Biomedical subjects
Publications and source records attributed to O Olsen.
In 2000, we reported that there is no reliable evidence that screening for breast cancer reduces mortality. As we discuss here, a Cochrane review has now confirmed and strengthened our previous findings. The review also shows that breast-cancer mortality is a misleading outcome measure. Finally, we use data supplemental to those in the Cochrane review to show that screening leads to more aggressive treatment.
OBJECTIVE: To assess the quality of Cochrane reviews. DESIGN: Ten methodologists affiliated with the Cochrane Collaboration independently examined, in a semistructured way, the quality of reviews first published in 1998. Each review was assessed by two people; if one of them noted any major problems, they agreed on a common assessment. Predominant types of problem were categorised. SETTING: Cyberspace collaboration coordinated from the Nordic Cochrane Centre. STUDIES: All 53 reviews first published in issue 4 of the Cochrane Library in 1998. MAIN OUTCOME MEASURE: Proportion of reviews with various types of major problem. RESULTS: No problems or only minor ones were found in most reviews. Major problems were identified in 15 reviews (29%). The evidence did not fully support the conclusion in nine reviews (17%), the conduct or reporting was unsatisfactory in 12 reviews (23%), and stylistic problems were identified in 12 reviews (23%). The problematic conclusions all gave too favourable a picture of the experimental intervention. CONCLUSIONS: Cochrane reviews have previously been shown to be of higher quality and less biased on average than other systematic reviews, but improvement is always possible. The Cochrane Collaboration has taken steps to improve editorial processes and the quality of its reviews. Meanwhile, the Cochrane Library remains a key source of evidence about the effects of healthcare interventions. Its users should interpret reviews cautiously, particularly those with conclusions favouring experimental interventions and those with many typographical errors.
The inwardly rectifying potassium channel Kir 2.3 is specifically targeted and expressed on the basolateral membrane of certain renal epithelial cells. In the present study, the structural basis for polarized targeting was elucidated. Deletion of a unique COOH-terminal domain produced channels that were mistargeted to the apical membrane, consistent with the removal of a basolateral membrane-sorting signal. By characterizing a series of progressively smaller truncation mutants, an essential targeting signal was defined (residues 431-442) within a domain that juxtaposes or overlaps with a type I PDZ binding motif (442). Fusion of the COOH-terminal structure onto CD4 was sufficient to change a random membrane-trafficking and expression pattern into a basolateral membrane one. Using metabolic labeling and pulse-chase and surface immunoprecipitation, we found that CD4-Kir2.3 COOH-terminal chimeras were rapidly and directly targeted to the basolateral membrane, consistent with a sorting signal that is processed in the biosynthetic pathway. Collectively, the data indicate that the basolateral sorting determinant in Kir 2.3 is composed of a unique arrangement of trafficking motifs, containing tandem, conceivably overlapping, biosynthetic targeting and PDZ-based signals. The previously unrecognized domain corresponds to a highly degenerate structure within the Kir channel family, raising the possibility that the extreme COOH terminus of Kir channels may differentially coordinate membrane targeting of different channel isoforms.
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BACKGROUND: Mammographic screening for breast cancer is controversial, as reflected in greatly varying national policies. OBJECTIVES: To assess the effect of screening for breast cancer with mammography on mortality and morbidity. SEARCH STRATEGY: MEDLINE (16 May 2000), The Cochrane Breast Cancer Group's trial register (24 Jan 2000) and reference lists. Letters, abstracts and unpublished trials. Authors were contacted. SELECTION CRITERIA: Randomised trials comparing mammographic screening with no mammographic screening. DATA COLLECTION AND ANALYSIS: Data were extracted by both authors independently. MAIN RESULTS: Seven completed and eligible trials involving half a million women were identified. The two best trials provided medium-quality data and, when combined, yield a relative risk for overall mortality of 1.00 (95% CI 0.96-1.05) after 13 years. However, the trials are underpowered for all-cause mortality, and confidence intervals include a possible worthwhile effect as well as a possible detrimental effect. If data from all eligible trials (excluding flawed studies) are considered then the relative risk for overall mortality after 13 years is 1.01 (95% CI 0.99-1.03). The best trials failed to show a significant reduction in breast cancer mortality with a relative risk of 0.97 (95% CI 0.82-1.14). If data from all eligible trials (excluding flawed studies) are considered then the relative risk for breast cancer mortality after 13 years is 0.80 (95% CI 0.71-0.89). However, breast cancer mortality is considered to be an unreliable outcome and biased in favour of screening. Flaws are due to differential exclusion of women with breast cancer from analysis and differential misclassification of cause of death. REVIEWER'S CONCLUSIONS: The currently available reliable evidence does not show a survival benefit of mass screening for breast cancer (and the evidence is inconclusive for breast cancer mortality). Women, clinicians and policy makers should consider these findings carefully when they decide whether or not to attend or support screening programs.
