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author:("lekholm, gear")
1.  Up-regulation of CLDN1 in gastric cancer is correlated with reduced survival 
BMC Cancer  2013;13:586.
The genetic changes in gastric adenocarcinoma are extremely complex and reliable tumor markers have not yet been identified. There are also remarkable geographical differences in the distribution of this disease. Our aim was to identify the most differentially regulated genes in 20 gastric adenocarcinomas from a Norwegian selection, compared to matched normal mucosa, and we have related our findings to prognosis, survival and chronic Helicobacter pylori infection.
Biopsies from gastric adenocarcinomas and adjacent normal gastric mucosa were obtained from 20 patients immediately following surgical resection of the tumor. Whole genome, cDNA microarray analysis was performed on the RNA isolated from the sample pairs to compare the gene expression profiles between the tumor against matched mucosa. The samples were microscopically examined to classify gastritis. The presence of H. pylori was examined using microscopy and immunohistochemistry.
130 genes showed differential regulation above a predefined cut-off level. Interleukin-8 (IL-8) and Claudin-1 (CLDN1) were the most consistently up-regulated genes in the tumors. Very high CLDN1 expression in the tumor was identified as an independent and significant predictor gene of reduced post-operative survival. There were distinctly different expression profiles between the tumor group and the control mucosa group, and the histological subsets of mixed type, diffuse type and intestinal type cancer demonstrated further sub-clustering. Up-regulated genes were mapped to cell-adhesion, collagen-related processes and angiogenesis, whereas normal intestinal functions such as digestion and excretion were associated with down-regulated genes. We relate the current findings to our previous study on the gene response of gastric epithelial cells to H. pylori infection.
CLDN1 was highly up-regulated in gastric cancer, and CLDN1 expression was independently associated with a poor post-operative prognosis, and may have important prognostic value. IL-8 and CLDN1 may represent central links between the gene response seen in acute H. pylori infection of gastric epithelial cells, and ultimately gastric cancer.
PMCID: PMC4029627  PMID: 24321518
Gastric cancer; Interlukin 8; Claudin-1; Helicobacter pylori; cDNA microarray; Survival; Prognosis
2.  A cross-sectional study to identify organisational processes associated with nurse-reported quality and patient safety 
BMJ Open  2012;2(6):e001967.
The purpose of this study was to identify organisational processes and structures that are associated with nurse-reported patient safety and quality of nursing.
This is an observational cross-sectional study using survey methods.
Respondents from 31 Norwegian hospitals with more than 85 beds were included in the survey.
All registered nurses working in direct patient care in a position of 20% or more were invited to answer the survey. In this study, 3618 nurses from surgical and medical wards responded (response rate 58.9). Nurses' practice environment was defined as organisational processes and measured by the Nursing Work Index Revised and items from Hospital Survey on Patient Safety Culture.
Outcome measures
Nurses' assessments of patient safety, quality of nursing, confidence in how their patients manage after discharge and frequency of adverse events were used as outcome measures.
Quality system, nurse–physician relation, patient safety management and staff adequacy were process measures associated with nurse-reported work-related and patient-related outcomes, but we found no associations with nurse participation, education and career and ward leadership. Most organisational structures were non-significant in the multilevel model except for nurses’ affiliations to medical department and hospital type.
Organisational structures may have minor impact on how nurses perceive work-related and patient-related outcomes, but the findings in this study indicate that there is a considerable potential to address organisational design in improvement of patient safety and quality of care.
PMCID: PMC3533052  PMID: 23263021
3.  In silico evolutionary analysis of Helicobacter pylori outer membrane phospholipase A (OMPLA) 
BMC Microbiology  2012;12:206.
In the past decade, researchers have proposed that the pldA gene for outer membrane phospholipase A (OMPLA) is important for bacterial colonization of the human gastric ventricle. Several conserved Helicobacter pylori genes have distinct genotypes in different parts of the world, biogeographic patterns that can be analyzed through phylogenetic trees. The current study will shed light on the importance of the pldA gene in H. pylori. In silico sequence analysis will be used to investigate whether the bacteria are in the process of preserving, optimizing, or rejecting the pldA gene. The pldA gene will be phylogenetically compared to other housekeeping (HK) genes, and a possible origin via horizontal gene transfer (HGT) will be evaluated through both intra- and inter-species evolutionary analyses.
