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PubMed1999

Allergy and other selected diseases and risk of colorectal cancer.

It has been reported that allergy and other diseases may be related to colorectal cancer risk. The aim of this study was to perform a systematic analysis using information about medical histories specifically to see if there was any relation between allergies or other medical conditions and colorectal cancer risk. A multicentric case-control study was conducted in six Italian areas between 1992 and 1996 on 1225 incident cases of colon cancer, 728 cases of rectal cancer and 4154 controls comparable with cases according to sex and age group, admitted for acute conditions to the same network of hospitals where cases had been identified. Unconditional logistic regression models including terms for sex, age, study centre, years of education, body mass index, physical activity, smoking, history of colorectal cancer in first-degree relatives and energy intake were used to estimate the odds ratios (OR) of colon and rectal cancer according to history of allergy and other selected diseases. The OR for history of allergy was 0.88 (95% confidence interval, CI, 0.67-1.14) for colon and 0.64 (95% CI, 0.44-0.92) for rectal cancer, and the inverse association was stronger when allergy was diagnosed at age 35 years or more, or less than 10 years before the cancer diagnosis. No clear pattern emerged in strata of age and sex. History of other selected diseases, including hypertension and cholelithiasis, was not related to colon or rectal cancer risk, though there was a moderate increase in the risk of colon cancer (OR = 1.18, 95% CI, 0.66-2.14) in patients with a history of intestinal polyps. This study lends support to the hypothesis that allergic individuals may be at a lower risk of developing colorectal cancer.

Adult↗
PubMed2003

Phylogenetic analyses of diplomonad genes reveal frequent lateral gene transfers affecting eukaryotes.

BACKGROUND: Lateral gene transfer (LGT) is an important evolutionary mechanism among prokaryotes. The situation in eukaryotes is less clear; the human genome sequence failed to give strong support for any recent transfers from prokaryotes to vertebrates, yet a number of LGTs from prokaryotes to protists (unicellular eukaryotes) have been documented. Here, we perform a systematic analysis to investigate the impact of LGT on the evolution of diplomonads, a group of anaerobic protists. RESULTS: Phylogenetic analyses of 15 genes present in the genome of the Atlantic Salmon parasite Spironucleus barkhanus and/or the intestinal parasite Giardia lamblia show that most of these genes originated via LGT. Half of the genes are putatively involved in processes related to an anaerobic lifestyle, and this finding suggests that a common ancestor, which most probably was aerobic, of Spironucleus and Giardia adapted to an anaerobic environment in part by acquiring genes via LGT from prokaryotes. The sources of the transferred diplomonad genes are found among all three domains of life, including other eukaryotes. Many of the phylogenetic reconstructions show eukaryotes emerging in several distinct regions of the tree, strongly suggesting that LGT not only involved diplomonads, but also involved other eukaryotic groups. CONCLUSIONS: Our study shows that LGT is a significant evolutionary mechanism among diplomonads in particular and protists in general. These findings provide insights into the evolution of biochemical pathways in early eukaryote evolution and have important implications for studies of eukaryotic genome evolution and organismal relationships. Furthermore, "fusion" hypotheses for the origin of eukaryotes need to be rigorously reexamined in the light of these results.

Adaptation, Physiological↗
PubMed1999

The role of evidence reports in evidence-based medicine: a mechanism for linking scientific evidence and practice improvement.

STUDY QUESTIONS: In this article two related questions are considered: (1) Why isn't evidence-based medicine (EBM) more consistently implemented? and (2) Using the EBM paradigm, by what mechanism can we link evidence reports to concrete practice improvement activities? STUDY DESIGN: To motivate a systematic analysis, answers to these questions are framed within the context of a general conceptual model for practice improvement, using as an example the application of this general model to the question of improving anticoagulation. CONCLUSIONS: The potential role of evidence reports is quite broad and to be most effective, they should (1) be considered as part of a comprehensive strategy for practice improvement and (2) be designed with their customers in mind. A system-based method for using the information from evidence reports involves ultimately suggesting specific practice improvement strategies in which the strategies are defined in terms of (1) a set of functional specifications and (2) a toolbox of implementation options. Such an approach brings to bear the specialized expertise and generalized fund of scientific knowledge used to produce the evidence report, but does so in a way that facilitates local tailoring. That is, while information synthesis should be global, implementation must be local.

