Gender bias in cultural tightness across the 50 US states, its correlates, and links to gender inequality in leadership and innovation.

Cultural tightness theory, which holds that "tight" cultures have rigid norms and sanctions, provides unique insights into cultural variations. However, current theorizing has not analyzed gender differences in cultural tightness. Addressing this gap, this research shows that women are more constrained than men by norms within the same society. By recruiting 15,425 respondents, we mapped state-level gender bias in cultural tightness across the United States. Variability in gender bias in cultural tightness was associated with state-level sociopolitical factors (religion and political ideology) and gender-related threats. Gender bias in cultural tightness was positively associated with state-level gender inequality in (business and political) leadership and innovation, two major challenges faced by women professionals. Overall, this research advances cultural tightness theory and offers a cultural norms account on persistent gender inequalities in society.

Pharmacological PINK1 activation ameliorates Pathology in Parkinson's Disease models.

PINK1 loss-of-function mutations and exposure to mitochondrial toxins are causative for Parkinson's disease (PD) and Parkinsonism, respectively. We demonstrate that pathological α-synuclein deposition, the hallmark pathology of idiopathic PD, induces mitochondrial dysfunction and impairs mitophagy, driving accumulation of the PINK1 substrate pS65-Ubiquitin (pUb) in primary neurons and in vivo. We synthesized MTK458, a brain penetrant small molecule that binds to PINK1 and stabilizes an active heterocomplex, thereby increasing mitophagy. MTK458 mediates clearance of α-synuclein pathology in PFF seeding models in vitro and in vivo and reduces pUb. We developed an ultrasensitive assay to quantify pUb levels in plasma and observed an increase in pUb in PD subjects that correlates with disease progression, paralleling our observations in PD models. Our combined findings from preclinical PD models and patient biofluids suggest that pharmacological activation of PINK1 is worthy of further study as a therapeutic strategy for disease modification in PD. Highlights: Discovery of a plasma Parkinson's Disease biomarker candidate, pS65-Ubiquitin (pUb)Plasma pUb levels correlate with disease status and progression in PD patients.Identification of a potent, brain penetrant PINK1 activator, MTK458MTK458 selectively activates PINK1 by stimulating dimerization and stabilization of the PINK1/TOM complexMTK458 drives clearance of α-synuclein pathology and normalizes pUb in in vivo Parkinson's models.

Do Credit Momentum Policies Through the 15 to Finish Improve Academic Progression and Completion of Low-Income, First-Generation Students? Evidence from a College Promise Program.

Credit momentum policies, or performance-based financial aid policies, have become increasingly popular among policymakers seeking to improve degree completion rates. This paper examines Indiana's 30-credit-hour completion policy on first-time, full-time students who receive the Twenty-First Century Scholars (TFCS) Promise Program. Using administrative data from the Indiana University's University Institutional Research and Reporting, representing 7842 low-income students who enrolled shortly before the policy was implemented, I use a difference-in-differences framework to explore the heterogeneous treatment effects of a credit (academic) momentum policy that was supported by the Complete College America 15 to Finish initiative on the academic progression and completion of promise scholarship recipients at Indiana University Bloomington and Indiana University-Purdue University, Indianapolis, compared to non-TFCS Pell recipients from the Fall 2011 cohorts through the Fall 2014 cohorts. I find some evidence to suggest that credit momentum policies are associated with small increases in cumulative credits and grades but had no effect on degree completion status (Year 4 Graduation Status, Year 6 Graduation Status). I also find evidence that TFCS female and first-generation recipients responded positively to the policy change but find no evidence that the policy affects promise recipients differently by race/ethnicity. While consistent with prior work on credit momentum, these findings are among the first to explore the academic performance of college promise recipients. Together, these findings indicate that credit momentum policies may improve academic progression and completion for low-income, first-generation students who receive a promise scholarship. Implications for policy and research are discussed.

Safety net, gateway, market, sport, and war: Exploring how emergency physicians conceptualize and ascribe meaning to emergency care.

