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PubMed2004

Differences in expression of retinal pigment epithelium mRNA between normal canines.

A reference database of differences in mRNA expression in normal healthy canine retinal pigment epithelium (RPE) has been established. This database identifies non-informative differences in mRNA expression that can be used in screening canine RPE for mutations associated with clinical effects on vision. Complementary DNA (cDNA) pools were prepared from mRNA harvested from RPE, amplified by PCR, and used in a subtractive hybridization protocol (representational differential analysis) to identify differences in RPE mRNA expression between canines. The effect of relatedness of the test canines on the frequency of occurrence of differences was evaluated by using 2 unrelated canines for comparison with 2 female sibling canines of blue heeler/bull terrier lineage. Differentially expressed cDNA species were cloned, sequenced, and identified by comparison to public database entries. The most frequently observed differentially expressed sequence from the unrelated canine comparison was cDNA with 21 base pairs (bp) identical to the human epithelial membrane protein 1 gene (present in 8 of 20 clones). Different clones from the same-sex sibling RPE contained repetitions of several short sequence motifs including the human epithelial membrane protein 1 (4 of 25 clones). Other prevalent differences between sibling RPE included sequences similar to a chicken genetic marker sequence motif (5 of 25), and 6 clones with homology to porcine major histocompatibility loci. In addition to identifying several repetitively occurring, noninformative, differentially expressed RPE mRNA species, the findings confirm that fewer differences occurred between siblings, highlighting the importance of using closely related subjects in representational difference analysis studies.

Animals↗

PubMed2026

Genome-based predictions of metabolic preferences and substrate phenotypes in psychrotrophic bacteria from permafrost environments.

Genomes reveal vast functional potential, but harbor genomic noise that obscures prediction of metabolic and environmental preferences. Genomic databases are skewed towards clinically relevant and easily cultivated bacteria, limiting predictions for diverse and underrepresented environmental taxa. Psychrotrophic bacteria, which can survive and grow in cold, nutrient-limited, dry, and saline environments, are especially underrepresented despite their relevance for understanding microbial responses to changing cold environments and potential biotechnological value given growth at low temperatures. Assembling complete genomes of 48 isolates from Alaskan permafrost, seasonally frozen active layer soils, and terrestrial ice, we used Kyoto Encyclopedia of Genes and Genomes (KEGG) ortholog annotations to evaluate the predictability of metabolic resource-use traits observed using phenotypic tests. Genome-predicted values for glycolytic versus gluconeogenic catabolic preference index, or sugar-acid preference (SAP), explained over 50% of the variance in empirically observed SAP. SAP was inversely correlated to genomic GC content, which follows phylum-level trends, indicating that coarse metabolic preference covaries with phylogeny. Regularized elastic net models offered a more granular view, linking KEGG genes to specific substrate utilization and sensitivity phenotypes and yielding moderate but reproducible accuracy (AUC 0.70-0.79) for 11 substrates, demonstrating that specific substrate responses may be predictable from relatively small subsets of KO genes. These results extend recent advances, such as the SAP metric, and highlight associations among genomic GC content, phylum, and broad metabolic strategy. Linking genomic content to phenotype using isolates is a necessary step toward predictive models of microbial function in environmental communities, and this work can be used for hypothesis generation, with applications towards more expansive data sets.IMPORTANCECold region soils and ice host psychrotrophic bacteria with metabolic traits and adaptations that enable persistence in harsh, resource-limited environments. However, these taxa are underrepresented in genomic reference databases dominated by well-studied, mesophilic organisms. This gap limits inference of ecological strategies and our ability to predict how these microbes may influence the large, thaw-vulnerable carbon reservoirs in permafrost. Here, we show that genomic GC content is associated with the sugar-versus-acid catabolic preference (SAP) of isolates across major phyla, suggesting that broad genomic features may provide a coarse signal of metabolic strategy. We demonstrate that a modified SAP metric, using binary (positive/negative) substrate utilization rather than detailed growth rate measurements, is moderately predictive, thus extending its application to slow-growing or difficult-to-culture taxa. Together, these advances broaden the toolkit for linking genome content to resource-use traits (phenotype) in poorly characterized, cold-adapted bacteria and offer a tractable entry point to broad prediction and hypothesis generation.

