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PubMed1997

[Demonstration on Z-D phenomenon in the occurrence of infectious diseases].

A systematic analysis, including retrospective test by means of correlation analysis and extrapolation test was carried out to demonstrate a new hypothesis named Z-D phenomenon which states that the skew of a seasonal case distribution curve of an infectious disease may appear to be the omen of its epidemic trend in the following year. A total number of 353 data sets belong to 17 notifiable infectious diseases in 29 provinces and the whole nation were chosen. Data from retrospective test showed that 91.2% (322/353) of the correlation coefficients of between the skew of the seasonal distribution curve of the previous year and the morbidity variation of its following year were negative. The extrapolation test showed that 68.1% (203/295) of the data sets accorded with the actually epidemic situation at the level of r < -0.5. The results proved the existence of Z-D phenomenon may serve as an indicator for the purpose of forecasting. Using this systematic analysis, we found that Z-D phenomenon was more expressive in viral hepatitis, pertussis, epidemic cerebrospinal meningitis and scarlet fever than in other diseases.

Bayes Theorem↗
PubMed2006

Serum gastrin in Zollinger-Ellison syndrome: II. Prospective study of gastrin provocative testing in 293 patients from the National Institutes of Health and comparison with 537 cases from the literature. evaluation of diagnostic criteria, proposal of new criteria, and correlations with clinical and tumoral features.

In two-thirds of patients with Zollinger-Ellison syndrome (ZES), fasting serum gastrin (FSG) levels overlap with values seen in other conditions. In these patients, gastrin provocative tests are needed to establish the diagnosis of ZES. Whereas numerous gastrin provocative tests have been proposed, only the secretin, calcium, and meal tests are widely used today. Many studies have analyzed gastrin provocative test results in ZES, but they are limited by small patient numbers and methodologic differences. To address this issue, we report the results of a prospective National Institutes of Health (NIH) study of gastrin provocative tests in 293 patients with ZES and compare these data with those from 537 ZES and 462 non-ZES patients from the literature. In 97%-99% of gastrinoma patients, an increase in serum gastrin post secretin (Delta secretin) or post calcium (Delta calcium) occurred. In NIH ZES patients with <10-fold increase in FSG, the sensitivity/specificity of the widely used criteria were as follows: Delta secretin > or =200 pg/mL (83%/100%), Delta secretin >50% (86%/93%), Delta calcium > or =395 pg/mL (54%/100%), and Delta calcium >50% (78%/83%). A systematic analysis of the sensitivity and specificity of other possible criteria for a positive secretin or calcium test allowed us to identify a new criterion for secretin testing (Delta > or =120 pg/mL) with the highest sensitivity/specificity (94%/100%) and to confirm the commonly used criterion for calcium tests (Delta > or =395 pg/mL) (62%/100%). This analysis further showed that the secretin test was more sensitive than the calcium test (94% vs. 62%). Our results suggest that secretin stimulation should be used as the first-line provocative test because of its greater sensitivity and simplicity and lack of side effects. In ZES patients with a negative secretin test, 38%-50% have a positive calcium test. Therefore the calcium test should be considered in patients with a strong clinical suspicion of ZES but a negative secretin test. Furthermore, we found that some clinical (diarrhea, duration of medical treatment), laboratory (basal acid output), and tumoral (size, extent) characteristics correlate with the serum gastrin increase post secretin and post calcium. However, using the proposed criteria, the result of these provocative tests (that is, positive or negative) is minimally influenced by these factors, so secretin and calcium provocative tests are reliable in patients with different clinical, laboratory, and tumor characteristics. A systematic analysis of meal testing showed that 54%-77% of ZES patients have a <50% postprandial serum gastrin increase. However, 9%-20% of ZES patients had a >100% increase post meal, causing significant overlap with antral syndromes. Furthermore, we could not confirm the usefulness of meal tests for localization of duodenal gastrinomas. We conclude that the secretin test is a crucial element in the diagnosis of most ZES patients, the calcium test may be useful in selected patients, but the meal test is not helpful in the management of ZES. For secretin testing, the criterion with the highest sensitivity and specificity is an increase of > or =120 pg/mL, which should replace other criteria commonly used today.

