilage are the common problems in tissue engineering. Current research is focused on improving mechanical and biochemical properties of scaffold to make it more efficient. The aim of this review is to provide a critical discussion on existing challenges, scaffold type and properties, and an update on ongoing recent developments in the architecture and composition of scaffold to enhance the proliferation and viability of mesenchymal stem cells.

TREM-1, HMGB1 and RAGE in the Shoulder Tendon: Dual Mechanisms for Inflammation Based on the Coincidence of Glenohumeral Arthritis

Rotator cuff injury (RCI) is a major musculoskeletal disorder in the adult population where inflammation and pain are major contributing factors. Coincidence of other clinical conditions like glenohumeral arthritis aggravates inflammation and delays the healing response. The mechanism and signaling factors underlying the sustenance of inflammation in the rotator cuff joint are largely unknown. The present article aims to elucidate the involvement of inflammatory molecule, TREM-1 (Triggering Receptors Expressed on Myeloid cells-1), and danger-associated molecular patterns (DAMPs), including high mobility group protein 1 (HMGB-1) and RAGE (receptor for advanced glycation end products), in the setting of RCI with respect to the severity of glenohumeral arthritis. Biceps tendons (15 specimens) from the shoulder and blood (11 samples) from patients with glenohumeral arthritis (Group-1, n = 4) and without glenohumeral arthritis (Group-2, n = 11) after RCI surgery were obtained for the study. Molecular and morphological alterations between the groups were compared using histology, immunofluorescence, RT-PCR and flow cytometry. MRI and histomorphology assessment revealed severe inflammation in Group-1 patients while in Group-2 ECM disorganization was prominent without any hallmarks of inflammation. A significant increase in TREM-1 expression in circulating neutrophils and monocytes was observed. Elevated levels of TREM-1, HMGB-1 and RAGE in Group-1 patients along with CD68+ and CD16+ cells confirmed DAMP-mediated inflammation. Expression of TREM-1 in the tendon of Group-2 patients even in the absence of immune cells presented a new population of TREM-expressing cells that were confirmed by real-time PCR analysis and immunofluorescence. Expression of HMGB-1 and RAGE in the biceps tendon from the shoulder of patients without glenohumeral arthritis implied TREM-1-mediated inflammation without involving immune cells, whereas in patients with glenohumeral arthritis, infiltration and the activation of the immune cells, primarily macrophages, release mediators to induce inflammation. This could be the reason for ECM disorganization without the classical signs of inflammation in patients without glenohumeral arthritis.

Triggering receptor expressed on myeloid cells and 5’adenosine monophosphate-activated protein kinase in the inflammatory response: a potential therapeutic target

ABSTRACT Introduction: The events in the cellular and molecular signaling triggered during inflammation mitigate tissue healing. The metabolic check-point control mediated by 5ʹ-adenosine monophosphate-activated protein kinase (AMPK) is crucial for switching the cells into an activated state capable of mediating inflammatory events. The cell metabolism involved in the inflammatory response represents a potential therapeutic target for the pharmacologic management of inflammation. Areas covered: In this article, a critical review is presented on triggering receptor expressed on myeloid cell (TREM) receptors and their role in the inflammatory responses, as well as homeostasis between different TREM molecules and their regulation. Additionally, we discussed the relationship between TREM and AMPK to identify novel targets to limit the inflammatory response. Literature search was carried out from the National Library of Medicine’s Medline database (using PubMed as the search engine) and Google Scholar and identified relevant studies up to 30 March 2016 using inflammation, TREM, AMPK, as the key words. Expert commentary: The prevention of phenotype switching of immune cells during inflammation by targeting AMPK and TREM-1 could be beneficial for developing novel management strategies for inflammation and associated complications.

MicroRNAs Associated with Shoulder Tendon Matrisome Disorganization in Glenohumeral Arthritis.

