TEM CELLS ARE UNDIFFERENTIated cells that through replication have the capability of both self-renewal and differentiation into mature specialized cells. In broad terms, there are 2 types of stem cells, embryonic stem cells and adult stem cells. Human embryonic stem cells are isolated from a 50-to 150-cell, 4-to 5-dayold postfertilization blastocyst. Embryonic stem cells generate every specialized cell in the human body and, while capable of indefinite ex vivo proliferation, exist only transiently in vivo (during embryogenesis). Adult stem cells are located in tissues throughout the body and function as a reservoir to replace damaged or aging cells. Under physiologic conditions, adult stem cells are traditionally thought to be restricted in their differentiation to cell lineages of the organ system in which they are located. Embryonic stem cells have great promise and versatility but, compared with adult stem cells, are currently difficult to control due to their tendency to form tumors containing all types of tissue, ie, teratomas. Embryonic stem cell biology has been associated with ethical controversy, and feeder cellfree and xenogeneic-free culture methods approved by the US Food and Drug Administration are still being per-Author Affiliations are listed at the end of this article.

clinicaltrials.gov Identifier: NCT01408901.

Functional impairment, functional decline, and mobility loss are major public health problems in people with lower extremity peripheral artery disease (PAD). Few medical therapies significantly improve walking performance in PAD. We describe methods for the PROgenitor cell release Plus Exercise to improve functionaL performance in PAD (PROPEL) Study, a randomized controlled clinical trial designed to determine whether granulocyte-macrophage colony stimulating factor (GM-CSF) combined with supervised treadmill walking exercise improves six-minute walk distance more than GM-CSF alone, more than supervised treadmill exercise alone, and more than placebo plus attention control in participants with PAD, respectively. PROPEL Study participants are randomized to one of four arms in a 2 by 2 factorial design. The four study arms are GM-CSF plus supervised treadmill exercise, GM-CSF plus attention control, placebo plus supervised exercise therapy, or placebo plus attention control. The primary outcome is change in six-minute walk distance at 12-week follow-up. Secondary outcomes include change in brachial artery flow-mediated dilation (FMD), change in maximal treadmill walking time, and change in circulating CD34+ cells at 12-week follow-up. Outcomes are also measured at six-week and six-month follow-up. Results of the PROPEL Study will have important implications for understanding mechanisms of improving walking performance and preventing mobility loss in the large and growing number of men and women with PAD.

Objective To examine the association between use of statin and non-statin cholesterol-lowering medications and risk of nontraumatic major lower-extremity amputations (LEA) and treatment failure (LEA or death). Design of Study A retrospective cohort of patients with Type I and Type 2 diabetes mellitus (diabetes) was followed for five years between 2004 and 2008. The follow-up exposure duration was divided into 90-day periods. Use of cholesterol-lowering agents, diabetic medications, hemoglobin A1c, body mass index, and systolic and diastolic blood pressures were observed in each period. Demographic factors were observed at baseline. Major risk factors of LEA including peripheral neuropathy, PAD, and foot ulcers were observed at baseline and were updated for each period. LEA and deaths were assessed in each period and their hazard ratios were estimated. Setting US Department of Veterans Affairs Healthcare system (VA) Subjects Cholesterol drug-naïve patients with Type I or II diabetes who were treated in the VA in 2003 and were <65 years old at the end of follow-up. Results Of 83,593 patients in the study cohort, 217 (0.3%) patients experienced a major LEA and 11,716 (14.0%) patients experienced an LEA or death (treatment failure) after a mean follow-up of 4.6 years. Compared to patients who did not use cholesterol-lowering agents, statin users were 35% - 43% less likely to experience an LEA (HR = 0.65; 95% CI, 0.42–0.99) and a treatment failure (HR = 0.57; 95% CI, 0.54–0.60). Users of other cholesterol-lowering medications were not significantly different in LEA risk (HR = 0.95; 95% CI, 0.35–2.60) but had a 41% lower risk of treatment failure (HR = 0.59; 95% CI, 0.51–0.68). Conclusions This is the first study to report a significant association between statin use and diminished amputation risk among patients with diabetes. In this non-randomized cohort, beneficial effects of statin therapy were similar to that seen in large-scale clinical trial experience. For LEA risk, those given non-statins did not have a statistically significant benefit and its effect on LEA risk was much smaller compared to statins.. Unanswered questions to be explored in future studies include a comparison of statins of moderate versus high potency in those with high risk of coronary heart disease and an exploration of whether the effects seen in this study are simply effects of cholesterol-lowering or possibly pleiotropic effects.