Calcium↗
PubMed2002

Systematic determination of patterns of gene expression during Drosophila embryogenesis.

BACKGROUND: Cell-fate specification and tissue differentiation during development are largely achieved by the regulation of gene transcription. RESULTS: As a first step to creating a comprehensive atlas of gene-expression patterns during Drosophila embryogenesis, we examined 2,179 genes by in situ hybridization to fixed Drosophila embryos. Of the genes assayed, 63.7% displayed dynamic expression patterns that were documented with 25,690 digital photomicrographs of individual embryos. The photomicrographs were annotated using controlled vocabularies for anatomical structures that are organized into a developmental hierarchy. We also generated a detailed time course of gene expression during embryogenesis using microarrays to provide an independent corroboration of the in situ hybridization results. All image, annotation and microarray data are stored in publicly available database. We found that the RNA transcripts of about 1% of genes show clear subcellular localization. Nearly all the annotated expression patterns are distinct. We present an approach for organizing the data by hierarchical clustering of annotation terms that allows us to group tissues that express similar sets of genes as well as genes displaying similar expression patterns. CONCLUSIONS: Analyzing gene-expression patterns by in situ hybridization to whole-mount embryos provides an extremely rich dataset that can be used to identify genes involved in developmental processes that have been missed by traditional genetic analysis. Systematic analysis of rigorously annotated patterns of gene expression will complement and extend the types of analyses carried out using expression microarrays.

Animals↗
PubMed2003

Gene-expression profiles of human tumor xenografts in nude mice treated orally with the EGFR tyrosine kinase inhibitor ZD1839.

To date, no single or multiple molecular markers have been successful in predicting sensitivity of individual patients to anti-cancer drugs. As the nature of a specific cancer is considered to be defined by the proteins being expressed in the tumor cells, systematic analysis of gene-expression profiles may provide information reflecting sensitivity of a given tumor to certain drugs. Recent progress in genome technology has enabled us to examine expression profiles of thousands of genes in a single experiment. We used this approach to examine 13 xenografts of human tumors implanted into nude mice for sensitivity to an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), ZD1839 (Iressa). To identify genes that might be associated with sensitivity to this drug we used a cDNA microarray representing 23,040 genes to analyze expression profiles of the 13 xenografts and identified 114 genes whose expression levels correlated significantly with sensitivity of the tumors to ZD1839. We then investigated alteration of expression profiles in response to the ZD1839 treatment in four non-small cell lung cancer (NSCLC) xenografts, of which two (LC6 and LC11) were sensitive and the other two (Lu116 and L27) were resistant to this EGFR-TKI. Systematic analysis of expression at various time points during oral treatment for 14 days, compared with corresponding untreated samples, identified a set of genes whose expression levels changed in the two sensitive tumors but not in the two resistant tumors. The data obtained here should provide useful information on the molecular mechanism underlying clinical responses to EGFR-TKIs, aid the development of novel therapies for lung cancer, and potentially identify predictive molecular markers for sensitivity to ZD1839.

Administration, Oral↗
PubMed1998

Validation of continuous thermodilution cardiac output in critically ill patients with analysis of systematic errors.