Cost-Benefit Analysis↗
PubMed1998

The vulnerable preschool child: the impact of biomedical and social risks on neurodevelopmental function.

The scope of preschool children with biological risk and social disadvantage is large and includes over 1 million (28%) newborns per year. Currently in 1996, 7% of children are born with low birth weight, 1% are born with very low birth weight, 20% have alcohol exposure, and 10% have other drug exposure. Poverty is dynamic and impacts on 25% of children less than 6 years old with increased frequency in children who are minority, have mothers with less than a high school education, or are unmarried. There has been a markedly increased survival in very low birth weight and extremely low birth weight infants in the past 10 years. Outcomes of these neonatal populations reveals that parenchymal brain injury is the major predictor of cerebral palsy which occurs in 7% to 10% of very low birth weight survivors. However, poverty is the major predictor of low IQ. Fetal alcohol syndrome occurs in 1.9 per 1,000 births and is most often associated with mild mental retardation and educational underachievement. Studies investigating cocaine revealed that it is a multifactorial problem overlapping with polysubstance abuse and other risk factors for social disadvantage. The overwhelming number of children do not have cerebral palsy or severe mental retardation. The long-term impact is more subtle and needs more systematic analysis as well as critical evaluation of cognitive impairments and educational under-achievement. Hypoxic ischemic encephalopathy (HIE) cannot be determined by one biological measure. Though multiple disability occurs in 70% of children with Sarnat stage 3 HIE, 30% of survivors are not disabled. Children with mild to moderate HIE have long-term outcomes that are influenced by 9- to 12-month neurodevelopmental status and social disadvantage. By combining strategies to lessen biological risks and enhance developmentally appropriate environments, long-term outcomes of preschool children can be optimized.

Asphyxia Neonatorum↗
PubMed1999

Some comments on clinical studies in orthodontics and their applications to orthodontic treatment.

This article indicates the origins and background of the current series of National Institute of Dental and Craniofacial Research-funded, university-based clinical studies of orthodontic treatment. It suggests that future studies should be less focused on refining our estimates of mean changes during treatment and concentrate research on the systematic analysis of individual differences among patients' responses to treatment, and study how skilled clinicians make in-course corrections in response to unexpected changes in treatment conditions. Finally, some suggestions are made concerning optimization of decision making in the presence of uncertainty.

Clinical Trials as Topic↗
PubMed2000

Alteration in the choice of DNA repair pathway with increasing sequence selective DNA alkylation in the minor groove.

BACKGROUND: Many conventional DNA alkylating anticancer drugs form adducts in the major groove of DNA. These are known to be chiefly repaired by both nucleotide (NER) and base (BER) excision repair in eukaryotic cells. Much less is known about the repair pathways acting on sequence specific minor groove purine adducts, which result from a promising new class of anti-tumour agents. RESULTS: Benzoic acid mustards (BAMs) tethering 1-3 pyrrole units (compounds 1, 2 and 3) show increasing DNA sequence selectivity for alkylation from BAM and 1, alkylating primarily at guanine-N7 in the major groove, to 3 which is selective for alkylation in the minor groove at purine-N3 in the sequence 5'-TTTTGPu (Pu=guanine or adenine). This increasing sequence selectivity is reflected in increased toxicity in human cells. In the yeast Saccharomyces cerevisiae, the repair of untargeted DNA adducts produced by BAM, 1 and 2 depends upon both the NER and BER pathways. In contrast, the repair of the sequence specific minor groove adducts of 3 does not involve known BER or NER activities. In addition, neither recombination nor mismatch repair are involved. Two disruptants from the RAD6 mutagenesis defective epistasis group (rad6 and rad18), however, showed increased sensitivity to 3. In particular, the rad18 mutant was over three orders of magnitude more sensitive to 3 compared to its isogenic parent, and 3 was highly mutagenic in the absence of RAD18. Elimination of the sequence specific DNA adducts formed by 3 was observed in the wild type strain, but these lesions persisted in the rad18 mutant. CONCLUSIONS: We have demonstrated that the repair of DNA adducts produced by the highly sequence specific minor groove alkylating agent 3 involves an error free adduct elimination pathway dependent on the Rad18 protein. This represents the first systematic analysis of the cellular pathways which modulate sensitivity to this new class of DNA sequence specific drugs, and indicates that the enhanced cytotoxicity of certain sequence specific minor groove adducts in DNA is the result of evasion of the common excision repair pathways.

