Polymorphisms in the platelet-specific collagen receptor GP6 are associated with risk of nonfatal myocardial infarction in Caucasians

Background and aims

Glycoprotein 6 (GP6) is a platelet-specific collagen receptor implicated in the thrombotic pathway to acute myocardial infarction (AMI), but a possible genetic relationship between GP6 and AMI is poorly understood. We tested for the genetic association between AMI and single nucleotide polymorphisms (SNPs) in 24 loci, including GP6.

Methods and results

We conducted a case-control study of AMI and GP6 in a community-based population (n = 652 cases, 625 controls). We also examined men and women separately and stratified the latter by use of hormone replacement therapy (HRT). Among both sexes, the strongest association was for a protective missense polymorphism (rs1163662) in the GP6 gene (OR = 0.70; Bonferroni-adjusted p < 0.05). SNPs in GP6 were also strongly associated with AMI among women who reported ever taking HRT, but not among women who never took HRT. Haplotype analyses were consistent with the single-SNP findings.

Conclusions

In this sample of white non-Hispanic men and women, several SNPs in GP6 were significantly related to risk of AMI. Development of pharmacologic therapy directed towards platelet activity and thrombosis may reduce the incidence of AMI among at-risk groups.     

High level expression of fms proto-oncogene mRNA is observed in clinically aggressive human endometrial adenocarcinomas

Six micron paraffin sections of paraformaldehyde-fixed endometrial currettings of 21 benign and neoplastic endometrial specimens were assayed for tumor cell-specific oncogene expression by in situ hybridization with probes for six oncogenes, beta-actin, and the E. coli plasmid pBR322. In the benign hyperplasias and invasive adenocarcinomas, multiple oncogenes, including erbB, fms, c-myc, and Ki-ras were expressed at significant levels. For the adenocarcinomas, statistical analysis demonstrated that high levels of expression of fms-complementary mRNA correlated strongly with clinicopathologic features (high FIGO histologic grade, high FIGO clinical stage, deep myometrial penetration) predictive of aggressive clinical behavior and poor outcome. The authors discuss the role which M-CSF receptor (the fms gene product) and locally-produced M-CSF may play in the development of the observed aggressively-malignant phenotypes. They also propose that pre-hysterectomy assay of fms gene expression in endometrial currettings in FIGO Stage I patients might be clinically useful to help identify preoperatively those patients with deep myometrial penetration or other locoregional spread.     

Endoscopic Congo red test during proximal gastric vagotomy

Although proximal gastric vagotomy is widely performed as an elective treatment for duodenal ulcer, the incidence of recurrent ulcer is troublesome. There are several theories to explain recurrent ulcers, and important technical steps should be considered when performing proximal gastric vagotomy. The use of an intraoperative test may allow more accurate performance of the operation and more complete vagotomy of the parietal cell mass. This report describes the use of the endoscopic Congo red test in patients during proximal gastric vagotomy. The test allows rapid and accurate mapping of areas of the stomach with intact vagus and secretory nerves after operative vagotomy, and can be repeated several times if necessary to verify completion of the vagotomy. The use of universally available equipment and the potential for intraoperative and postoperative use are other attractive features of the test. Use of the endoscopic Congo red test provides physiologic evidence that vagus secretory nerve fibers traverse the right and left gastroepiploic nerves, leading us to believe that the gastroepiploic nerves should be routinely divided during proximal gastric vagotomy. In patients with recurrent duodenal ulcer requiring reoperation, the endoscopic Congo red test allows preoperative demonstration of the site of the intact vagal nerve trunks. The endoscopic Congo red test deserves further investigation and wider application during operations for chronic duodenal ulcer.     