BACKGROUND: Metaphorical expressions and conceptualisations are widely used in medical discourse to convey complex and abstract concepts. Our study uses a novel way to examine the spontaneous use of metaphors by emergency physicians as they articulate their experiences of practicing emergency care. These co-constructions shed light on the values and beliefs that shape their emergency care practice. METHODS: We invited 25 Taiwanese emergency physicians to participate in one-to-one semi-structured interviews. RESULTS: Drawing on social constructionism theory, systematic metaphor analysis method and Metaphor Identification Procedure (MIP) we identified metaphorical linguistic expressions in their talk, grouping them into five-overarching conceptual metaphors. We argue that these metaphors underpin emergency physicians' experiences of practicing emergency medical care: Safety Net, Gateway, Market, War, and Sport. DISCUSSION: The Safety Net, Gateway, and Market conceptualisations highlight physician-patient relationships and the social mission, resource allocation, and consumerism aspects of emergency care practice. The Sport and War conceptualisations highlight the physician-physician relationship and the demanding, team-based nature of emergency care practice. CONCLUSION: We propose that the choice of metaphorical conceptualisation deployed by emergency physicians has implications on their embodiment of professional identities. This discussion of using metaphors to study professional identities contributes to the literature concerned with finding creative and innovative ways to research identities. Future studies may utilize metaphors to gain a comprehensive understanding of physicians' professional identities in other specialties.

Exploring emergency physicians' professional identities: a Q-method study.

Professional identities research in medical education has made significant contributions to the field. However, what comprises professional identities is rarely interrogated. This research tackles this relatively understudied component of professional identities research by understanding emergency medicine physicians' perspectives on the important elements that comprise their professional identities. Q-methodology was used to identify different clusters of viewpoints on professional identities; by extension, the core components that comprise emergency medicine physicians' professional identities are disclosed. Thirty-three emergency medicine physicians were recruited, through purposive sampling, from five hospitals across Taiwan. R software was used to analyse the Q-sorts, determine loadings on each viewpoint and formulate the viewpoint array. Analysis of interview data enhanced our understanding of these viewpoints. In total, twenty-five emergency medicine physicians loaded onto four distinct viewpoints, reflecting dominant perspectives of emergency medicine physicians' understanding of their professional identities. These distinct viewpoints demonstrated what emergency medicine physicians deemed significant in how they understood themselves. The viewpoints comprised: skills acquisition, capabilities and practical wisdom; coping ability and resilience; professional recognition and self-esteem; and wellbeing and quality of life. All viewpoints stressed the importance of trust between colleagues. These findings demonstrate the multitude of ways in which seemingly unified professional identities diverge across groups of individuals. An enhanced understanding of speciality work culture is gained. By understanding facets of professional identities, the development of future educational interventions and departmental initiatives, which might support key components of professional identities, can be explored.

Modification of a Constitutive to Glucose-Responsive Liver-Specific Promoter Resulted in Increased Efficacy of Adeno-Associated Virus Serotype 8-Insulin Gene Therapy of Diabetic Mice.

We have previously used a hepatotropic adeno-associated viral (AAV) vector with a modified human insulin gene to treat diabetic mice. The HLP (hybrid liver-specific promoter) used was constitutively active and non-responsive to glucose. In this study, we examined the effects of addition of glucose responsive elements (R3G) and incorporation of a 3' albumin enhancer (3'iALB) on insulin expression. In comparison with the original promoter, glucose responsiveness was only observed in the modified promoters in vitro with a 36 h lag time before the peak expression. A 50% decrease in the number of viral particles at 5 × 109 vector genome (vg)/mouse was required by AAV8-R3GHLP-hINSco to reduce the blood sugar level to near normoglycemia when compared to the original AAV8-HLP-hINSco that needed 1 × 1010 vg/mouse. The further inclusion of an 860 base-pairs 3'iALB enhancer component in the 3' untranslated region increased the in vitro gene expression significantly but this increase was not observed when the packaged virus was systemically injected in vivo. The addition of R3G to the HLP promoter in the AAV8-human insulin vector increased the insulin expression and secretion, thereby lowering the required dosage for basal insulin treatment. This in turn reduces the risk of liver toxicity and cost of vector production.

Examining the association of career stage and medical specialty with personality preferences - a cross-sectional survey of junior doctors and attending physicians from various specialties.