PURPOSE: Bolus thermodilution cardiac output (BCO) measurements are affected by variations in injectate volume, rate, and temperature. These variations are eliminated when CO is measured by a continuous automated thermal technique (CCO). Further, CCO eliminates the need for fluid boluses, reduces contamination risk, requires no operator, and provides a continuous CO trend. We prospectively evaluated CCO versus BCO in a population of critically ill adults with low, normal, and high CO states. We sought to discern any systematic effects of temperature fluctuations or signal-to-noise-ratios (SNR) on disparities between BCO and CCO measurements and also sought to assess the relative cost effectiveness of the CCO system. MATERIALS AND METHODS: Pulmonary artery catheterizations were performed in a convenience sample of 20 patients over 6 months. BCO data were obtained using a standardized protocol. Three bolus injections of 5% dextrose were given when each CO was within 10% of the median before averaging; otherwise five boluses were given, with the high and low values eliminated before averaging. Injectates were administered randomly through the respiratory cycle and at 1-minute intervals. CCO measurements were recorded from a Vigilance monitor pre and post BCO measurements, yielding an average CCO value. Also recorded were pre- and post-core temperatures and SNR during the first CCO measurement. Cost data included estimates of operator time for BCO determinations as well as costs of Intellicath (Baxter-Edwards, Irvine, CA) pulmonary artery catheters, Vigilance (Baxter-Edwards, Irvine, CA) monitors, conventional catheters, and injectates. RESULTS: Of the 20 patients, 15 were mechanically ventilated. A total of 306 paired CO values were obtained for analysis. CCO ranged from 2.5 to 14.4 L/min and BCO from 2.4 to 13.3 L/min. Absolute differences between CCO and BCO measurements increased with increasing CO, but percentage differences did not. Of the paired values, 77% were within 1 L/min of one another. Temperature instability and SNR independently had weak correlations with CCO/BCO disparities. The Vigilance system had a slightly higher net cost than conventional BCO, although no economical value was assigned to the clinical usefulness of continuous, as opposed to intermittent, CO monitoring. CONCLUSIONS: Continuous CO is a reliable and cost-effective alternative to bolus thermodilution CO for critically ill patients in low, normal, and high CO states.

Adolescent↗
PubMed2003

Analysis of systematic effects on congenital sensorineural deafness in German Dalmatian dogs.

We have analysed the systematic influences, phenotypic colour markers and the additive genetic variation for congenital sensorineural deafness (CSD) in German Dalmatian dogs in order to help elucidate the importance of phenotypic breed characteristics for genetic differences of CSD. Linear animal models using restricted maximum likelihood methods were employed to estimate variance components. Data were obtained from all three German Dalmatian kennel clubs associated with the German Association for Dog Breeding and Husbandry (VDH). CSD was recorded by standardized protocols for brainstem auditory-evoked response (BAER). The material included 1899 German Dalmatian dogs from 354 litters in 169 different kennels. BAER testing results were from the years 1986 to 1999. Pedigree information was available for up to seven generations. The animal model regarded the fixed effects of sex, coat colour, eye colour, presence of patches, litter size, percentage of examined puppies per litter, kennel club, and inbreeding coefficient. The common environment of the litter and kennel as well as the additive genetic effect of the animal were taken into account as randomly distributed effects. The fixed effects of eye colour, percentage of puppies examined per litter and kennel club were significant in the mixed model analysis. A significant proportion of additive genetic variation could be shown despite corrections for phenotypic colour variants. The heritability estimate for CSD in German Dalmatian dogs was h(2)=0.27+/-0.07. The additive genetic correlation of CSD with presence of blue eyes was r(g)=0.53+/-0.41 and with presence of patches r(g)=-0.36+/-0.24. We concluded that additional genes other than those associated with phenotypic colour markers in German Dalmatian dogs significantly contribute to the occurrence of CSD.

Animals↗
PubMed2006

Off-pump surgery is associated with reduced occurrence of stroke and other morbidity as compared with traditional coronary artery bypass grafting: a meta-analysis of systematically reviewed trials.

