Effects of Mesenchymal Stem Cell and Growth Factor Delivery on Cartilage Repair in a Mini-Pig Model

Objective We have recently shown that mesenchymal stem cells (MSCs) embedded in a hyaluronic acid (HA) hydrogel and exposed to chondrogenic factors (transforming growth factor-3 [TGF-3]) produce a cartilage-like tissue in vitro. The current objective was to determine if these same factors could be combined immediately prior to implantation to induce a superior healing response in vivo relative to the hydrogel alone. Design Trochlear chondral defects were created in Yucatan mini-pigs (6 months old). Treatment groups included an HA hydrogel alone and hydrogels containing allogeneic MSCs, TGF-3, or both. Six weeks after surgery, micro-computed tomography was used to quantitatively assess defect fill and subchondral bone remodeling. The quality of cartilage repair was assessed using the ICRS-II histological scoring system and immunohistochemistry for type II collagen. Results Treatment with TGF-3 led to a marked increase in positive staining for collagen type II within defects (P 0.05). Neither condition had an impact on other histological semiquantitative scores (P > 0.05), and inclusion of MSCs led to significantly less defect fill (P 0.05). Conclusions At this early healing time point, treatment with TGF-3 promoted the formation of collagen type II within the defect, while allogeneic MSCs had little benefit. Combination of TGF-3 and MSCs at the time of surgery did not produce a synergistic effect. An in vitro precultured construct made of these components may be required to enhance in vivo repair in this model system

Effects of Mesenchymal Stem Cell and Growth Factor Delivery on Cartilage Repair in a Mini-Pig Model

We have recently shown that mesenchymal stem cells (MSCs) embedded in a hyaluronic acid (HA) hydrogel and exposed to chondrogenic factors (transforming growth factor–β3 [TGF-β3]) produce a cartilage-like tissue in vitro. The current objective was to determine if these same factors could be combined immediately prior to implantation to induce a superior healing response in vivo relative to the hydrogel alone

Enhanced CO2 outgassing in the Southern Ocean from a positive phase of the Southern Annular Mode

Author Posting. © American Geophysical Union, 2007. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Global Biogeochemical Cycles 21 (2007): GB2026, doi:10.1029/2006GB002900.We investigate the interannual variability in the flux of CO2 between the atmosphere and the Southern Ocean on the basis of hindcast simulations with a coupled physical-biogeochemical-ecological model with particular emphasis on the role of the Southern Annular Mode (SAM). The simulations are run under either pre-industrial or historical CO2 concentrations, permitting us to separately investigate natural, anthropogenic, and contemporary CO2 flux variability. We find large interannual variability (±0.19 PgC yr−1) in the contemporary air-sea CO2 flux from the Southern Ocean (<35°S). Forty-three percent of the contemporary air-sea CO2 flux variance is coherent with SAM, mostly driven by variations in the flux of natural CO2, for which SAM explains 48%. Positive phases of the SAM are associated with anomalous outgassing of natural CO2 at a rate of 0.1 PgC yr−1 per standard deviation of the SAM. In contrast, we find an anomalous uptake of anthropogenic CO2 at a rate of 0.01 PgC yr−1 during positive phases of the SAM. This uptake of anthropogenic CO2 only slightly mitigates the outgassing of natural CO2, so that a positive SAM is associated with anomalous outgassing in contemporaneous times. The primary cause of the natural CO2 outgassing is anomalously high oceanic partial pressures of CO2 caused by elevated dissolved inorganic carbon (DIC) concentrations. These anomalies in DIC are primarily a result of the circulation changes associated with the southward shift and strengthening of the zonal winds during positive phases of the SAM. The secular, positive trend in the SAM has led to a reduction in the rate of increase of the uptake of CO2 by the Southern Ocean over the past 50 years.This work was supported by NASA headquarters under the Earth System Science Fellowship Grant NNG05GP78H to N. S. L. and grants NAG5-12528 and NNG04GH53G to N. G. Both S. C. D. and I. D. L. were supported by NSF/ONR NOPP (N000140210370) and NASA (NNG05GG30G)

Episodic homelessness and health care utilization in a prospective cohort of HIV-infected persons with alcohol problems

BACKGROUND: Because individuals with HIV/AIDS often have complex medical and social needs, the impact of housing status on medical service utilization is difficult to isolate from the impact of conditions that may worsen during periods of homelessness such as depression and substance abuse. We examine whether episodes of homelessness are independently associated with suboptimal medical utilization even when accounting for concurrent addiction severity and depression. METHODS: We used data from a 30-month cohort of patients with HIV/AIDS and alcohol problems. Housing status, utilization (ambulatory visits, emergency department (ED) visits, and hospitalizations) and other features were assessed with standardized research interviews at 6-month intervals. Multivariable longitudinal regression models calculated incidence rate ratios (IRR) comparing utilization rates during 6-month intervals (homeless versus housed). Additional models assessed whether addiction severity and depressive symptoms could account for utilization differences. RESULTS: Of the 349 subjects, 139 (39%) reported homelessness at least once during the study period; among these subjects, the median number of nights homeless per 6-month interview period was 30. Homelessness was associated with higher ED utilization (IRR = 2.17; 95% CI = 1.72–2.74) and hospitalizations (IRR = 2.30; 1.70–3.12), despite no difference in ambulatory care utilization (IRR = 1.09; 0.89–1.33). These associations were attenuated but remained significant when adjusting for addiction severity and depressive symptoms. CONCLUSION: In patients with HIV/AIDS and alcohol problems, efforts to improve housing stability may help to mitigate intensive medical utilization patterns

Persistent STAT5 phosphorylation and epigenetic dysregulation of GM-CSF and PGS2/COX2 expression in Type 1 diabetic human monocytes.

