Polymyositis Presenting With Nontraumatic Rhabdomyolysis and Dysphagia: A Case Report.

Idiopathic inflammatory myopathies (IIMs) are a rare, heterogeneous group of diseases with a characteristic clinical presentation consisting of muscle inflammation and weakness. They often present with accompanying extra-muscular findings, most notably in the skin, lungs, and joints. Inflammatory myopathies are also identified by their characteristic laboratory abnormalities, including a 10- to 50-fold increase in creatinine kinase, elevated liver enzymes, and characteristic electromyography and magnetic resonance imaging findings. Distinct autoimmune markers and clinical phenotypes have advanced our understanding of IIMs and have led to the recognition of 5 distinct entities, each with its unique pathophysiology, autoimmune markers, and clinical features. While autoimmune panels and muscle biopsies help clinicians distinguish one entity from the other, their sensitivity and specificity vary. Of the various inflammatory myopathies, polymyositis remains the most elusive. Often, the diagnosis is ultimately made by combining clinical findings and laboratory data. As our case report illustrates, clinicians must use this constellation of data to initiate treatment for suspected polymyositis despite negative autoimmune panels and negative muscle biopsy.

Macrophage Activation Syndrome in Adults: A Retrospective Case Series.

Macrophage activation syndrome (MAS) is a form of hemophagocytic lymphohistocytosis that occurs in patients with a variety of inflammatory rheumatologic conditions. Traditionally, it is noted in pediatric patients with systemic juvenile idiopathic arthritis and systemic lupus erythematous. It is a rapidly progressive and life-threatening syndrome of excess immune activation with an estimated mortality rate of 40% in children. It has become clear recently that MAS occurs in adult patients with underlying rheumatic inflammatory diseases. In this article, we describe 6 adult patients with likely underlying MAS. This case series will outline factors related to diagnosis, pathophysiology, and review present therapeutic strategies.

Mesenchymal stem cells to treat type 1 diabetes.

What is clear is we are in the era of the stem cell and its potential in ameliorating human disease. Our perspective is generated from an in vivo model in a large animal that offers significant advantages (complete transplantation tolerance, large size and long life span). This review is an effort to meld our preclinical observations with others for the reader and to outline potential avenues to improve the present outlook for patients with diabetes. This effort exams the history or background of stem cell research in the laboratory and the clinic, types of stem cells, pluripotency or lack thereof based on a variety of pre-clinical investigations attempting endocrine pancreas recovery using stem cell transplantation. The focus is on the use of hematopoietic and mesenchymal stem cells. This review will also examine recent clinical experience following stem cell transplantation in patients with type 1 diabetes.

Immune ontogeny and engraftment receptivity in the sheep fetus.

OBJECTIVE: The biologic explanation for fetal receptivity to donor engraftment and subsequent long-term tolerance following transplantation early in gestation is not known. We investigated the role fetal immune ontogeny might play in fetal transplantation tolerance in sheep. METHODS: Engraftment of allogeneic and xenogeneic HSC was determined 60 days following transplantation at different time points in sheep fetal gestation. Parallel analysis of surface differentiation antigen expression on cells from lymphoid organs of timed gestational age fetal sheep was determined by flow cytometry using available reagents. RESULTS: An engraftment window was identified after day 52 gestation lasting until day 71 (term gestation: 145 days). This period was associated with the expression of the leukocyte common antigen CD45 on all cells in the thymus. Double-positive and single-positive CD4 and CD8 cells began appearing in the thymus just prior (day 45 gestation) to the beginning of the engraftment window, while single-positive CD4 or CD8 cells do not begin appearing in peripheral organs until late in the engraftment period, suggesting deletional mechanisms may be operative. In concert, surface IgM-positive cells express CD45 in the thymus at day 45, with a comparable delay in the appearance of IgM/CD45 cells in the periphery until late in the engraftment window. CONCLUSIONS: These findings support a central role for the thymus in multilineage immune cell maturation during the period of fetal transplantation receptivity. Further, they suggest that fetal engraftment receptivity is due to gestational age-dependent deletional tolerance.

Transduction of long-term-engrafting human hematopoietic stem cells by retroviral vectors.