BACKGROUND AND PURPOSE: There is growing enthusiasm for coronary artery bypass grafting (CABG) without cardiopulmonary bypass (CPB). Although deleterious effects of CPB are known, it remains to be proven that avoiding CPB will result in reduction in morbidity. We sought to determine whether off-pump surgery is associated with reduced occurrence of adverse outcomes as compared with CABG with CPB. METHODS: Studies were identified by searching the MEDLINE, EMBASE and the Cochrane Register 1980 to 2006 (February). We also searched the reference lists of randomized clinical trials (RCT) and reviews to look for additional studies. STUDY SELECTION: RCTs comparing off-pump surgery to CABG with CPB. No restriction applied on the size of the trial or end point reports. DATA EXTRACTION: 2 reviewers independently searched for studies, read abstracts and abstracted all data. DATA SYNTHESIS: combined estimates were obtained using fixed or random effect meta-analyses. Relative risks and risk differences were calculated. Heterogeneity was assessed using chi(2) and I(2) values. RESULTS: There were 3996 patients enrolled in 41 RCTs (mean age 62, 22% female). No study reported information on race. Off-pump CABG was associated with a 50% reduction in the relative risk of stroke (95% CI, 7% to 73%), 30% reduction in atrial fibrillation (AF; 95% CI, 16% to 43%) and 48% reduction in wound infection (95% CI, 26% to 63%) with no heterogeneity among RCTs. This translated into avoidance of 10 strokes, 80 cases of AF and 40 infections per 1000 CABG. Fewer distal grafts were performed and there was evidence for >10 reinterventions per 1000 with off-pump CABG. Long-term follow-up is not yet reported in the trials. CONCLUSIONS: Off-pump CABG is associated with reduced risk of stroke, AF and infections as compared with CABG with CPB. Evidence should be generalized taking into account RCT enrollment limitations, drawbacks related to training requirements, propensity to perform fewer grafts and likely reinterventions after off-pump surgery.

Aged↗
PubMed2005

[Role of surgery in spinal degenerative disease. Analysis of systematic reviews on surgical and conservative treatments from an evidence-based approach].

INTRODUCTION: The lifetime prevalence of invalidating back pain in general population caused by Spinal Degenerative Disease (SDD) is about 70-80%. Global costs related to this disease are enormous (1-2% gross domestic product). From an Evidence-based point of view, there is a striking discrepancy between the use of many available surgical techniques (especially for spinal fusion) and the lack of scientific support. METHODS: The authors carefully reviewed all published metaanalysis on SDD therapies up to December 2003. Treatment recommendations were classified according to levels of evidence (strong, moderate, mild or lack of evidence) for both surgical and conservative measures. RESULTS: Forty-four metaanalysis were selected (nine on lumbar surgery, three on cervical surgery and thirty-two on other therapies). Relating surgery, there is strong evidence favouring early laminectomy in cauda equina syndrome secondary to lumbar disc herniation; discectomy or microdiscectomy are superior to chemo-nucleolysis in lumbar prolapse and spondylosis; and fusion surgery (probably noninstrumented) in adult isthmic spondylolysthesis or degenerative spondylolysthesis with spinal stenosis. In cervical spondylosis and radiculomyelopathy, discectomy seems as effective as discectomy plus fusion, which does not seem to be better than untreated SDD beyond 24 months. Preoperative antibiotics seem to prevent infection in spinal surgery. No benefit of surgery is demonstrated in discogenic pain. None of conservative therapies are supported by strong evidence. Antidepressants improve pain perception but do not influence the functional status. DISCUSSION: Although lumbar instrumented surgery has nearly doubled over two decades and the annual growth is about 20%, clinical results do not seem to have improved, not even global fusion rates. The increasing use of fusion surgery for cases other than spinal deformities, spondylolysthesis or spinal stenosis plus lysthesis may be related to multiple technical and clinical-epidemiological factors where huge financial and commercial interests must be considered. It is crucial to differentiate subsets of patients prone to benefit from surgery. It is discussed whether randomized trials incorporating sham operations are ethically justifiable, because of the lack of sound evidence for many spinal procedures. The efficacy of most conservative treatments is mild or moderate (mainly transient) and they should be probably used in combination. CONCLUSIONS. There is no strong evidence favouring most of surgical procedures for SDD from an evidence-based approach. It seems necessary that scientific organizations studying SDD create clinical guidelines relating its multidisciplinary and integral management, recognizing that, up to now, few interventions positively modify in the long-term the natural history of the disease.