Alkalophilic Bacillus alpha-amylase (ABA) was produced in the yeast Pichia pastoris with a yield of 50 mg L(-1) of culture supernatant. The recombinant protein, rABA, was glycosylated at seven of the nine sites for potential N-glycosylation as identified by automated peptide sequencing and MALDI-TOF MS of tryptic fragments. The number of hexose units within each glycan chain was found to vary from 8 to 18 as calculated from the masses of glycosylated peptide fragments. Temperature stability measurements in the absence of substrate showed that the T(50) of glycosylated rABA and its endoglycosidase H-deglycosylated form was 76 degrees C while that of ABA purified from Bacillus was 89 degrees C thus demonstrating that the original temperature stability of ABA was not retained by rABA. The relative thermoperformance, i.e., the activity at 80 degrees C relative to that at 37 degrees C was 0.9 +/- 0.3 for rABA. Removal of all seven N-linked glycans by endoglycosidase H increased the relative thermoperformance to 2.4 +/- 0.6, compared to the value of 3.5 +/- 1.1 for ABA. Thus, removal of the N-linked glycans did not improve the thermostability of rABA but modified its thermoperformance to approach that of the original Bacillus enzyme. rABA had the highest activity around pH 6. Treatment of rABA with endoglycosidase H shifted the pH activity profile in a more alkaline direction approaching the pH activity profile of ABA.
Membrane-associated guanylate kinases (MAGUKs), such as PSD-95, are modular scaffolds that organize signaling complexes at synapses and other cell junctions. MAGUKs contain PDZ domains, which recruit signaling proteins, as well as a Src homology 3 (SH3) and a guanylate kinase-like (GK) domain, implicated in scaffold oligomerization. The crystal structure of the SH3-GK module from PSD-95 reveals that these domains form an integrated unit: the SH3 fold comprises noncontiguous sequence elements divided by a hinge region and the GK domain. These elements compose two subdomains that can assemble in either an intra- or intermolecular fashion to complete the SH3 fold. We propose a model for MAGUK oligomerization in which complementary SH3 subdomains associate by 3D domain swapping. This model provides a possible mechanism for ligand regulation of oligomerization.
Acute pancreatitis is a common disease with significant morbidity and mortality. Despite recent improvements in our understanding of the disease process and the development of a range of supportive measures, today's treatment approaches are still less than ideal. Here I present some of the key points from generally accepted guidelines for the management of acute pancreatitis, including the operational classification system approved in Atlanta, USA, 1992. Moreover, the diagnostic value of magnetic resonance as well as new approaches to treatment, including data on prophylactic antibiotics, selective digestive decontamination, and enteral nutrition in acute pancreatitis, are discussed in more detail.
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BACKGROUND: A 1999 study found no decrease in breast-cancer mortality in Sweden, where screening has been recommended since 1985. We therefore reviewed the methodological quality of the mammography trials and an influential Swedish meta-analysis, and did a meta-analysis ourselves. METHODS: We searched the Cochrane Library for trials and asked the investigators for further details. Meta-analyses were done with Review Manager (version 4.0). FINDINGS: Baseline imbalances were shown for six of the eight identified trials, and inconsistencies in the number of women randomised were found in four. The two adequately randomised trials found no effect of screening on breast-cancer mortality (pooled relative risk 1.04 [95% CI 0.84-1.27]) or on total mortality (0.99 [0.94-1.05]). The pooled relative risk for breast-cancer mortality for the other trials was 0.75 (0.67-0.83), which was significantly different (p=0.005) from that for the unbiased trials. The Swedish meta-analysis showed a decrease in breast-cancer mortality but also an increase in total mortality (1.06 [1.04-1.08]); this increase disappeared after adjustment for an imbalance in age. INTERPRETATION: Screening for breast cancer with mammography is unjustified. If the Swedish trials are judged to be unbiased, the data show that for every 1000 women screened biennially throughout 12 years, one breast-cancer death is avoided whereas the total number of deaths is increased by six. If the Swedish trials (apart from the Malmö trial) are judged to be biased, there is no reliable evidence that screening decreases breast-cancer mortality.