Autologous breast reconstruction: the Vanderbilt experience (1998 to 2005) of independent predictors of displeasing outcomes

BACKGROUND: Optimal surgical outcomes are dependent on an appreciation of comorbid conditions that may handicap results. The purpose of this retrospective analysis was to delineate risk factors for complications after autologous breast reconstruction. STUDY DESIGN: An institutional database was constructed of patients who underwent autologous breast reconstruction from 1998 to 2005. Variables captured included age, diabetes and smoking status, prereconstruction radiation therapy, concomitant breast resection, preoperative albumin, flap type, and body mass index (BMI; based on World Health Organization classifications: BMI>25, overweight; >30, obese). The primary outcome was noninfectious wound complications (NIWC), a novel classification based on the extent of tissue derangement and need for operative intervention. Secondary outcomes were wound infection, hematoma, hernia, and fat necrosis. Statistical analysis was performed using chi-square tests and multiple logistic regression. RESULTS: The analysis included 200 flaps (transverse rectus abdominis myocutaneous [TRAM]=171; latissimus dorsi=29) in 180 patients. There were 19 infections (9.5%), 3 total flap losses (1.5%), 14 hematomas (7%), and 11 donor-site hernias (6%). The incidences of fat necrosis and any NIWC were 18% and 36%, respectively. Mean followup was 13.1 months (range 1.1 to 51.7 months). Multiple logistic regression demonstrated that obesity (BMI>30) is a statistically significant independent risk factor for any NIWC (hazards ratio=6.58; 95% CI, 2.85 to 15.18; p < 0.01) and for NIWC requiring operative treatment (NIWC>or=3; hazard ratio=6.23; 95% CI 2.15 to 18.05; p < 0.01). Increased BMI predicts NIWC, NIWC requiring operative intervention, and wound infection (p < 0.01). CONCLUSIONS: These data suggest that obesity is a strong predictor of simple and complex NIWC and of wound infection after autologous breast reconstruction. Obese patients should be counseled about their significantly increased risk of experiencing these unwanted outcomes.     

CXCR2 and RET Single Nucleotide Polymorphisms in Pancreatic Cancer

Enhanced angiogenesis and perineural invasion are markers of poor prognosis in patients with pancreatic cancer. Systemic therapies for pancreatic cancer have been largely ineffective, and thus improved, targeted therapies are needed. Single nucleotide polymorphisms (SNP) are DNA sequence variations that result in vast diversity of disease susceptibility and response to disease. CXCR2 is an important mediator of CXC chemokine-induced angiogenesis and is upregulated in pancreatic cancer. In a preclinical corneal micropocket assay, treatment of pancreatic cancer cell lines that express CXCR2 with anti-CXCR2 antibody inhibited angiogenesis. To date, there have not been any CXCR2 SNP associated with pancreatic cancer, but CXCR2 SNP has been postulated to be associated with angiogenesis in systemic sclerosis. The receptor tyrosine kinase encoded by the RET gene and its ligand glial derived neurotrophic factor (GDNF) are upregulated in pancreatic cancer. In vitro treatment of pancreatic cancer cell lines that express RET with anti-RET antibody or RET siRNA-inhibited GDNF-induced invasiveness. G691S RET SNP has been previously shown to be associated with enhanced pancreatic cancer invasiveness. We suggest that molecular profiling of each patient’s tumor for G691S RET SNP, potentially CXCR2 SNP, and also other yet-to-be identified SNP associated with pancreatic cancer will allow for both improved understanding of individual prognosis and allow for utilization of more personalized, targeted adjuvant therapies. This work was presented at the Molecular Surgeon Symposium on Personalized Genomic Medicine and Surgery at the Baylor College of Medicine, Houston, TX, USA, April 12, 2008. The symposium was supported by a grant from the National Institutes of Health (R13 CA132572 to Changyi Chen).     