Genome, Bacterial↗

PubMed2006

Mining ORESTES no-match database: can we still contribute to cancer transcriptome?

The Human Cancer Genome Project generated about 1 million expressed sequence tags by the ORESTES method, principally with the aim of obtaining data from cancer. Of this total, 341,680 showed no similarity with sequences in the public transcript databases, referred to as "no-match". Some of them represent low abundance or difficult to detect human transcripts, but part of these sequences represent genomic contamination or immature mRNA. We performed a bioinformatics pipeline to determine the novelty of ORESTES "no-match" datasets from prostate or breast tissues. We started with 14,908 clusters mapped on the human genome. A total of 2226 clusters originating from more than two libraries or singletons with gaps upon genome alignment were selected. Ninety-four clusters with canonical splice sites representing the most stringent criteria to be considered a gene were subjected to manual inspection regarding genomic hits. Of the manually inspected clusters, 49.6% contained new sequences where 42.2% were probable low-expression alternative forms of the characterized genes and 7.4% unpredicted genes. RT-PCR followed by sequencing was performed to validate the largest spliced sequence from 8 clusters, resulting in the confirmation of five sequences as true human transcript fragments. Some of them were differentially expressed between tumor and normal tissue by an in silico analysis. We can conclude that after clean up of the no-match dataset, we still have about 939 new exons and 165 unpredicted genes that could complete the prostate or breast transcriptome.

Breast Neoplasms↗

PubMed1994

Assessment of age-related bone loss in normal South African women by means of the Hologic QDR 1000 system.

The aim of this study was to evaluate age-related changes in cortical and trabecular bone mineral density (BMD) in South African subjects, and to develop a local reference database for dual energy X-ray absorptiometry with the QDR 1000 densitometer. A questionnaire was used to recruit volunteers. Age, years since menopause, use of medications and medical diseases were recorded. Men were excluded. Only whites and coloureds were studied. Three hundred and eleven women had single measurements over a 2-year period. Seven sets of subjects were defined according to age (18-44; 45-49; 50-54; 55-59; 60-64; 65-69; > 70 years) (N = 163; 32; 35; 23; 25; 16; 17 respectively). Height and weight did not change significantly with age. There were significant differences in lumbar and femoral BMD (Ward's) compared with those of American subjects in the different age categories. Both the lumbar and total femoral BMD began to fall significantly between the ages of 60 and 65 years (P < 0.01). Ward's triangle showed a significant fall in BMD between 45 and 50 years of age (P < 0.01). Ward's BMD predicted 36% of the variation in lumbar BMD at 45 years but 10% at 70 years. Ward's triangle is a useful predictor of femoral bone loss in later years. The fracture threshold at the lumbar vertebrae was 0.822 g/cm2; at Ward's triangle it was 0.443 g/cm2. This gave a 16% prevalence of osteopenia in the lumbar region and a prevalence of 24% at Ward's area.

Adult↗

PubMed2004

An XML standard for the dissemination of annotated 2D gel electrophoresis data complemented with mass spectrometry results.