BACKGROUND: A meta-analysis of observational studies have suggested that planned home birth may be safe and with less interventions than planned hospital birth. OBJECTIVES: The objective of this review was to assess the effects of planned home birth compared to hospital birth on the rates of interventions, complications and morbidity as determined in randomised trials. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register and the Cochrane Controlled Trials Register. Date of last search: September 1999. SELECTION CRITERIA: Controlled trials comparing planned hospital birth to planned home birth in selected women, assisted by an experienced home birth practitioner, and backed up by a modern hospital system in case transfer should be necessary. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data were extracted by one reviewer and checked by the other reviewer. Study authors were contacted for additional information. MAIN RESULTS: One study involving 11 women was included. The trial was of reasonable quality, but was too small to be able to draw conclusions. REVIEWER'S CONCLUSIONS: There is no strong evidence to favour either planned hospital birth or planned home birth for low risk pregnant women.
Barley zygote protoplasts were mechanically isolated, embedded in agarose droplets, and microinjected with a rice actin promoter Act1-gusA-nos gene construct. On average 62% of the cells survived the injection and of these 55% continued development into embryo-like structures and eventually to plants. PCR screening for the presence of a 307-bp fragment in the middle of the gusA gene showed that on average 21% of the derived structures contained this fragment. However, among the hundreds of injected zygotes, derived structures and regenerants we only found significant GUS expression in two cases (embryo-like structures nine days after injection). Two lines of green plants, derived from zygotes microinjected with linearized plasmid (line A147-1) or an isolated Act1-gusA-nos gene cassette (line A166-h) proved to be transgenic. Line A147-1 appeared to contain a single and intact copy of the expression cassette but a PCR based progeny analysis indicated the presence of additional shorter fragments of the cassette. Line A166-h appeared to contain a single fragment of the gusA gene that was transferred to the progeny as a single Mendelian trait. One additional fragment of the gusA gene was identified in this line. The present data show that transformation of barley by microinjection of DNA into isolated zygotes is feasible but also that gene expression rarely is achieved, possibly due to degradation of the introduced DNA.
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BACKGROUND: Gastric lipase contributes significantly to overall lipolysis and is regulated by interacting neuro-hormonal mechanisms. Patients with alcoholic chronic pancreatitis (ACP) have low, or even absent, activity of pancreatic lipases. In that state the secretion of gastric lipase could be essential and compensate for the pancreatic defect. However, conflicting studies have not resolved the order of magnitude of gastric lipase secretion in these patients. This could be explained by differences in regulatory mechanisms, gastric mucosal changes, and abdominal vagal tone. METHODS: Nasogastric intubation with modified sham feeding and upper endoscopy including biopsies for histologic classification and Helicobacter pylori infection status were performed in eight ACP patients, and eight healthy volunteers were studied on separate occasions. Vagal nerve function was assessed by calculation of heart rate variability in ACP patients. Gastric lipase was measured in aspirates by means of enzyme-linked immunosorbent assay and an enzyme kinetic assay. Plasma concentrations of gastrin, secretin, cholecystokinin, and pancreatic polypeptide were measured throughout the study. RESULTS: Sham feeding rapidly and significantly increased gastric lipase secretion in healthy volunteers, whereas ACP patients did not respond to sham feeding. Two of eight patients were infected with H. pylori and had mucosal changes accordingly. The lack of lipase response could not be ascribed to dysfunction of the abdominal vagus. CONCLUSIONS: The cephalic phase of gastric lipase secretion is impaired in ACP patients. Although their fundic cells continue to secrete gastric lipase, they are not subject to normal neuro-hormonal regulation.
The effect of a potato fibre preparation on exocrine pancreatic secretions and on gastrointestinal hormone levels in plasma was studied in three 8 weeks old piglets that were surgically fitted with a jugular vein catheter for blood sampling, a pancreatic duct catheter and a T-shaped duodenal cannula for collection of pancreatic juice. The animals were fed for 2 weeks a control diet (experimental period 1), thereafter for 2 weeks the control diet supplemented with 2% potato fibre (experimental period 2) and for another 2 weeks the control diet again (experimental period 3). Additionally, intraduodenal (i.d.) infusions of the experimental diet, the control diet and potato fibre as well as i.v. infusions of a solution containing cholecystokinin (CCK) and secretin were administered. Potato fibre in the diet evoked in tendency an increase in the volume of secretion of pancreatic juice and a significant increase both in the mean values of the total protein content and total activities of lipase, trypsin and alpha-amylase when compared to the control diet. The i.d. infusion of the control diet, experimental diet and fibre infusate as well as the i.v. administration of the hormone infusate led to a spontaneous secretory response of the exocrine pancreas. Besides gastrointestinal hormones, such as CCK, other factors such as short chain fatty acids may be involved in the regulation of the exocrine pancreas.
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