Alkylating Agents↗
PubMedDate not supplied

Age-associated changes in gene expression patterns in the liver.

Aging is one of the least clearly understood biological processes. Alteration of oxidation/reduction (redox) enzymes has been demonstrated with aging; however, a systematic analysis of expression patterns has not been performed. The liver plays a key role in homeostasis and detoxification; therefore alteration of hepatic gene expression with aging may affect outcome after surgery. The purpose of our study was to assess changes in gene expression patterns in aged livers from both rats and humans using gene array analysis. Total RNA was extracted from young (2-month-old) and aged (2-year-old) rat livers, as well as young (1-year-old) and aged (78-year-old) human livers. Gene expression patterns were compared using Affymetrix GeneChip arrays. The expression pattern of selected genes was confirmed by reverse transcription-polymerase chain reaction. A threefold or greater change in gene expression was noted in 582 genes in the aged rat livers and 192 genes in the aged human livers. Comparison of the genes that were increased with aging demonstrated some similar patterns of expression in the rat and human livers, particularly in members of the antioxidant family and the cytochrome P-450 genes. Our findings demonstrate changes in the expression pattern of genes in the liver with aging. Concomitant increases in the expression of important antioxidant and detoxifying genes were noted in the livers of both rats and humans. This induction pattern suggests a complex link between changing hepatic detoxification/redox capability and senescence.

Aged↗
PubMedDate not supplied

The minimum effective concentration of opioids: a revisitation with patient controlled analgesia fentanyl.

BACKGROUND AND OBJECTIVES: Whether patients titrate themselves to an individualized blood or plasma opioid concentration (the so-called minimum effective concentration or [MEC]) has been debated extensively. Nevertheless, there is consistent opinion that during patient controlled analgesia (PCA) patients balance acceptable pain relief against unacceptable side effects. This study sought to characterize fentanyl used by PCA with respect to MEC and factors influencing PCA use. METHODS: An intensive study of 25 patients with observations over the first 24 hours after orthopedic surgery was planned on the premise that this approach would provide a measure of the fentanyl MEC. This necessitated repeated measurements of pain scores and plasma fentanyl concentrations before and 10 minutes after every PCA demand. In addition, a battery of psychological tests was given before and approximately 48 hours after surgery. RESULTS: Logistic difficulties of maintaining a 24-hour study design resulted in its termination after 5 patients. The patients had convincingly distinct MECs (ranging from 0.23 to 0.99 ng/mL). The relationship between plasma fentanyl concentration and pain score was steep, such that small changes in concentration coincided with marked changes in pain relief. Despite preoperative expectations of achieving satisfaction in postoperative analgesia, not all patients titrated themselves to a pain-free state; all but one were satisfied with PCA. Surprisingly few side effects were reported. Unfortunately, the small sample size made systematic analysis of the psychological tests impossible. CONCLUSIONS: This study found evidence to support the concepts of an individual MEC and a therapeutic window of fentanyl used with PCA.

Adult↗
PubMed2001

Characteristics of the human ocular surface epithelium.

An appreciation of the biological characteristics of the human ocular surface epithelium affords us a great insight into the physiology of the human ocular surface in health and disease. Here, we review five important aspects of the human ocular surface epithelium. First, we recognize the discovery of corneal epithelial stem cells, and note how the palisades of Vogt have been suggested as a clinical marker of their presence. Second, we introduce the concept of the gene expression profile of the ocular surface epithelium as arrived at using a new strategy for the systematic analysis of active genes. We also provide a summary of several genes abundantly or uniquely expressed in the human corneal epithelium, namely clusterin, keratin 3, keratin 12, aldehyde dehydrogenase 3 (ALDH3), troponin-I fast-twitch isoform, ssig-h3, cathepsin L2 (cathepsin V), uroplakin Ib, and Ca(2+)-activated chloride channel. Genes related to limbal and conjunctival epithelia are also described. Third, we touch upon the genetic abnormalities thought to be involved with epithelial dysfunction in Meesmann's dystrophy, gelatinous drop-like corneal dystrophy, and the ssig-h3-mutated corneal dystrophies. Fourth, we provide an update regarding the current state of knowledge of the role of cytokines, growth factors and apoptosis in relation to ocular surface homeostasis and tissue reconstruction; the main factors being epidermal growth factor (EGF), keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), transforming growth factor-ss (TGF-ss), and some inflammatory cytokines. Fifth, corneal epithelial barrier function and dysfunction as measured by fluorophotometry is remarked upon, with an explanation of the FL-500 fluorophotometer and its ability to detect corneal epithelial dysfunction at a subclinical level. The research described in this review has undoubtedly generated a complete understanding of corneal epithelial pathophysiology-an understanding that, directly or indirectly, has helped advance the development of new therapeutic modalities for ocular surface reconstruction.

