Influence of cholesteryl ester transfer protein, peroxisome proliferator-activated receptor α, apolipoprotein E, and apolipoprotein A-I polymorphisms on high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein A-I, and lipoprotein A-I:A-II concentrations: the Prospective Epidemiological Study of Myocardial Infarction study

The plasma level of high-density lipoprotein cholesterol (HDL-C) is known to be inversely associated with cardiovascular risk. However, besides lifestyle, gene polymorphism may influence the HDL-C concentration. The aim of this study was to investigate the possibility of interactions between CETP, PPARA, APOE, and APOAI polymorphisms and HDL-C, apolipoprotein (apo) A-I, lipoprotein (Lp) A-I, and Lp A-I:A-II in a sample selected from the Prospective Epidemiological Study of Myocardial Infarction (PRIME) study population who remained free of cardiovascular events over 5 years of follow-up. Healthy individuals (857) were randomly selected for genotyping the PRIME study subjects. The population was selected so as to provide 25% of subjects in the lowest tertile of HDL-C (≤28 mg/dL) in the whole PRIME study sample, 25% of subjects in the highest tertile of HDL-C (≥73 mg/dL), and 50% of subjects in the medium tertile of HDL-C (28-73 mg/dL). Genotyping was performed by using a polymerase chain reaction system with predeveloped TaqMan allelic discrimination assay. The CETP A373P rare allele c was less frequent in the group of subjects with high HDL-C, apo A-I, Lp A-I, and Lp A-I:A-II concentrations. Apolipoprotein A-I and Lp A-I were also found to be higher in the presence of the ?2 allele coding for APOE. The effect of the CETP A373P rare allele c on HDL-C was independent of all tested parameters except triglycerides. The respective effect of these polymorphisms and triglycerides on cardiovascular risk should be evaluated prospectively.     

A theory of microtubule catastrophes and their regulation

Dynamic instability, in which abrupt transitions occur between growing and shrinking states, is an intrinsic property of microtubules that is regulated by both mechanics and specialized proteins. We discuss a model of dynamic instability based on the popular idea that growth is maintained by a cap at the tip of the fiber. The loss of this cap is thought to trigger the transition from growth to shrinkage, called a catastrophe. The model includes longitudinal interactions between the terminal tubulins of each protofilament and “gating rescues” between neighboring protofilaments. These interactions allow individual protofilaments to transiently shorten during a phase of overall microtubule growth. The model reproduces the reported dependency of the catastrophe rate on tubulin concentration, the time between tubulin dilution and catastrophe, and the induction of microtubule catastrophes by walking depolymerases. The model also reproduces the comet tail distribution that is characteristic of proteins that bind to the tips of growing microtubules.     

Dental occlusion and postural control in adults

We studied the influence of a dental occlusion perturbation on postural control. The tests were performed in three dental occlusion conditions: (Rest Position: no dental contact, Maximal Intercuspal Occlusion: maximal dental contact, and Thwarted Laterality Occlusion: simulation of a dental malocclusion) and four postural conditions: static (stable platform) and dynamic (unstable platform), with eyes open and eyes closed. A decay of postural control was noted between the Rest Position and Thwarted Laterality Occlusion conditions with regard to average speed and power indexes in dynamic conditions and with eyes closed. However, the head position and stabilization were not different from those in the other experimental conditions, which means that the same functional goal was reached with an increase in the total energetic cost. This work shows that dental occlusion differently affects postural control, depending on the static or dynamic conditions. Indeed, dental occlusion impaired postural control only in dynamic postural conditions and in absence of visual cues. The sensory information linked to the dental occlusion comes into effect only during difficult postural tasks and its importance grows as the other sensory cues become scarce.     

Tissue segmentation in Monte Carlo treatment planning: a simulation study using dual-energy CT images.

