A genome-wide association scan on estrogen receptor-negative breast cancer

Introduction

Breast cancer is a heterogeneous disease and may be characterized on the basis of whether estrogen receptors (ER) are expressed in the tumour cells. ER status of breast cancer is important clinically, and is used both as a prognostic indicator and treatment predictor. In this study, we focused on identifying genetic markers associated with ER-negative breast cancer risk.

Methods

We conducted a genome-wide association analysis of 285,984 single nucleotide polymorphisms (SNPs) genotyped in 617 ER-negative breast cancer cases and 4,583 controls. We also conducted a genome-wide pathway analysis on the discovery dataset using permutation-based tests on pre-defined pathways. The extent of shared polygenic variation between ER-negative and ER-positive breast cancers was assessed by relating risk scores, derived using ER-positive breast cancer samples, to disease state in independent, ER-negative breast cancer cases.

Results

Association with ER-negative breast cancer was not validated for any of the five most strongly associated SNPs followed up in independent studies (1,011 ER-negative breast cancer cases, 7,604 controls). However, an excess of small P-values for SNPs with known regulatory functions in cancer-related pathways was found (global P = 0.052). We found no evidence to suggest that ER-negative breast cancer shares a polygenic basis to disease with ER-positive breast cancer.

Conclusions

ER-negative breast cancer is a distinct breast cancer subtype that merits independent analyses. Given the clinical importance of this phenotype and the likelihood that genetic effect sizes are small, greater sample sizes and further studies are required to understand the etiology of ER-negative breast cancers.     

The influence of flexed-knee gait on the energy cost of walking in children

There is ah understanding that walking with flexed knees contributes to the increased energy cost of walking found in children with neurological conditions. To determine the influence of flexed-knee gait on energy cost of walking in a group of children without neurological abnormality, the gait patterns of 10 normal children were studied using a Vicon system and standard marker set. A telemetric system (Cosmed K2) was then used to measure the oxygen cost of walking of the same children. The tests were repeated restricting the subjects' knee extension bilaterally, using hinged braces, set to 0, 15, 30, and 45° of flexion. Although the braces themselves caused a significant increase in O₂ cost (mL/kg/m) (P<0.05), due to a decrease in walking speed, no further significant increase in oxygen cost was demonstrated regardless of the degree of knee flexion imposed, despite a significant increase in measured hip flexion and ankle dorsiflexion at the 45° of knee flexion setting (P<0.05). We propose that moderate flexed-knee gait does not of itself cause an increase in the energy cost of walking and that other factors present in the physically disabled child are likely to be implicated.     

CO2 measurements during transcranial Doppler examinations in headache patients: methodological considerations

Transcranial Doppler (TCD) examinations are increasingly being used in studies of headache pathophysiology. Because blood velocity is highly dependent on pCO₂, these parameters should be measured simultaneously. The most common way of performing measurements during TCD examinations is as end-tidal pCO₂ witch a capnograph. When patients are nauseated and vomit, as in migraine, the mask or mouthpiece connected to the capnograph represents a problem. We therefore evaluated whether a transcutaneous pCO₂ electrode was as useful as the capnograph for pCO₂ measurements in TCD examinations. We conclude that this is not the case, and recommend capnographic end-tidal pCO₂ measurements during TCD examinations. However, transcutaneous pCO₂ measurements may represent a supplement to spot measurements of end-tidal pCO₂ in stable conditions when long-term monitoring is needed, and the mask or mouthpiece of the capnograph has to be taken on and off between recordings.     

Effect of a nitric oxide donor (glyceryl trinitrate) on nociceptive thresholds in man

Several animal studies suggest that nitric oxide (NO) plays a role in central and peripheral modulation of nociception. Glyceryl trinitrate GTN) exerts its physiological actions via donation of NO. The purpose of the present study was to examine the effect of this NO donor on nociceptive thresholds in man. On two different study days separated by at least , week 12 healthy subjects received a staircase infusion of GTN (0.015, 0.25. 1.0 ,2.0 mg/kg/min. 20 min each dose) or placebo in a randomized double-blind crossover design. Before the infusion and after 15 min of infusion on each dose, pressure pain detection and tolerance thresholds were determined by pressure a gometry (Somomedic AB, Sweden) in three different anatomic regions (finger, a temporal region with interposed myofascial tissue and a temporal region without interposed myofascial tissue. Relative to placebo, the three higher GTN doses induced a decrease in both detection and tolerance thresholds in the temporal region with interposed myofascial tissue ( p =0.003 detection and p =0.002 tolerance threshold: Friedman). No such changes were observed in the other two stimulated regions. These results could reflect central facilitation of nociception by NO. However, we regard convergence, of nociceptive input from pericranial myofascial tissue and from cephalic blood vessels dilated by NO as a more likely, explanation of our findings.     

Effects of resuscitation fluids on nonadaptive immune responses

BACKGROUND: Colloidal plasma-expander fluids are commonly used as an alternative to blood components in the resuscitation of patients suffering from hemorrhagic shock and trauma. Of these, hydroxyethyl starch is also used as a cryopreservative, and these dual properties have been utilized in the development of a blood storage system that allows the direct transfusion of red cells. The prolonged intravascular persistence of hydroxyethyl starch suggests that phagocytic clearance may be impaired and that the presence of hydroxyethyl starch could exacerbate transfusion-induced immunomodulation. STUDY DESIGN AND METHODS: The effects of colloidal resuscitation fluids on the activation response and phagocytic function of polymorphonuclear cells (PMNs) and monocytes in normal peripheral blood were examined. To mimic the hemolysis associated with cryopreservation, the effects of 1- and 5- percent red cell lysate were studied. Flow cytometric assays were used in all cases. RESULTS: The percentage of phagocytic monocytes and PMNs was not altered; nor were the rates of phagocytosis impaired after incubation with resuscitation fluids. Upregulation of cell surface integrin during activation was similarly unmodified by the fluids. CONCLUSION: Hydroxyethyl starch and other resuscitation fluids do not affect some important antimicrobial functions of the nonadaptive arm of the immune response. This suggests that posttrauma or transfusion- induced immunomodulation is not exacerbated by inhibition at this level.