Apoptosis↗
PubMed2003

Role of proteasomes in the degradation of short-lived proteins in human fibroblasts under various growth conditions.

Degradation of proteins in the cells occurs by proteasomes, lysosomes and other cytosolic and organellar proteases. It is believed that proteasomes constitute the major proteolytic pathway under most conditions, especially when degrading abnormal and other short-lived proteins. However, no systematic analysis of their role in the overall degradation of truly short-lived cell proteins has been carried out. Here, the degradation of short-labelled proteins was examined in human fibroblasts by release of trichloroacetic acid-soluble radioactivity. The kinetics of degradation was decomposed into two, corresponding to short- and long-lived proteins, and the effect of proteasomal and lysosomal inhibitors on their degradation, under various growth conditions, was separately investigated. From the degradation kinetics of proteins labelled for various pulse times it can be estimated that about 30% of newly synthesised proteins are degraded with a half-life of approximately 1h. These rapidly degraded proteins should mostly include defective ribosomal products. Deprivation of serum and confluent conditions increased the degradation of the pool of long-lived proteins in fibroblasts without affecting, or affecting to a lesser extent, the degradation of the pool of short-lived proteins. Inhibitors of proteasomes and of lysosomes prevented more than 80% of the degradation of short-lived proteins. It is concluded that, although proteasomes are responsible of about 40-60% of the degradation of short-lived proteins in normal human fibroblasts, lysosomes have also an important participation in the degradation of these proteins. Moreover, in confluent fibroblasts under serum deprivation, lysosomal pathways become even more important than proteasomes in the degradation of short-lived proteins.

Autophagy↗
PubMed2006

What makes a good anti-inflammatory drug target?

This review focuses on the major, 'successful' target families in inflammation and attempts to identify some of the key features of what makes a good anti-inflammatory target. The review is based on a systematic analysis of approved anti-inflammatory drugs grouped according to their drug-target family. The cytokine family is a drug-dense area. They have yielded and continue to yield a rich stream of drugs. As in other therapeutic areas, G-protein-coupled receptors (GPCRs), also known as seven-transmembrane pass receptors, have provided significant drug targets. In addition, the superfamilies of cell adhesion molecules and co-stimulatory molecules, which have special relevance to immune processes, have begun to provide the first approved drugs and might yield many more. The recent, rapid increase in the number of defined targets in the immune system -- leukocyte surface antigens, cytokines, GPCRs, adhesion molecules and co-stimulatory molecules -- will ensure a rich stream of future anti-inflammatory drug targets.

Anti-Inflammatory Agents↗
PubMed1999

Proteomics: a major new technology for the drug discovery process.

Proteomics is a new enabling technology that is being integrated into the drug discovery process. This will facilitate the systematic analysis of proteins across any biological system or disease, forwarding new targets and information on mode of action, toxicology and surrogate markers. Proteomics is highly complementary to genomic approaches in the drug discovery process and, for the first time, offers scientists the ability to integrate information from the genome, expressed mRNAs, their respective proteins and subcellular localization. It is expected that this will lead to important new insights into disease mechanisms and improved drug discovery strategies to produce novel therapeutics.

Journal Article↗
PubMed2000

Mass spectrometry and proteomics.

