Mesenchymal stromal cells: current understanding and clinical status.

Multipotent mesenchymal stromal cells (MSCs) represent a rare heterogeneous subset of pluripotent stromal cells that can be isolated from many different adult tissues that exhibit the potential to give rise to cells of diverse lineages. Numerous studies have reported beneficial effects of MSCs in tissue repair and regeneration. After culture expansion and in vivo administration, MSCs home to and engraft to injured tissues and modulate the inflammatory response through synergistic downregulation of proinflammatory cytokines and upregulation of both prosurvival and antiinflammatory factors. In addition, MSCs possess remarkable immunosuppressive properties, suppressing T-cell, NK cell functions, and also modulating dentritic cell activities. Tremendous progress has been made in preclinical studies using MSCs, including the ability to use allogeneic cells, which has driven the application of MSCs toward the clinical setting. This review highlights our current understanding into the biology of MSCs with particular emphasis on the cardiovascular and renal applications, and provides a brief update on the clinical status of MSC-based therapy.

Modulated inflammation by injection of high-mobility group box 1 recovers post-infarction chronically failing heart.

BACKGROUND: Inflammation plays an important role in the progress of adverse ventricular remodeling after myocardial infarction. High-mobility group box 1 (HMGB1) is a nuclear protein, which has recently been uncovered to also act as a modifier of inflammation when released. We hypothesized that HMGB1 injection could preferentially modulate local myocardial inflammation, attenuate ventricular remodeling, and subsequently improve cardiac performance of postinfarction chronic heart failure. METHODS AND RESULTS: Three weeks after left coronary artery ligation, HMGB1 (2.5 mug) or PBS was intramyocardially injected into rat hearts. At 28 days after injection, left ventricular ejection fraction was significantly improved after HMGB1 injection compared to PBS (39.3+/-1.4 versus 33.3+/-1.8%; P<0.01). Accumulation of CD45(+) inflammatory cells, two thirds of which were OX62(+) dendritic cells, in the peri-infarct area was significantly attenuated by HMGB1 injection. Dramatic changes in the expression of major proinflammatory cytokines were not detected by microarray or RT-PCR. Adverse ventricular remodeling including cardiomyocyte hypertrophy (cardiomyocyte cross-sectional area; 439+/-7 versus 458+/-6 mum(2); P<0.05) and extracellular collagen deposition (collagen volume fraction; 11.9+/-0.4 versus 15.2+/-0.6%; P<0.01) was attenuated by HMGB1 injection. Analyses of signal transduction pathways revealed that HMGB1 injection activated ERK1/2, but not p38, Akt, and Smad3. Cardiac regeneration and neovascularization were not observed. CONCLUSIONS: HMGB1 injection modulated the local inflammation in the postinfarction chronically failing myocardium, particularly via reducing the accumulation of dendritic cells. This modulated inflammation resulted in attenuated fibrosis and cardiomyocyte hypertrophy, which thereby improved global cardiac function. These data suggest that HMGB1 may be valuable for the chronic heart failure treatment.

Hepatoprotective effect of cinnamon extracts against carbon tetrachloride induced oxidative stress and liver injury in rats.

Cinnamon is used to flavor most foods in Arabian countries. The aim of this study was to evaluate the medicinal importance, reflecting an important trend in research. The hepatoprotective activity of aqueous and ethanolic extracts of cinnamon was investigated against carbon tetrachloride (CC1(4)) induced lipid peroxidation and hepatic injury in rats. The elevated serum AST and ALT enzymatic activities induced by CC1(4) were significantly restored to near normal by oral administration of 200 mg/kg of either extracts once daily for 7 days, as compared to untreated rats. There was a significant elevation in the level of liver malondialdhyde (MDA), while the activities of antioxidant enzymes superoxide dismutase and catalase (SOD and CAT) were significantly decreased in CC1(4) intoxicated rats. The results obtained indicated that ethanolic extract has more potent hepatoprotective action than water extract against CC1(4) by lowering the MDA level and elevating antioxidants enzymes activities (SOD and CAT). The possible mechanism of this activity may be free radical-scavenging polyphenol compounds. The hepatoprotective properties were documented by the histopathological data obtained. Consequently, this extract can be used as a therapeutic regime in treatment of some hepatic disorders without any side effects. Further study will be done for separation and identification of active components and for testing antitumor activity.