Diskectomy↗
PubMed1994

Saccades to remembered target locations: an analysis of systematic and variable errors.

We studied the effects of varying delay interval on the accuracy and velocity of saccades to the remembered locations of visual targets. Remembered saccades were less accurate than control saccades. Both systematic and variable errors contributed to the loss of accuracy. Systematic errors were similar in size for delay intervals ranging from 400 msec to 5.6 sec, but variable errors increased monotonically as delay intervals were lengthened. Compared to control saccades, remembered saccades were slower and the peak velocities were more variable. However, neither peak velocity nor variability in peak velocity was related to the duration of the delay interval. Our findings indicate that a memory-related process is not the major source of the systematic errors observed on memory trials.

Animals↗
PubMed2005

Local RNA target structure influences siRNA efficacy: a systematic global analysis.

The efficiency with which small interfering RNAs (siRNAs) down-regulate specific gene expression in living cells is variable and a number of sequence-governed, biochemical parameters of the siRNA duplex have been proposed for the design of an efficient siRNA. Some of these parameters have been clearly identified to influence the assembly of the RNA-induced silencing complex (RISC), or to favour the sequence preferences of the RISC endonuclease. For other parameters, it is difficult to ascertain whether the influence is a determinant of the siRNA per se, or a determinant of the target RNA, especially its local structural characteristics. In order to gain an insight into the effects of local target structure on the biological activity of siRNA, we have used large sets of siRNAs directed against local targets of the mRNAs of ICAM-1 and survivin. Target structures were classified as accessible or inaccessible using an original, iterative computational approach and by experimental RNase H mapping. The effectiveness of siRNA was characterized by measuring the IC50 values in cell culture and the maximal extent of target suppression. Mean IC50 values were tenfold lower for accessible local target sites, with respect to inaccessible ones. Mean maximal target suppression was improved. These data illustrate that local target structure does, indeed, influence the activity of siRNA. We suggest that local target screening can significantly improve the hit rate in the design of biologically active siRNAs.

Cell Line↗
PubMed2002

Analysis by systematic deletion of amino acids of the action of the ribotoxin restrictocin.

A series of contiguous deletions were made in a cDNA encoding the ribonuclease restrictocin with the purpose of identifying the amino acids that are essential for the cleavage of the phosphodiester bond on the 3' side of G4325 in the alpha-sarcin/ricin domain of mammalian (rat) 28S rRNA. In all 93 of 149 amino acids, 62% of the residues in restrictocin, were not essential for the action of the toxin. Of the five residues that have been proposed to constitute the active site, three could be deleted without loss of activity if they were part of a deletion of three or five amino acids but not if they were removed singly. It is likely that the loss of these three residues is compensated for by a neighboring residue that occupies the structural space created by the larger amino acid deletions. This was demonstrated to be the case for the active site residue Glu95 which in the deletion mutant Delta91-95 is replaced by Asp90. Systematic deletion of amino acids is a rapid, cost effective method for identifying the residues in a protein likely to contribute directly to function and, hence, deserving of closer scrutiny. Moreover, a semiquantitative estimate of the contribution of the residue to function can be made. For this reason the method may be useful for functional proteomics.

Allergens↗
PubMed2000

Systematic function analysis of Bacillus subtilis genes.

Information on the complete genome sequence needs to be transformed into information related to function. Toward this goal, research consortia in Japan and Europe have been organized so as to acquire a collection of knockout mutants of genes with no established function. The current status of the Japanese project concerning mutant creation and characterization is summarized.

Bacillus subtilis↗
PubMed2000

Moment analysis as a systematic tool for NMR powder pattern analysis.

The low order moments for chemical shift and second-order quadrupolar powder patterns have been calculated as functions of the anisotropy and asymmetry parameter of the governing interaction, and the expressions inverted to give these parameters as a function of the moments. Theoretical simulations and experimental experience show that moment analysis in most cases equals and in some cases exceeds the accuracy of direct inspection as a method of obtaining NMR parameters. We illustrate the efficacy of the method applied to 31P chemical shift spectra of nucleic acids, and 39K second-order patterns of series of potassium salts.

