Angiographic changes in saphenous vein grafts are predictors of clinical outcomes

Background Previous studies have suggested that angiographic evidence of disease progression in coronary arteries increases the risk of subsequent coronary clinical events. This study ascertained whether patients enrolled in the Post Coronary Artery Bypass Graft Clinical Trial (POST CABG) who had substantial progression of atherosclerosis in ≥1 saphenous vein grafts (on the basis of assessment of baseline and follow-up angiograms obtained 4-5 years after study entry), but who had not reported clinical symptoms before follow-up angiography, were at a higher risk of subsequent events than patients who did not have substantial progression of atherosclerosis (decrease ≥0.6 mm in lumen diameter at site of greatest change from baseline). Methods All 1351 patients enrolled in the trial underwent baseline angiography; only the 961 patients who had follow-up angiography and no coronary events before the follow-up study were included in this analysis. The clinical center staff contacted patients to ascertain the events that had occurred after follow-up angiography (approximately 3.4 years later). Results Sixty-nine patients had died; 870 patients or relatives were interviewed, and 22 patients could not be contacted. Univariable estimates of relative risk associated with substantial progression ranged from 2.2 (P < .001) for cardiovascular death or nonfatal myocardial infarction to 3.3 (P < .001) for revascularization. Multivariable and univariable estimates of risk were similar. Conclusions The findings provide evidence that patients who had substantial progression of atherosclerosis in vein grafts are at an increased risk for subsequent coronary events and suggest that angiographic changes in vein grafts are appropriate surrogate measures for clinical outcomes. (Am Heart J 2003;145:262-9.)     

Diamond-Blackfan anemia: promotion of marrow erythropoiesis in vitro by recombinant interleukin-3

To clarify the defective erythropoiesis in eight patients with Diamond- Blackfan anemia, we studied their bone marrow response in vitro to recombinant human interleukin-3 (IL-3) and recombinant granulocyte- macrophage colony-stimulating factor (GM-CSF). In an erythropoietin- containing assay system, specimens from six of the eight patients yielded low numbers of erythroid colonies compared to control values, and in five of these no erythropoietin dose-response could be elicited. Addition of IL-3, GM-CSF or both to cultures from the six patients had no effect on CFU-E-derived colonies. In contrast, IL-3 but not GM-CSF induced a marked increase in the number (183%) and size of the BFU-E- derived colonies in five of the six cases and partially corrected the impaired dose-response to erythropoietin in four. Bone marrow from the other two patients yielded numbers of CFU-E and BFU-E colonies comparable to controls and manifested similar increments in colonies with increasing concentrations of erythropoietin. When IL-3 was added to these cultures, further increments were observed in the number and size of BFU-E colonies. We conclude that IL-3 enhanced the marrow erythropoiesis in most of the patients and exerted a corrective effect on the aberrant colony formation in the presence of erythropoietin. The data raise the possibility of IL-3 as a therapeutic agent in Diamond- Blackfan anemia.     

DNA repair gene expression in biological tissues exposed to low-intensity infrared laser

Special properties of laser light have led to its usefulness in many applications in therapy. Excitation of endogenous chromophores in biotissues and generation of free radicals could be involved in its biological effects. DNA lesions induced by free radicals are repaired by base excision repair pathway. In this work, we evaluated the expression of APE1 and OGG1 genes related to repair of DNA lesions induced by free radicals. Skin and muscle tissues of Wistar rats were exposed to low-intensity infrared laser at different fluences and frequencies. After laser exposition of 1 and 24 h, tissue samples were withdrawn for total RNA extraction, cDNA synthesis, and evaluation of APE1 and OGG1 gene expression by quantitative polymerase chain reaction. Data obtained show that laser radiation alters the expression of APE1 and OGG1 mRNA differently in skin and muscle tissues of Wistar rats depending of the fluence, frequency, and time after exposure. Our study suggests that low-intensity infrared laser affects expression of genes involved in repair of DNA lesions by base excision repair pathway.     

