Effects of donor T-cell trafficking and priming site on graft-versus-host disease induction by naive and memory phenotype CD4 T cells

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic stem cell transplantation. Effector memory T cells (T_EM) do not cause GVHD but engraft and mount immune responses, including graft-versus-tumor effects. One potential explanation for the inability of T_EM to cause GVHD is that T_EM lack CD62L and CCR7, which are instrumental in directing naive T cells (T_N) to lymph nodes (LN) and Peyer patches (PP), putative sites of GVHD initiation. Thus T_EM should be relatively excluded from LN and PP, possibly explaining their inability to cause GVHD. We tested this hypothesis using T cells deficient in CD62L or CCR7, transplant recipients lacking PNAd ligands for CD62L, and recipients without LN and PP or LN, PP, and spleen. Surprisingly, CD62L and CCR7 were not required for T_N-mediated GVHD. Moreover, in multiple strain pairings, GVHD developed in recipients that lacked LN and PP. Mild GVHD could even be induced in mice lacking all major secondary lymphoid tissues (SLT). Conversely, enforced constitutive expression of CD62L on T_EM did not endow them with the ability to cause GVHD. Taken together, these data argue against the hypothesis that T_EM fail to induce GVHD because of inefficient trafficking to LN and PP.      

Acute combined effects of olive oil and wine on pressure wave reflections: another beneficial influence of the Mediterranean diet antioxidants?

OBJECTIVES: Combined consumption of olive oil and wine is common in the Mediterranean diet, but there are no data concerning their synergistic haemodynamic response. We sought to determine the combined postprandial effects of wine and olive oil on wave reflections and central haemodynamics. METHODS: Fifteen healthy subjects consumed four standard meals on different days, containing 50 g of olive oil and 250 ml of wine, in a randomized cross-over study design. Two types of wine [red (R) and white (W)] and two types of olive oil [green (G) and refined (O) (rich and poor in antioxidants, respectively)] were used in all possible combinations (RO, RG, WO and WG). Applanation tonometry and aortic pulse wave analysis were performed when fasting and 1, 2 and 3 h postprandially. A second group of 15 healthy individuals matched for age, gender and body mass index served as the control group. RESULTS: All meals decreased AIx (RO and RG, P < 0.001; WO, P = 0.007; and WG, P = 0.039). The AIx reduction after RG, RO, WO and WG was significantly different from the respective AIx response of the control group. No difference was observed in the reduction of AIx between sessions, but a significantly earlier peak decrease in AIx, as well as a more prolonged decreasing effect, was observed after RG and RO consumption compared to WO and WG. Central systolic and diastolic pressures were diminished after all four combinations of wine and olive oil (P < 0.05). CONCLUSIONS: Combined consumption of wine and olive oil provided beneficial postprandial effects on haemodynamics. These findings reveal an additional favourable effect of components of the Mediterranean diet on haemodynamics in the postprandial state.     

Wives of patients with acute myocardial infarction are at an increased risk of developing coronary artery disease

BACKGROUND: The present study was carried out to investigate risk factors for developing coronary artery disease in wives of patients with acute myocardial infarction. SUBJECTS AND METHODS: Risk factors for developing coronary artery disease were investigated in 50 wives of patients who developed an acute myocardial infarction (group A) and were compared with those of 50 wives of normal healthy men (group B). The average age was 50.20 +/- 1.56 years (mean +/- SD) and 50.20 +/- 1.53 years for group A and group B respectively. The parameters assessed were: plasma cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), systolic and diastolic blood pressure, smoking habits and body mass index (BMI). RESULTS: The levels of LDL-C in the wives of patients with myocardial infarction were higher than those of the wives of normal healthy men (167.8 +/- 5.84 mg/dl and 148.4 +/- 4.85 mg/dl, respectively, P < 0.01). Moreover, HDL-C concentrations were lower in the wives of the patients (51.34 +/- 0.92 mg/dl) than in the wives of the healthy men (58.14 +/- 1.39 mg/dl), (P < 0.001). Finally, TG levels were higher in the wives of the patients (132.2 +/- 7.9 mg/dl) than in the wives of the normal healthy men (96.9 +/- 5.94 mg/dl) (P < 0.01). CONCLUSIONS: Although plasma lipid levels themselves were not excessively high, the wives of patients with an acute myocardial infarction are at a higher risk of developing coronary artery disease than the wives of normal healthy men, in the long term, due to higher levels of LDL-C and TG as well as lower levels of HDL-C.     