PURPOSE: Tissue segmentation is an important step in Monte Carlo (MC) dose calculation and is often done uncritically. A new approach to tissue segmentation using dual-energy CT images is studied in this work. MATERIALS AND METHODS: A simple MC model of a CT scanner was built and CT images of phantoms with ten tissue-equivalent cylinders were simulated using soft and hard X-ray spectra. The Z and rho(e) of the cylinders were extracted using a formalism based on a parameterization of the linear attenuation coefficient. RESULTS: It was shown that in order to extract Z and rho(e) with a reasonable accuracy, hard X-ray beams have to be used for scanning. When an additional filtration of 9 mm of aluminium in the CT X-ray beam is used, beam hardening in high density materials is suppressed and the mean errors of the extraction of Z and rho(e) for 10 tissue-equivalent materials in a small tissue-equivalent phantom are 3.7% and 3.1%, respectively. CONCLUSIONS: MC simulations were used to show that the extraction of Z and rho(e) for a number of tissue-equivalent materials using dual-energy CT images is possible which improves tissue segmentation for Monte Carlo dose calculations, as demonstrated with a 250 kVp photon beam dose calculation.     

Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series.

PURPOSE: Recently, a 76-gene prognostic signature able to predict distant metastases in lymph node-negative (N(-)) breast cancer patients was reported. The aims of this study conducted by TRANSBIG were to independently validate these results and to compare the outcome with clinical risk assessment. EXPERIMENTAL DESIGN: Gene expression profiling of frozen samples from 198 N(-) systemically untreated patients was done at the Bordet Institute, blinded to clinical data and independent of Veridex. Genomic risk was defined by Veridex, blinded to clinical data. Survival analyses, done by an independent statistician, were done with the genomic risk and adjusted for the clinical risk, defined by Adjuvant! Online. RESULTS: The actual 5- and 10-year time to distant metastasis were 98% (88-100%) and 94% (83-98%), respectively, for the good profile group and 76% (68-82%) and 73% (65-79%), respectively, for the poor profile group. The actual 5- and 10-year overall survival were 98% (88-100%) and 87% (73-94%), respectively, for the good profile group and 84% (77-89%) and 72% (63-78%), respectively, for the poor profile group. We observed a strong time dependence of this signature, leading to an adjusted hazard ratio of 13.58 (1.85-99.63) and 8.20 (1.10-60.90) at 5 years and 5.11 (1.57-16.67) and 2.55 (1.07-6.10) at 10 years for time to distant metastasis and overall survival, respectively. CONCLUSION: This independent validation confirmed the performance of the 76-gene signature and adds to the growing evidence that gene expression signatures are of clinical relevance, especially for identifying patients at high risk of early distant metastases.     

Molecular detection of localized prostate cancer using quantitative methylation-specific PCR on urinary cells obtained following prostate massage.

PURPOSE: The diagnosis of localized prostate cancer is difficult due to a lack of cancer-specific biomarkers. Many patients require repeat prostate biopsies to diagnose the disease. We investigated whether aberrant promoter hypermethylation in prostatic fluid could reliably detect prostate cancer. EXPERIMENTAL DESIGN: Urine samples were collected after prostate massage from 95 patients with localized prostate cancer undergoing radical prostatectomy (63 pT(1), 31 pT(2), and 1 pT(3)) and from 38 control patients. Ten genes (GSTP1, RASSF1a, ECDH1, APC, DAPK, MGMT, p14, p16, RARbeta2, and TIMP3) were investigated using quantitative real-time methylation-specific PCR. Receiver operator curves were generated. RESULTS: The frequency of gene methylation ranged from 6.3% (p14) to 83.2% (GSTP1) in prostate cancer patients. At least one gene was hypermethylated in 93% of cancer patients. The specificity of methylation was 0.74. Methylation was significantly more frequent (P < 0.05) in cancer than control patients for all genes except p14 and p16. According to receiver operator curve analysis, the four-gene combination of GSTP1 (0.86), RASSF1a (0.85), RARbeta2 (0.80), and APC (0.74) best discriminated malignant from nonmalignant cases. The sensitivity and accuracy of this four-gene set were 86% and 89%, respectively. CONCLUSIONS: The presence of aberrant methylation in urinary cells obtained after prostate massage is significantly associated with prostate cancer. A panel of four genes could stratify patients into low and high risk of having prostate cancer and optimize the need for repeat prostatic biopsies.     