BACKGROUND: Many proteomics initiatives require a seamless bioinformatics integration of a range of analytical steps between sample collection and systems modeling immediately assessable to the participants involved in the process. Proteomics profiling by 2D gel electrophoresis to the putative identification of differentially expressed proteins by comparison of mass spectrometry results with reference databases, includes many components of sample processing, not just analysis and interpretation, are regularly revisited and updated. In order for such updates and dissemination of data, a suitable data structure is needed. However, there are no such data structures currently available for the storing of data for multiple gels generated through a single proteomic experiments in a single XML file. This paper proposes a data structure based on XML standards to fill the void that exists between data generated by proteomics experiments and storing of data. RESULTS: In order to address the resulting procedural fluidity we have adopted and implemented a data model centered on the concept of annotated gel (AG) as the format for delivery and management of 2D Gel electrophoresis results. An eXtensible Markup Language (XML) schema is proposed to manage, analyze and disseminate annotated 2D Gel electrophoresis results. The structure of AG objects is formally represented using XML, resulting in the definition of the AGML syntax presented here. CONCLUSION: The proposed schema accommodates data on the electrophoresis results as well as the mass-spectrometry analysis of selected gel spots. A web-based software library is being developed to handle data storage, analysis and graphic representation. Computational tools described will be made available at http://bioinformatics.musc.edu/agml. Our development of AGML provides a simple data structure for storing 2D gel electrophoresis data.

Computational Biology↗

PubMed2000

Measurements used to characterize the foot and the medial longitudinal arch: reliability and validity.

BACKGROUND AND PURPOSE: Abnormality in the structure of the medial longitudinal arch of the foot is commonly thought to be a predisposing factor to injury. The purpose of this investigation was to compare the reliability and validity of several measurements used to characterize various aspects of the foot, including the medial longitudinal arch. SUBJECTS: One hundred two feet (both feet of 51 subjects) were measured to establish a reference database. From this group, a subset of 20 feet (both feet of 10 subjects) was used to determine intertester and intratester reliability. Radiographs of a further subset of 10 feet (right feet of 10 subjects) were used to determine validity. METHODS: Five foot measurements were taken in 2 stance conditions: 10% of weight bearing and 90% of weight bearing. RESULTS: Intraclass correlation coefficients (ICCs) for intertester and intratester measurements were between.480 and.995. The most reliable method of characterizing arch type in 10% of weight bearing between testers was dividing navicular height by foot length in 10% of weight bearing. However, this measure yielded highly unreliable measurements in 90% of weight bearing. The most valid measurements were navicular height divided by truncated foot length, navicular height divided by foot length in 10% of weight bearing, and navicular height divided by foot length in 90% of weight bearing. Dorsum height at 50% of foot length divided by truncated foot length showed relatively high intertester reliability (ICC=.811 in 10% of weight bearing, ICC=.848 in 90% of weight bearing) and validity (ICC=.844 in 10% of weight bearing, ICC=.851 in 90% of weight bearing). CONCLUSION AND DISCUSSION: These data suggest that, of the measures tested, the most reliable and valid method of clinically assessing arch height across 10% and 90% of weight bearing was dividing the dorsum height at 50% of foot length by truncated foot length.

Adult↗

PubMed1997

Diversity of Streptococcus agalactiae and Staphylococcus aureus ribotypes recovered from New York dairy herds.

OBJECTIVES: To develop a reference database for characterization of bovine Staphylococcus aureus and Streptococcus agalactiae strains by automated ribotyping and to use it to assess the discriminatory power of this typing procedure and the geographic distribution of Sta aureus and Str agalactiae strains in New York state dairy herds. SAMPLE POPULATION: 22 commercial dairy herds. PROCEDURE: Isolates of Sta aureus and Str agalactiae from bovine milk were identified by standard bacteriologic procedures, then typed by automated ribotyping. Antimicrobial susceptibility of isolates was tested in vitro. Two indicators made from the data were percentage of farms with multiple ribotypes and percentage of single ribotypes found in several geographic regions. Standard bacteriologic diagnosis, automated ribotyping, and determination of antibiograms (Kirby-Bauer method) also were done. RESULTS: Of 50 Sta aureus and 44 Str agalactiae isolates from composite milk samples of 12 and 10 herds, respectively, 18 and 14 ribotypes, respectively, were identified. The discriminatory power of automated ribotyping was approximately 0.96 (Hunter-Gaston's formula). A higher percentage of herds with Sta aureus had multiple ribotypes. The most common Sta aureus ribotypes tended to have broader geographic distribution. Some Sta aureus ribotypes were significantly associated with antibiotic resistance profiles. CONCLUSIONS: Automated ribotyping appears to characterize bovine strains of bacteria associated with intramammary infections with a high discriminatory index. Potential applications include identification of strains that appear to have broad geographic distribution suggesting interfarm transfer, discrimination between recurrent versus new intramammary infections (ie, for control of Str agalactiae and Sta aureus), and evaluation of antibiotic therapy.