Biophysical Regulation of Stem Cell Differentiation

Bone adaptation to its mechanical environment, from embryonic through adult life, is thought to be the product of increased osteoblastic differentiation from mesenchymal stem cells. In parallel with tissue-scale loading, these heterogeneous populations of multipotent stem cells are subject to a variety of biophysical cues within their native microenvironments. Bone marrow-derived mesenchymal stem cells—the most broadly studied source of osteoblastic progenitors—undergo osteoblastic differentiation in vitro in response to biophysical signals, including hydrostatic pressure, fluid flow and accompanying shear stress, substrate strain and stiffness, substrate topography, and electromagnetic fields. Furthermore, stem cells may be subject to indirect regulation by mechano-sensing osteocytes positioned to more readily detect these same loading-induced signals within the bone matrix. Such paracrine and juxtacrine regulation of differentiation by osteocytes occurs in vitro. Further studies are needed to confirm both direct and indirect mechanisms of biophysical regulation within the in vivo stem cell niche.     

The management of epilepsy in pregnancy

While most women with epilepsy can expect a normal pregnancy outcome, epilepsy remains a significant contributor to both maternal and perinatal morbidity. Pre-pregnancy planning must address reliable contraception and optimisation of antiepileptic drug (AED) regimens to minimise teratogenic risk while maintaining seizure control. The most recent data from the AED registries regarding malformations is presented in this review, as is the limited data on the newer AEDs and studies linking neurocognitive outcomes to AED exposure. During pregnancy, important considerations include; therapeutic drug monitoring, surveillance for obstetric complications and vigilance for seizures during the intrapartum and postpartum period.     

Feasibility of using interpolated contours of targets and organs at risk in intensity‐modulated radiation therapy treatment planning for advanced‐stage nasopharyngeal carcinoma

To assess the dosimetric effect of using interpolated contours in planning intensity‐modulated radiation therapy (IMRT) for advanced T‐stage nasopharyngeal carcinoma. The present study focused on T3–T4 tumours where the proximity of targets to neurological organs poses a stringent test on the feasibility of such an approach. Contours of targets and organs were delineated on CT images of 2.5‐mm interval and a reference IMRT plan was generated. An investigative (INV) IMRT plan was then generated with the same planning protocol, but based on interpolated contours that replaced deleted contours on alternate slices. The reference and INV plans were compared. Regarding target coverage, all targets in the INV plans met the acceptance criteria except for the PTV in one case. Regarding organs, the mean dose to 1% volume of the brainstem and spinal cord in the INV plans were kept below their dose limits. No significant differences in the mean doses to others organs were found. Satisfactory target coverage and protection of critical organs to a degree similar to full‐scale contouring could be achieved with use of interpolated contours. The saving in manpower time for contouring is expected to significantly improve the throughput of the IMRT planning process.     

Field evaluation of the Welch Allyn SureSight vision screener: incorporating the vision in preschoolers study recommendations.

INTRODUCTION: The prospective Vision in Preschoolers (VIP) study evaluated 11 methods of screening and proposed referral criteria for the Welch Allyn SureSight(trade mark) Vision Screener with 90% and 94% specificity. The SureSight had a higher sensitivity than most other screening techniques when these criteria were applied. We evaluated the usefulness of these criteria in a field study of healthy preschool children. METHODS: The SureSight software was altered to recommend referral using the VIP referral criteria with 90% specificity. Lions Club volunteers screened preschool children throughout Tennessee. Referred children underwent comprehensive eye examinations with cycloplegic refraction. Examination failure criteria were based upon published standards. Reanalysis using the 94% specificity criteria was then performed. Outcomes included referral rate and positive predictive value. RESULTS: The SureSight was used to screen 4,733 children, and screening was successful in 99.7% of children. The referral rate using the 90% specificity criteria was 12.2%. Most children (73%) were referred for suspected astigmatism. The positive predictive value was 30%. Using the 94% specificity criteria from the VIP study decreased the referral rate to 7.9% and substantially decreased over referral for suspected astigmatism; however, several anisometropes went undetected. Higher specificity was achieved by raising astigmatism referral criteria to 2.2 diopters while leaving the anisometropia criteria unchanged. CONCLUSIONS: The SureSight can be used successfully for preschool screening in the field provided that criteria with high specificity are incorporated into the instrument's software program. Higher rates of positive predictive value can be achieved without jeopardizing sensitivity by raising astigmatism referral criteria to 2.2 diopters.