Surgery and the randomised controlled trial: past, present and future

Randomised controlled trials (RCTs), with their prospective definition of methods and outcome measures, double-blind assessment of outcomes and unbiased selection of subjects and controls, provide the best possible evidence for deciding the value of a medical or surgical intervention. Few surgical studies are designed as RCTs, and those that are should be of a higher quality. The lack of good surgical RCTs may be a result of surgeons lacking the necessary training, expertise and desire to perform RCTs, inadequate funding from granting agencies, difficulties in securing patient consent or a lack of sufficient patient numbers. If an RCT is not feasible for a particular study, then alternative research designs, such as prospective matched-pair trials, may need to be better developed and used. If RCTs can be performed, other strategies to increase the number and quality of RCTs may be needed: Education of surgeons in clinical research methods Improved funding of surgical RCTs Compulsory evaluation of new techniques and technology before their general adoption is permitted.     

Detection of atomic deuterium in the upper atmosphere of Mars

High-resolution spectroscopy of Mars' atmosphere with the Hubble Space Telescope revealed the deuterium Lyman alpha line at an intensity of 23 +/- 6 rayleighs. This measured intensity corresponds to HD/H2 = 1.5 +/- 0.6 x 10(-4), which is smaller by a factor of 11 than HDO/H2O. This indicates that fractionation of HD/H2 relative to that of HDO/H2O is not kinetically controlled by the rates of formation and destruction of H2 and HD but is thermodynamically controlled by the isotope exchange HD + H2O left and right arrow HDO + H2. Molecular hydrogen is strongly depleted in deuterium relative to water on Mars because of the very long lifetime of H2 (1200 years). The derived isotope fractionation corresponds to an estimate of a planetwide reservoir of water ice about 5 meters thick that is exchangeable with the atmosphere.     

Downregulation of the pro-apoptotic protein Bak is required for the ras-induced transformation of intestinal epithelial cells

Anoikis is a form of programmed cell death induced in normal epithelial cells by detachment from the extracellular matrix [1] [2] [3]. In epithelial cells of the intestine and other organs, activated rasinduces resistance to anoikis [3] [4], but the actual molecular effectors directly involved in the apoptotic machinery that execute or block anoikis have not yet been identified. Bak, a pro-apoptotic member of the Bcl-2 family, is downregulated in a high proportion of colorectal tumours [5]. In addition, Bak is an important regulator of apoptosis in normal intestinal epithelial cells [6] [7]. Here, we show that activated rasinduces the downregulation of Bak in rat and human intestinal epithelial cells. This ras-induced downregulation of Bak expression could be suppressed by an inhibitor of phosphatidylinositol (PI) 3-kinase, an enzyme already implicated in ras-induced resistance to anoikis [8]. Ectopic expression of Bak in ras-transformed rat intestinal epithelial IEC-18 cells inhibited ras-induced resistance to anoikis and significantly reduced their tumorigenicity. We conclude, therefore, that the ability of rasto downregulate Bak, and the consequent resistance to anoikis, are essential components of the transforming capacity of this oncogene in intestinal epithelial cells.     

Prediction of indications for valve replacement among asymptomatic or minimally symptomatic patients with chronic aortic regurgitation and normal left ventricular performance

BACKGROUND: Optimal criteria for valve replacement are unclear in asymptomatic/minimally symptomatic patients with aortic regurgitation (AR) and normal left ventricular (LV) performance at rest. Moreover, previous studies have not assessed the prognostic capacity of load-adjusted LV performance ("contractility") variables, which may be fundamentally related to clinical state. Therefore, 18 years ago, we set out to test prospectively the hypothesis that objective noninvasive measures of LV size and performance and, specifically, of load-adjusted variables, assessed at rest and during exercise (ex), could predict the development of currently accepted indications for operation for AR. METHODS AND RESULTS: Clinical variables and measures of LV size, performance, and end-systolic wall stress (ESS) were assessed annually in 104 patients by radionuclide cineangiography at rest and maximal ex and by echocardiography at rest; ESS was derived during ex. During an average 7.3-year follow-up among patients who had not been operated on, 39 of 104 patients either died suddenly (n = 4) or developed operable symptoms only (n = 22) or subnormal LV performance with or without symptoms (n = 13) (progression rate=6.2%/y). By multivariate Cox model analysis, change (delta) in LV ejection fraction (EF) from rest to ex, normalized for deltaESS from rest to ex (deltaLVEF-deltaESS index), was the strongest predictor of progression to any end point or to sudden cardiac death alone. Unadjusted deltaLVEF was almost as efficient. Symptom status modified prediction on the basis of the deltaLVEF-deltaESS index. The population tercile at highest risk by deltaLVEF-deltaESS progressed to end points at a rate of 13.3%/y, and the lowest-risk tercile progressed at 1.8%/y. CONCLUSIONS: Currently accepted symptom and LV performance indications for valve replacement, as well as sudden cardiac death, can be predicted in asymptomatic/minimally symptomatic patients with AR by load-adjusted deltaLVEF-deltaESS index, which includes data obtained during exercise.     