Animals↗

PubMed2006

Cross-sectional reference data for phalangeal quantitative ultrasound from early childhood to young-adulthood according to gender, age, skeletal growth, and pubertal development.

Bone mineral status by phalangeal quantitative ultrasound (QUS, DBM Sonic, IGEA, Carpi, Modena, Italy) was examined in 3044 (1513 males and 1531 females) healthy subjects, aged 2-21 years. The aim of the study was to provide a reference database for phalangeal QUS parameters, amplitude-dependent speed of sound (AD-SoS) and bone transmission time (BTT), both expressed as centiles and Z score, according to gender, age, height, weight, body mass index (BMI), and pubertal stage to be used for estimating bone mineral status in patients with disorders of growth or of bone and mineral metabolism. In both sexes, AD-SoS and BTT increased significantly (P<0.0001) according to all the anthropometric variables. Females showed higher values than males in the age groups 9-14 for AD-SoS (P<0.04-P<0.0001) and in the age groups 11-13 for BTT (P<0.02). Males had higher BTT values than females in the age groups 6-8 and 15-21 (P<0.04-P<0.0001). AD-SoS was higher (P<0.02-P<0.0001) in females than in males at pubertal stages 2, 3, and 4, but it was higher (P=0.001) in males compared with females at pubertal stage 5. BTT was higher in males than females at pubertal stages 1 (P<0.0001), 2 (P<0.01), and 5 (P<0.0001). In both sexes, AD-SoS and BTT were significantly correlated between them (r=0.92, P<0.0001) and with all the anthropometric variables (r=0.53-r=0.85, P<0.0001). Age, weight, BMI, and pubertal stage were independent predictors of AD-SoS in males; age and pubertal stage were independent predictors of AD-SoS in females. In both sexes, height and pubertal stage, and also age only in females, were independent predictors of BTT. In conclusion, our data show that gender, age, height, and timing of sexual maturation are main determinants of bone structure and geometry, and that both these two processes may be captured by phalangeal QUS. It may be a useful tool to assess bone mineral status from early childhood to young-adulthood with a very small confounding effect related to bone sizes and without exposing the subjects to a source of radiation.

Adolescent↗

PubMed2003

The incidence of recurrent venous thromboembolism after treatment with vitamin K antagonists in relation to time since first event: a meta-analysis.

BACKGROUND: After a first episode of venous thromboembolism, patients are treated with vitamin K (phytonadione) antagonists. There are indications that the risk of recurrence after treatment with vitamin K antagonists decreases relative to the time since the first event. The aim of the present meta-analysis is to describe the risk of recurrent venous thromboembolism after treatment with vitamin K antagonist in relation to the time since the index event. METHODS: Computerized searches in MEDLINE and EMBASE databases; reference checks of pertinent articles; personal communication with colleagues to find randomized clinical trials and cohort studies in which patients with venous thromboembolism were treated with vitamin K antagonists. Per treatment arm, 2 reviewers independently extracted data on the number of recurrent events and the duration of follow-up per time period of 3 months. RESULTS: A total of 135 potentially eligible studies were identified. Of these, 18 studies could be included, comprising 25 treatment arms that could be analyzed. Treatment arms were divided into 3 groups based on treatment duration (short, medium, and long). For all 3 groups, the monthly incidence immediately after discontinuation of treatment was high and declined rapidly thereafter. The monthly incidence after 9 months seemed independent of the treatment duration. CONCLUSIONS: There is a diminishing risk of recurrent venous thromboembolism over time and a stabilization after 9 months independent of the duration of the initial treatment with vitamin K antagonists. These findings have important implications for decision making about the optimal duration of treatment with vitamin K antagonists.

