Bone Marrow Transplantation Reproduces the Tristetraprolin-Deficiency Syndrome in Recombination Activating Gene-2 (-/-) Mice: Evidence That Monocyte/Macrophage Progenitors May Be Responsible for TNFα Overproduction

Tristetraprolin-deficient [TTP (-/-)] mice exhibit a complex syndrome of myeloid hyperplasia, cachexia, dermatitis, autoimmunity, and erosive arthritis. Virtually the entire syndrome can be prevented by the repeated injection of anti-TNFα antibodies (Taylor, G.A., E. Carballo, D.M. Lee, W.S. Lai, M.J. Thompson, D.D. Patel, D.I. Schenkman, G.S. Gilkeson, H.E. Broxmeyer, B.F. Haynes, and P.J. Blackshear. 1996. Immunity. 4:445–454). In the present study, we transplanted bone marrow from TTP (-/-) and (+/+) mice into recombination activating gene-2 (-/-) mice. After a lag period of several months, marrow transplantation from the (-/-) but not the (+/+) mice resulted in the full syndrome associated with TTP deficiency, suggesting that hematopoietic progenitors are responsible for the development of the syndrome. Western blot analysis of supernatants from cultured TTP-deficient macrophages derived from the peritoneal cavity or bone marrow of adult TTP (-/-) mice, or from fetal liver, demonstrated an increased accumulation of TNFα after stimulation with LPS compared to control cells, and also increased accumulation of TNFα mRNA. This difference was not observed with cultured fibroblasts or T and B lymphocytes. These data suggest that macrophages are among the cells responsible for the effective excess of TNFα that leads to the pathology reported in TTP (-/-) animals, and that macrophage progenitors may be involved in the transplantability of this syndrome

Confidence intervals for ranks of age-adjusted rates across states or counties

Health indices provide information to the general public on the health condition of the community. They can also be used to inform the government’s policy making, to evaluate the effect of a current policy or healthcare program, or for program planning and priority setting. It is a common practice that the health indices across different geographic units are ranked and the ranks are reported as fixed values. We argue that the ranks should be viewed as random and hence should be accompanied by an indication of precision (i.e., the confidence intervals). A technical difficulty in doing so is how to account for the dependence among the ranks in the construction of confidence intervals. In this paper, we propose a novel Monte Carlo method for constructing the individual and simultaneous confidence intervals of ranks for age-adjusted rates. The proposed method uses as input age-specific counts (of cases of disease or deaths) and their associated populations. We have further extended it to the case in which only the age-adjusted rates and confidence intervals are available. Finally, we demonstrate the proposed method to analyze US age-adjusted cancer incidence rates and mortality rates for cancer and other diseases by states and counties within a state using a website that will be publicly available. The results show that for rare or relatively rare disease (especially at the county level), ranks are essentially meaningless because of their large variability, while for more common disease in larger geographic units, ranks can be effectively utilized

Allogenic Mesenchymal Stem Cell Transplantation Ameliorates Nephritis in Lupus Mice Via Inhibition of B-Cell Activation

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Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: A pilot clinical study

Objective: To determine the safety and efficacy of allogeneic mesenchymal stem cell transplantation (MSCT) in refractory systemic lupus erythematosus (SLE). Methods: A total of 15 patients with persistently active SLE underwent MSCT. Outcome was evaluated by changes in the SLE disease activity index (SLEDAI), serological features (anti-nuclear antibodies and antidouble-stranded DNA (anti-dsDNA)), renal function and percentage of peripheral blood regulatory T cells. Results: From 11 March 2007 to 4 November 2008, 15 patients with persistently active SLE were enrolled and underwent MSCT. The mean follow-up period was 17.2±9.5 months. A total of 13 patients have been followed for more than 12 months. All patients clinically improved following treatment with mesenchymal stem cells with a marked decrease in the SLEDAI score and 24 h proteinuria. At 12-month follow-up, SLEDAI scores decreased from 12.2±3.3 to 3.2±2.8 and proteinuria decreased from 2505.0±1323.9 to 858.0±800.7 mg/24 h (all p<0.05, by paired t test, n=12). At 1-year follow-up in 13 patients, 2 had a relapse of proteinuria, while the other 11 continue to have decreased disease activity on minimal treatment. Anti-dsDNA levels decreased. Improvement in glomerular filtration rate was noted in two patients in which formal testing was performed. Non-renal-related manifestations also improved significantly. No serious adverse events were reported. Conclusion: Allogeneic MSCT in patients with refractory lupus resulted in amelioration of disease activity, improvement in serological markers and stabilisation of renal function. MSCT appears beneficial in treatment of patients with SLE refractory to conventional treatment options.published_or_final_versio

Allogeneic mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus: 4 years of experience