BACKGROUND: Personality preference research on medical students and physicians demonstrates that personality preferences may affect one's choice of specialty and transform over the course of one's academic career as well as during one's time spent in the clinical setting. The literature offers valuable methods for evaluating medical curricula, understanding medical specialties, and rethinking communication techniques between educators and learners. In line with this encompassing body of work, this study examines the personality preferences of junior doctors and attending physicians from various specialties to investigate how career stage and medical specialty are associated with personality preferences. METHOD: The Myers-Briggs Type Indicator (MBTI) was applied to assess the personality preferences of junior doctors (postgraduates year 1-3) and attending physicians from six major medical specialties. Participants completed a self-administered 93-item questionnaire, while a certified MBTI practitioner explained the personality dichotomies as well as facilitated the self-evaluation process and the questionnaire's interpretation. Contrasted dichotomous scores and radar plots were employed to illustrate the distinction between junior doctors and attending physicians' personality preferences. All analyses were performed using the SAS statistical software, while a Wilcoxon rank-sum test was used to quantify the polarisation of personality preferences between junior doctors and attending physicians. RESULTS: In total, 98 participants were recruited, of whom 59 were attending physicians and 39 were junior doctors. The most common personality types among the junior doctors were ESTJ (15.4%), INTP (12.8%), and ESFJ (10.3%), while among the attending physicians, the most common types were ISTJ (23.7%) and ESTJ (18.6%). Both junior doctors and attending physicians expressed personality preferences for sensing, thinking, and judging. However, compared to the junior doctors, more polarised personality preferences were noted among the attending physicians for sensing (p = 0.038), thinking (p = 0.032), and judging (p = 0.024). Moreover, junior doctors exhibited less distinct personality preferences in this study. CONCLUSION: Attending physicians and junior doctors exhibited greater personality inclinations for sensing, thinking, and judging, although the former expressed these personality preferences more strongly than the latter. These findings highlight that, amongst physicians, career stage is strongly associated with the expression of personality preferences.

Mapping cultural tightness and its links to innovation, urbanization, and happiness across 31 provinces in China.

We conduct a 3-y study involving 11,662 respondents to map cultural tightness-the degree to which a society is characterized by rules and norms and the extent to which people are punished or sanctioned when they deviate from these rules and norms-across 31 provinces in China. Consistent with prior research, we find that culturally tight provinces are associated with increased governmental control, constraints in daily life, religious practices, and exposure to threats. Departing from previous findings that tighter states are more rural, conservative, less creative, and less happy, cultural tightness in China is associated with urbanization, economic growth, better health, greater tolerance toward the LGBT (lesbian, gay, bisexual, and transgender) community, and gender equality. Further, analyzing about 3.85 million granted patents in China (1990-2013), we find that provinces with tighter cultures have lower rates of substantive/radical innovations yet higher rates of incremental innovations; individuals from culturally tighter provinces reported higher levels of experienced happiness.

Isolation of Plasma Lipoproteins as a Source of Extracellular RNA.

Plasma lipoproteins are essential vehicles of lipid distribution for cellular energy and structural requirements as well as for excretion of lipid excess. Imbalances in lipoprotein metabolism are known to contribute to metabolic diseases ranging from vascular inflammation and atherosclerosis to obesity and diabetes. The lipid and protein cargo carried by lipoprotein subclasses have long been the focus of studies exploring the contribution of plasma lipoproteins in health and in metabolic disorders. More recent studies have revealed the presence of noncoding RNA as a new form of cargo carried by plasma lipoproteins. Lipoprotein-associated microRNAs have been identified to distribute differentially among plasma lipoprotein subclasses and contribute to cellular signaling. These findings highlight plasma lipoprotein-associated RNA as a potential source of biological signaling and warrant a renewed interest in the study of plasma lipoprotein biology. This chapter describes principles and methods based on density ultracentrifugation and size exclusion chromatography for the isolation of plasma lipoproteins as a source of extracellular RNA.

Oestrogen receptor β ligand acts on CD11c+ cells to mediate protection in experimental autoimmune encephalomyelitis.