In this study, pldA gene sequences were phylogenetically analyzed and compared with a large reference set of concatenated HK gene sequences. A total of 246 pldA nucleotide sequences were used; 207 were from Norwegian isolates, 20 were from Korean isolates, and 19 were from the NCBI database. Best-fit evolutionary models were determined with MEGA5 ModelTest for the pldA (K80 + I + G) and HK (GTR + I + G) sequences, and maximum likelihood trees were constructed. Both HK and pldA genes showed biogeographic clustering. Horizontal gene transfer was inferred based on significantly different GC contents, the codon adaptation index, and a phylogenetic conflict between a tree of OMPLA protein sequences representing 171 species and a tree of the AtpA HK protein for 169 species. Although a vast majority of the residues in OMPLA were predicted to be under purifying selection, sites undergoing positive selection were also found.
Our findings indicate that the pldA gene could have been more recently acquired than seven of the HK genes found in H. pylori. However, the common biogeographic patterns of both the HK and pldA sequences indicated that the transfer occurred long ago. Our results indicate that the bacterium is preserving the function of OMPLA, although some sites are still being evolutionarily optimized.
PMCID: PMC3490997  PMID: 22974200
OMPLA; pldA; Phospholipase A; Outer membrane; Helicobacter pylori; Biogeography; Adaptation
4.  Interleukin-8 is the single most up-regulated gene in whole genome profiling of H. pylori exposed gastric epithelial cells 
BMC Microbiology  2012;12:9.
The association between Helicobacter pylori infection and upper gastrointestinal disease is well established. However, only a small fraction of H. pylori carriers develop disease, and there are great geographical differences in disease penetrance. The explanation to this enigma lies in the interaction between the bacterium and the host. H. pylori Outer Membrane Phospholipase A (OMPLA) has been suggested to play a role in the virulence of this bacterium. The aim of this study was to profile the most significant cellular pathways and biological processes affected in gastric epithelial cells during 24 h of H. pylori exposure, and to study the inflammatory response to OMPLA+ and OMPLA- H. pylori variants.
Interleukin-8 was the most significantly up-regulated gene and appears to play a paramount role in the epithelial cell response to H. pylori infection and in the pathological processes leading to gastric disease. MAPK and NF-kappaB cellular pathways were powerfully activated, but did not seem to explain the impressive IL-8 response. There was marked up-regulation of TP53BP2, whose corresponding protein ASPP2 may interact with H. pylori CagA and cause marked p53 suppression of apoptosis. Other regulators of apoptosis also showed abberant regulation. We also identified up-regulation of several oncogenes and down-regulation of tumor suppressor genes as early as during the first 24 h of infection. H. pylori OMPLA phase variation did not seem to influence the inflammatory epithelial cell gene response in this experiment.
In whole genome analysis of the epithelial response to H. pylori exposure, IL-8 demonstrated the most marked up-regulation, and was involved in many of the most important cellular response processes to the infection. There was dysregulation of apoptosis, tumor suppressor genes and oncogenes as early as in the first 24 h of H. pylori infection, which may represent early signs of gastric tumorigenesis. OMPLA+/-did not affect the acute inflammatory response to H. pylori.
PMCID: PMC3292955  PMID: 22248188
5.  The Generic Short Patient Experiences Questionnaire (GS-PEQ): identification of core items from a survey in Norway 
Questionnaires are commonly used to collect patient, or user, experiences with health care encounters; however, their adaption to specific target groups limits comparison between groups. We present the construction of a generic questionnaire (maximum of ten questions) for user evaluation across a range of health care services.
Based on previous testing of six group-specific questionnaires, we first constructed a generic questionnaire with 23 items related to user experiences. All questions included a "not applicable" response option, as well as a follow-up question about the item's importance. Nine user groups from one health trust were surveyed. Seven groups received questionnaires by mail and two by personal distribution. Selection of core questions was based on three criteria: applicability (proportion "not applicable"), importance (mean scores on follow-up questions), and comprehensiveness (content coverage, maximum two items per dimension).