Effects of cyanobacterial crude extracts from Planktothrix agardhii on embryo-larval development of medaka fish, Oryzias latipes.

Embryonic toxicity from exposure to microcystins, cyclic hepatotoxic heptapeptides from cyanobacteria, receives increasing attention as a public human health biohazard. Using a microinjection technology, we have introduced cyanobacterial extracts from Planktothrix agardhii directly into the vitellus of late neurula embryos (stage 19) of medaka (Oryzias latipes). Microinjection (2 nL) of P. agardhii PMC 75.02 extract containing microcystins (MC) resulted in a dose-dependent mortality of embryos. Survival rates were reduced up to 81% with extract concentrations of 10 mg mL(-1) (EC(50)=7.8 microg mL(-1)). On the other hand, injection of P. agardhii PMC 87.02 extract in which no microcystin could be detected resulted in much less embryonal toxicity (EC(50)=460 microg mL(-1)). In addition, advanced embryonic hatching processing was limited with PMC 75.02 crude extract and less obvious than had been described with pure MC-LR injections. In agreement with the known hepatotoxic effects of microcystin, embryos injected with PMC 75.02 extract consistently displayed hepatobiliary abnormalities. Loss of glycogen content of the hepatocytes and hepatic haemorrhage were evidenced in surviving post-hatching juveniles. Thus, the methodology presented in this paper should be a valuable tool to analyse the effects of crude extracts of cyanobacterial toxins on the development of aquatic vertebrate embryos.     

Emergency department visits caused by adverse drug events: results of a French survey.

BACKGROUND: Adverse drug events (ADEs) are a substantial cause of hospital admissions. However, little is known about the incidence, preventability and severity of ADEs resulting in emergency department visits. To address this issue, we conducted a prospective survey in emergency departments of French public hospitals. METHODS: This study was performed over two periods of 1 week each, one in June 1999 and one in December 1999, in emergency departments of five university hospitals and five general hospitals throughout France. All patients aged>or=15 years presenting with medical complaints were included in the study. Trauma patients, those with gynaecological conditions and those with alcohol intoxication or intentional drug poisoning were excluded from the study. Each patient was assessed by two local emergency physicians to determine whether the visit was the result of an ADE. All medical records were subsequently validated by an independent group of medical lecturers in iatrogenic disorders. RESULTS: Out of a total of 1937 patients consulting, 1562 were taking at least one drug during the previous week and were included for analysis; 328 (21%; 95% CI 19, 23) of these patients consulted an emergency physician because of an ADE. Patients with ADEs were older than those without (mean age 63.5 vs 54.8 years; p<0.0001). Furthermore, ADE patients were more likely to have a higher severity presentation than the non-ADE group (p=0.019). The number of drug exposures was significantly higher in patients with an ADE than in those without (mean number of medications 5.17 vs 3.82; p<0.0001). On multivariate analysis, only age and the number of medications taken were significantly associated with adverse events. In total, 410 drugs were incriminated in the occurrence of 328 ADEs. The most frequently incriminated drug classes were: (i) psychotropic agents (n=84; 20.5%); (ii) diuretics (n=48; 11.7%), anticoagulants (n=38; 9.3%) and other cardiovascular drugs (n=63; 15.4%); and (iii) analgesics, including NSAIDs (n=57; 13.9%). Preventability could be assessed in 280 of the 328 cases. In 106 cases (37.9%), the ADE was judged to be preventable. CONCLUSION: ADEs leading to emergency department visits are frequent, and many are preventable, confirming that there is a need to develop prevention strategies.