Oestrogen treatments are neuroprotective in a variety of neurodegenerative disease models. Selective oestrogen receptor modifiers are needed to optimize beneficial effects while minimizing adverse effects to achieve neuroprotection in chronic diseases. Oestrogen receptor beta (ERβ) ligands are potential candidates. In the multiple sclerosis model chronic experimental autoimmune encephalomyelitis, ERβ-ligand treatment is neuroprotective, but mechanisms underlying this neuroprotection remain unclear. Specifically, whether there are direct effects of ERβ-ligand on CD11c+ microglia, myeloid dendritic cells or macrophages in vivo during disease is unknown. Here, we generated mice with ERβ deleted from CD11c+ cells to show direct effects of ERβ-ligand treatment in vivo on these cells to mediate neuroprotection during experimental autoimmune encephalomyelitis. Further, we use bone marrow chimeras to show that ERβ in peripherally derived myeloid cells, not resident microglia, are the CD11c+ cells mediating this protection. CD11c+ dendritic cell and macrophages isolated from the central nervous system of wild-type experimental autoimmune encephalomyelitis mice treated with ERβ-ligand expressed less iNOS and T-bet, but more IL-10, and this treatment effect was lost in mice with specific deletion of ERβ in CD11c+ cells. Also, we extend previous reports of ERβ-ligand’s ability to enhance remyelination through a direct effect on oligodendrocytes by showing that the immunomodulatory effect of ERβ-ligand acting on CD11c+ cells is necessary to permit the maturation of oligodendrocytes. Together these results demonstrate that targeting ERβ signalling pathways in CD11c+ myeloid cells is a novel strategy for regulation of the innate immune system in neurodegenerative diseases. To our knowledge, this is the first report showing how direct effects of a candidate neuroprotective treatment on two distinct cell lineages (bone marrow derived myeloid cells and oligodendrocytes) can have complementary neuroprotective effects in vivo.awx315media15688130498001.

Efficacy of a series of alpha-pyrone derivatives against Leishmania (L.) infantum and Trypanosoma cruzi.

The neglected tropical diseases Chagas disease and leishmaniasis affect together more than 20 million people living mainly in developing countries. The mainstay of treatment is chemotherapy, however the drugs of choice, which include benznidazole and miltefosine, are toxic and have numerous side effects. Safe and effective therapies are urgently needed. Marine alpha-pyrones have been previously identified as scaffolds with potential antiprotozoan activities. In this work, using a phenotypic screen, twenty-seven examples of 3-substituted 4-hydroxy-6-methyl alpha-pyrones were synthesized and their antiparasitic efficacy evaluated against Leishmania (L.) infantum and Trypanosoma cruzi in order to evaluate structure-activity relationships within the series. The mechanism of action and the in vivo efficacy of the most selective compound against T. cruzi were evaluated using different techniques. In vitro data indicated that compounds 8, 15, 25, 26 and 28 presented IC50 values in the range between 13 and 54 µM against L. infantum intracellular amastigotes. Among them, hexanoyl substituted pyrone 8 was the most selective and potent, with a Selectivity Index (SI) > 14. Fifteen of the alpha-pyrones were effective against T. cruzi trypomastigotes, with 3-undecanoyl (11) and 3-tetradecanoyl (12) substituted pyrones being the most potent against trypomastigotes, with IC50 values of 1 and 2 µM, respectively, and SI higher than 70. Using flow cytometry and fluorescent-based assays, pyrone 12 was found to induce hyperpolarization of the mitochondrial membrane potential of T. cruzi, without affecting plasma membrane permeability. An experimental acute phase-murine model, demonstrated that in vivo dosing of 12 (30 mg/kg/day; 5 days), had no efficacy at the first parasitemia onset of T. cruzi, but reduced the second onset by 55% (p < 0.05), suggesting a delayed action in BALB/c mice. Additionally, a histopathology study demonstrated no toxic effects to the treated mice. The finding that several 3-substituted alpha-pyrones have in vitro efficacy against both L. infantum and T. cruzi, and that one analogue exhibited moderate and non-toxic in vivo efficacy against T. cruzi is encouraging, and suggests that this compound class should be explored as long-term treatments in experimental Chagas disease.

Direct sac puncture versus transarterial embolization of type II endoleaks: An evaluation and comparison of outcomes.