Adenosine Monophosphate↗
PubMed2003

Systematic toxicological analysis: computer-assisted identification of poisons in biological materials.

A new software was developed to improve the chances for identification of a "general unknown" in complex biological materials. To achieve this goal, the total ion current chromatogram was simplified by filtering the acquired mass spectra via an automated subtraction procedure, which removed mass spectra originating from the sample matrix, as well as interfering substances from the extraction procedure. It could be shown that this tool emphasizes mass spectra of exceptional compounds, and therefore provides the forensic toxicologist with further evidence-even in cases where mass spectral data of the unknown compound are not available in "standard" spectral libraries.

Body Fluids↗
PubMed2003

Suitability testing of commercial solid-phase extraction sorbents for sample clean-up in systematic toxicological analysis using liquid chromatography-(tandem) mass spectrometry.

An entire series of SPE sorbents, classified into three different categories (apolar, mixed-mode and polymeric) was evaluated for sample preparation of a data-dependent LC-MS-MS "general unknown" screening procedure. An extraction procedure was formulated for each individual column, in agreement with the enclosed instructions, according to the characteristics of each packing. For conciseness, only neutral and basic compounds were chosen for this sorbent suitability test. Thus, the goal of our research was to select the best sorbent with regard to extraction yield and cleanliness of the extracts, all with respect to data-dependent acquisition (DDA) mediated LC-MS-MS general unknown screening. We conclude that for that purpose an Isolute C(8) sorbent performs best in terms of extraction yield and clean-up potential.

Chromatography, Liquid↗
PubMed2004

Expression of MUC1 (EMA) and E-cadherin in renal cell carcinoma: a systematic immunohistochemical analysis of 188 cases.

MUC1 (epithelial membrane antigen) is a membrane-associated mucin known to interfere with both cell-cell and cell-matrix adhesions. Overexpression has been associated with poor prognosis in a variety of cancers. We investigated the expression of MUC1 (using two different antibodies, MA695 and E29) and E-cadherin in renal cell carcinomas (137 conventional, 23 chromophobe, 20 papillary, and eight unclassified tumors) with respect to diagnostic and prognostic significance using a tissue microarray technique. Immunoreactivity was correlated with histological subtype, pT-stage, and grade using the chi2 test or the Fisher's exact test, respectively. Impact on disease-free survival was analyzed using the Kaplan-Meier method and the log-rank test. Immunoreactivity of more than 10% of cancer cells with MA695, E 29, and E-cadherin antibodies was found in 112/133 (84%), 86/133 (65%), and 7/131 (5%) conventional, 20/22 (91%), 19/22 (86%), and 21/22 (95%) chromophobe, 13/20 (65%), 8/20 (40%), and 3/20 (15%) papillary as well as 5/8 (63%), 5/8 (63%), and 4/8 (50%) unclassified carcinomas, respectively. The two different MUC1 antibodies yielded comparable staining results. A diffuse cytoplasmic staining pattern for MUC1 was found exclusively in chromophobe carcinomas, whereas conventional and papillary subtypes showed predominantly membranous staining (P<0.0001). Regarding papillary carcinomas, MUC1 was predominantly associated with type 1 (P=0.0001), and E-cadherin with type 2 (P=0.049) tumors. The cellular staining pattern of MUC1 in conventional tumors was related to pT-stage (P=0.002) and tumor grade (P=0.001): Low-stage (pT1/pT2) and grade (G1/G2) tumors showed a predominantly apical membranous staining, high-stage (pT3a/pT3b) and grade (G3/G4) tumors a predominantly circumferential membranous staining (with or without additional diffuse cytoplasmic immunoreactivity), which, in the conventional subtype, was associated with poor prognosis (P<0.0001). In conclusion, MUC1 and E-cadherin are diagnostically and prognostically useful markers in renal tumor pathology, especially when cellular staining patterns are considered.

Adult↗