Beta-adrenoceptor blockade markedly attenuates transgene expression from cytomegalovirus promoters within the cardiovascular system.

OBJECTIVE: The major immediate-early cytomegalovirus enhancer/promoter (MIECMV), widely used in cardiovascular gene therapy, contains several positively regulatory cAMP response elements (CRE). Catecholamine signaling via beta-adrenoceptors might increase transgene expression from MIECMV, and if so, beta-blockers may have a detrimental effect on the efficacy of clinical cardiovascular gene therapy strategies. METHODS AND RESULTS: Cultured smooth muscle cells were exposed to isoprenaline, atenolol, or propranolol, alone and in combination before infection with adenoviruses expressing beta-galactosidase. beta-galactosidase expression was assayed 72 hours later. Isoprenaline increased transgene expression from MIECMV up to 8-fold (P<0.001), but had no effect on a promoter containing no CRE. The effect of isoprenaline was inhibited by beta-blockade and by specific CRE-decoy oligonucleotides. Beta-blockers did not reduce transgene expression below basal levels. After adenovirus-mediated porcine intracoronary gene transfer, however, beta-blockade reduced beta-galactosidase expression by up to 250-fold compared with non-beta-blocked animals (P<0.01). CONCLUSIONS: Enhancement of promoter activity by endogenous catecholamines is essential for high-level transgene expression from MIECMV within the vasculature. Beta-blocker-mediated suppression of transgene expression from MIECMV in vascular tissues has a significant bearing on clinical studies of cardiovascular gene transfer. This is the first described interaction to our knowledge between widely prescribed pharmaceuticals and a commonly used promoter of clinical transgene expression.

Developing a primary health care management information system that supports the pursuit of equity, effectiveness and affordability.

A key set of goals of primary health care (PHC) includes equity, effectiveness and affordability. By equity, we mean universal coverage and care according to need; by effectiveness, that the system has a favorable impact on mortality and serious morbidity; by affordability, that the system is within the budgetary reach of government and communities. There are other requirements of PHC as well: that the system be socially and culturally acceptable, and that communities are active participants in the development and implementation of the system. Further, the PHC system should be compatible with larger system of a region or country, and possibly serve as a prototype for the development of larger health systems. With these requirements in mind, the Aga Khan University has developed a series of community-based, urban PHC systems, each serving a population of about 10,000, in the katchi abadis (squatter settlements) of Karachi. These communities are severely deprived, with high infant, child and maternal mortality rates. The PHC systems are designed to achieve equity, effectiveness and affordability, and within 3-5 years have advanced substantially toward those goals. A key factor in those developments has been the management information system (MIS), which has served as a basis for planning, managing and evaluating the PHC systems. Central questions about such an MIS are: What kind of MIS design is necessary to support the pursuit of those goals? What problems arise in the MIS as such a system is implemented? What kinds of changes and adaptations need to be considered in the MIS as the PHC system itself matures? What does the PHC system cost, and what part of the total cost of the PHC system is attributable to the MIS? How practical is this kind of MIS, developed in small prototype PHC systems, for replicability in larger health systems? What are the possibilities and requirements for simplification in order to be used in health systems that are less intensively managed? The experience of AKU in Pakistan in the development of PHC systems, with associated management information systems, helps to answer these questions.

The "P" in GMP--a major shift in growth monitoring program of a primary health care project.

Growth monitoring and promotion (GMP) is the monitoring of a child's growth to promote, maintain and restore health. The "P" in GMP relates to the promotive, preventive and curative actions which accompany the monitoring process. Data from two of the Primary Health Care field sites of The Aga Khan University, Essa Nagri and Azam Basti (squatter settlements), in Karachi for May 1989 was analyzed to determine the relationship between weight change and nutritional status. 21% of 2,838 children had a decrease in weight from April to May 1989. Children in Grade I malnutrition (n = 274) contributed much more to this decrease than children with Grades II and III (54 and 5, respectively). By focusing attention only on those with Grades II and III malnutrition, the obvious ones, we have been missing the opportunity to prevent a deterioration of those in Grade I, though it is easier and less time consuming to reverse this trend in early stages of malnutrition. To ensure more quality-time for community health workers' focus on the at-risk population, three alternative "high-risk" groups are proposed. Promotion of growth and weight change needs to be stressed more, instead of the nutritional status only in GMP programs.