Ankle-brachial index as a predictor of the extent of coronary atherosclerosis and cardiovascular events in patients with coronary artery disease

Resting ankle-brachial pressure index (ABI) is a noninvasive method to assess the patency of the lower extremity arterial system. This study aimed to examine the relation between ABI and the extent of coronary atherosclerosis, the extracoronary atherosclerosis lesions, and the prognosis of patients referred for elective coronary angiography. One hundred sixty-five consecutive patients underwent coronary angiography, ultrasound imaging for intima-media thickness measurement of carotid and femoral arteries and ABI evaluation; subjects were followed up for 14.5 +/- 2.4 months. With regard to vascular risk factors, only smoking (p = 0.025) and diabetes (p = 0.01) were related to ABI in the multiple regression analysis. ABI was independently and inversely related to carotid bifurcation (p = 0.0002) and common femoral artery intima-media thickness (p = 0.018). ABI was related to the extent of coronary artery disease as measured by number of coronary arteries diseased (analysis of variance, p = 0.04) and Gensini angiographic score (p = 0.01). In the follow-up study ABI < 0.90 was a univariate predictor of cardiovascular events (cardiac death, nonfatal myocardial infarction, unstable angina) and revascularization procedures. The estimated cumulative rate free of cardiovascular events was 90% for ABI > 0.90 and 73% for ABI < 0.90 (p = 0.02). In logistic regression analysis, ABI < 0.90 was an independent predictor for cardiovascular events after adjustment for age, low-density lipoprotein cholesterol, carotid and femoral intima-media thickness, and Gensini score. Further adjustment for the confounding effect of insulin weakened the relation between ABI and cardiovascular events (p = 0.1). In conclusion, ABI is a simple index related to the extent of atherosclerosis in coronary and noncoronary arterial beds, reflecting generalized atherosclerosis. ABI could be useful in assessing the risk for cardiovascular events in patients with coronary artery disease.     

Cetuximab plus FOLFOX6 or FOLFIRI in metastatic colorectal cancer: CECOG trial

AIM: To investigate efficacy and safety of cetuximab combined with two chemotherapy regimens in patients with unresectable metastatic colorectal cancer (mCRC). METHODS: Randomized patients received cetuximab with 5-fluorouracil (5-FU), folinic acid (FA) and oxaliplatin (FOLFOX) 6 (arm A, n = 74) or 5-FU, FA and irinotecan (FOLFIRI) (arm B, n = 77). KRAS mutation status was determined retrospectively in a subset of tumors (n = 117). RESULTS: No significant difference was found between treatment arms A and B ...     

Endogenous estrogen levels are associated with endothelial function in males independently of lipid levels

Estrogens and androgens may play an important role in vascular health in both sexes. The aim of this study was to examine the relation of endogenous sex hormone levels with early markers of atherosclerosis in a cohort of apparently healthy males. 124 males (age 46.25 ± 9.56) attending a preventive medicine program were examined for unrecognised features of the metabolic syndrome. Flow-mediated dilatation (FMD) and intima-media thickness (IMT) of the common carotid artery were evaluated. Obesity parameters were recorded; estradiol, testosterone, SHBG, free testosterone, insulin, as well as glucose and lipid levels were measured. FMD was positively correlated with estradiol (r = 0.201, P = 0.041) and negatively with total cholesterol (r = -0.205, P = 0.022), low density lipoproteins (r = -0.232, P = 0.009), and triglyceride levels (r = -0.179, P = 0.046). In multivariate analysis, the association of FMD with estrogen was independent of BMI and lipid levels. No significant association between FMD and testosterone levels was found. Subjects with an increased mean IMT (> 0.73 mm, i.e., > 3rd tertile) had lower levels of free (P = 0.021) and bioavailable (P = 0.016) testosterone. In multivariate logistic regression analysis, this association was no longer significant when age or cholesterol levels were considered. Endogenous estrogen levels are associated with FMD, independently of age and lipid levels, showing a protective effect in middle-age male subjects. Circulating androgens are associated, although not independently, with structural changes such as the IMT of carotid artery; this effect is possibly influenced by lipid levels and age.     