Anticoagulants↗

PubMed1998

Complementary therapies for depression: an overview.

Depression is one of the most common reasons for using complementary and alternative therapies. The aim of this article is to provide an overview of the evidence available on the treatment of depression with complementary therapies. Systematic literature searches were performed using several databases, reference list searching, and inquiry to colleagues. Data extraction followed a predefined protocol. The amount of rigorous scientific data to support the efficacy of complementary therapies in the treatment of depression is extremely limited. The areas with the most evidence for beneficial effects are exercise, herbal therapy (Hypericum perforatum), and, to a lesser extent, acupuncture and relaxation therapies. There is a need for further research involving randomized controlled trials into the efficacy of complementary and alternative therapies in the treatment of depression.

Acupuncture Therapy↗

PubMed2003

A meta-analysis of the efficacy of second-generation antipsychotics.

BACKGROUND: Consensus panel recommendations regarding choice of an antipsychotic agent for schizophrenia differ markedly, but most consider second-generation antipsychotics (SGAs) as a homogeneous group. It has been suggested that SGAs seem falsely more efficacious than first-generation antipsychotics (FGAs) as a result of reduced efficacy due to use of a high-dose comparator, haloperidol. We performed (1) a meta-analysis of randomized efficacy trials comparing SGAs and FGAs, (2) comparisons between SGAs, (3) a dose-response analysis of FGAs and SGAs, and (4) an analysis of the effect on efficacy of an overly high dose of an FGA comparator. METHODS: Literature search of clinical trials between January 1953 and May 2002 of patients with schizophrenia from electronic databases, reference lists, posters, the Food and Drug Administration, and other unpublished data. We included 124 randomized controlled trials with efficacy data on 10 SGAs vs FGAs and 18 studies of comparisons between SGAs. Two of us independently extracted the sample sizes, means, and standard deviation of the efficacy data. RESULTS: Using the Hedges-Olkin algorithm, the effect sizes of clozapine, amisulpride, risperidone, and olanzapine were 0.49, 0.29, 0.25, and 0.21 greater than those of FGAs, with P values of 2 x 10-8, 3 x 10-7, 2 x 10-12, and 3 x 10-9, respectively. The remaining 6 SGAs were not significantly different from FGAs, although zotepine was marginally different. No efficacy difference was detected among amisulpride, risperidone, and olanzapine. We found no evidence that the haloperidol dose (or all FGA comparators converted to haloperidol-equivalent doses) affected these results when we examined its effect by drug or in a 2-way analysis of variance model in which SGA effectiveness is entered as a second factor. CONCLUSION: Some SGAs are more efficacious than FGAs, and, therefore, SGAs are not a homogeneous group.

Algorithms↗

PubMed2001

Accuracy of positron emission tomography for diagnosis of pulmonary nodules and mass lesions: a meta-analysis.

