Biomedical subjects

Asa Johansson

Publications and source records attributed to Asa Johansson.

9 recordsLinked to original sources

PubMed2006

Microwave-accelerated synthesis of P1'-extended HIV-1 protease inhibitors encompassing a tertiary alcohol in the transition-state mimicking scaffold.

Two series of P1'-extended HIV-1 protease inhibitors comprising a tertiary alcohol in the transition-state mimic exhibiting Ki values ranging from 2.1 to 93 nM have been synthesized. Microwave-accelerated palladium-catalyzed cross-couplings were utilized to rapidly optimize the P1' side chain. High cellular antiviral potencies were encountered when the P1' benzyl group was elongated with a 3- or 4-pyridyl substituent (EC50 = 0.18-0.22 microM). X-ray crystallographic data were obtained for three inhibitors cocrystallized with the enzyme.

Alcohols↗

PubMed2006

Inhibition of p38 MAP kinase in the early posttransplantation phase redistributes blood vessels from the surrounding stroma into the transplanted endocrine tissue.

Transplanted pancreatic islets attain a chronically decreased vascular density following transplantation, despite the increased concentrations of vascular endothelial growth factor (VEGF) secreted from beta-cells in response to hypoxia during culture and in the immediate posttransplantation phase. VEGF, however, exerts dual effects on endothelial cells, and in islet endothelial cells of the adult, the vascular permeability-inducing effects of VEGF seem normally more pronounced than those to induce angiogenesis. p38 MAP kinase activity has recently been shown to serve as a switch to separate these properties of VEGF; inhibition of p38 MAP kinase activity enhances VEGF-induced angiogenesis and, at the same time, abrogates VEGF-induced vascular permeability. We hypothesized that the revascularization of transplanted islets may be hampered by a predisposition of adult islet endothelial cells to react to VEGF by forming fenestrae rather than migrating and proliferating. We therefore administered the p38 MAP kinase inhibitor SB203580 by daily IP injections for the first 14 days following transplantation, and then studied the influence of this treatment on the oxygen tension, blood perfusion, and vascular density of the islet grafts 1 month posttransplantation. SB203580 treatment redistributed islet graft blood vessels from the stroma into the endocrine tissue, and this redistribution of blood vessels into the endocrine tissue was accompanied by an increased oxygenation of the islet cells. However, the total number of blood vessels in the tissue was not affected. The blood perfusion of the islet grafts was also similar in control and SB203580-treated animals. Our results suggest that effects of VEGF to preferentially induce vascular permeability may partially contribute to, but is not the main cause of, low revascularization of transplanted islets.

Animals↗

PubMed2006

Lifestyle, genetics, and disease in Sami.

AIM: To present a summary of the lifestyle, genetic origin, diet, and disease in the population of Sami, indigenous people of northern Fennoscandia. METHOD: A survey of the available scientific literature and preliminary results from our own study of the Swedish Sami population. RESULTS: The Sami probably have a heterogeneous genetic origin, with a major contribution of continental or Eastern European tribes and a smaller contribution from Asia. The traditional Sami diet, high in animal products, persists in Sami groups still involved with reindeer herding, but others have adopted a diet typical of Western cultures. Early reports indicated a lower prevalence of heart disease and most cancers, except stomach cancer. Recent studies have not found a lower risk of heart disease, but have consistently shown an overall reduced cancer risk. Sami have been reported to share some specific health-related genetic polymorphisms with other European populations, but none that would explain the observed differences in disease risk. CONCLUSION: The genetic structure of the Sami population makes it suitable for studies of the genetic and environmental factors influencing the development of common diseases. The difference in incidence of heart disease between studies may reflect the ongoing transition from a traditional to a more Westernized lifestyle. The ability to compare population segments with different lifestyles, combined with the genetic structure of the population, creates unusual possibilities for studies of the genetic and environmental factors involved in the development of common disease.

Cardiovascular Diseases↗

PubMed2004

Linkage disequilibrium between microsatellite markers in the Swedish Sami relative to a worldwide selection of populations.

The pattern of linkage disequilibrium (LD) is affected by a number of factors, including population demography. High LD is seen in populations with a relatively limited and constant size, presumably because of genetic drift. We have examined the extent of LD among over 300 genome-wide pattern microsatellite loci in 29 populations from around the world. The pattern of LD varied between populations, with a larger extent of LD in populations with limited size relative to larger populations. In addition, the LD between 88 less well-spaced microsatellite markers from 10 different genomic regions was examined in the Sami compared with the general Swedish population. For these markers, increased LD extending up to 5 Mb was detected in the Sami. The amount of LD also differed between the chromosomal regions. The amount of LD in the Sami makes this population suitable for the mapping of complex genetic traits.

Genetic Markers↗

PubMed2004

Mishaps in the management of stroke: a review of 214 complaints to a medical responsibility board.

BACKGROUND: This is the first survey of formal complaints to a Medical Responsibility Board (MRB) in the literature concerning stroke management and the disciplinary actions to which the complaints lead. METHODS: All available complaints submitted to the Swedish MRB during a 5-year period that concerned stroke management (n = 214) were reviewed. We compiled information on the plaintiffs, the health care staff the complaints were directed against, the area of stroke management involved and the disciplinary actions taken by the MRB. RESULTS: Only 1% of all complaints to the MRB concerned stroke. Three quarters of these complaints were directed against physicians and one fifth against nurses. 23 complaints (11%) resulted in a warning or an admonition. Nearly all disciplinary actions against physicians (12 of 13) concerned misdiagnoses, of subarachnoid hemorrhage in particular. The most common reason for a nurse receiving a warning or an admonition was negligent handling of drugs. CONCLUSIONS: The survey has identified two areas in which educational programs to improve patient safety seem essential. The small number of formal complaints and disciplinary actions suggest that other, blameless procedures have a greater potential than MRB actions to reduce mishaps in routine stroke care.