Adult mortality in slums of Karachi, Pakistan.

OBJECTIVE: Cause-specific death rates are rarely available to guide health interventions for adults in South Asia. We report mortality patterns among Karachi's urban poor. METHODS: We conducted verbal autopsies for adult deaths under active surveillance during 1990-1993 in five urban slums of Karachi. Two physicians assigned underlying cause of death by consensus. Analysis included cause- and category-specific rates, 45Q15s and comparison with 1991 Japanese national statistics. RESULTS: All 345 adult deaths (15-59 years) in the 5 slums (total population 45,389) were included. Male mortality exceeded female (4.4 vs 3.3/1000, p = .02). Noncommunicable diseases claimed 59% of deaths, communicable and reproductive 27% and injuries, 15%. The leading identified death rates (/100,000) among women were: circulatory disorders (66), maternal causes (33), tuberculosis (30), and burns (23); and among men they were: circulatory disorders (124) tuberculosis (30) and road traffic accidents (30). Overall Karachi adult mortality was 3.7 times Japanese rate. Compared to Japan, adults in Karachi had one to two orders of magnitude excess mortality due to maternal causes, tuberculosis and burns. Circulatory disorders and tuberculosis accounted for 47% of excess male mortality; these plus maternal causes and burns accounted for 55% of excess female mortality. CONCLUSION: These mortality levels and patterns compel interventions and research for poor urban adults beyond maternal health. Women's health would equally benefit from tuberculosis control or burn prevention. Men need safer travel. Both need improved cardiovascular health.

Hepatoprotective effect of Cinnamon extracts against carbon tetrachloride induced oxidative stress and liver injury in rats

Cinnamon is used to flavor most foods in Arabian countries. The aim of this study was to evaluate the medicinal importance, reflecting an important trend in research. The hepatoprotective activity of aqueous and ethanolic extracts of cinnamon was investigated against carbon tetrachloride (CC1(4)) induced lipid peroxidation and hepatic injury in rats. The elevated serum AST and ALT enzymatic activities induced by CC1(4) were significantly restored to near normal by oral administration of 200 mg/kg of either extracts once daily for 7 days, as compared to untreated rats. There was a significant elevation in the level of liver malondialdhyde (MDA), while the activities of antioxidant enzymes superoxide dismutase and catalase (SOD and CAT) were significantly decreased in CC1(4) intoxicated rats. The results obtained indicated that ethanolic extract has more potent hepatoprotective action than water extract against CC1(4) by lowering the MDA level and elevating antioxidants enzymes activities (SOD and CAT). The possible mechanism of this activity may be free radical-scavenging polyphenol compounds. The hepatoprotective properties were documented by the histopathological data obtained. Consequently, this extract can be used as a therapeutic regime in treatment of some hepatic disorders without any side effects. Further study will be done for separation and identification of active components and for testing antitumor activity.

A developing country's university oriented toward strengthening health systems: challenges and results.

OBJECTIVES: The Aga Khan University in Karachi has a mission to educate leaders and to contribute to the development of health systems for Pakistan amid challenges of scarcity and complexity. METHODS: Its key activities are (1) to design and test urban and rural health system prototypes, (2) to develop faculty in medical and nursing postgraduate community health sciences programs, and (3) to design and implement community-based undergraduate medical and nursing curricula. RESULTS: The university has developed equity-based, cost-effective primary health care prototypes in Karachi slums. With government counterparts it has tested village-, facility-, and district-level interventions in a poor rural district. Federal policymakers have taken models from each for widespread replication. The university is training 49 medical and 19 nursing faculty for postgraduate programs in community health sciences. Most faculty retain institutional leadership positions, including teaching community-based, problem-solving, community health sciences as 20% of the medical and nursing undergraduate curriculum. CONCLUSIONS: The mission and experience of the Aga Khan University in population-based health systems design and health sciences education can guide universities in both developing and developed countries.