CONTEXT: Focal pulmonary lesions are commonly encountered in clinical practice, and positron emission tomography (PET) with the glucose analog 18-fluorodeoxyglucose (FDG) may be an accurate test for identifying malignant lesions. OBJECTIVE: To estimate the diagnostic accuracy of FDG-PET for malignant focal pulmonary lesions. DATA SOURCES: Studies published between January 1966 and September 2000 in the MEDLINE and CANCERLIT databases; reference lists of identified studies; abstracts from recent conference proceedings; and direct contact with investigators. STUDY SELECTION: Studies that examined FDG-PET or FDG with a modified gamma camera in coincidence mode for diagnosis of focal pulmonary lesions; enrolled at least 10 participants with pulmonary nodules or masses, including at least 5 participants with malignant lesions; and presented sufficient data to permit calculation of sensitivity and specificity were included in the analysis. DATA EXTRACTION: Two reviewers independently assessed study quality and abstracted data regarding prevalence of malignancy and sensitivity and specificity of the imaging test. Disagreements were resolved by discussion. DATA SYNTHESIS: We used a meta-analytic method to construct summary receiver operating characteristic curves. Forty studies met inclusion criteria. Study methodological quality was fair. Sample sizes were small and blinding was often incomplete. For 1474 focal pulmonary lesions of any size, the maximum joint sensitivity and specificity (the upper left point on the receiver operating characteristic curve at which sensitivity and specificity are equal) of FDG-PET was 91.2% (95% confidence interval, 89.1%-92.9%). In current practice, FDG-PET operates at a point on the summary receiver operating characteristic curve that corresponds approximately to a sensitivity and specificity of 96.8% and 77.8%, respectively. There was no difference in diagnostic accuracy for pulmonary nodules compared with lesions of any size (P =.43), for semiquantitative methods of image interpretation compared with qualitative methods (P =.52), or for FDG-PET compared with FDG imaging with a modified gamma camera in coincidence mode (P =.19). CONCLUSIONS: Positron emission tomography with 18-fluorodeoxyglucose is an accurate noninvasive imaging test for diagnosis of pulmonary nodules and larger mass lesions, although few data exist for nodules smaller than 1 cm in diameter. In current practice, FDG-PET has high sensitivity and intermediate specificity for malignancy.

Glucose-6-Phosphate↗

PubMedDate not supplied

Scope and impact of financial conflicts of interest in biomedical research: a systematic review.

CONTEXT: Despite increasing awareness about the potential impact of financial conflicts of interest on biomedical research, no comprehensive synthesis of the body of evidence relating to financial conflicts of interest has been performed. OBJECTIVE: To review original, quantitative studies on the extent, impact, and management of financial conflicts of interest in biomedical research. DATA SOURCES: Studies were identified by searching MEDLINE (January 1980-October 2002), the Web of Science citation database, references of articles, letters, commentaries, editorials, and books and by contacting experts. STUDY SELECTION: All English-language studies containing original, quantitative data on financial relationships among industry, scientific investigators, and academic institutions were included. A total of 1664 citations were screened, 144 potentially eligible full articles were retrieved, and 37 studies met our inclusion criteria. DATA EXTRACTION: One investigator (J.E.B.) extracted data from each of the 37 studies. The main outcomes were the prevalence of specific types of industry relationships, the relation between industry sponsorship and study outcome or investigator behavior, and the process for disclosure, review, and management of financial conflicts of interest. DATA SYNTHESIS: Approximately one fourth of investigators have industry affiliations, and roughly two thirds of academic institutions hold equity in start-ups that sponsor research performed at the same institutions. Eight articles, which together evaluated 1140 original studies, assessed the relation between industry sponsorship and outcome in original research. Aggregating the results of these articles showed a statistically significant association between industry sponsorship and pro-industry conclusions (pooled Mantel-Haenszel odds ratio, 3.60; 95% confidence interval, 2.63-4.91). Industry sponsorship was also associated with restrictions on publication and data sharing. The approach to managing financial conflicts varied substantially across academic institutions and peer-reviewed journals. CONCLUSIONS: Financial relationships among industry, scientific investigators, and academic institutions are widespread. Conflicts of interest arising from these ties can influence biomedical research in important ways.

Academies and Institutes↗

PubMed2006

Instruments for evaluating education in evidence-based practice: a systematic review.