Proteomics is the systematic analysis of the proteins expressed by a cell or tissue, and mass spectrometry is its essential analytical tool. In the past two years, incremental advances in standard proteome technology have increased the speed of protein identification with higher levels of automation and sensitivity. Furthermore, new approaches have provided landmark advances in determining functionally relevant properties of proteins, including their quantity and involvement within protein complexes.

Mass Spectrometry↗
PubMed2002

Advances in quantitative proteomics using stable isotope tags.

A great deal of current biological and clinical research is directed at the interpretation of the information contained in the human genome sequence in terms of the structure, function and control of biological systems and processes. Proteomics, the systematic analysis of proteins, is becoming a critical component in this endeavor because proteomic measurements are carried out directly on proteins--the catalysts and effectors of essentially all biological functions. To detect changes in protein profiles that might provide important diagnostic or functional insights, proteomic analyses necessarily have to be quantitative. This article summarizes recent technological advances in quantitative proteomics.

Animals↗
PubMed2002

Mouse models for human DNA mismatch-repair gene defects.

The mammalian DNA mismatch-repair genes belong to a family of genes that comprise several homologs of the Escherichia coli mutS and mutL genes. The observation that mutations in the two human repair genes MSH2 and MLH1 are responsible for hereditary nonpolyposis colorectal cancer, as well as a significant number of sporadic colorectal cancers, raises several questions about the role of these proteins and their family members in the initiation and progression of colorectal cancer. To address these questions, mice with inactivating mutations in all the known mutS and mutL homologs have been generated. The development of these mouse lines has permitted the systematic analysis of the role of each gene in the repair process and has underscored their significance in mutation avoidance and cancer susceptibility. These analyses were critical for our understanding of the function of these genes at the organismal level and also revealed an essential role for some of the DNA mismatch-repair genes in mammalian meiosis.

Adenosine Triphosphatases↗
PubMedDate not supplied

Malignancy-associated regions of transcriptional activation: gene expression profiling identifies common chromosomal regions of a recurrent transcriptional activation in human prostate, breast, ovarian, and colon cancers.

Despite remarkable advances in our understanding of a genetic basis of cancer, the precise molecular definition of the phenotypically relevant genetic features associated with human epithelial malignancies remains a significant and highly relevant challenge. Here we performed a systematic analysis of the chromosomal positions of cancer-associated transcripts for prostate, breast, ovarian, and colon tumors, and identified short segments of human chromosomes that appear to represent a common target for transcriptional activation in major epithelial malignancies in human. These cancer-associated transcriptomeres correspond well to the regions of transient transcriptional activity on chromosomes 1q21-q23 (144-160 Mbp), 12q13 (52-63 Mbp), 17q21 (38-50 Mbp), 17q23-q25 (72-82 Mbp), 19p13 (1-16 Mbp), and Xq28 (132-142 Mbp) during human cell cycle, suggesting a common epigenetic mechanism of transcriptional activation. Consistent with this idea, two of these transcriptomeres (12q13 and 17q21) seemed to be related to the p53-regulated transcriptional clusters, and some of the cancer-associated transcriptomeres appeared to correspond well to the recently identified regions of increased gene expression on human chromosomes.

Breast Neoplasms↗
PubMed2002

Cancer genomics.

The draft human genome sequence and the dissemination of high throughput technology provides opportunities for systematic analysis of cancer cells. Genome-wide mutation screens, high resolution analysis of chromosomal abberations and expression profiling all give comprehensive views of genetic alterations in cancer cells. From these analyses will come a complete list of the genetic changes that drive malignant transformation and of the therapeutic targets that may be exploited for clinical benefit.

Cell Transformation, Neoplastic↗
PubMed2003

Spatial and temporal expression patterns of selenoprotein genes during embryogenesis in zebrafish.

Selenium is important for embryogenesis in vertebrates but little is known about the expression patterns and biological functions of most selenoprotein genes. Taking advantage of the zebrafish model, systematic analysis of selenoprotein gene expression was performed by in situ hybridization on whole-mount embryos at different developmental stages. Twenty-one selenoprotein mRNAs were analyzed and all of them exhibited expression patterns restricted to specific tissues. Moreover, we demonstrated that highly similar selenoprotein paralogs were expressed within distinct territories. Therefore, tissue- and development-specific expression patterns provided new information for selenoproteins of unknown function.

Animals↗