Localization of putative tumor suppressor loci by genome-wide allelotyping in human pancreatic endocrine tumors

Only two tumor suppressor gene loci, one on 3p25 and the MEN1 gene on 11q13, have thus far been implicated in the pathogenesis of sporadic human pancreatic endocrine tumors (PETs). A genome-wide allelotyping study of 28 human PETs was undertaken to identify other potential tumor suppressor gene loci. In addition to those on chromosomes 3p and 11q, frequent allelic deletions were identified on 3q (32%), 11p (36%), 16p (36%), and 22q (29%). Finer deletion mapping studies localized the smallest regions of common deletion to 3q27, 11p13, and 16p12.3-13.11. Potential candidate genes at these loci include WT1 (11p13), TSC2 (16p13), and NF2 (22q12), but no known tumor suppressor gene localizes to 3q27. The mean fractional allelic loss among these human PETs is 0.126, and no correlation was observed between allelic loss and clinical parameters, including age, sex, hormonal subtype, and disease stage. These findings highlight novel locations of tumor suppressor gene loci that contribute to the pathogenesis of human PETs, and several of these on 3p, 3q, and 22q are syntenic with loci on mouse chromosomes 9 and 16 that are implicated in a murine transgenic model of PETs.     

Parallelism in ILU-preconditioned GMRES

A parallel implementation of the preconditioned GMRES method is described. The method is used to solve the discretized incompressible Navier–Stokes equations. A parallel implementation of the inner product is given, which appears to be scalable on a massively parallel computer. The most difficult part to parallelize is the ILU-preconditioner. We parallelize the preconditioner using ideas proposed by Bastian and Horton (P. Bastian, G. Horton, SIAM. J. Stat. Comput. 12 (1991) 1457–1470). Contrary to some other parallel methods, the required number of iterations is independent of the number of processors used. A model is presented to predict the efficiency of the method. Experiments are done on the Cray T3D, computing the solution of a two-dimensional incompressible flow. Predictions of computing time show good correspondence with measurements.     

Fifteen years experience with finger arterial pressure monitoring: assessment of the technology

We review the Finapres technology, embodied in several TNO-prototypes and in the Ohmeda 2300 and 2300e Finapres NIBP. Finapres is an acronym for FINger Arterial PRESsure, the device delivers a continuous finger arterial pressure waveform. Many papers report on the accuracy of the device in comparison with intra-arterial or with noninvasive but intermittent blood pressure measurements. We compiled the results of 43 such papers and found systolic, diastolic and mean accuracies, in this order, ranging from -48 to 30 mmHg, from -20 to 18 mmHg, and from -13 to 25 mmHg. Weighted for the number of subjects included pooled accuracies were -0.8 (SD 11.9), -1.6 (8.3) and -1.6 (7.6) mmHg respectively. Subdividing the pooled group according to criteria such as reference blood pressure, place of application, and prototype or commercial device we found no significant differences in mean differences or SD. Measurement at the finger allows uninterrupted recordings of long duration. The transmission of the pressure pulse along the arm arteries, however, causes distortion of the pulse waveform and depression of the mean blood pressure level. These effects can be reduced by appropriate filtering, and upper arm 'return-to-flow' calibration to bring accuracy and precision within AAMI limits. For the assessment of beat-to-beat changes in blood pressure and assessment of blood pressure variability Finapres proved a reliable alternative for invasive measurements when mean and diastolic pressures are concerned. Differences in systolic pressure are larger and reach statistical significance but are not of clinical relevance. Finger arteries are affected by contraction and dilatation in relation to psychological and physical (heat, cold, blood loss, orthostasis) stress. Effects of these phenomena are reduced by the built-in Physiocal algorithm. However, full smooth muscle contraction should be avoided in the awake patient by comforting the patient, and covering the hand. Arterial state can be monitored by observing the behaviour of the Physiocal algorithm. We conclude that Finapres accuracy and precision usually suffice for reliable tracking of changes in blood pressure. Diagnostic accuracy may be achieved with future application of corrective measures.     

The direct activating effect of a nonapeptide neurohormone (vasotocin) on the thyroid and interrenal glands of sturgeons in in-vitro experiments

An in-vitro effect of nonapeptide neurohormone vasotocin on thyroid and interrenal glands was studied in hybrid of Siberian and Lena sturgeons [correction of salmons] at light microscopy level using morphometric method. At a concentration of 0.1 and 1 nmol/l vasotocin was shown to exert undirectional stimulating effect on the thyroid and interrenal gland functions. In the presence of vasotocin at a concentration of 1 nmol/l in culture media the activity of glands is even more pronounced than under the influence of adenohypophyseal hormones, adrenocorticotropic (8 x 10 ng/ml) and thyrotropic (5 ng/ml).     