1324 questionnaires were returned providing subsample sizes ranging from 52 to 323. Ten questions were excluded because the proportion of "not applicable" responses exceeded 20% in at least one user group. The number of remaining items was reduced to ten by applying the two other criteria. The final short questionnaire included items on outcome (2), clinician services (2), user involvement (2), incorrect treatment (1), information (1), organisation (1), and accessibility (1).
The Generic Short Patient Experiences Questionnaire (GS-PEQ) is a short, generic set of questions on user experiences with specialist health care that covers important topics for a range of groups. It can be used alone or with other instruments in quality assessment or in research. The psychometric properties and the relevance of the GS-PEQ in other health care settings and countries need further evaluation.
PMCID: PMC3111343  PMID: 21510871
6.  The Prognostic Impact of Protein Expression of E-Cadherin-Catenin Complexes Differs between Rectal and Colon Carcinoma 
The E-cadherin-catenin complex provides cell-cell adhesion. In order for a carcinoma to metastasize, cancer cells must let go of their hold of neighboring cells in the primary tumor. The presence of components of the E-cadherin-catenin complex in 246 rectal adenocarcinomas was examined by immunohistochemistry and compared to their presence in 219 colon carcinomas. The expression data were correlated to clinical information from the patients' records. There were statistically significant differences in protein expression between the rectal and the colon carcinomas regarding membranous β-catenin, γ-catenin, p120-catenin, and E-cadherin, as well as nuclear β-catenin. In the rectal carcinomas, there was a significant inverse association between the expression of p120-catenin in cell membranes of the primary tumors and the occurrence of local recurrence, while membranous protein expression of β-catenin was inversely related to distant metastases.
PMCID: PMC2931401  PMID: 20814557
7.  Usefulness of a national parent experience survey in quality improvement: views of paediatric department employees 
This study presents results from an electronic survey among paediatric department employees, addressing employees' attitudes and use of results from a national parent experience survey carried out in 2005.
Electronic questionnaire survey of employees from each of the 20 paediatric departments included in the national survey, with a response rate of 87%.
The employees had favourable opinions of user experience surveys, and the results from the national survey were well known among both managers and other personnel. User experience surveys were considered important, and 56% reported that they had implemented improvement actions addressing problems identified in the national survey. Managers reported more often than staff without managerial responsibility that the results had been informally discussed, and that the survey was useful for their own department. Department leaders were more positive to the usefulness of the survey than non-leaders. Significant differences in attitudes were found between physicians and other health personnel.
Employees in the paediatric departments were positive to user experience surveys, and the surveys have a potential to be actively used in quality improvement actions. Effects of the quality improvement initiatives should be assessed in future parent experience surveys.
PMCID: PMC2975967  PMID: 20513791
Quality improvement; patient satisfaction; electronic questionnaire; quality of healthcare; paediatrics; continuous quality improvement; healthcare quality improvement; patient-centred; quality of care
8.  International health policy survey in 11 countries: assessment of non-response bias in the Norwegian sample 
International health policy surveys are used to compare and evaluate health system performance, but little is known about the effects of non-response. The objective of this study was to assess the effects of non-response in the Norwegian part of the Commonwealth Fund international health policy survey in 2009.
As part of an international health policy survey in 2009 a cross-sectional survey was conducted in Norway among a representative sample of Norwegian general practitioners. 1 400 randomly selected GPs were sent a postal questionnaire including questions about the Norwegian health care system, the quality of the GPs' own practice and the cooperation with specialist health care. The survey included three postal reminders and a telephone follow-up of postal non-respondents. The main outcome measures were increase in response rate for each reminder, the effects of demographic and practice variables on response, the effects of non-response on survey estimates, and the cost-effectiveness of each reminder.
After three postal reminders and one telephone follow-up, the response rate was 59.1%. Statistically significant differences between respondents and non-respondents were found for three variables; group vs. solo practice (p = 0.01), being a specialist or not (p < 0.001) and municipality centrality (least central vs. most central, p = 0.03). However, demographic and practice variables had little association with five outcome variables and the overall survey estimates changed little with additional reminders. In addition, the cost-effectiveness of the final reminders was poor.
The response rate in the Norwegian survey was satisfactory, and the effect of non-response was small indicating adequate representativeness. The cost-effectiveness of the final reminders was poor. The Norwegian findings strengthen the international project, but restrictions in generalizability warrant further study in other countries.