Purpose To determine the outcomes of type II endoleak embolization with aneurysm sac obliteration and whether the approach - direct sac puncture or transarterial - affects outcome. Methods A retrospective review of patients who underwent endovascular aneurysm repairs and subsequent type II endoleak embolization over 10 years was performed. Twenty-three patients (median age: 73 years, range: 40-88 years) underwent 35 embolizations. Embolization was performed with the goal of obliterating both the endoleak sac and feeding vessels. Embolization agents used include cyanoacrylate glue only (48%), glue and coils (36%), coils only (13%), and other (3%). Results Mean follow-up was 21.8 months. Patients underwent an average of 1.5 embolizations, with 35% requiring more than one. Technical success rate was 89%. Freedom from aneurysm sac expansion was achieved in 91%. Freedom from type II endoleak was accomplished in 70%. There were no ruptured aneurysms during the follow-up period. Direct sac puncture and transarterial approaches had similar incidences of aneurysm sac growth ( p = 0.74), persistent type II endoleak ( p = 0.32), and complications ( p = 0.64). However, direct sac puncture had significantly shorter fluoroscopy ( p < 0.001) and total procedure times ( p < 0.001) than transarterial embolizations. Conclusion Direct sac puncture and transarterial embolization of type II endoleak with aneurysm sac obliteration are similarly effective for the prevention of aneurysm sac growth. However, direct sac puncture is our preferred approach given its significantly shorter fluoroscopic and procedural times.

Immunosuppression With FTY720 Reverses Cardiac Dysfunction in Hypomorphic ApoE Mice Deficient in SR-BI Expression That Survive Myocardial Infarction Caused by Coronary Atherosclerosis.

AIMS: We recently reported that immunosuppression with FTY720 improves cardiac function and extends longevity in Hypomorphic ApoE mice deficient in scavenger receptor Type-BI expression, also known as the HypoE/SR-BI(­/­) mouse model of diet-induced coronary atherosclerosis and myocardial infarction (MI). In this study, we tested the impact of FTY720 on cardiac dysfunction in HypoE/SR-BI(­/­) mice that survive MI and subsequently develop chronic heart failure. METHODS/RESULTS: HypoE/SR-BI(­/­) mice were bred to Mx1-Cre transgenic mice, and offspring were fed a high-fat diet (HFD) for 3.5 weeks to provoke hyperlipidemia, coronary atherosclerosis, and recurrent MIs. In contrast to our previous study, hyperlipidemia was rapidly reversed by inducible Cre-mediated gene repair of the HypoE allele and switching mice to a normal chow diet. Mice that survived the period of HFD were subsequently given oral FTY720 in drinking water or not, and left ventricular (LV) function was monitored using serial echocardiography for up to 15 weeks. In untreated mice, LV performance progressively deteriorated. Although FTY720 treatment did not initially prevent a decline of heart function among mice 6 weeks after Cre-mediated gene repair, it almost completely restored normal LV function in these mice by 15 weeks. Reversal of heart failure did not result from reduced atherosclerosis as the burden of aortic and coronary atherosclerosis actually increased to similar levels in both groups of mice. Rather, FTY720 caused systemic immunosuppression as assessed by reduced numbers of circulating T and B lymphocytes. In contrast, FTY720 did not enhance the loss of T cells or macrophages that accumulated in the heart during the HFD feeding period, but it did enhance the loss of B cells soon after plasma lipid lowering. Moreover, FTY720 potently reduced the expression of matrix metalloproteinase-2 and genes involved in innate immunity-associated inflammation in the heart. CONCLUSIONS: Our data demonstrate that immunosuppression with FTY720 prevents postinfarction myocardial remodeling and chronic heart failure.

Cannabinoid hyperemesis syndrome: Marijuana is both antiemetic and proemetic.

Although marijuana is sometimes used to treat chemotherapy-induced nausea and vomiting, when used long-term it can have a paradoxical hyperemetic effect known as cannabinoid hyperemesis syndrome. Knowledge of this phenomenon may reduce the ordering of unnecessary and expensive investigations, as well as inappropriate medical and surgical treatment in patients presenting with recurrent vomiting of unknown cause. This article reviews the pathophysiology, clinical presentation, diagnosis, and management of this emerging condition.

Evaluation of percutaneous ultrasound-guided biopsies of solid mass lesions of the pancreas: a center's 10-year experience.