Mesenchymal stem cells (MSCs) are multipotential nonhematopoietic progenitors and are capable of differentiating into several tissues of mesenchymal origin. We have shown that bone marrow-derived MSCs from both SLE patients and lupus-prone MRL/lpr mice are defective structurally and functionally. Here we observe the long-term safety and efficacy of allogeneic MSC transplantation (MSCT) in treatment-resistant SLE patients. Eighty-seven patients with persistently active SLE who were refractory to standard treatment or had life-threatening visceral involvement were enrolled. Allogeneic bone marrow or umbilical cord-derived MSCs were harvested and infused intravenously (1 × 10(6) cells/kg of body weight). Primary outcomes were rates of survival, disease remission and relapse, as well as transplantation-related adverse events. Secondary outcomes included SLE disease activity index (SLEDAI) and serologic features. During the 4-year follow-up and with a mean follow-up period of 27 months, the overall rate of survival was 94% (82/87). Complete clinical remission rate was 28% at 1 year (23/83), 31% at 2 years (12/39), 42% at 3 years (5/12), and 50% at 4 years (3/6). Rates of relapse were 12% (10/83) at 1 year, 18% (7/39) at 2 years, 17% (2/12) at 3 years, and 17% (1/6) at 4 years. The overall rate of relapse was 23% (20/87). Disease activity declined as revealed by significant changes in the SLEDAI score, levels of serum autoantibodies, albumin, and complements. A total of five patients (6%) died after MSCT from non-treatment-related events in the 4-year follow-up, and no transplantation-related adverse event was observed. Allogeneic MSCT resulted in the induction of clinical remission and improvement in organ dysfunction in drug-resistant SLE patients.published_or_final_versio

Methylated BSA Mimics Amyloid-Related Proteins and Triggers Inflammation

The mechanistic study of inflammatory or autoimmune diseases requires the generation of mouse models that reproduce the alterations in immune responses observed in patients. Methylated bovine serum albumin (mBSA) has been widely used to induce antigen-specific inflammation in targeted organs or in combination with single stranded DNA (ssDNA) to generate anti-nucleic acids antibodies in vivo. However, the mechanism by which this modified protein triggers inflammation is poorly understood. By analyzing the biochemical properties of mBSA, we found that mBSA exhibits features of an intermediate of protein misfolding pathway. mBSA readily interact with a list of dyes that have binding specificity towards amyloid fibrils. Intriguingly, mBSA displayed cytotoxic activity and its binding to ssDNA further enhanced formation of beta-sheet rich amyloid fibrils. Moreover, mBSA is recognized by the serum amyloid P, a protein unanimously associated with amyloid plaques in vivo. In macrophages, we observed that mBSA disrupted the lysosomal compartment, signaled along the NLRP3 inflammasome pathway, and activated caspase 1, which led to the production of IL-1β. In vivo, mBSA triggered rapid and prominent immune cell infiltration that is dependent on IL-1β induction. Taken together, these data demonstrate that by mimicking amyloidogenic proteins mBSA exhibits strong innate immune functions and serves as a potent adjuvant. These findings advance our understanding on the underlying mechanism of how aberrant immune responses lead to autoimmune reactions

Fatal stroke after completion pneumonectomy for torsion of left upper lobe following left lower lobectomy

BACKGROUND: The lobar torsion after lung surgery is a rare complication with an incidence of 0.09 to 0.4 %. It may occur after twisting of the bronchovascular pedicle of the remaining lobe after lobectomy, usually on the right side. The 180-degree rotation of the pedicle produces an acute obstruction of the lobar bronchus (atelectasis) and of the lobar vessels as well. Without prompt treatment it progresses to lobar ischemia, pulmonary infarction and finally fatal gangrene. CASE PRESENTATION: A 62 years old female patient was admitted for surgical treatment of lung cancer. She underwent elective left lower lobectomy for squamous cell carcinoma (pT2 N0). The operation was unremarkable, and the patient was extubated in the operating room. After eight hours the patient established decrease of pO(2 )and chest x-ray showed atelectasis of the lower lobe. To establish diagnosis, bronchoscopy was performed, demonstrating obstructed left lobar bronchus. The patient was re-intubated, and admitted to the operating room where reopening of the thoracotomy was performed. Lobar torsion was diagnosed, with the diaphragmatic surface of the upper lobe facing in an anterosuperior orientation. A completion pneumonectomy was performed. At the end of the procedure the patient developed a right pupil dilatation, presumably due to a cerebral embolism. A subsequent brain angio-CT scan established the diagnosis. She died at the intensive care unit 26 days later. CONCLUSION: The thoracic surgeon should suspect this rare early postoperative complication after any thoracic operation in every patient with atelectasis of the neighboring lobe. High index of suspicion and prompt diagnosis may prevent catastrophic consequences, such as, infarction or gangrene of the pulmonary lobe. During thoracic operations, especially whenever the lung or lobe hilum is full mobilized, fixation of the remaining lobe may prevent this life threatening complication

Georgia Abortion Law and Our Commitment to Patients

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153775/1/art41143.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153775/2/art41143_am.pd