Olfactory ensheathing cells form the microenvironment of migrating GnRH‐1 neurons during mouse development

During development, GnRH‐1 neurons differentiate extracerebraly from the nasal placode and migrate from the vomeronasal organ to the forebrain along vomeronasal and terminal nerves. Numerous studies have described the influence of different molecules on the migration of GnRH‐1 neurons, however, the role of microenvironment cells remains poorly understood. This study used GFAP‐GFP transgenic mice to detect glial cells at early developmental stages. Using nasal explant cultures, the comigration of glial cells with GnRH‐1 neurons was clearly demonstrated. This in vitro approach showed that glial cells began migrating from the explants before GnRH‐1 neurons. They remained ahead of the GnRH‐1 migratory front and stopped migrating after the GnRH‐1 neurons. The association of these glial cells with the axons combined with gene expression analysis of GFAP‐GFP sorted cells enabled them to be identified as olfactory ensheathing cells (OEC). Immunohistochemical analysis revealed the presence of multiple glial cell‐type markers showing several OEC subpopulations surrounding GnRH‐1 neurons. Moreover, these OEC expressed genes whose products are involved in the migration of GnRH‐1 neurons, such as Nelf and Semaphorin 4. In situ data confirmed that the majority of the GnRH‐1 neurons were associated with glial cells along the vomeronasal axons in nasal septum and terminal nerves in the nasal forebrain junction as early as E12.5. Overall, these data demonstrate an OEC microenvironment for migrating GnRH‐1 neurons during mouse development. The fact that this glial cell type precedes GnRH‐1 neurons and encodes for molecules involved in their nasal migration suggests that it participates in the GnRH‐1 system ontogenesis. © 2013 Wiley Periodicals, Inc. © 2013 Wiley Periodicals, Inc.     

Comorbidity indices for clinical trials: adaptation of two existing indices for use with the FREEDOM trial in women with postmenopausal osteoporosis

Summary

Two comorbidity indices were adapted for use in the FREEDOM trial and significantly correlated with the number of medications and impaired health status at baseline. The indices have applications for the analysis of clinical trial data and would allow for the appropriate adjustment of comorbidities when evaluating clinical trial outcomes.

Introduction

The purpose of this study is to adapt two published comorbidity indices for use with the FREEDOM clinical trial evaluating postmenopausal women with osteoporosis.

Methods

FREEDOM enrolled women aged 60–90 years with a bone mineral density T-score <?2.5 at the lumbar spine or total hip and ≥?4.0 at both sites. Comorbidity indices were calculated using methods described by Sangha (Arthritis Rheum 49:156–163, 2003) and Wolfe (J Rheumatol 37:305–315, 2010) following modification. The adapted Sangha index included 12 conditions with a summary score of 0–12; the adapted Wolfe index included 7 conditions with a weighted summary score of 0–8. Higher scores indicated greater comorbidity. A panel of clinicians independently reviewed subjects’ medical histories using a systematic process based on Medical Dictionary for Regulatory Activities (MedDRA) preferred terms to map specified comorbid conditions. Spearman correlations between the adapted indices and baseline subject characteristics expected to be associated with comorbidities were examined.

Results

Of the 7808 subjects in this study, 74 % had ≥1 comorbidities based on the adapted Sangha or Wolfe comorbidity indices. The mean (SD) adapted Sangha and Wolfe comorbidity indices were 1.4 (1.2) and 1.4 (1.3), respectively. Both indices correlated positively with age, body mass index, and the number of medications (r?=?0.54 to 0.55) at baseline and inversely correlated with health-related quality of life (r?=??0.22 to ?0.30) (all P?<?0.0001). Further, when either the adapted Sangha or Wolfe index was included as a covariate for assessing mortality over 36 months in the FREEDOM population, the hazard ratio of the comorbidity index indicated that the mortality risk increased by 27 or 28 %, respectively, for each unit increase in the adapted index (both P?<?0.0001).

Conclusions

Our work suggests these comorbidity indices may be adapted for use with clinical trial data, thereby allowing for the appropriate adjustment and reporting of covariates in the evaluation of clinical trial outcomes in an osteoporotic population.