OBJECTIVE: To assess the efficacy and complication rates of percutaneous ultrasound (US)-guided pancreatic mass biopsy and to determine if location of the mass or method of biopsy affects efficacy. METHODS: Imaging, pathology, and clinical records of all patients undergoing percutaneous US-guided pancreatic mass sampling from January 2001 until November 2011 were reviewed. Of 88 pancreatic masses, 13 underwent fine needle aspiration (FNA) only, 60 underwent core needle biopsy only, and 15 underwent both. Diagnostic rate, sensitivity, specificity, accuracy, and positive predictive value and negative predictive value (NPV) based on location of the mass (head/neck vs. body/tail) and method of biopsy (core vs. FNA vs. combined) were determined. The final diagnosis was determined on the basis of follow-up imaging, clinical course, and/or surgical pathology. Complications were assessed by reviewing clinical notes and postprocedural imaging. RESULTS: The overall diagnostic rate, sensitivity, accuracy, and NPV of all 88 biopsies were 94%, 93%, 93%, and 57%, respectively. Five samples were nondiagnostic and considered false negatives. There were no false-positive biopsy results. No significant difference was observed in the diagnostic rate, sensitivity, accuracy, and NPV between core biopsies, FNAs, and combined core and FNA biopsies. Furthermore, no significant difference was found between head/neck and body/tail samplings. In 96.7% (85/88) of the cases, the procedure was uneventful. There were no major complications. CONCLUSIONS: Percutaneous US-guided sampling of pancreatic mass is safe and effective irrespective of location of the mass and method of biopsy.

A screen in mice uncovers repression of lipoprotein lipase by microRNA-29a as a mechanism for lipid distribution away from the liver.

UNLABELLED: Identification of microRNAs (miRNAs) that regulate lipid metabolism is important to advance the understanding and treatment of some of the most common human diseases. In the liver, a few key miRNAs have been reported that regulate lipid metabolism, but since many genes contribute to hepatic lipid metabolism, we hypothesized that other such miRNAs exist. To identify genes repressed by miRNAs in mature hepatocytes in vivo, we injected adult mice carrying floxed Dicer1 alleles with an adenoassociated viral vector expressing Cre recombinase specifically in hepatocytes. By inactivating Dicer in adult quiescent hepatocytes we avoided the hepatocyte injury and regeneration observed in previous mouse models of global miRNA deficiency in hepatocytes. Next, we combined gene and miRNA expression profiling to identify candidate gene/miRNA interactions involved in hepatic lipid metabolism and validated their function in vivo using antisense oligonucleotides. A candidate gene that emerged from our screen was lipoprotein lipase (Lpl), which encodes an enzyme that facilitates cellular uptake of lipids from the circulation. Unlike in energy-dependent cells like myocytes, LPL is normally repressed in adult hepatocytes. We identified miR-29a as the miRNA responsible for repressing LPL in hepatocytes, and found that decreasing hepatic miR-29a levels causes lipids to accumulate in mouse livers. CONCLUSION: Our screen suggests several new miRNAs are regulators of hepatic lipid metabolism. We show that one of these, miR-29a, contributes to physiological lipid distribution away from the liver and protects hepatocytes from steatosis. Our results, together with miR-29a's known antifibrotic effect, suggest miR-29a is a therapeutic target in fatty liver disease.

Characterization of Insulin-Secreting Porcine Bone Marrow Stromal Cells Ex Vivo and Autologous Cell Therapy In Vivo.

Cell therapy could potentially meet the need for pancreas and islet transplantations in diabetes mellitus that far exceeds the number of available donors. Bone marrow stromal cells are widely used in clinical trials mainly for their immunomodulatory effects with a record of safety. However, less focus has been paid to developing these cells for insulin secretion by transfection. Although murine models of diabetes have been extensively used in gene and cell therapy research, few studies have shown efficacy in large preclinical animal models. Here we report optimized conditions for ex vivo expansion and characterization of porcine bone marrow stromal cells and their permissive expression of a transfected insulin gene. Our data show that these cells resemble human bone marrow stromal cells in surface antigen expression, are homogeneous, and can be reproducibly isolated from outbred Yorkshire-Landrace pigs. Porcine bone marrow stromal cells were efficiently expanded in vitro to >10(10) cells from 20 ml of bone marrow and remained karyotypically normal during expansion. These cells were electroporated with an insulin expression plasmid vector with high efficiency and viability, and secreted human insulin and C-peptide indicating appropriate processing of proinsulin. We showed that autologous insulin-secreting bone marrow stromal cells implanted and engrafted in the liver of a streptozotocin-diabetic pig that modeled type 1 diabetes resulted in partial, but significant, improvement in hyperglycemia that could not be ascribed to regeneration of endogenous ß-cells. Glucose-stimulated insulin secretion in vivo from implanted cells in the treated pig was documented by a rise in serum human C-peptide levels during intravenous glucose tolerance tests. Compared to a sham-treated control pig, this resulted in significantly reduced fasting hyperglycemia, a slower rise in serum fructosamine, and prevented weight loss. Taken together, this study suggests that bone marrow stromal cells merit further development as autologous cell therapy for diabetes.