PMCID: PMC2833149  PMID: 20146819
9.  Differences in Protein Expression and Gene Amplification of Cyclins between Colon and Rectal Adenocarcinomas 
Adenocarcinomas of rectum and colon may be different with regard to the cellular biological basis for cancer development. A material of 246 rectal cancers removed surgically at Akershus University Hospital in the years 1992–2000 was investigated and was compared to a material of 219 colon cancers operated on at Akershus University Hospital during the years 1988, 1990 and 1997–2000. There were highly significant differences between the rectal and the colon cancers in the protein expression of cyclin D1, cyclin D3, cyclin E, nuclear β-catenin, and c-Myc and in gene amplification of cyclin A2, cyclin B1, cyclin D1, and cyclin E. Gene amplification and protein expression in the rectal cancers correlated significantly for the cyclins B1, D3, and E. A statistically significant relation was observed between overexpression of cyclin A2 and local relapse of rectal carcinomas, as higher expression of cyclin A2 was associated with lower local recurrence rate.
PMCID: PMC2796221  PMID: 20029639
10.  Two novel connexin32 mutations cause early onset X-linked Charcot-Marie-Tooth disease 
BMC Neurology  2007;7:19.
X-linked Charcot-Marie Tooth (CMT) is caused by mutations in the connexin32 gene that encodes a polypeptide which is arranged in hexameric array and form gap junctions.
We describe two novel mutations in the connexin32 gene in two Norwegian families.
Family 1 had a c.225delG (R75fsX83) which causes a frameshift and premature stop codon at position 247. This probably results in a shorter non-functional protein structure. Affected individuals had an early age at onset usually in the first decade. The symptoms were more severe in men than women. All had severe muscle weakness in the legs. Several abortions were observed in this family. Family 2 had a c.536 G>A (C179Y) transition which causes a change of the highly conserved cysteine residue, i.e. disruption of at least one of three disulfide bridges. The mean age at onset was in the first decade. Muscle wasting was severe and correlated with muscle weakness in legs. The men and one woman also had symptom from their hands.
The neuropathy is demyelinating and the nerve conduction velocities were in the intermediate range (25–49 m/s). Affected individuals had symmetrical clinical findings, while the neurophysiology revealed minor asymmetrical findings in nerve conduction velocity in 6 of 10 affected individuals.
The two novel mutations in the connexin32 gene are more severe than the majority of previously described mutations possibly due to the severe structural change of the gap junction they encode.
PMCID: PMC1999495  PMID: 17620124
11.  Whole blood gene expression in infants with respiratory syncytial virus bronchiolitis 
Respiratory syncytial virus (RSV) is a major cause of viral bronchiolitis in infants worldwide, and environmental, viral and host factors are all of importance for disease susceptibility and severity. To study the systemic host response to this disease we used the microarray technology to measure mRNA gene expression levels in whole blood of five male infants hospitalised with acute RSV, subtype B, bronchiolitis versus five one year old male controls exposed to RSV during infancy without bronchiolitis. The gene expression levels were further evaluated in a new experiment using quantitative real-time polymerase chain reaction (QRT-PCR) both in the five infants selected for microarray and in 13 other infants hospitalised with the same disease.
Among the 30 genes most differentially expressed by microarray nearly 50% were involved in immunological processes. We found the highly upregulated interferon, alpha-inducible protein 27 (IFI27) and the highly downregulated gene Charcot-Leyden crystal protein (CLC) to be the two most differentially expressed genes in the microarray study. When performing QRT-PCR on these genes IFI27 was upregulated in all but one infant, and CLC was downregulated in all 18 infants, and similar to that given by microarray.
The gene IFI27 is upregulated and the gene CLC is downregulated in whole blood of infants hospitalised with RSV, subtype B, bronchiolitis and is not reported before. More studies are needed to elucidate the specificity of these gene expressions in association with host response to this virus in bronchiolitis of moderate severity.
PMCID: PMC1713240  PMID: 17166282
12.  Dissemination of Community-Acquired Methicillin-Resistant Staphylococcus aureus Clones in Northern Norway: Sequence Types 8 and 80 Predominate 
Journal of Clinical Microbiology  2005;43(5):2118-2124.