The association between BMI and amputation risk is not currently well known. We used data for a cohort of diabetic patients treated in the US Department of Veterans Affairs Healthcare System in 2003. Men aged <65 years at the end of follow-up were examined for their amputation risk and amputation-free survival during the next 5 years (2004–2008). Compared to overweight individuals (BMI 25–29.9 kg/m2), the risks of amputation and treatment failure (amputation or death) were higher for patients with BMI <25 kg/m2 and were lower for those with BMI ≥30 kg/m2. Individuals with BMI ≥40 kg/m2 were only half as likely to experience any (hazard ratios (HR) = 0.49; 95% confidence interval (CI), 0.30–0.80) and major amputations (HR = 0.53; 95% CI, 0.39–0.73) during follow-up as overweight individuals. While the amputation risk continued to decrease for higher BMI, amputation-free survival showed a slight upturn at BMI >40 kg/m2. The association between obesity and amputation risk in our data shows a pattern consistent with “obesity paradox” observed in many health conditions. More research is needed to better understand pathophysiological mechanisms that may explain the paradoxical association between obesity and lower-extremity amputation (LEA) risk.

IntroductionOur objectives were to examine mononuclear cell gene expression profiles in patients with systemic lupus erythematosus (SLE) and healthy controls and to compare subsets with and without atherosclerosis to determine which genes’ expression is related to atherosclerosis in SLE.MethodsMonocytes were obtained from 20 patients with SLE and 16 healthy controls and were in vitro-differentiated into macrophages. Subjects also underwent laboratory and imaging studies to evaluate for subclinical atherosclerosis. Whole-genome RNA expression microarray was performed, and gene expression was examined.ResultsGene expression profiling was used to identify gene signatures that differentiated patients from controls and individuals with and without atherosclerosis. In monocytes, 9 out of 20 patients with SLE had an interferon-inducible signature compared with 2 out of 16 controls. By looking at gene expression during monocyte-to-macrophage differentiation, we identified pathways which were differentially regulated between SLE and controls and identified signatures based on relevant intracellular signaling molecules which could differentiate SLE patients with atherosclerosis from controls. Among patients with SLE, we used a previously defined 344-gene atherosclerosis signature in monocyte-to-macrophage differentiation to identify patient subgroups with and without atherosclerosis. Interestingly, this signature further classified patients on the basis of the presence of SLE disease activity and cardiovascular risk factors.ConclusionsMany genes were differentially regulated during monocyte-to-macrophage differentiation in SLE patients compared with controls. The expression of these genes in mononuclear cells is important in the pathogenesis of SLE, and molecular profiling using gene expression can help stratify SLE patients who may be at risk for development of atherosclerosis.

The efficacy of the traditionally recommended ampicillin (Amp) plus gentamicin (GM) regimen was compared with that of a trimethoprim-sulfamethoxazole (TMP/SMZ)-plus-GM regimen and the adequacy of 14 days total therapy for acute uncomplicated pyelonephritis (AUPN). Eighty-five women hospitalized for AUPN were randomly assigned to receive either Amp, 1 g intravenously (iv) every 6 h for 3 days, then 500 mg orally four times daily, or TMP/SMZ, 160/800 mg iv every 12 h for 3 days, then 160/800 mg orally twice daily. Initially, all patients also received GM every 8 h iv (mean, 606 doses). Antimicrobial resistance necessitated modifying therapy of 14 (32%) of the Amp recipients but of none of the TMP/SMZ recipients (P less than .001). Both regimens produced a satisfactory bacteriologic and clinical response in all cases. Reinfection occurred in 11% of Amp and in 8% of TMP/SMZ recipients. No patient experienced relapsing infection. The TMP/SMZ regimen was less costly and less likely to require modification due to antimicrobial resistance.

Objective Women with SLE have an increased incidence of premature CVD. A relationship between depression and increased inflammation leading to CVD has been proposed. The aim of this study was to evaluate the relationship between depression and the progression of subclinical atherosclerosis in women with SLE. Methods In this prospective case-control study, 149 participants with SLE and 126 controls were followed over 5 years. Evaluation included laboratory studies, assessment of CVD risk factors, depression screening, ultrasound evaluations of CIMT and carotid plaque, and assessment of SLE disease activity for the SLE cases. Results The SLE group had a higher rate of depression, 29% compared with 11% in the control group (p 0.003). When controlling for traditional CVD risk factors, the presence of baseline depression correlated with increased progression of CIMT in the SLE group, but not in the control group. The mean increase in CIMT was 0.026mm in the SLE group without depression versus 0.064mm in the depressed SLE group (p=0.0096).There was no association between depression and carotid plaque in either group, with the calculated OR for plaque progression in the depressed SLE group of 1.118 (95% CI 0.476–2.623) in the adjusted model. Conclusion Women with SLE and concomitant depression have an increased risk of developing subclinical atherosclerosis, as measured by CIMT, but not by carotid plaque. The data suggest that depression, a potentially modifiable risk factor, may contribute to the increased risk of subclinical atherosclerosis in women with SLE.