Astrocyte CCL2 sustains immune cell infiltration in chronic experimental autoimmune encephalomyelitis.

Chemokine (C-C motif) ligand 2 (CCL2), initially identified as monocyte chemoattractant protein-1 (MCP-1), recruits immune cells to the central nervous system (CNS) during autoimmune inflammation. CCL2 can be expressed by multiple cell types, but which cells are responsible for CCL2 function during acute and chronic phases of autoimmune disease is not known. We determined the role of CCL2 in astrocytes in vivo during experimental autoimmune encephalomyelitis (EAE) by using Cre-loxP gene deletion. Mice with a conditional gene deletion of CCL2 from astrocytes had less severe EAE late in disease while having a similar incidence and severity of disease at onset as compared to wild type (WT) control littermates. EAE mice devoid of CCL2 in astrocytes had less macrophage and T cell inflammation in the white matter of the spinal cord and less diffuse activation of astrocytes and microglia in both white and gray matter as well as less axonal loss and demyelination, compared to WT littermates. These findings demonstrate that CCL2 in astrocytes plays an important role in the continued recruitment of immune cells and activation of glial cells in the CNS during chronic EAE, thereby suggesting a novel cell specific target for neuroprotective treatments of chronic neuroinflammatory diseases.

Mesenchymal stem cells reduce intervertebral disc fibrosis and facilitate repair.

Intervertebral disc degeneration is associated with back pain and radiculopathy which, being a leading cause of disability, seriously affects the quality of life and presents a hefty burden to society. There is no effective intervention for the disease and the etiology remains unclear. Here, we show that disc degeneration exhibits features of fibrosis in humans and confirmed this in a puncture-induced disc degeneration (PDD) model in rabbit. Implantation of bone marrow-derived mesenchymal stem cells (MSCs) to PDD discs can inhibit fibrosis in the nucleus pulposus with effective preservation of mechanical properties and overall spinal function. We showed that the presence of MSCs can suppress abnormal deposition of collagen I in the nucleus pulposus, modulating profibrotic mediators MMP12 and HSP47, thus reducing collagen aggregation and maintaining proper fibrillar properties and function. As collagen fibrils can regulate progenitor cell activities, our finding provides new insight to the limited self-repair capability of the intervertebral disc and importantly the mechanism by which MSCs may potentiate tissue regeneration through regulating collagen fibrillogenesis in the context of fibrotic diseases.

The immunosuppressant FTY720 prolongs survival in a mouse model of diet-induced coronary atherosclerosis and myocardial infarction.

FTY720, an analogue of sphingosine-1-phosphate, is cardioprotective during acute injury. Whether long-term FTY720 affords cardioprotection is unknown. Here, we report the effects of oral FTY720 on ischemia/reperfusion injury and in hypomorphic apoE mice deficient in SR-BI receptor expression (ApoeR61(h/h)/SRB1(-/- mice), a model of diet-induced coronary atherosclerosis and heart failure. We added FTY720 (0.3 mg·kg(-1)·d(-1)) to the drinking water of C57BL/6J mice. After ex vivo cardiac ischemia/reperfusion injury, these mice had significantly improved left ventricular (LV) developed pressure and reduced infarct size compared with controls. Subsequently, ApoeR61(h/h)/SRB1(-/-) mice fed a high-fat diet for 4 weeks were treated or not with oral FTY720 (0.05 mg·kg(-1)·d(-1)). This sharply reduced mortality (P < 0.02) and resulted in better LV function and less LV remodeling compared with controls without reducing hypercholesterolemia and atherosclerosis. Oral FTY720 reduced the number of blood lymphocytes and increased the percentage of CD4+Foxp3+ regulatory T cells (Tregs) in the circulation, spleen, and lymph nodes. FTY720-treated mice exhibited increased TGF-ß and reduced IFN-γ expression in the heart. Also, CD4 expression was increased and strongly correlated with molecules involved in natural Treg activity, such as TGF-ß and GITR. Our data suggest that long-term FTY720 treatment enhances LV function and increases longevity in mice with heart failure. These benefits resulted not from atheroprotection but from systemic immunosuppression and a moderate reduction of inflammation in the heart.