Diagnostic Errors↗

PubMed2004

Inconsistent susceptibility to autoimmunity in inbred LEW rats is due to genetic crossbreeding involving segregation of the arthritis-regulating gene Ncf1.

We recently identified a single-nucleotide polymorphism in the Ncf1 gene, a component of the NADPH oxidase complex, to be the cause of one of the strongest identified loci for arthritis severity in rats. This polymorphism was found to be naturally occurring in a collection of inbred rat strains as well as in wild rats. Among the inbred strains we found that different LEW substrains (LEW/Ztm and LEW/Mol), originating from different breeders, showed an allelic discrepancy in Ncf1, suggesting an impact on arthritis susceptibility between these substrains. In fact, the LEW/Mol strain was completely resistant to pristane-induced arthritis, in contrast to the LEW/Ztm strain, which was susceptible. Moreover, the LEW/Mol strain had higher production of radical oxygen species in peripheral blood leukocytes, a phenomenon most likely regulated by the polymorphisms in the Ncf1 gene. However, the phenotypic difference between LEW/Mol and LEW/Ztm is most likely a combination of several genes, of which Ncf1 is suggested to be the major regulating gene. This has also been confirmed by previous linkage analyses involving the LEW/Ztm strain which shows that a QTL on chromosome 12, most likely caused by polymorphism of Ncf1, is the major regulatory gene but that other loci are contributing. That more genes are likely to contribute was shown by a complete genome comparison of the LEW/Ztm and the LEW/Mol rat strains that uncovered an introduction of approximately 37% non-LEW genome into the LEW/Mol strain, which probably was caused by past crossbreeding. Therefore, the LEW/Mol should be regarded as a recombinant inbred strain.

Animals↗

PubMed2003

A novel method for automatic genotyping of microsatellite markers based on parametric pattern recognition.

Genetic mapping of loci affecting complex phenotypes in human and other organisms is presently being conducted on a very large scale, using either microsatellite or single nucleotide polymorphism (SNP) markers and by partly automated methods. A critical step in this process is the conversion of the instrument output into genotypes, both a time-consuming and error prone procedure. Errors made during this calling of genotypes will dramatically reduce the ability to map the location of loci underlying a phenotype. Accurate methods for automatic genotype calling are therefore important. Here, we describe novel algorithms for automatic calling of microsatellite genotypes using parametric pattern recognition. The analysis of microsatellite data is complicated both by the occurrence of stutter bands, which arise from Taq polymerase misreading the number of repeats, and additional bands derived form the non-template dependent addition of a nucleotide to the 3' end of the PCR products. These problems, together with the fact that the lengths of two alleles in a heterozygous individual may differ by only two nucleotides, complicate the development of an automated process. The novel algorithms markedly reduce the need for manual editing and the frequency of miscalls, and compares very favourably with commercially available software for automatic microsatellite genotyping.

Algorithms↗

PubMed2002

IL-4-deficient mice develop less acute but more chronic relapsing collagen-induced arthritis.

Rheumatoid arthritis as well as collagen-induced arthritis (CIA) is thought to involve T cell autoimmunity of the Th1 type and the Th2 cytokine IL-4 has been proposed to play a suppressive role. To exclude a possible skewing role of the mycobacteria used in the complete Freund's adjuvant (CFA) we induced CIA with type II collagen (CII) in incomplete Freund's adjuvant (IFA). Our results show that IL-4 deficiency leads to a lesser susceptibility to arthritis and lower B and T cell responses if induced with CII/IFA but not if induced with CII/CFA. In addition, IL-4-deficient mice were less susceptible to arthritis induced with monoclonal anti-CII antibodies. However, mice immunized with CII/IFA later developed a chronic relapsing disease, which was promoted by IL-4 deficiency. We conclude that IL-4 plays different roles depending on the type of adjuvant used and the phase (acute or chronic) of the clinical disease.

Acute Disease↗

PubMed2002

Abnormal release of incretins and cortisol after oral glucose in subjects with insulin-resistant myotonic dystrophy.

OBJECTIVE: Although the incretins, gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), as well as glucagon and cortisol, are known to influence islet function, the role of these hormones in conditions of insulin resistance and development of type 2 diabetes is unknown. An interesting model for the study of hormonal perturbations accompanying marked insulin resistance without concomitant diabetes is myotonic dystrophy (DM1). DESIGN: The work was carried out in an out-patient setting. METHODS: An oral glucose tolerance test was performed in 18 males with DM1 and 18 controls to examine the release of incretins and counter-regulatory hormones. Genetic analyses were also performed in patients. RESULTS: We found that the increment in GLP-1 after oral glucose was significantly greater in patients, while there was no significant difference in GIP or glucagon responses between patients and controls, although long CTG repeat expansions were associated with a more pronounced GIP response. Interestingly, the GLP-1 response to oral glucose correlated with the insulin response in patients but not in controls whereas, in controls, the insulin response closely correlated with the GIP response. Furthermore, cortisol and ACTH levels increased paradoxically in patients after glucose; this was more pronounced in patients with long CTG repeat expansions. CONCLUSIONS: This study showed that the GLP-1 and ACTH/cortisol responses to oral glucose are abnormal in insulin-resistant DM1 patients and that CTG triplet repeats are linked to GIP release. These abnormalities may contribute both to the severe insulin resistance and hyperinsulinemia in DM1 and to the preservation of adequate islet function, enabling glucose tolerance to be normal in spite of this marked insulin resistance in DM1.

Adult↗