Increasing frequencies of community-acquired methicillin-resistant Staphylcoccus aureus (MRSA) strain isolation have been reported from many countries. The overall prevalence of MRSA in Norway is still very low. MRSA isolates (n = 67) detected between 1995 and 2003 in northern Norway were analyzed by pulsed-field gel electrophoresis, multilocus sequence typing, and staphylococcal cassette chromosome mec (SCCmec) typing. Sixty-seven isolates were associated with 13 different sequence types. Two successful MRSA clones predominated. Sequence type 8 (ST8) (40%) and ST80 (19%) containing SCCmec type IV were detected in hospitals and communities in different geographic regions during a 7-year period. In general, there was a low level of antimicrobial resistance. Only 26% of the isolates were multiresistant. International epidemic clones were detected. The frequent findings of SCCmec type IV (91%) along with heterogeneous genetic backgrounds suggest a horizontal spread of SCCmec type IV among staphylococcal strains in parallel with the clonal spread of successful MRSA strains.
PMCID: PMC1153739  PMID: 15872230
13.  Phase Variation in the Helicobacter pylori Phospholipase A Gene and Its Role in Acid Adaptation 
Infection and Immunity  2001;69(12):7334-7340.
Previously, we have shown that Helicobacter pylori can spontaneously and reversibly change its membrane lipid composition, producing variants with low or high content of lysophospholipids. The “lyso” variant contains a high percentage of lysophospholipids, adheres better to epithelial cells, and releases more proteins such as urease and VacA, compared to the “normal” variant, which has a low content of lysophospholipids. Prolonged growth of the normal variant at pH 3.5, but not under neutral conditions, leads to enrichment of lyso variant colonies, suggesting that the colony switch is relevant to acid adaptation. In this study we show that the change in membrane lipid composition is due to phase variation in the pldA gene. A change in the (C) tract length of this gene results in reversible frameshifts, translation of a full-length or truncated pldA, and the production of active or inactive outer membrane phospholipase A (OMPLA). The role of OMPLA in determining the colony morphology was confirmed by the construction of an OMPLA-negative mutant. Furthermore, variants with an active OMPLA were able to survive acidic conditions better than variants with the inactive form. This explains why the lyso variant is selected at low pH. Our studies demonstrate that phase variation in the pldA gene, resulting in an active form of OMPLA, is important for survival under acidic conditions. We also demonstrated the active OMPLA genotype in fresh isolates of H. pylori from patients referred to gastroscopy for dyspepsia.
PMCID: PMC98819  PMID: 11705905
14.  An observational study: associations between nurse-reported hospital characteristics and estimated 30-day survival probabilities 
BMJ Quality & Safety  2014;23(9):757-764.
There is a growing body of evidence for associations between the work environment and patient outcomes. A good work environment may maximise healthcare workers’ efforts to avoid failures and to facilitate quality care that is focused on patient safety. Several studies use nurse-reported quality measures, but it is uncertain whether these outcomes are correlated with clinical outcomes. The aim of this study was to determine the correlations between hospital-aggregated, nurse-assessed quality and safety, and estimated probabilities for 30-day survival in and out of hospital.
In a multicentre study involving almost all Norwegian hospitals with more than 85 beds (sample size=30, information about nurses’ perceptions of organisational characteristics were collected. Subscales from this survey were used to describe properties of the organisations: quality system, patient safety management, nurse–physician relationship, staffing adequacy, quality of nursing and patient safety. The average scores for these organisational characteristics were aggregated to hospital level, and merged with estimated probabilities for 30-day survival in and out of hospital (survival probabilities) from a national database. In this observational, ecological study, the relationships between the organisational characteristics (independent variables) and clinical outcomes (survival probabilities) were examined.
Survival probabilities were correlated with nurse-assessed quality of nursing. Furthermore, the subjective perception of staffing adequacy was correlated with overall survival.
This study showed that perceived staffing adequacy and nurses’ assessments of quality of nursing were correlated with survival probabilities. It is suggested that the way nurses characterise the microsystems they belong to, also reflects the general performance of hospitals.
PMCID: PMC4145461  PMID: 24728887
health service research; quality indicator; organizational characteristics; mortality; nurse-reported outcome; patient safety; quality of care

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