Spinal interneuron circuits reduce approximately 10-Hz movement discontinuities by phase cancellation

Tremor imposes an important limit to the accuracy of fine movements in healthy individuals and can be a disabling feature of neurological disease. Voluntary slow finger movements are not smooth but are characterized by large discontinuities (i.e., steps) in the tremor frequency range (approximately 10 Hz). Previous studies have shown that these discontinuities are coherent with activity in the primary motor cortex (M1), but that other brain areas are probably also involved. We investigated the contribution of three important subcortical areas in two macaque monkeys trained to perform slow finger movements. Local field potential and single-unit activity were recorded from the deep cerebellar nuclei (DCN), medial pontomedullary reticular formation, and the intermediate zone of the spinal cord (SC). Coherence between LFP and acceleration was significant at 6 to 13 Hz for all areas, confirming the highly distributed nature of the central network responsible for this activity. The coherence phase at 6 to 13 Hz for DCN and pontomedullary reticular formation was similar to our previous results in M1. By contrast, for SC the phase differed from M1 by approximately π rad. Examination of single-unit discharge confirmed that this was a genuine difference in neural spiking and could not be explained by different properties of the local field potential. Convergence of antiphase oscillations from the SC with cortical and subcortical descending inputs will lead to cancellation of approximately 10 Hz oscillations at the motoneuronal level. This could appreciably limit drive to muscle at this frequency, thereby reducing tremor and improving movement precision.     

Multiple genetic alterations involved in the tumorigenesis of human cholangiocarcinoma: a molecular genetic and clinicopathological study

PURPOSE: Cholangiocarcinoma (CC) is the second most common malignant tumor in the liver and the molecular genetic alterations involved in the tumorigenesis of CC have not been well studied. PATIENTS AND METHODS: The authors analyzed the loss of heterozygosity (LOH) in four tumor suppressor genes, including the adenomatous polyposis coli (APC) gene, the deleted in colon cancer (DCC) gene, the 8-hydroguanine-specific DNA glycosylase (OGG1) gene, and the p53 gene in 22 surgically resected primary CCs by using microdissection-based PCR amplification and direct DNA sequencing. RESULTS: A total of 19 (86.4%) out of 22 CCs exhibited genetic alterations, of which 11 (57.9%) and eight (42.1%) cases showed one and more than one gene alterations, respectively. The frequency of genetic alterations of the four genes studied ranged in order from high to low as APC (68.8%) > DCC (46.2%) > OGG1 (41.7%) > p53 (37.5%). Based on the pattern of altered genes and their correlation with clinical and pathological parameters, the genetic alterations were classified into three groups: group I: no detectable genetic alterations (n = 3, 13.6%); group II: LOH in APC and/or DCC (n = 9, 40.9%); and group III: LOH in OGG1 and/or p53 occurred separately or combined with LOH in APC and/or DCC (n = 10, 45.5%). The > or = 3-year survival rates between group II and group III are 88.9% and 30%, respectively (P < 0.05). No significant differences were found between genetic alterations and tumor size, tumor type, tumor invasion, TNM staging, and tumor differentiation (P > 0.05). CONCLUSION: Accumulation of multiple genetic alterations are involved in the tumorigenesis of CC, of which genetic alterations of APC and DCC occur at a relatively early stage, and of OGG1 and p53 occur at a relatively late stage during development of CC.     

Targeted Physician Education and Standardizing Documentation Improves Documented Reporting with Inflammatory Bowel Disease Quality Measures in a Large Academic and Private Practice

Background

Prior studies have shown poor compliance with quality measures for IBD at academic and private practices. We sought to provide focused interventions to improve compliance and documentation with the IBD measures.

Methods

Two centers, academic practice (AP) and private practice (PP), initially reviewed their compliance with eight established IBD quality measures in consecutive charts. A multi-faceted intervention was developed to improve awareness and documentation of these measures. The initial data and the quality measures were reviewed at a group meeting. Following this, a handout summarizing the measures was placed in each exam room. The AP added a new screen to the EHR that summarized the relevant IBD history, while the PP added a new template that was filled out and imported into the charts. Three months after this intervention, charts were reviewed for compliance with the measures.

Results

The intervention cohort consisted of 768 patients (AP = 569/PP = 199) compared to the initial cohort of 566 patients (AP = 367/PP = 199). Improvement was seen throughout all measures compared to the initial cohort. The AP reported compliance with all relevant measures in 21% and the PP in 60% compared to 7 and 10% in the initial cohort. PP had ≥ 75% compliance with every measure, of which only assessment for bone loss and pneumococcal vaccination was under 80%. In contrast, the AP compliance ranged from 35 to 100% with assessment for bone loss, influenza, and pneumococcal vaccination scoring lowest.

Conclusion

Our study demonstrates that focused low-cost interventions can significantly improve compliance with IBD quality measures in different practice settings.