Role of p53 gene in colorectal neoplasms

A prospective study on the role of the p53 gene in sporadic colorectal neoplasms is presented and the level of mutant p53 protein was measured in the tissue removed during colonoscopy from: patients previously operated for colorectal malignant neoplasms, patients with active neoplasms, first degree relatives and during regular checks. 72% of patients with an active tumour showed a positive p53 and 38% in follow-up checks. Longer follow-up periods and a major number of patients are necessary to assess the prognostic importance of the p53 protein.     

EMS1 gene expression in primary breast cancer: relationship to cyclin D1 and oestrogen receptor expression and patient survival

The EMS1 and CCND1 genes at chromosome 11q13 are amplified in about 15% of primary breast cancers but appear to confer different phenotypes in ER positive and ER negative tumours. Since there are no published data on EMS1 expression in large series of breast cancers we examined the relationship of EMS1 expression with EMS1 gene copy number and expression of mRNAs for cyclin D1 and ER. In a subset of 129 patients, where matched tumour RNA and DNA was available, EMS1 mRNA overexpression was associated predominantly with gene amplification (P = 0.0061), whereas cyclin D1 mRNA overexpression was not (P = 0.3142). In a more extensive series of 351 breast cancers, there was no correlation between cyclin D1 and EMS1 expression in the EMS1 and cyclin D1 overexpressors (P = 0.3503). Although an association between EMS1 mRNA expression and ER positivity was evident (P = 0.0232), when the samples were divided into quartiles of EMS1 or cyclin D1 mRNA expression, the increase in the proportion of ER positive tumours in the ascending EMS1 mRNA quartiles was not statistically significant (P = 0.0951). In marked contrast there was a significant stepwise increase in ER positivity in ascending quartiles of cyclin D1 mRNA (P = 0.030). A potential explanation for this difference was provided by the observation that in ER positive breast cancer cells oestradiol treatment resulted in increased cyclin D1 gene expression but was without effect on EMS1. The relationship between EMS1 expression and clinical outcome was examined in a subset of 234 patients with median follow-up of 74 months. High EMS1 expression was associated with age > 50 years (P = 0.0001), postmenopausal status (P = 0.0008), lymph node negativity (P = 0.019) and an apparent trend for worse prognosis in the ER negative subgroup. These data demonstrate that overexpression of EMS1 mRNA is largely due to EMS1 gene amplification, is independent of cyclin D1 and ER expression and, in contrast to cyclin D1, is not regulated by oestrogen. Independent overexpression of these genes may confer different phenotypes and disease outcomes in breast cancer as has been inferred from recent studies of EMS1 and CCND1 gene amplification.     

Physiologically relevant one-compartment pharmacokinetic models for skin. 1. Development of models

Many studies have used pharmacokinetic (compartment) models for skin to predict or analyze absorption of chemicals through skin. In these studies, several different definitions of the rate constants were used. The purpose of this study was to develop a general procedure for relating compartment model rate constants to dermal absorption parameters, such as permeability and partition coefficients, and to assess whether different definitions of the rate constants produce different results. Rate constant expressions were developed by requiring a one-compartment model to match a one-membrane model at specific conditions. Because a membrane model contains more information than a compartment model, a compartment model cannot match the membrane model in all respects. Consequently, many compartment models (i.e., different definitions of the rate constants) can be developed which match the membrane model for different conditions. Using this procedure, 11 different compartment models were developed and compared to the membrane model for four different dermal absorption scenarios. The compartment model that most closely matches the membrane model depends on the specific exposure scenario and what is to be predicted. One of the new compartment models agrees reasonably well with the membrane model, for the cases considered.     

The distribution of SMN protein complex in human fetal tissues and its alteration in spinal muscular atrophy

Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder characterized by degeneration of motor neurons of the spinal cord and muscular atrophy. SMA is caused by alterations to the survival of motor neuron (SMN) gene, the function of which has hitherto been unclear. Here, we present immunoblot analyses showing that normal SMN protein expression undergoes a marked decay in the postnatal period compared with fetal development. Morphological and immunohistochemical analyses of the SMN protein in human fetal tissues showed a general distribution in the cytoplasm, except in muscle cells, where SMN protein was immunolocalized to large cytoplasmic dot-like structures and was tightly associated with membrane-free heavy sedimenting complexes. These cytoplasmic structures were similar in size to gem. The SMN protein was markedly deficient in tissues derived from type I SMA fetuses, including skeletal muscles and, as previously shown, spinal cord. While our data do not help decide whether SMA results from impaired SMN expression in spinal cord, skeletal muscle or both, they suggest a requirement for SMN protein during embryo-fetal development.