The extracellular matrix (ECM) provides core support which is essential for the cell and tissue architectural development. The role of ECM in many pathological conditions has been well established and ECM-related abnormalities leading to serious consequences have been identified. Though much has been explored in regards to the role of ECM in soft tissue associated pathologies, very little is known about its role in inflammatory disorders in tendon. In this study, we performed microRNA (miRNA) expression analysis in the long head of the human shoulder biceps tendon to identify key genes whose expression was altered during inflammation in patients with glenohumeral arthritis. We identified differential regulation of matrix metalloproteinases (MMPs) that could be critical in collagen type replacement during tendinopathy. The miRNA profiling showed consistent results between the groups and revealed significant changes in the expression of seven different miRNAs in the inflamed tendons. Interestingly, all of these seven miRNAs were previously reported to have either a direct or indirect role in regulating the ECM organization in other pathological disorders. In addition, these miRNAs were also found to alter the expression levels of MMPs, which are the key matrix degrading enzymes associated with ECM-related abnormalities and pathologies. To our knowledge, this is the first report which identifies specific miRNAs associated with inflammation and the matrix reorganization in the tendons. Furthermore, the findings also support the potential role of these miRNAs in altering the collagen type ratio in the tendons during inflammation which is accompanied with differential expression of MMPs.

Potassium as a Toxic Factor in Intestinal Obstruction

Summary It has been shown that hyperpotassemia cannot be considered as a contributing factor to the cause of collapse and death in experimental intestinal obstruction in the dog.

Immunological basis for treatment of graft versus host disease after liver transplant

ABSTRACT Graft versus host disease (GVHD) after liver transplant, although a rare disease, has a very high mortality rate. GVHD occurs due to immunoreactions caused by donor T lymphocytes and host cell surface antigens resulting in proliferation and clonal expansion of T lymphocyte. Migration of effector cells, including macrophages, NK cells and cytotoxic T lymphocyte, to the target organs such as skin, intestine and bone marrow results in skin rashes, diarrhea and bone marrow depression. GVHD is diagnosed by clinical symptoms, histopathological findings and by the presence of chimerism. The delayed diagnosis, opportunistic infections and lack of definitive treatment of post orthotopic liver transplant (OLT)-GVHD results in sepsis and multi-organ failure leading to very low survival rates. In this review, we have focused on early diagnosis and critically discuss novel treatment modalities to decrease the incidence of GVHD.

Discovery of novel and clinically relevant markers in formalin-fixed paraffin-embedded esophageal cancer specimen

Due to the ineffectiveness of chemoradiation and targeted therapy in esophageal anticancer care and the subsequent low survival rates, we constructed a high throughput method to discover and investigate new markers with prognostic, diagnostic, and therapeutic clinical utility. This was accomplished by developing a quick, inexpensive, and dependable platform to simultaneously quantify thousands of proteins which subsequently revealed novel markers involved in the pathogenesis of esophageal adenocarcinoma (EAC) via discovery mass spectrometry paired with conservative biostatistics. Our method uncovered a perfect storm of tumor suppressors being downregulated, proliferation markers ramped up, and chemoresistance markers overexpressed—many of which could serve as new therapy targets for EAC. The 12 markers discovered by this method are novel regarding their involvement in the pathogenesis of EAC. The molecular oncology arena now has a dozen new proteomic targets suitable for validation and elucidation of their clinical utility via gene knockdown in cellular and animal models. This new method can be replicated and applied to other cancers or disease states for research and development and discovery-based investigations. Our findings, which serve as a proof of concept, will hopefully motivate research groups to further expound on the molecular processes involved in the aggressiveness of EAC and other solid tumor diseases, ultimately leading to improved patient management strategies.

A Novel Presentation of Bladder Mass: Self-palpation by a Patient with Cystocele

INTRODUCTION This case describes diagnosis of a T2 transitional cell carcinoma in an 89-year-old woman with known cystocele and urinary retention managed with clean intermittent self-catheterization. CASE While self-catheterizing, the patient noted a palpable mass in her cystocele. She eventually pursued urologic evaluation of this mass, which ultimately led to her diagnosis. This is the first reported case of transitional cell carcinoma being found on self-examination by palpating a cystocele.

Mycobacterium avium Infection of Nasal Septum in a Diabetic Adult: A Case Report

Mycobacterium avium complex (MAC) is primarily a pulmonary pathogen that affects individuals who are immune deficient or immunocompromised. In this report, we describe a very rare case of MAC infection clinically presenting as a nasal polyp in a patient with type 2 diabetes mellitus. This case illustrates an atypical anatomic location for MAC, the anterior nasal septum in nasal cavity, as well as often overlooked cause of immune compromise, diabetes mellitus. We present the laboratory findings that lead to the diagnosis as well as a brief review of MAC infections.