CONTEXT: Evidence-based practice (EBP) is the integration of the best research evidence with patients' values and clinical circumstances in clinical decision making. Teaching of EBP should be evaluated and guided by evidence of its own effectiveness. OBJECTIVE: To appraise, summarize, and describe currently available EBP teaching evaluation instruments. DATA SOURCES AND STUDY SELECTION: We searched the MEDLINE, EMBASE, CINAHL, HAPI, and ERIC databases; reference lists of retrieved articles; EBP Internet sites; and 8 education journals from 1980 through April 2006. For inclusion, studies had to report an instrument evaluating EBP, contain sufficient description to permit analysis, and present quantitative results of administering the instrument. DATA EXTRACTION: Two raters independently abstracted information on the development, format, learner levels, evaluation domains, feasibility, reliability, and validity of the EBP evaluation instruments from each article. We defined 3 levels of instruments based on the type, extent, methods, and results of psychometric testing and suitability for different evaluation purposes. DATA SYNTHESIS: Of 347 articles identified, 115 were included, representing 104 unique instruments. The instruments were most commonly administered to medical students and postgraduate trainees and evaluated EBP skills. Among EBP skills, acquiring evidence and appraising evidence were most commonly evaluated, but newer instruments evaluated asking answerable questions and applying evidence to individual patients. Most behavior instruments measured the performance of EBP steps in practice but newer instruments documented the performance of evidence-based clinical maneuvers or patient-level outcomes. At least 1 type of validity evidence was demonstrated for 53% of instruments, but 3 or more types of validity evidence were established for only 10%. High-quality instruments were identified for evaluating the EBP competence of individual trainees, determining the effectiveness of EBP curricula, and assessing EBP behaviors with objective outcome measures. CONCLUSIONS: Instruments with reasonable validity are available for evaluating some domains of EBP and may be targeted to different evaluation needs. Further development and testing is required to evaluate EBP attitudes, behaviors, and more recently articulated EBP skills.

Educational Measurement↗

PubMed1997

Risk of adverse effects of intensified treatment in insulin-dependent diabetes mellitus: a meta-analysis.

While the benefits of intensified insulin treatment in insulin-dependent (Type 1) diabetes mellitus (IDDM) are well recognized, the risks have not been comprehensively characterized. We examined the risk of severe hypoglycaemia, ketoacidosis, and death in a meta-analysis of randomized controlled trials. The MEDLINE database, reference lists, and specialist journals were searched electronically or by hand to identify relevant studies with at least 6 months of follow-up and the monitoring of glycaemia by glycosylated haemoglobin measurements. Logistic regression was used for calculation of combined odds ratios and 95% confidence intervals (95% CI). The influence of covariates was examined by including covariate-by-treatment interaction terms. Methodological study quality was assessed and sensitivity analyses were performed. Fourteen trials were identified. These contributed 16 comparisons with 1028 patients allocated to intensified and 1039 allocated to conventional treatment. A total of 846 patients suffered at least one episode of severe hypoglycaemia, 175 patients experienced ketoacidosis and 26 patients died. The combined odds ratio (95% CI) for hypoglycaemia was 2.99 (2.45-3.64), for ketoacidosis 1.74 (1.27-2.38) and for death from all causes 1.40 (0.65-3.01). The risk of severe hypoglycaemia was determined by the degree of normalization of glycaemia achieved (p=0.005 for interaction term), with the results from the Diabetes Control and Complications Trial (DCCT) in line with the other trials. Ketoacidosis risk depended on the type of intensified treatment used. Odds ratios (95% CI) were 7.20 (2.95-17.58) for exclusive use of pumps, 1.13 (0.15-8.35) for multiple daily injections and 1.28 (0.90-1.83) for trials offering a choice between the two (p = 0.004 for interaction). Mortality was significantly (p = 0.007) increased for causes potentially associated with acute complications (7 vs 0 deaths, 5 deaths attributed to ketoacidosis, and 2 sudden deaths), and non-significantly (p = 0.16) decreased for macrovascular causes (3 vs 8 deaths). We conclude that there is a substantial risk of severe adverse effects associated with intensified insulin treatment. Mortality from acute metabolic causes is increased; however, this is largely counterbalanced by a reduction in cardiovascular mortality. The excess of severe hypoglycemia in the DCCT is not exceptional. Multiple daily injection schemes may be safer than treatment with insulin pumps.