Direct communication on the Internet. Uninet: the university link for Integrate Telematic Services

The importance of Internet as a communication medium is clear due to the amount of information it distributes and the high number of potential recipients it has. The appearance of virtual user communities (CMV) focuses to information classification within subjects of interest for certain groups of people in order to facilitate its search and use. The UniNet project of Integrated Telematic Services for CMV through, as well as other subprojects, the 'propuesta RedUni' encourages the creation of CMV by mean of integration of various computer and Internet resources, such as distribution mailing list, web pages, Internet Relay Chat (IRC), etc. The current state of IRC in such context is presented and the utilities of the known as Scientific-IRC as a professional real time communication tool are discussed.     

Biotransformation of tirilazad in human: 3. tirilazad A-ring reduction by human liver microsomal 5alpha-reductase type 1 and type 2

Connexin 43, a member of the highly conserved connexin family of gap junction proteins, is expressed in the pig ovary. In other species, ovarian connexin 43 expression and phosphorylation are hormonally regulated. We characterized connexin 43 expression and phosphorylation in the ovaries of mature pigs during the estrous cycle and in prepubertal gilts during follicular development induced by eCG (750 IU)/hCG (500 IU; 72 h later). Ovarian connexin 43 protein expression and phosphorylation were examined by immunoblot analysis. Connexin 43 was localized to specific follicular cell types during development by immunofluorescence. While no change in total connexin 43 protein expression was seen during the cycle, connexin 43 phosphorylation was significantly higher (p < 0.05) during the late follicular stage of the cycle than during the early luteal and early to mid-follicular stages. In ovaries of eCG/hCG-primed prepubertal pigs, connexin 43 protein levels remained steady, while phosphorylation of the protein increased significantly at 72 h and 84 h after eCG treatment (p < 0.05), then declined to pretreatment levels by 96 h (24 h post-hCG administration). Immunoreactive connexin 43 was localized predominantly to granulosa cells of cyclic pigs and eCG/hCG-primed prepubertal gilts. Follicular connexin 43 was highest between 60 h and 84 h after eCG and declined after hCG administration. Connexin 43 was not detected in morphologically atretic follicles, stroma, or vascular tissue of the ovary. This is the first evidence that porcine ovarian connexin 43 phosphorylation is differentially regulated during follicular development. The results suggest that hormonally induced changes in connexin 43 phosphorylation may play a coordinating role in porcine follicular development.     

Differential inducibility of specific mRNA corresponding to five CYP3A isoforms in female rat liver by RU486 and food deprivation: comparison with protein abundance and enzymic activities

Cranial neural fold fusion in the chick embryo is known to commence in the midbrain region before progressing cranially and caudally to involve the fore- and hindbrain regions, respectively. The two epithelial layers at the tips of the neural folds that participate in fusion are the surface ectoderm and the neuroepithelium. We have examined and compared cranial neural fold fusion in both layers, and our results show that fusion of the neuroepithelial component of the neural folds, unlike that of the surface ectoderm, starts in the caudal portion of the forebrain. Second, contrary to the widely accepted opinion, we have demonstrated that in the hindbrain region, fusion of the neuroepithelial component of the neural folds does not occur. Soon after neural fold apposition, a neuroepithelial eminence appears in rhombomeres 1 and 2, and this, together with other neuroepithelial cells in the dorsal midline of the hindbrain, undergoes massive apoptosis. The absence of neuroepithelial fusion in the hindbrain may be due to the presence of massive apoptosis among neuroepithelial cells that should have participated in the fusion process. The events described above may predispose the hindbrain to the development of neural tube defects. The appearance of cranial neural crest cells in the midline during their migration may enhance the fusion of the surface ectodermal portion of the neural folds.