STAT5 proteins are adaptor proteins for histone acetylation enzymes. Histone acetylation at promoter and enhancer chromosomal regions opens the chromatin and allows access of transcription enzymes to specific genes in rapid response cell signals, such as in inflammation. Histone acetylation-mediated gene regulation is involved in expression of 2 key inflammatory response genes: CSF2, encoding granulocyte-macrophage colony stimulating factor (GM-CSF), and PTGS2, encoding prostaglandin synthase 2/cyclooxygenase 2 (PGS2/COX2). Prolonged CSF2 expression, high GM-CSF production, and GM-CSF activation of PTGS2 gene expression all are seen in type 1 diabetes (T1D) monocytes. Persistent phosphorylation activation of monocyte STAT5 (STAT5Ptyr) is also found in individuals with or at-risk for T1D. To examine whether elevated T1D monocyte STAT5Ptyr may be associated with aberrant inflammatory gene expression in T1D, blood monocytes from non-autoimmune controls and T1D patients were analyzed by flow cytometry for STAT5Ptyr activation, and by chromatin immuno-precipitation (ChIP) analyses for STAT5Ptyr's ability to bind at CSF2 and PTGS2 regulatory sites in association with histone acetylation. In unstimulated monocytes, STAT5Ptyr was elevated in 59.65% of T1D, but only 2.44% of control subjects (p<0.0001). Increased STAT5Ptyr correlated with T1D disease duration (p = 0.0030, r(2) = 0.0784). Unstimulated (p = 0.140) and GM-CSF-stimulated (p = 0.0485) T1D monocytes, had greater STAT5Ptyr binding to epigenetic regulatory sites upstream of CSF2 than control monocytes. Increased STAT5Ptyr binding in T1D monocytes was concurrent with binding at these sites of STAT6Ptyr (p = 0.0283), CBP/P300 histone acetylase, acetylated histones H3, SMRT/NCoR histone deacetylase (p = 0.0040), and RNA Polymerase II (p = 0.0040). Our study indicates that in T1D monocytes, STAT5Ptyr activation is significantly higher and that STAT5Ptyr is found bound to CSF2 promoter and PTGS2 enhancer regions coincident with histone acetylation and RNA polymerase II. These findings suggest that the persistent activation of STAT5 by GM-CSF may be involved in altering the epigenetic regulation of these inflammatory response genes in T1D monocytes

Effects of Mesenchymal Stem Cell and Growth Factor Delivery on Cartilage Repair in a Mini-Pig Model

OBJECTIVE: We have recently shown that mesenchymal stem cells (MSCs) embedded in a hyaluronic acid (HA) hydrogel and exposed to chondrogenic factors (transforming growth factor–β3 [TGF-β3]) produce a cartilage-like tissue in vitro. The current objective was to determine if these same factors could be combined immediately prior to implantation to induce a superior healing response in vivo relative to the hydrogel alone. DESIGN: Trochlear chondral defects were created in Yucatan mini-pigs (6 months old). Treatment groups included an HA hydrogel alone and hydrogels containing allogeneic MSCs, TGF-β3, or both. Six weeks after surgery, micro-computed tomography was used to quantitatively assess defect fill and subchondral bone remodeling. The quality of cartilage repair was assessed using the ICRS-II histological scoring system and immunohistochemistry for type II collagen. RESULTS: Treatment with TGF-β3 led to a marked increase in positive staining for collagen type II within defects (P < 0.05), while delivery of MSCs did not (P > 0.05). Neither condition had an impact on other histological semiquantitative scores (P > 0.05), and inclusion of MSCs led to significantly less defect fill (P < 0.05). For all measurements, no synergistic interaction was found between TGF-β3 and MSC treatment when they were delivered together (P > 0.05). CONCLUSIONS: At this early healing time point, treatment with TGF-β3 promoted the formation of collagen type II within the defect, while allogeneic MSCs had little benefit. Combination of TGF-β3 and MSCs at the time of surgery did not produce a synergistic effect. An in vitro precultured construct made of these components may be required to enhance in vivo repair in this model system

PREDICT HF: Risk stratification in advanced heart failure using novel hemodynamic parameters

Background: Invasive hemodynamics are fundamental in assessing patients with advanced heart failure (HF). Several novel hemodynamic parameters have been studied; however, the relative prognostic potential remains ill-defined. Hypothesis: Advanced hemodynamic parameters provide additional prognostication beyond the standard hemodynamic assessment. Methods: Patients from the PRognostic Evaluation During Invasive CaTheterization for Heart Failure (PREDICT-HF) registry who underwent right heart catheterization (RHC) were included in the analysis. The primary endpoint was survival to orthotopic heart transplant (OHT) or durable left ventricular assist device (LVAD), or death within 6 months of RHC. Results: Of 846 patients included, 176 (21%) met the primary endpoint. In a multivariate model that included traditional hemodynamic variables, pulmonary capillary wedge pressure (PCWP) (OR: 1.10, 1.04-1.15, p Conclusion: The advanced hemodynamic parameters API and CPO are independently associated with death or the need for OHT or LVAD within 6 months. Further prospective studies are needed to validate these parameters and elucidate their role in patients with advanced HF.</p