Blood Glucose↗

PubMedDate not supplied

Two-dimensional map of human brain proteins.

Samples of human brain from the parietal cortex lobe were analyzed by two-dimensional gel electrophoresis, using immobilized pH gradient strips covering the various pH regions. The protein spots were visualized with colloidal Coomassie blue stain and identified by matrix-assisted laser desorption/ionization mass spectrometry. Approximately 400 spots were identified, corresponding to 180 different brain proteins. The list of identified proteins includes a large number of structural proteins and of enzymes or enzyme subunits with various catalytic activities. The majority of proteins are localized in the cytoplasma and in mitochondria. The two-dimensional map may be useful as a reference database to study changes in the protein level caused by various disorders, such as Alzheimer's disease, major depression and schizophrenia.

Animals↗

PubMed1999

Information transfer between large and small two-dimensional polyacrylamide gel electrophoresis.

To determine the feasibility of data transfer, an interlaboratory comparison was conducted on colon carcinoma cell line (DLD-1) proteins resolved by two-dimensional polyacrylamide gel electrophoresis either on small (6 x 7 cm) or large (16x18 cm) gels. The gels were silver-stained and scanned by laser densitometry, and the image obtained was analyzed using Melanie software. The number of spots detected was 1337+/-161 vs. 2382+/-176 for small vs. large format gels, respectively. After gel calibration using landmarks determined using pl and Mr markers, large- and small-format gels were matched and 712+/-36 proteins were found on both types of gels. Having performed accurate gel matching it was possible to acquire additional information after accessing a 2-D PAGE reference database (http://www.expasy.ch/ cgibin/map2/def?DLD1_HUMAN). Thus, the difference in gel size is not an obstacle for data transfer. This will facilitate exchanges between laboratories or consultation concerning existing databases.

Adenocarcinoma↗

PubMed2000

Systemic treatments for metastatic cutaneous melanoma.

BACKGROUND: Systemic therapies for metastatic cutaneous melanoma, the most aggressive of all skin cancers, remain disappointing. Few lasting remissions are achieved and the therapeutic aim remains one of palliation. Many agents are used alone or in combination with varying degrees of toxicity and cost. It is unclear whether evidence exists to support these complex regimens over best supportive care / placebo. OBJECTIVES: To review the benefits from the use of systemic therapies in metastatic cutaneous melanoma compared to best supportive care/placebo, and to establish whether a 'standard' therapy exists which is superior to other treatments. SEARCH STRATEGY: Randomised controlled trials were identified from the MEDLINE, EMBASE and CCTR/CENTRAL databases. References, conference proceedings, and Science Citation Index/Scisearch were also used to locate trials. Cancer registries and trialists were also contacted. SELECTION CRITERIA: Randomised controlled trials of adults with histologically proven metastatic cutaneous melanoma in which systemic anti-cancer therapy was compared with placebo or supportive care. DATA COLLECTION AND ANALYSIS: Study selection was performed by two independent reviewers. Data extraction forms were used for studies which appeared to meet the selection criteria and, where appropriate, full text articles were retrieved and reviewed independently. MAIN RESULTS: No randomised controlled trials were found comparing a systemic therapy with placebo or best supportive care in metastatic cutaneous melanoma. REVIEWER'S CONCLUSIONS: There is no evidence from randomised controlled clinical trials to show superiority of systemic therapy over best supportive care / placebo in the treatment of malignant cutaneous melanoma. Given that patients with metastatic melanoma frequently receive systemic therapy, it is our pragmatic view that a future systematic review could compare any systemic treatment, or combination of treatments, to single agent dacarbazine.

Antineoplastic Agents↗