Publications

Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed. We report that Cre under control of the promoter of Pdgfrb (Pdgfrb-Cre) inactivates loxP-flanked genes in mouse HSCs with high efficiency. We used this system to delete the gene encoding α(v) integrin subunit because various α(v)-containing integrins have been suggested as central mediators of fibrosis in multiple organs. Such depletion protected mice from carbon tetrachloride-induced hepatic fibrosis, whereas global loss of β₃, β₅ or β₆ integrins or conditional loss of β₈ integrins in HSCs did not. We also found that Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of the α(v) integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis. Pharmacological blockade of α(v)-containing integrins by a small molecule (CWHM 12) attenuated both liver and lung fibrosis, including in a therapeutic manner. These data identify a core pathway that regulates fibrosis and suggest that pharmacological targeting of all α(v) integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.

In multicellular organisms, transcription regulation is one of the central mechanisms modelling lineage differentiation and cell-fate determination. Transcription requires dynamic chromatin configurations between promoters and their corresponding distal regulatory elements. It is believed that their communication occurs within large discrete foci of aggregated RNA polymerases termed transcription factories in three-dimensional nuclear space. However, the dynamic nature of chromatin connectivity has not been characterized at the genome-wide level. Here, through a chromatin interaction analysis with paired-end tagging approach using an antibody that primarily recognizes the pre-initiation complexes of RNA polymerase II, we explore the transcriptional interactomes of three mouse cells of progressive lineage commitment, including pluripotent embryonic stem cells, neural stem cells and neurosphere stem/progenitor cells. Our global chromatin connectivity maps reveal approximately 40,000 long-range interactions, suggest precise enhancer-promoter associations and delineate cell-type-specific chromatin structures. Analysis of the complex regulatory repertoire shows that there are extensive colocalizations among promoters and distal-acting enhancers. Most of the enhancers associate with promoters located beyond their nearest active genes, indicating that the linear juxtaposition is not the only guiding principle driving enhancer target selection. Although promoter-enhancer interactions exhibit high cell-type specificity, promoters involved in interactions are found to be generally common and mostly active among different cells. Chromatin connectivity networks reveal that the pivotal genes of reprogramming functions are transcribed within physical proximity to each other in embryonic stem cells, linking chromatin architecture to coordinated gene expression. Our study sets the stage for the full-scale dissection of spatial and temporal genome structures and their roles in orchestrating development.

Cor triatriatum is a rare congenital heart defect in which a fibromuscular membrane forms an anomalous septum within the left atrium, dividing it into a posterosuperior higher pressure chamber and an anteroinferior anatomically true left atrium. Typically, in cor triatriatum, all four pulmonary veins enter into this accessory chamber, we present an unusual variant of cor triatriatum, in which only the right sided pulmonary veins were involved.

BACKGROUND

Venoarterial extracorporeal membrane oxygenation (ECMO) has been used successfully for treatment of cardiogenic shock or cardiac arrest. The exact complication rate is not well understood, in part because of small study sizes. In the absence of large clinical trials, performance of pooled analysis represents the best method for ascertaining complication rates for ECMO.

METHODS

A systematic PubMed search was conducted on ECMO for treatment of cardiogenic shock or cardiac arrest in adult patients only, updated to November 2012. Studies with more than 10 patients published in the year 2000 or later that reported complication rates for ECMO were included. Specific complications analyzed included lower extremity ischemia, fasciotomy or compartment syndrome, amputation, stroke, neurologic complications, acute kidney injury, renal replacement therapy, major or significant bleeding, rethoracotomy for bleeding or tamponade, and significant infection. For studies that included overlapping patients, the largest study was included and the others excluded. Cochran's Q and I-squared were calculated. A more conservative random-effects model was chosen for all analyses.

RESULTS

Twenty studies were included in the analyses encompassing 1,866 patients. Seventeen studies reported survival to hospital discharge, with a cumulative survival rate of 534 of 1,529, and a range of 20.8% to 65.4%. Analyses encompassed 192 to 1,452 patients depending on the specific complication analyzed. The pooled estimate rates of complications with 95% confidence intervals were as follows: lower extremity ischemia, 16.9% (12.5% to 22.6%); fasciotomy or compartment syndrome, 10.3% (7.3% to 14.5%); lower extremity amputation, 4.7% (2.3% to 9.3%); stroke, 5.9% (4.2% to 8.3%); neurologic complications, 13.3% (9.9% to 17.7%); acute kidney injury, 55.6% (35.5% to 74.0%); renal replacement therapy, 46.0% (36.7% to 55.5%); major or significant bleeding, 40.8% (26.8% to 56.6%); rethoracotomy for bleeding or tamponade in postcardiotomy patients, 41.9% (24.3% to 61.8%); and significant infection, 30.4% (19.5% to 44.0%).

CONCLUSIONS

Although ECMO can improve survival of patients with advanced heart disease, there is significant associated morbidity with performance of this intervention. These findings should be incorporated in the risk-benefit analysis when initiation of ECMO for cardiogenic shock is being considered.

BACKGROUND

Due to the significantly high levels of comorbid substance use and mental health diagnosis among urban poor populations, examining the intersection of drug policy and place requires a consideration of the role of housing in drug user mental health. In San Francisco, geographic boundedness and progressive health and housing polices have coalesced to make single room occupancy hotels (SROs) a key urban built environment used to house poor populations with co-occurring drug use and mental health issues. Unstably housed women who use illicit drugs have high rates of lifetime and current trauma, which manifests in disproportionately high rates of post-traumatic stress disorder (PTSD), anxiety, and depression when compared to stably housed women.

METHODS

We report data from a qualitative interview study (n=30) and four years of ethnography conducted with housing policy makers and unstably housed women who use drugs and live in SROs.

RESULTS

Women in the study lived in a range of SRO built environments, from publicly funded, newly built SROs to privately owned, dilapidated buildings, which presented a rich opportunity for ethnographic comparison. Applying Rhodes et al.'s framework of socio-structural vulnerability, we explore how SROs can operate as "mental health risk environments" in which macro-structural factors (housing policies shaping the built environment) interact with meso-level factors (social relations within SROs) and micro-level, behavioral coping strategies to impact women's mental health. The degree to which SRO built environments were "trauma-sensitive" at the macro level significantly influenced women's mental health at meso- and micro-levels. Women who were living in SROs which exacerbated fear and anxiety attempted, with limited success, to deploy strategies on the meso- and micro-level to manage their mental health symptoms.

CONCLUSION

Study findings underscore the importance of housing polices which consider substance use in the context of current and cumulative trauma experiences in order to improve quality of life and mental health for unstably housed women.