Gene therapy using retroviral vectors to transfer functional exogenous genes into hematopoietic stem cells (HSCs) promises to provide a permanent cure for a wide array of both hematopoietic and nonhematopoietic disorders by virtue of the fact that retroviral vectors permanently integrate into the host cell genome and HSCs are able to self-renew and give rise to differentiated progeny throughout the life span of the patient. However, for transduction and genomic integration to occur, the target cells must undergo cell division and express the appropriate retroviral receptor, requirements that have thus far hindered attempts at inserting exogenous genes into human HSCs in vitro. In the present studies, we used the fetal sheep xenograft model of human hematopoiesis to evaluate whether human long-term engrafting HSCs could be transduced in vivo, within a fetal microenvironment. We transplanted adult human bone marrow-derived CD34(+)Lin(-) cells into preimmune fetal sheep recipients and subsequently (19 days later) administered clinical-grade murine retroviral vector supernatants to these fetal hematopoietic chimeras. Our results demonstrate that this approach successfully transduced adult human HSCs within all seven sheep that survived the procedure, and that these transduced HSCs had the ability to serially engraft primary, secondary, and tertiary fetal sheep recipients. Transgene expression persisted throughout the serial transplantation. The successful in vivo transduction of long-term engrafting human HSCs with the existing generation of murine retroviral vectors has significant implications for developing new approaches to pre- and postnatal gene therapy.

In utero transplantation: Disparate ramifications.

In utero stem cell transplantation, which promises treatment for a host of genetic disorders early in gestation before disease effect stems from Ray Owen's seminal observation that self-tolerance, is acquired during gestation. To date, in utero transplantation (IUT) has proved useful in characterizing the hematopoietic stem cell. Recent observations support its use as an in vivo method to further understanding of self-tolerance. Preclinical development continues for its application as a treatment for childhood hematolymphoid diseases. In addition, IUT may offer therapeutic options in the treatment of diabetes among other diseases. Thus IUT serves as a technique or system important in both a basic and applied format. This review summarizes these findings.

Persistent circulating human insulin in sheep transplanted in utero with human mesenchymal stem cells.

OBJECTIVE: To determine if mesenchymal stem cells (MSC) derived from human fetal pancreatic tissue (pMSC) would engraft and differentiate in sheep pancreas following transplantation in utero. MATERIALS AND METHODS: A three-step culture system was established for generating human fetal pMSC. Sheep fetuses were transplanted during the fetal transplant receptivity period with human pMSC and evaluated for in situ and functional engraftment in their pancreas, liver, and bone marrow. RESULTS: Isolation and expansion of adherent cells from the human fetal pancreas yielded a cell population with morphologic and phenotypic characteristics similar to MSC derived from bone marrow. This putative stem cell population could undergo multilineage differentiation in vitro. Three to 27 months after fetal transplantation, the pancreatic engraftment frequency (chimeric index) was 79%, while functional engraftment was noted in 50% of transplanted sheep. Hepatic and marrow engraftment and expression was noted as well. CONCLUSION: We have established a procedure for isolation of human fetal pMSC that display characteristics similar to bone marrow-derived MSC. In vivo results suggest the pMSC engraft, differentiate, and secrete human insulin from the sheep pancreas.

The effect of hypoxia and stem cell source on haemoglobin switching.

This study investigated whether relative changes that accompany the naturally occurring shifts in haematopoietic sites during human development play a role in haemoglobin (Hb) switching or whether Hb switching is innately programmed into cells. CD34(+)/Lineage(-) haematopoietic stem/progenitor cells (HSCs) were isolated from human fetal liver (F-LVR), cord blood (CB), and adult bone marrow (ABM), and the Hb was characterized by flow cytometry on cultures that generated enucleated red cells. All feeder layers (stroma from F-LVR, ABM, and human fetal aorta) enhanced cell proliferation and erythropoiesis but did not affect Hb type. HSCs from CB and F-LVR generated the same Hb profile under normoxia and hypoxia. HSCs from ABM had single-positive HbA and double-positive HbA and HbF cells at normoxia and almost entirely double-positive cells at hypoxia. Further characterization of these ABM cultures was determined by following mRNA expression for the transcription factors erythroid Kruppel-like factor (EKLF) and fetal Kruppel-like factor (FKLF) as a function of time in cultures under hypoxia and normoxia. The erythroid-specific isoform of 5-amino-levulinate synthase (ALAS2) was also expressed under hypoxic conditions. We conclude that Hb switching is affected by the environment but not all HSCs are preprogrammed to respond.